Hereditary Motor Syndromes

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Motor Syndromes, Hereditary (SMA, ALS + ...)

ALS: Hereditary & Familial

Spinal muscular atrophy (SMA): Types
Recessive SMA
SMA: SMN 5q13
Congenital with arthrogryposis
Werdnig-Hoffmann
Kugelberg-Welander
Spinal muscular atrophy 2 (SMA2)
Spinal motor neuropathy: RBM7; 11q232
SMA + Congenital fractures
TRIP4; 15q22
ASCC1: 10q22
SMA + Encephalopathy: TBCD; 17q25
SMA + Myoclonus Epilepsy: ASAH1; 8q22
SMA + Pontocerebellar hypoplasia (PCH)
PCH1A: VRK1; 14q32
PCH1B: EXOSC3; 9p11
Other: Motor + Cerebellar
EXOSC8; 3q13
EXOSC9; 4q27
Mitochondrial
DGUOK: 2p13
SCO2: 22q13
SLC25A21: 14q13
TK2: 16q22
Congenital contractures
Dominant, Proximal
Adult: VAPB; 20q13
Adult + Cramps (SMAJ): CHCHD10; 22q11
Bulbar
Congenital + Legs weak: TRPV4; 12q24
HMSN-P (Okinawa type): TFG; 3q12
Respiratory & Proximal arms: MAPT; 17q21
Scapuloperoneal syndromes
SMALED
1: Leg predominant; DYNC1H1; 14q32
2: Early-onset; Contractures; BICD2; 9q22
X-linked SMA (Recessive)
Bulbospinal (Kennedy): AR; Xq12
SMAX
2: Infant + Arthrogryposis; UBE1; Xp11
3: Distal; ATP7A; Xq21

HMN
1: 7q34; Dominant
2
A: HSPB8 (HSP22); 12q24; Dominant
B: HSPB1 (HSP27); 7q11; Dom or Rec
C: HSPB3 (HSPL27); 5q11; Dominant
D: FBXO38; 5p31; Dom or Rec
5: Upper limb predominance
A: GARS; 7p15; Dominant
B: REEP1; 2p11.2; Dominant
C: BSCL2; 11q13; Dominant
6: IGHMBP2; 11q13; Recessive
7: + Vocal cord paralysis, Dominant
A: SLC5A7; 2q12
B: Dynactin 1 (DCTN1); 2p13
8: Congenital, Legs: TRPV4; 12q24
9 (dHMN): WARS; 14q32; Dominant
+ Upper motor neuron
Senataxin; 9q34; Dominant
4q34: Dominant
HMN
J: 9p21; Recessive
2B: HSPB1; 7q11; Dominant
5C: BSCL2; 11q13; Dominant
7B: Dynactin; 2p13; Dominant
SPG + Motor neuropathy
HMN: 11p; Recessive
HMN: 16p
HMN: KCC3; 15q14; Dominant
HMN: SPTAN1; 9q34; Dominant
HMN: MME; 3q25; Recessive
CMT 2N: AARS; 16q22; Dominant
CMT 2O: DYNC1H1; 14q32; Dominant
Neuromyotonia: HINT1; 5q31; Recessive
Childhood: BICD2; 9q22
Intellectual Disability: TBCK; 4q24

Motor Neuropathy
Differential diagnosis
General, Distal
Lower motor neuron
Motor syndromes
Also: NMJ disorders

Distal SMA (DSMA; dHMN)
Recessive
1 (SMARD1): IGHMBP2; 11q13
2 (HMN J): 9p21
3: 11q13
4: PLEKHG5; 1p36
5: DNAJB2 (HSJ1); 2q35
dHMN: SIGMAR1: 9p13
dHMN: SYT2; 1q32
+ Ataxia telangectasia: ATM; 11q22
+ Encephalopathy: TBCE; 1q42
Lethal congenital contractures
MND, Distal: VRK1; 14q32
Dominant
Calf predominant: FBXO38; 5p31
Leg predominant
Distal Ulnar-Median
Childhood: BICD2; 9q22
+ Macular Δ: FBLN5; 14q32
+ Hearing loss: MYH14; 19q13
Scapuloperoneal: TRPV4; 12q24
HMN: HARS; 5q31
X-linked
dHMN: AIFM1; Xq26
SMAX 3: ATP7A; Xq21
SMARD2: LAS1L; Xq12
Mitochondrial
mtATP6 ± Episodic weakness
mtATP8
Sporadic: Hirayama
Distal Motor Neuropathy or Myopathy

Multisystem disorders
Recessive
AAA syndrome: Aladin; 12q13
ANE: RBM28; 7q31
Chediak-Higashi: LYST; 1q42
CONDCA: AGTPBP1; 9q21
Hexosaminidase A: HEXA; 15q23
Leukoencephalopathy: SCP2; 1p32
MND + Dementia & Ophthalmoplegia
MPAN: c19orf12; 9q12
STAT5B: 17q21
TBX5: 12q24
Dominant
Cataracts & Skeletal abnormalities
DDPAC: MAPT; 17q21
Machado-Joseph: Ataxin-3; 14q32
Myopathy + Paget: HNRNPA2B1; 7p15
X-linked
Cabezas: CUL4B; Xq23
Neuroaxonal dystrophy 2
Polyglucosan body: GBE1; 3p12
Mitochondrial: SCO2
Sporadic: Camera-Marugo-Cohen
Spastic paraparesis
Spastic paraparesis + Motor neuropathy

Bulbar syndromes
AAA syndrome: Aladin; 12q13; Recessive
Brown-Vialetto-van Laere: SLC52A2/A3
BSMA: Androgen Receptor; Xq12
BSMA: Dominant
Bulbar ALS
Fazio-Londe: Recessive or Dominant
PLS, Juvenile: Alsin; 2q33; Recessive
Worster-Drought

Distal SMA

From: Spiller

Spinal Muscular Atrophy (SMA0; SMA1; SMA2; SMA3; SMA4; SMA 5q)

● Survival Motor Neuron 1 (SMN1) protein

; Chromosome 5q13.2; Recessive

Epidemiology & History
Genes
Clinical - Genetic correlations
SMN1
SMN2
Modifiers
Neighboring & Related
SMN Protein
Clinical features
Congenital
Arthrogryoposis
SMA 0
Types: 1; 2; 3; 4
Lower motor neuron
Pathology

From: Andrew Kornberg MD

Hoffman ~1891

SMN1 mRNA
90% of pre-mRNA spliced to full length SMN

SMN2 mRNA
80% of pre-mRNA spliced to SMN with no exon 7
SMN without exon 7 is unstable & rapidly degraded

Epidemiology
- Incidence of SMA disease: 1 in 6,000 to 10,000 births ²⁵
- 2^nd most frequent autosomal recessive disease of childhood (After cystic fibrosis)
- Carrier frequency of SMN1 mutations
  - General Western population: 2% to 3%
  - Sub-Saharan Africa
    - Frequency of carriers lower: 0.05%
    - Higher SMN1 copy numbers: 53% with 3 copies vs 6% with 3 in West
    - Fewer SMN2 copy numbers: 24% with none vs 8% in West
History
- SMA described independently by Werdnig and Hoffmann in 1891
- Werdnig described the condition as "neurogenic dystrophy"
- Hoffmann
  - Established the spinal nature of the disease
  - Coined term: "spinale muskelatrophie"
SMN1 (Telomeric SMN (SMN^T)) gene
- Disease relations
  - SMA: Mutated in 95% of patients
  - ALS: Increased frequency (2x) of 1 or 3 gene copies
- Contains 9 exons
- Codes for protein containing 294 amino acids
- Number of SMN1 gene copies ⁸: Varies
  - 1 SMN1 copy on each chromosome
    - 82% to 96% of normal individuals
  - 2 SMN1 copies on one chromosome
    - 4% to 18% of normal individuals
  - Variability makes heterozygote testing complicated
- SMN1 structure: Strongly homologous to SMN2
  - Exons 7 & 8 contain gene-specific nucleotide sequences
    - Some differences from SMN2
  - AG-rich exonic splice enhancer in SMN1 exon 7
    - Enhancer increases inclusion of exon 7 in protein
- SMN1 gene chromosomal surrounding DNA
  - Composition: Large inverted duplication
  - Duplication has telomeric (t) & centromeric (c) copies
  - Each copy of duplication contains at least 4 genes
    - SMN
    - Other: p44; NAIP; H4F5
  - Repeated DNA unit features
    - Present on each chromosome
    - 0 to 4 copies
- Telomeric (SMN1; SMN^T) gene mutations
  - Related to presence of SMA disease syndromes
SMN2 gene (Centromeric SMN (SMN^C))
- Disease relations
  - Number of Copies: More related to less severity of SMA
  - c.859G>C substitution: SMA less severe
- Gene location: Centromeric to SMN 1 gene
- Strong homology to SMN1: 5 nucleotide differences
  - Introns: One difference in 6; Two in 7
  - Exons: 2 Differences
    - Exon 7 (C to T): Translationally silent
    - Exon 8: 3' untranslated region
- Nucleotide differences from SMN1 produce altered SMN splicing
  - Can produce identical amino acid sequences to SMN1
    - If fully translated
    - Quantitative: 10% of SMN1 gene
  - Often produces smaller SMN proteins than SMN1
    - SMN2 gene transcript often spliced at exon 5 or 7
    - 70% to 80% of SMA2 transcripts lack exon 5 and/or exon 7
  - Mechanism of altered splicing
    - Single-nucleotide change from SMN1 to SMN2 occurs in heptamer motif of the exon splicing enhancer
    - New nucleotide sequence (C to T)
      - Creates exonic splicing silencer: Inhibition is hnRNP A1 dependent ³⁷
      - ? Eliminates motif recognized by splicing factor
        
        Heptamer motif is recognized by: Splicing factor, arginine/serine-rich (SF2/ASF)
        
        Nucleotide change abrogates SF2/ASF-dependent exon splice enhancer
- SMN2 Gene number ⁸: One or Multiple copies
  - Normals: No SMN2 copy 9%; 1 SMN2 copy 42%; 2 SMN2 copies 46%; 3 SMN2 copies 3%
  - SMA carriers: No SMN2 copy 1%; 1 SMN2 copy 18%; 2 SMN2 copies 47%; 3 SMN2 copies 31%; 4 SMN2 copies 3%
  - SMA patients
    - 2 or more SMN2 copies
    - Reduced SMN2 Gene number correlates with increased SMA severity
- Homozygous SMN2 Deletions: Disease associations
  - More common in Lower motor neuron syndromes & MMN
  - Sporadic ALS: More common; ? Shorter survival
SMA modifier genes
- Plastin 3 (PLS3)
  - Ca²⁺-dependent protein
  - Overexpression
    - Protective in SMA
    - Improves endocytosis
- Neurocalcin Delta (NCALD)
  - Protein
    - Neuronal calcium sensor
    - Interacts with: Clathrin
    - Endocytosis suppressor
  - Suppression
    - Mutations: 17-bp deletion upstream of NCALD; SNP rs147264092 in intron 1
    - Clinical effect: Protective
      - SMN1 mutations with 3 or 4 copies of SMN2
      - Patients continue to be photosensitive
    - Epidemiology: 2 families
Related or neighboring genes on chromosome 5q
- SMN1 chromosomal locus: General
  - Complex 500 kb region of Chromosome 5q13
  - Contains large- and small-scale repetitive genetic elements
  - Locus of unusual genetic instability
  - Frequent spontaneous mutations
  - The 500 kb region contains 3 genes: SMN, NAIP, and p44
    - The 3 genes are located in a locus of duplicated and inverted DNA (6 genes)
    - Telomeric genes are functional genes
    - Centromeric genes represent dysfunctional copies
    - Genetic structure is unique to humans
- Neuronal Apoptosis Inhibitory Protein (NAIP)
  - Females: Absence of NAIP strongly associated with severe phenotype
  - Males: No relation between NAIP deletion & phenotype
- Basal transcription factor (Btf2-p44)
  - Deleted in 15% of SMA patients
- C212/H4F5
  - C212: Multicopy microsatallite marker in an intron of H4F5
  - Reduction or absent alleles in
    - SMA type I: 94%
    - SMA type II: Frequency between type I and controls
    - SMA type III: Slightly more frequent than controls
  - Closest gene to SMN
  - Function unknown
- Retrotransposon-like sequences
  - Transcribed into RNA
  - Reverse transcribed into cDNA
  - Reintegrated as cDNAs into the genome at a new location
SMN protein: 38 kD or smaller splice variants
- SMN Expression
  - From both SMN1 & SMN2 genes
  - Transcript splicing
    - SMN1 (SMN^T) proteins
      - 90% full length
      - 10% missing exon 5
      - AG-rich exonic splice enhancer in SMN exon 7
        
        Increases inclusion of exon 7 in protein
    - SMN2 (SMN^C) proteins
      - Full length: 20% to 40%
      - Missing exon 5, or 7, or both: 60% to 80%
      - Most SMN2 spliced to generate short isoform of SMN protein without exon 7
        
        Less stable: Short half-life
        Poor self-oligomerization
  - Anatomical locations
    - High levels: Brain & spinal cord; Kidney; Liver
    - Moderate levels: Skeletal & cardiac muscle
  - Cell locations: Nuclear & cytoplasmic inclusions (gems)
    - Nucleus: 34kDa variant
      - Localized to gem bodies & nucleoli
      - Near nuclear membrane
    - Cytoplasm: 38kDa variant
      - Especially in motor neurons
      - Sub-cellular locations
        
        Perikarya; Proximal dendrites; Axons
        Motor neurons: May be associated with cytoskeletal elements & mitochondrial membranes
        Most cells: Not associated with organelles
  - Levels in tissue
    - Highest during development
    - Downregulation of SMN: From early postnatal periods to adulthood
- SMN Interacts with other proteins
  - General
    - Self oligomerization: Via N- & C-terminus (Exon 7)
    - SMN & Gemins 2 to 5 form a multiprotein complex
  - SIP1 (Gemin 2)
    - Strong interaction: forms heteromeric complex with SMN
    - Attachment Via N-terminus of SMN
    - Location: Gem bodies in nucleus
    - Localization
      - Colocalizes with SMN in nucleus & cytoplasm
      - SMN does not colocalize with SIP1 in neurites of motor neurons
    - SMN & SIP1 form part of protein complex with Sm core proteins & snRNP U1
  - Other Gemins
    - Gemin 3 (dp103) : DEAD box putative RNA helicase
    - Gemin 4
    - Gemin 5
    - Gemin 6
  - Spliceosomal snRNP core proteins (Sm)
    - B/B'; D1-3; E; F; G
    - Via central tudor domain
    - Needed for U snRNP assembly: 5'cap hypermethylation; Import into nucleus
  - Spliceosomal snRNA U1 & U5
    - Via N-terminus of SMN
    - Located in cytoplasm
  - HnRNP protein U & fibrillarin : Located in nucleoli
  - Bcl-2 : Coexpression with SMN
    - Provide synergistic protection against Bax or Fas induced apoptosis
  - Nuclear transcription activator E2 of papillomavirus: Via C-terminus
  - Profilin 2
    - Motoneuron-specific microfilament-associated, actin-binding protein
    - Action: Inhibits polymerization of actin
    - SMN interaction: Via Pro5-X17-Pro10-X17-Pro5 motif encoded by exons 4, 5 and 6 of SMN gene
- SMN: General functions ⁵¹
  - Nuclear: Regeneration of active splicing complex
    - Part of complex regulating assembly of spliceosomal U snRNPs (RNA-protein complex)
    - Essential component of the spliceosome that catalyses pre-mRNA splicing
    - Linked to control of protein synthesis & to expression of new protein isoforms
  - Axons
    - May play role in axonal transport of mRNA
    - Promotes neurite outgrowth and/or neuromuscular maturation ²³: Downregulation causes
      - Aberrant guidance of axons with excessive axonal branching
      - Reduced growth velocity
      - Reduced growth cone sizes
      - Anomalous calcium-channel clustering in growth cone
      - Abnormal presynaptic motor axon nerve terminals
        
        Presynaptic defects in synaptic vesicles, mitochondria, active zones, neurofilaments & microtubules
    - Axonogenesis: May be related to spliced isoform of SMN protein
    - Presynaptic motor axon terminals: Postnatal organization & maintenance ⁸⁴
  - Muscle: SMN knockout produces myopathy
  - Disease correlations
    - SMN mutant proteins: Reduced RNA-binding activity
    - Less SMN protein & gem bodies in more severe SMA types
    - Mutations: Impaired endocytosis
- SMN: Neuromuscular localization
  - Nerve
    - SMN accumulates in growth-cone-like structures during neuronal differentiation
    - Selective deletion of SMN in nerve causes loss of motor neurons
  - Muscle
    - SMN concentrated at NMJs
    - Cytoplasmic SMN high during NMJ formation & reduced with NMJ maturation
    - Selective deletion of SMN in muscle produces myopathy ²⁴
- Splicing functions of SMN: Ubiquitous
  - Interacts with both RNA-binding proteins and RNA
  - RNA-binding element in exon 2a
  - Post-transcriptional nuclear RNA metabolism
    - During spliceosomal snRNP biogenesis and pre-mRNA splicing
    - Related to spliceosomes
  - Spliceosomal snRNPs: SMN-related proteins promote transport from cytoplasm to nucleus
  - Inhibition leads to
    - Reduced spliceosomal snRNP biogenesis
    - ? Reduced conversion of pre-mRNA (with introns) to mRNA (no introns)

SMN: Clinical - Genetic correlations ²

SMN1 (SMN^T; telomeric SMN gene) mutations & disease

SMN1 mutations present in 95% of SMA patients

SMN1 & SMN2 genes: Correlation with disease severity

5q CHROMOSOMES Typical SMN mutations in SMA

SMN1 Normal gene SMN1 Mutation types Deletion : More severe SMA Conversion to SMN2 gene : Milder SMA SMN2 gene : Variations More copies: Correlate with milder SMA. SMN2 mutations alone: Don't produce SMA

Milder disease (SMA II or III)
- Increased SMN2 gene copy number
Absence of both SMN1 & SMN2 genes
- Lethal
SMA type 0: No SMN1 gene & 1 copy of SMN2
- Severe weakness
- Death < 1 month of age
SMA type I: Mutations
- Mostly SMN1 deletions
- Few missense point mutations in SMN1
- SMN2 gene copy number: Often 2
SMA type II
- Mutations convert SMN1 gene to SMN2
- SMN2 gene copy number: > 3
- Missense point mutations more common
SMA type III
- SMN2 gene copy number: > 3
- Missense point mutations more common

Total amount of full length SMN protein
- ? Best correlation with SMA severity

SMN1 (SMN^T) deletions
- Usually involve exons 3, 6, 7 & 8
- 95% of SMA: Exon 7 of SMN1 gene homozygous absent
- Rare homozygotes for selective 7 & 8 deletion
  - Clinically normal, or only mildly weak
- Larger SMN deletions
  - Associated with earlier onset & more severe disease
  - May affect other neighboring genes
- Hybrids of SMN2 (centromeric) & SMN1 (telomeric) SMN genes may occur
  - Centromeric exon 7 & telomeric exon 8
  - Usually associated with SMA 2 or 3
- Mechanisms producing SMN1 deletions in offspring ²⁵
  - Both parents with one SMN1 copy
    - SMN1 mutations on one chromosome in each parent
    - Recurrence risk for another child with SMA: High (25%)
  - De novo rearrangements
    - New SMN1 deletion in gene from 1 parent: Parental SMN1 copy number is 2
    - Other parent is carrier of SMN1 deletion: SMN1 copy number is 1
    - Frequency: 2% of SMA
    - Mechanisms of rearrangements: 2 Diferent types
      - Unequal crossing over between repeated units during paternal meiosis
      - Conversion of part of SMN1 gene into SMN2: Exon 7 of SMN2 & Exon 8 of SMN1
    - Recurrence risk for another child with SMA: Low
  - SMN duplication in cis: One parent with 2 SMN genes on one allele and 0 on other
    - Normal total SMN1 copy number: 2
    - 50% chance of transmitting gene with SMN1 deletion
    - Recurrence risk for another child with SMA: High (25%)
    - Frequency of SMN duplication in cis in SMA parents: 3% to 8%
    - Frequency of SMN duplication in cis: 0.1% of population
- Deletions in SMN2 gene alone not related to SMA
SMN1 (SMN^T) missense point mutations
- Frequency: Rare
  - 3.6% of 5q13 SMA
  - Highest in type III SMA
  - Lowest in type I SMA
  - ? Higher in some non-European populations: South African blacks
  - Other allele: SMN1 deletion
- Location
  - Cluster at the 3' end of gene
  - Exon 6: Between codons 258 to 279
  - Modular oligomerization domain
    - Correlation between residual SMN oligomerization (self-association) & severity
    - SMN I: Severe loss of function mutations (G279V & Y272C)
    - SMN II & III: T274I & S262I
  - In tyrosine/glycine-rich motif also present in RNA binding proteins
  - Exon 3 termination mutations (425del5; W102X): Exon skipping; Mild phenotype
- Mutation consequences
  - Most interfere with SMN oligomerization
  - E134K: Alters binding of Sm proteins; Severe SMA phenotype
  - Clinical: SMA II & III phenotypes common
SMN2 (SMN^C)
- Copy number associated with SMA disease severity
  - Most SMA patients have ≥ 2 SMN2 genes
  - SMA I (Severe): 2 or 3 gene copies of SMN2
  - SMA II: 3 copies of SMN2
  - SMA III: 4 to 8 copies of SMN2, except with SMN2 G287R mutation
  - Asymptomatic with homozygous SMN1 deletion: 5 copies of SMN2 ⁴⁷
- c.859G>C substitution (G287R) ⁶⁹
- SMN2 Deletions ²⁰: Homozygous
  - Genetics
    - Mutation: Deletion of exon 7 in SMN2 gene
    - Normal population: Homozygous deletion in 5% to 9%
    - Increased incidence of homozygous SMN2 deletion in D-LMN syndromes: 36%
  - Clinical: Distal lower motor neuron syndromes
    - Weakness: Distal; Asymmetric; Upper & Lower extremities
    - Course: Rapidly or slowly progressive
  - Differences from other LMN syndromes
    - Earlier age of onset (40 vs 56 years): Some as young as 15 years
    - Lower preponderance of males: M:F ratio of 1.5 vs 2.5
    - Both arms & legs involved
SMN mutations not found in sporadic or familial ALS
Neuronal Apoptosis Inhibitory Protein (NAIP) deletions
- Occur in 35% of SMA patients
- In SMA: Virtually always occur with SMN deletion
- Involve exon 5
- Rarely also occur in unaffected
- More common in SMA type I (45% - 66%) than in II or III (5% - 16%)
- NAIP absence: Correlates with severe phenotype in females, not males
Rare (2%) SMA 5q patients with neither SMN or NAIP deletion
Modifier protein: Plastin 3 (PLS3)
- Unaffected SMN1-deleted females: Higher expression

Clinical features: Congenital SMA (5q) with arthrogryposis
- Onset age: Congenital
- Severe hypotonia
- Movements: Absent; Respiratory failure at birth
- Cranial nerves: Facial diplegia; � External ophthalmoplegia
- Contractures: Especially knees
- Course: Death < 30 days
- Pathology
  - Loss of motor & sensory myelinated axons
  - Motor neurons: Preserved, swollen
- Rule out X-linked SMA
Clinical features: SMA Type 0 ¹³⁸
- Onset age: Prenatal
- Fetal
  - Movements: Reduced
  - Nuchal translucency
- Gestational age at delivery: Mean 39 weeks
- Muscle weakness: Severe
  - Hypotonia: Severe
  - Few spontaneous movements
  - Respiratory failure
  - Cranial nerves: Inability to suck or swallow; Face
  - Posture: Frog-like
- Tendon reflexes: Absent
- Tongue fasciculations
- Fetal akinesia deformation sequence
  - Contractures: At one or multiple joints
  - Micrognathia
  - Palate: High arched
  - Edema, peripheral
  - Intrauterine growth retardation (50%)
- Cardiac
  - Congenital defects (85%): Septal
  - Bradycardia
- Extraocular movements: Normal
- Death: 1st month
Clinical features: Werdnig-Hoffmann (Type 1)
- Onset
  - Usually before 3 months
  - Range
    - 0 to 6 months
    - Some with in utero decreased fetal movements
  - Acute onset in occasional patient ¹³
    - Early weeks or months: Normal development
    - After 1st few months: New weakness; No new motor milestones
    - Motor neuron loss
- Clinical
  - Weakness
    - Diffuse; Proximal > Distal
    - Severe
    - Poor feeding
    - Respiratory insufficiency: Paradoxical respirations
    - Sparing of facial & oculomotor
  - Hypotonia
  - Fasciculations: Tongue
  - Tendon reflexes: Reduced or absent
  - Intellect: Normal; Alert faces
  - Prognosis
    - Respiratory failure
    - Death: 50% by 7 months; 95% by 17 months
    - Chronic course in 5%
- Pathology
  - Muscle
    - Large regions of grouped muscle fiber atrophy
    - Most larger fibers are type I
  - Spinal cord
    - Anterior horn: Motor neuron loss
  - Cell pathology
    - # of gem bodies in fibroblasts correlates with disease severity
    - SMA I spinal cords: 100-fold reduction in SMN protein
- Variant: Facial weakness & Ophthalmoplegia
Clinical features: Kugelberg-Welander (Types II & III )

From: M Ryan MD
- Classification
  - Type II: Intermediate
    - Onset: Often < 18 months
    - Never stand
    - Life span
      - Often shortened
      - Death > 2 years
    - Rule out: SMA2
  - Type III: Mild
    - Onset: Often > 18 months
    - Stand independently
    - Life span
      - ± Shortened
      - Death in adulthood
- Onset
  - Childhood or Juvenile
  - Cramps may be 1st symptom
    - EMG: Mild neurogenic changes
- Clinical
  - Weakness
    - Proximal; Symmetric
    - Variable degrees of severity
      - Some never walk
        
        Poor prognosis
        
        Scoliosis early
      - Later onset: Better prognosis
      - Respiratory: Sleep disorders with vital capacity < 65%
    - Progression
      - Most have loss of function over time
      - ? Change in strength over time
        
        Difficult to measure
      - Electrophysiology
        
        Progressive loss of motor units
  - Tremor
  - Tendon reflexes: Reduced
  - Fasciculations
Clinical features: SMA 5q - Later onset (Type IV)
- Onset: Juvenile or Adult
- Clinical
  - Weakness
    - Distribution
      - Proximal
      - Patchy: Psoas; Quadriceps > Hamstrings; Triceps
      - Symmetric or Asymmetric
    - Progression
      - Most have very slow loss of function over time
      - ? Change in strength over time: Difficult to measure
  - Fasciculations
  - Tendon reflexes: Reduced
- Course
  - Often continue ambulatory
  - Lifespan: Normal
Lower motor neuron syndromes

SMA Spinal cord
Anterior roots are atrophic
- Genetics
  - SMN2 deletions: Increased incidence of homozygosity
    - Distal lower motor neuron syndromes (36% vs 5% in general population)
  - Occasional homozygous SMN1 deletions
- Clinical
  - Distal > Proximal
  - Asymmetric
  - Progressive weakness
    - Slower with SMN^C than with SMN^T deletion
  - No family history
Pathology
- Muscle Pathology
  - Grouped atrophy
  - Large fibers: Mostly type 1; Hypertrophied
  - Small fibers mixed or type 2
  - Development: Muscle weakness & atrophy may precede loss of motor neurons
- Spinal cord ²⁶
  - Loss of motor neurons in anterior horn
    - Time period: 12 weeks of gestation to birth; Similar to period of normal cell death
    - Apoptosis: Increased only at 12 to 16 weeks, Not post-natal
  - Post-natal: Morphological changes in some motor neurons
    - Reduction in central Nissel
    - Peripheral displacemnet of nuclei
  - Anterior roots: Atrophic
Gene testing
- SMN deletions in > 95%: Exons 7 & 8 tested for deletions
- Carrier testing
  - Quantitation of number of SMN1 genes
  - Does not detect carriers with more than 1 SMN1 gene on a chromosome
Care & Treatment
- Respiratory support
- Scoliosis care
- Nutrition
Experimental treatments
- Hydroxy-Urea: No benefit in SMA2 & SMA3
- Histone deacetylase (HDAC) inhibitors: Non-specific increase
  - Phenylbutyrate
  - Valproate: 250 mg to 500 mg bid po
  - Possible mechanism: Increase SMN2 expression
Mouse models: Mice normally have no SMN2 gene
- Absent SMN1 with transgenic SMN2 expression: More SMN2 expression ® Less severe disease
- SMN1 heterozygotes with ~50% reduction of SMN protein: SMA Type 3 phenotype

Bulbo-Spinal Muscular Atrophy (BSMA; Kennedy's Syndrome; X-linked)

● Androgen Receptor (AR) (Increased CAG repeats)

;

Xq12; Recessive

Androgen receptor protein Clinical features Clinical-genetic correlations Epidemiology Laboratory features Onset Pathogenic mechanisms Pathology
	Bulbo-Spinal Muscular Atrophy Gynecomastia

Epidemiology
- Most common adult onset SMA
- General frequency: 1 in 50,000
- SBMA especially common in
  - Vasa region of western Finland: Scandanavian founder haplotype
  - Some regions in Japan: Founder effect
- Other founder effects
  - Different founder haplotypes in various European & Asian countries
  - No founder haplotype identified in Canadian patients
Genetics
- Mutation: Increased CAG repeats
CAG repeat length: Genetic-Clinical Correlations
- Normal CAG repeats ⁴⁶
  - Length: 9 to 39 repeats
  - Median lengths in populations
    - African American: 19�20
    - White Caucasian: 21�22
    - Asian: 22�23
    - Hispanic: 23
  - Location: Exon 1
- BSMA: Long CAG repeats
  - BSMA: 40-68 CAG repeats
  - CAG repeat length effects
    - Longer
      - Earlier disease onset
      - ? More severe SBMA disease
      - Impaired spermatogenesis
      - More somatic mosaicism
      - No effect on specific clinical features
    - Length inversely correlated with transcriptional activity by the androgen receptor
  - Transmission
    - Normal repeat lengths: Transmitted without change; De novo mutations rare
    - Expanded repeats: Expansions or contractions in 25% of meiotic events
    - Paternal transmission: Larger expansions in CAG repeat number
    - Maternal transmission: Contractions or expansions in CAG repeat number
- Prostate cancer
  - Fewer CAG repeats (< 18)
    - Increased Frequency, especially at young age
    - Extraprostatic extension, distant metastases, or high histologic grade
  - Prostatic tumor cells
    - Dual somatic missense mutations within the AR-CAG repeat
      - (CAG)22CAA to (CAG)12CTG(CAG)6CTGCAA
    - Interrupts PolyQ tract with 2 leucines
  - AR point mutations: Metastatic prostate cancer cells
- Androgen insensitivity
  - Complete : Premature stop codons
  - Partial
    - Reifenstein Syndrome : Point mutations
    - Kennedy's syndrome: Bulbo-Spinal Muscular Atrophy
- Other disorders associated with AR-CAG repeat length
  - Hereditary hearing impairment
  - Schizophrenia
  - Benign prostatic hyperplasia
  - Risk of developing breast & endometrial cancers
Androgen receptor (AR) protein
- Family: Steroid/thyroid hormone receptor
- Phosphoprotein
- Domains
  - N-terminal: Contains polyglutamine repeat (Exon 1)
  - Central
    - DNA binding
    - Contains 9 invariant cysteine residues
    - Binds zinc ions in 2 zinc fingers
    - Nuclear localization signal
  - C-terminal
    - Binds 2 biologically active ligands
      - Testosterone
      - Dihydrotestosterone
- Cell locations
  - Unbound receptor in aporeceptor complex with heat shock proteins
  - Hormone binding
    - Receptor translocates to nucleus
    - Binds as dimer to DNA through zinc finger domain
- Neuronal function: Plays role in cell survival and dendritic growth
- External link: Androgen Receptor
BSMA pathogenic mechanisms:Toxic gain of function → Neuronal degeneration
- Large polyglutamine tract → Partial proteolysis due to abnormal folding of Androgen receptor
- Truncated forms of androgen receptor may be produced
- Aggregate location: Cytoplasm & Nucleus
- Aggregates
  - May contain
    - Androgen receptor fragments: Only N-terminal epitopes
    - Proteasome components & ubiquitin; PA700 proteasome caps
    - Chaperones & Nuclear components with long polyglutamine tracts
    - Mitochondria
    - Other: Steroid receptor coactivator 1; NEDD8, Hsp70, Hsp90; HDJ-2/HSDJ; CREB binding protein
  - Formation suppressed by HDJ-2 chaperone
  - ? Toxic to cell
    - Nuclear location of aggregates may be necessary for toxicity
    - Truncated forms of AR with expanded repeat more toxic than full length protein
    - No correlation between frequency of aggregates & cytotoxicity
- Proteins possibly involved in mechanism of CAG repeat toxicity
  - Caspases: May cleave androgen receptor
  - CREB binding protein (CBP) ⁴²
    - Polyglutamine-expanded androgen receptor: Interferes with CBP-mediated transcription of VEGF
    - VEGF: May rescue cultured cells with mutant androgen receptor
  - Sir2 pathway ⁵⁰
    - Increased Sir2.1 levels reduce polyglutamine repeat toxicity
    - Resveratrol may reduce polyglutamine repeat toxicity
- Loss of Androgen Receptor function
  - Non-CAG repeat mutations in androgen receptor reducing function: Do not produce BSMA by themselves
  - Reduced androgen receptor function with CAG expansions: May exacerbate BSMA disease
Clinical features
- Onset
  
  Mouth in BSMA
  Attempted smile & At rest
  - Age: Mean 27 to 43 years; Range 14 to 75 years
  - Early symptoms & signs: Adolescence ³²
    - Muscle discomfort: Cramps or Pain
    - Fatigue: General; Chewing
    - Gynecomastia: May be asymmetric
    - Weakness: Not common early; May be distal
  - Symptoms at 30 years
    - Lower > Upper limb weakness
    - Occasionally cramps
- Weakness
  - Distribution
    - Proximal
      - Symmetric or Asymmetric (55%; Dominant side 70%)
      - Legs > Arms
    - Face: Upper & Lower
    - Tongue: Weakness; Atrophy; Fasciculations
  - Bulbar dysfunction
    - Dysphagia: Aspiration
    - Dysarthria
    - Masseter weakness
  - Symmetric
  - Slowly progressive: Over decades
- Other muscle features
  - Fasciculations
    - Large
    - Face (Especially lower), Tongue, Trunk & Limbs
    - Contraction evoked or Spontaneous
  - Atrophy: Especially face & tongue
  - Cramps: 50%
- Tendon reflexes: Absent or reduced
- Sensory: Often subclinical changes
  - Vibration: Reduced; Legs > Arms
  - Small sensory nerve action potentials (SNAPs)
- Tremor
  - Hands
  - Postural & Action
  - Early disease manifestation: 4th decade
    
    Tongue in BSMA
    Wasted; Weak; Moves rapidly
- NO upper motor neuron signs
- Systemic
  - Nonalcoholic fatty liver disease: Most patients detected by MRS
  - Androgen insensitivity related
    - Gynecomastia (50% to 70%)
    - Reduced fertility: Oligospermia
    - Testicular atrophy
    - Erectile dysfunction
  - Groin hernia: 33%
  - Other endocrine
    - Diabetes mellitus in some patients: Fasting glucose high in 40%
    - Pituitary microadenoma: Rare
Variant: Patient with 68 CAG repeats ¹¹⁵
- Clinical
  - Onset age: 18 years
  - Fatigue
  - Weakness: Face; Tongue; Proximal; Toes
  - Fasciculations
  - Cramps
  - Tremor
  - Dysesthesias: Distal legs & Hands
  - Sensory loss: Distal; Panmodal
  - Gynecomastia
- Laboratory
  - Autonomic: Reduced sweating; Postural tachycardia
  - Skin axons: Normal
Clinical manifestations: Heterozygous females
- General: Mild manifestations later in life
- Muscle cramps: 58%
- Fasciculations: 20%
- Tongue atrophy & fasciculations: 20% in 7th & 8th decade
- Electrophysiology: Chronic denervation in 57%
Laboratory
- Electrodiagnostic
  - NCV
    - CMAP amplitude: Reduced in 23% to 40%
    - SNAP amplitude: Reduced in 80% in sural
  - EMG
    - Face Twitching: Correlate
      - Grouped repetitive motor unit discharges
      - Occur with mild activation of face muscles: Not spontaneous
      - Not fasciculations, myokymia or neuromyotonia
    - Neuropathy: Chronic partial denervation with reinnervation
      - Fibrillations: Legs > Arms
      - Motor units: Large, Long, Polyphasic
      - Recruitment: Reduced
    - Insertion activity: Increased
  - Cortical SSEPs: Absent or Prolonged latencies
- Serum
  - CK: High (94%); May be elevated early in disease course
  - Serum estradiol & gonadotropin: Elevated
  - Lipid disorders
    - Type II hyperlipoproteinemia
    - Type IV hyperlipoproteinemia
    - Hypobetalipoproteinemia
    - Abnormal
      - Total cholesterol (54.7%)
      - Low-density lipoproteins cholesterol (40%)
      - Triglyceride (48%)
- Muscle biopsy
  - Chronic partial denervation
  - Type I muscle fiber predominance
- CNS pathology
  - Lower motor neurons: Reduced number in spinal cord & brainstem
  - Sensory ganglion cells: Reduced number in dorsal root ganglia
  - Aggregates
    - In motor neurons, skin & other tissues expressing androgen receptor
    - Intranuclear & Cytoplasmic
Eternal link: e-Medicine

Bulbo-Spinal Muscular Atrophy with Gynecomastia (Autosomal Dominant) ¹

● Autosomal Dominant

Onset
- 2nd or 3rd decade
- Nasal voice
- Postural tremor
Lower motor neuron syndrome
- Tongue: Atrophy; Fasciculations
- Limbs
  - Weakness: Mild asymmetry; Proximal + Tibialis anterior
  - Atrophy
  - Fasciculations
- Tendon reflexes: absent
- Normal: Sensation & Autonomic function
Cranial nerves: Decreased Upgaze & Convergence (50%)
Systemic
- Gynecomastia
- No other signs of androgen insensitivity
Laboratory
- Serum CK: Mildly elevated
- EMG: Acute & Chronic denervation
- Motor evoked potentials (Magnetic stimulation: Prolonged central conduction time

Spinal Motor Neuropathy ¹⁵⁰

● RNA-binding motif protein 7 (RBM7)

; Chromosome 11q23.2; Recessive

Epidemiology: 1 Palestinian patient
Genetics
- Mutation: Homozygous; c.236C>G (p.Pro79Arg)
RBM7 protein
- RNA-binding
- Nuclear exosome targeting (NEXT) complex
  - Related proteins: MTR4 (MTREX) ; Zn-knuckle protein (ZCCHC8)
  - Assists exosome driven degradation of PROMoter uPstream Transcripts & other non-coding RNAs
- Location: Nucleoplasm
Clinical
- Onset
  - Age: 1 month
  - Hypotonia
- General
  - Size (Height, Head circumference & Weight): Low
- Weakness
  - Diffuse
  - Respiratory
- Muscle: Atrophy; No fasciculations
- Tendon reflexes: Reduced
- Death: 28 months
Laboratory
- Muscle: Grouped fiber atrophy; Large fibers all type 1
- Brain MRI: Normal

Spinal Muscular Atrophy 2 ⁵

● Autosomal Recessive (Not linked to SMA 5q)

Clinical
- Onset: 1 year
- Weakness
  - Proximal > Distal
  - Symmetric
  - Legs > Arms
  - Motor functions: Sit but never stand or walk
- Hypotonia
- Muscle atrophy
- Tendon reflexes: Absent
- Tremor: Mild
- Skeletal: Small head circumference; Pes valgus
- Cognitive: Normal
- Progression: ?; May develop respiratory disorders
Laboratory
- Serum CK: Normal
- Electrophysiology
  - EMG: Fibrillations; Large amplitude action potentials
  - NCV: Small amplitude CMAPs; Mild slowing; Sensory normal
- Muscle biopsy
  - Grouped atrophy
  - Type I muscle fiber predominance

Motor Neuropathies: Hereditary (dHMN & HMN) ^49, ^85, ¹⁵²

Hereditary Motor Neuropathies: General features

Prevalence: 2 per 100,000
Clinical
- Weakness Patterns: Varied
  - Distal
    - Onset: Distal weakness of toe extensors
    - Distribution: Distal; Legs > Arms
  - Other: Diffuse or Legs
  - Course: Slowly progressive
- Sensory: Normal
- Foot deformities
- Other features in some patients
  - Vocal cord paralysis
  - Diaphragm weakness
  - Pyramidal signs
Types
- General
- Overlap: dHMN; HMN; Motor CMT2
- Harding classification
  - Type 1: AD; Onset 2 to 20 years
  - Type 2: AD; Onset 20 to 40 years
  - Type 3: AR; Mild; Onset 2 to 10 years
  - Type 4: AR; Severe; Onset 0.3 to 20 years
  - Type 5: AD or Sporadic; Upper limb; Onset 5 to 20 years
  - Type 6: AR; Severe infantile
  - Type 7: AD; Vocal cord; Onset 10 to 20 years
Protein types
- Axon
  - Transport: DCTN1, DYNC1H1, BICD2
  - Repair: FBXO38
  - Cytoskeleton: MAPT; SPTAN1
- Chaperone
  - Small heat shock protein: HSPB1, HSPB3, HSPB8
  - DNAJB2
  - Tubulin-specific: TBCD, TBCE
  - Endoplasmic reticulum: SIGMAR1
  - Mitochondrial: SACS
- DNA/RNA
  - Processing: IGHMBP2, SETX, TRIP4, ASCC1, HINT1
  - tRNA synthetase (ARS): AARS, GARS, HARS, WARS
  - GLE1
  - Exosome: EXOSC3, EXOSC8, EXOSC9
- Endoplasmic Reticulum: BSCL2, REEP1, SIGMAR1, TFG
- Membrane & Synapse functions
  - Neurotransmitter processing & synthesis: SLC5A7, SYT2
  - Synaptic: SIGMAR1
  - Ion flux: TRPV4, KCC3, ATP7A
- Cell Proliferation/Mitosis & Growth: TBCK
- Nuclear envelope: VRK1
- Signal transduction
  - NFKB1: PLEKHG5
  - Guanine-nucleotide exchange factor: ARHGEF10, PLEKHG5
  - PI3K pathway antagonist: PTEN
  - STAT5B
  - TBX5
- Mitochondria: DHTKD1, MFN2, AIFM1, MPAN, SLC25A21,
  DNM2, HSPB8, SACS, c12orf65, FIG4, CHCHD10, SLC25A46

J Nervous & Mental Disease 1894

Distal hereditary motor neuropathy I (HMN 1; Distal HMN I)

● Chromosome 7q34-q36; Dominant ⁵⁹

Epidemiology: Australian family
Nosology
- Juvenile ALS
- Distal HMN
Clinical
- Onset
  - Age: Median 10 years; Range 3�40 years
  - Disordered walking & running
- Weakness
  - Legs: Ankle extensors & Intrinsic foot muscles
  - Hands: Mild or None
  - Symmetric
  - Atrophy: In regions of weakness
- Upper motor neuron
  - Muscle tone: Increased (67%)
  - Extensor plantar response (56%)
- Tendon reflexes: Preserved
- Sensory: Normal or Vibration reduced
- Foot deformities: Pes cavus; Hammer toes
- Progression: Slow
Laboratory
- Electrophysiological studies
  - Motor NCV: Median normal; Tibial slowed; CMAPs normal
  - SNAPs: Reduced with age
- Nerve pathology: Axonal loss
- MRI: Normal

Distal hereditary motor neuropathy, type 2 (HMN 2A; Distal HMN II)

● Heat-shock 22-kD protein 8 (HSPB8; HSP22)

; Chromosome 12q24.23; Dominant

Epidemiology: 4 families
Genetics
- HSPB8 mutations: Missense; Lys141Asn, Lys141Glu
- Allelic disorders
HSPB8 protein
- Heat shock protein
- High expression in motor & sensory neurons of spinal cord
- Interacts with HSBP1
- Z-disk-associated CASA complex
- Mutated protein promotes formation of intracellular aggregates
Clinical
- Onset
  - 14 to 35 years
  - Weakness of toe extension
- Weakness
  - Extensor muscles of feet
  - Progression over 5 years to complete paralysis of all distal muscles of legs
  - Legs > Arms
Nerve conduction velocity: Normal
HSPB8 variant syndrome: Motor neuropathy + Distal Myopathy ¹²⁵
- Epidemiology: 2 families, 7 patients
- Genetics
  - Inheritance: Dominant
  - Mutations: c.421A>G (p.K141E); c.151insC
  - Allelic disorders
- Clinical
  - Onset age: 1st to 3rd decade
  - Weakness
    - Distal
    - Legs > Arms
    - Proximal with disease progression
  - Cramps
  - Fasciculations
  - Tendon reflexes: Reduced in legs or Normal
  - Sensation: Normal
  - Scapular winging: Some patients
  - Camptocormia: Some patients
  - Course: Slow progression
- Laboratory
  - NCV: Motor neuropathy
    - Motor axon loss: Length dependant, Legs > Arms
  - EMG: Distal leg denervation
  - Muscle
    - Fiber size: Varied
    - Fiber type grouping
    - Vacuoles: Rimmed & Non-rimmed; p62 & SMI-31 positive
    - Aggregates: Desmin; Myotilin, αB-crystallin; Dystrophin
  - Serum CK: 250 to 2,000
  - Muscle MRI: Anterior leg involvement

Distal hereditary motor neuropathy (HMN 2B)

● Heat-shock 27-kD protein 1 (HSPB1; HSP 27)

; Chromosome 7q11.23; Dominant or Recessive

Epidemiology: Families from UK, Croatia, Belgium, Austria
Genetics
- Missense mutations: R127W; S135F; T151I; P182L
- Same gene mutated in: CMT 2F
- Mutations in C-terminal domain: More severe phenotype; Onset 4 to 7 years
Clinical
- Onset age: 21 to 54 years
- Weakness
  - Legs: Distal; Early in course
  - Arms: Distal; After 5 to 10 years
- Tendon reflexes: Reduced or Brisk
- Course: Slow progression
MRI: Anterolateral lower legs relatively spared

Distal hereditary motor neuropathy with upper motor neuron signs ²²

● Senataxin (SETX)

; Chromosome 9q34.13; Dominant

Epidemiology: Belgian, Austrian & English families
Genetics
- Allelic with
  - ALS4
  - AOA2
- Similar locus to
  - SPG19
Clinical
- Onset age
  - 4 to 49 years
- Weakness
  - Legs & Arms
  - Distal: Intrinsic hands & ankles
  - Bulbar: Normal
- Sensory: Usually normal
- Tendon reflexes: Normal or Increased
- Babinski sign: Positive in 50%
- Pes cavus (50%)
Laboratory
- Electrophysiology
  - Nerve conduction velocity: Normal or Mildly reduced
  - CMAPs: Reduced amplitude
  - Sensory: Normal SNAP amplitude; Conduction velocity borderline or mildly slow
  - Central motor conduction latencies: Slow
  - EMG: Distal denervation
- Sural nerve pathology: Minor changes
- MRI: White matter changes in 1 patient
Differential Diagnosis

Distal SMA: Upper limb predominance (HMN 5A; SMAD1)

● Glycyl tRNA Synthetase (GARS)

; Chromosome 7p14.3; Dominant or de novo

Epidemiology: Multiple ethnic origins
Genetics
- Allelic with CMT 2D
- Mutations: Missense; E71G, L129P, G240R, Leu272Arg, G526R
- Asymptomatic parent: May be mosaic\
- ARS mutations
GARS protein
Clinical
- Onset
  - Age
    - Mean 17 years
    - Range: 7 months to 4th decade
  - Weakness: Hands
- Weakness: Varied severity
  - Thenar eminence & 1st Dorsal Interosseous
  - Lower extremities involved in 50% after 2 years
  - Severe cases: Axial; Respiratory
- Tendon reflexes: Reduced
- Cramps: Related to cold exposure or exercise
- Joints: Hyperlaxity
- Rare Pyramidal signs: Rare
- Progression: Very slow to
Laboratory
- NCV: Motor axon loss
- Muscle: SMA-like denervation

Distal SMA: Upper limb predominance (HMN 5C) ⁶

● BSCL2 gene (Seipin)

; Chromosome 11q12.3; Dominant

Nosology: Also called HMN 5A
Epidemiology
- European families
- Most common D-HMN
Genetics
- Mutations
  - Missense
  - Exon 3
  - Asn88Ser; Ser90Leu
  - Located at N-glycosylation site
- Mutation effects
  - Alters N-glycosylation site
  - Aggregate formation
- BSCL2 allelic disorders
Seipin protein
- Integral membrane protein: Endoplasmic reticulum
- Glycosylated
Onset
- Age: Mean 15 years; Range 2 to 40 years
- Weakness: Hands
Clinical
- Weakness
  - Hands
    - Early involvement
    - Thenar eminence > 1st Dorsal Interosseous
    - Asymmetric
  - Lower extremities
    - Peroneal weakness (60%)
    - Symmetric
    - Foot deformities (95%)
  - Proximal: Normal
- Upper motor neuron
  - Tendon reflexes: Brisk
  - Tone: May be increased in legs
  - Plantar responses: Flexor
- Sensory loss: Vibration reduced in legs
- Hyperhidrosis (40%): Hands & Feet
- Progression
  - Very slow over decades
  - No patients severely handicapped
Laboratory
- Electrophysiology
  - CMAPs: Small
  - Motor NCV: Normal or Mildly reduced
  - Sensory NCV amplitude: Mild reduction, especially older patients
  - EMG: Large MUPs; Reduced Recruitment
  - Central motor conduction times: Prolonged (60%)
- Sural nerve: Mild loss of myelinated axons
Variant syndromes
- CMT2-like ⁹⁹
  - BSCL2 Mutation: S90W; Dominant
  - Clinical
    - Onset ages: 5 to 30 years
    - Weakness: Legs early; Thenar; Distal
    - Sensory loss: Pan-modal; Distal
    - Spastic: Gait; Tendon reflexes increased (Legs); Extensor plantar response
    - Skeletal: Pes cavus
  - NCV
    - CMAPs: Small amplitudes, especially median
    - SNAPs: Small amplitude in some
    - Velocities: Normal
  - Sensory myelinated axons: Loss or Increased; Regeneration; Thin myelin
- SPG 17 (Silver syndrome)
- Spastic paraparesis
- Asymptomatic: 4%

Hereditary Distal Ulnar-Median Muscular Atrophy ⁷

● Autosomal Dominant

? HMN 5 variant
Weakness
- Distal
- Arms at onset; Legs later
- Symmetric
Onset: Childhood - Teens
Upper motor neuron signs
- Brisk tendon reflexes
- Plantars reflexes: Flexor, Equivocal or Extensor
Sensory: Normal
Electrodiagnostic
- Normal nerve conduction velocities
- Prolonged distal latencies

Distal Hereditary Motor Neuronopathy 7A (HMN 7A; dHMN-VII; dHMN7) (Vocal cord involvement)

● Solute carrier family 5 (Choline transporter), Member 7 (SLC5A7; CHT)

; Chromosome 2q12.3; Dominant

Epidemiology: 4 families
Genetics ⁹⁸
- Mutations
  - Types: Frameshift or Tuuncating
  - c.1497delG (p.Lys499Asnfs*13), p.His521Gln*fs2, p.Lys510Asnfs*2, c.1526del (p.Pro509Leufs*3)
- Allelic disorders
  - Congenital MG with Episodic Apnea: Recessive, Missense mutations
  - Lethal Congenital Arthrogryposis
SLC5A7 protein
- Choline transporter
- Presynaptic: Motor neurons
- Determinant of synaptic acetylcholine synthesis & release at NMJs
- Mutation: Reduced choline transport; Remove endoytic trafficking motif
Clinical
- Onset
  - Age: Early childhood to Teens
  - Voice or Gait disorder
- Distal weakness
  - Onset: Hands; Median distributaion
  - Progression to distal leg weakness
  - Wasting: Prominent distally
  - Usually symmetric but occcasional asymmetry
- Vocal cord involvement (70%)
  - Distribution: Often asymmetric; Eventually bilateral
  - Onset: 1st or 2nd decade
  - Voice: Hoarse; Quiet
  - Respiratory failure: 2° Bilateral vocal cord paralysis
- ± Sensorineural hearing loss
- Tendon reflexes
  - May be brisk
  - Reduced distally in arms & legs with disease progression
- Sensation: Normal
- Course: Slow progression
Electrodiagnostic
- EMG: Distal denervation in feet & hands
- NCV
  - Velocities: Normal
  - CMAPs: Small distally
- Repetitive nerve stimulation: No decrement
- SFEMG: Excess jitter
SLC5A7 variant disorder: Congenital MG 20 (CMS20), Presynaptic, with Episodic Apnea ¹³³
- Epidemiology: 6 families
- Genetics
  - Inheritance: Recessive
  - Mutations: Missense; Loss of function
  - Allelic disorders
- Clinical
  - Onset
    - Age: Congenital to 2 months
    - Apnea
  - Weakness
    - Bulbar: Dysphonia; Dysphagia
    - Face
    - Eye: Ptosis; Ophthalmoparesis
    - Limbs: Proximal > Distal
    - Axial: Neck & Other
    - Variability
      - Apnea: Episodic
      - Fatigability
  - Arthrogryposis
    - Fingers & Knees
    - In more severe syndromes
    - Associated with: Hypotonia
  - Intellectual disability
  - Course: Fluctuating weakness; Improvement with treatment
  - Treatment: AChE inhibitors
- Laboratory
  - Repetitive nerve stimulation decrement: 0% to 70%
  - Neuromuscular junctions
    - Young patient: Immature, Reduced definition of AChR patches; Polyinnervated
    - Older patient: NMJs often Denervated or Remodeled; Butyrylcholinesterase (BChE) increased

Distal Hereditary Motor Neuronopathy 7B (Vocal cord involvement) (HMN 7B) ³⁴

● Dynactin 1 (DCTN1)

; Chromosome 2p13.1; Dominant

Epidemiology: Single family
Genetics
- Mutation: Missense; G59S
- DCTN1 allelic disorders
  - Perry disease : Parkinsonism, Depression, Weight loss, Hypoventilation, TDP-43 immunostaining of brain
  - May be associated with
    - ALS susceptibility
    - Progressive supranuclear palsy (K56R)
Dynactin protein
- Largest subunit of 10 million dalton dynactin complex
- Binds to
  - Microtubules
  - Dynein: Cytoplasmic
  - Also see: Rab proteins, CMT 2B
- Functions
  - Associated with axonal transport of vesicles & organelles
  - May promote synapse stability at neuromuscular junctions
- Mutation
  - Located in p150^Glued subunit
  - May distort folding of microtubule binding domain: Reduced tubulin binding
  - Induces dynactin self-aggregation & with dynein (in vitro) ⁵⁶
    - Associated with mitochondria
    - Aggregation reversed by overexpression of Hsp70
Clinical features
- Onset
  - Early adulthood
  - Respiratory difficulty due to vocal cord paralysis
- Weakness
  - Face: Progressive
  - Vocal cord paralysis
  - Limbs: Distal; Hands then Feet
- Sensory: Normal
Variant syndrome: ALS or ALS susceptibility
- Genetics
  - Inheritance: Dominant or Sporadic
  - Mutations: Missense; Thr1249Ile, Met571Thr, Arg785Trp, Arg1101Lys
  - Incomplete penetrance
- Clinical
  - Onset
    - Age: 48 to 64 years
    - Weakness: Arms, Legs, Posterior neck or Bulbar
  - Weakness
    - Arms, Legs or Bulbar
    - Progression: Slow; symptom duration = 4 to > 9 years
  - Upper motor neuron signs: Present
    - Tendon reflexes: Brisk
  - Fronto-Temporal Dementia
    - Some patients without motor neuron disease
    - 1 family
- Laboratory
  - EMG: Widespread denervation
  - MRI: Normal

Distal SMA: Calf predominant (HMN2D) ¹⁰⁶

● F-box only protein 38 (FBXO38; MOKA)

; Chromosome 5p31.1; Dominant

Nosology: Neuronopathy, distal hereditary motor, type IID
Epidemiology: 2 families
Genetics
- Mutation: Cys206Arg
- Allelic disorder: dHMN, Recessive
FBXO38 protein
- Coactivator of transcription factor Kruppel-like factor 7 (KLF7)
- Regulates genes required for neuronal axon outgrowth & repair
Clinical
- Onset
  - Age: 13 to 48 years
  - Difficulty standing or running
- Weakness
  - Initial: Calves
  - Distal predominant: Hands, Intrinsic; Feet
  - Other weak muscles: Triceps
  - Proximal: With disease progression in some patients
- Tendon reflexes: Ankle absent
- Fasciculations
- Course
  - Slowly progressive
  - Some patients lose ambulation
Laboratory
- NCV
  - Motor amplitudes: Reduced
  - Sensory: Normal
- EMG: Neurogenic; Fibrillations
- Muscle biopsy: Grouped atrophy; Large fibers types II > I
FBXO38 variant: Distal hereditary motor neuronopathy type (dHMN) IID, Recessive ¹⁵⁶
- Epidemiology: Turkish patient
- Genetics
  - Inheritance: Recessive
  - Mutation: Homozygous; p.Arg526Gln
- Clinical
  - Onset: Childhood
  - Weakness: Distal; Legs > Arms
  - Tendon reflexes: Normal
  - Sensory: Normal
  - Skeletal: Pes cavus
  - Hearing loss
  - Systemic: Duplex collective system, Arcuate uterus, Choanal atresia
- Laboratory
  - EMG: Denervation, distal
  - NCV: CMAP amplitudes small
  - Brain MRI: Normal

Distal SMA: Leg predominant ¹⁹

● Dominant

Epidemiology: Single Italian family
Onset: 8 to 30 years; Difficulty with heel walking
Clinical
- Weakness
  - Legs: Distal; Tibio-Peroneal
  - Arms: Mild; Later in disease course
  - Proximal: Mild; Arms & Legs; Late in course
- Hearing: Sensorineural loss in older patients
Laboratory
- EMG: Denervation in distal muscles
- Nerve conduction: CMAPS small; Normal NCV
- Muscle biopsy: Chronic denervation
- Auditory evoked potentials: Cochlear hearing loss
See: Congenital SMA of lower limbs

Distal SMA 3 (DSMA 3) ²¹

● Chromosome 11q13.3; Recessive

Nosology: HMN types III & IV
Epidemiology
- Lebanese & European families
- Most patients probably from single ancestor
Genetics: Normal IGHMBP2 gene
Clinical
- Onset
  - Age: Infancy to Early adult
  - Distal weakness
- Weakness & Atrophy
  - Distal
  - Feet > Hands
  - Diaphragm: With childhood onset
  - Proximal & Trunk: With disease progression
- Cranial nerves: Normal
- Sensation: Normal
- Tendon reflexes: Reduced or Normal
- No upper motor neuron involvement
- Course: Slow progression
Electrophysiology
- EMG: Denervation
- NCV: Normal
Muscle biopsy: Denervation

Distal HMN: Childhood onset

● Autosomal Recessive

Clinical features
- Onset: Early childhood
- Weakness: Distal; ± Quadriceps
- Progression: Very slow; Survival until at least middle life

Distal infantile spinal muscular atrophy with diaphragm paralysis (DSMA1; SMARD1; HMN 6)

● Immunoglobulin μ-binding protein 2 (IGHMBP2)

; Chromosome 11q13.3; Recessive

Epidemiology
- > 50 patients
- Up to 1% of early onset SMA
IGHMBP2 genetics
- Mutations: Missense; Nonsense; Frameshift deletion (exon 5) & Splice donor-site
- Allelic disorders
  - DSMA1 (SMARD1; HMN6)
  - SMARD, milder
  - AR-CMT2S
IGHMBP2 protein ⁶⁶
- Transcription factor: DNA binding protein
- ATP-dependent 5' --> 3' helicase: Separates double-stranded RNA & DNA
- Regulates: DNA replication, Pre-mRNA splicing, Transcription ± Translation
- Localization
  - Similar to SMN1 protein
  - Co-localization
    - RNA-processing machinery in both cytoplasm and nucleus
    - Ribosomes
- Tissue distribution: Widespread
- Mutations: Impair ATPase & Helicase activity
Clinical features
- Onset
  - Age: Congenital to 2 years
  - Intrauterine growth retardation
  - Respiratory failure
  - Hypotonia
- Respiratory distress: Severe
  - Diaphragmatic paralysis
  - Intercostal muscles: Relatively spared
- Weakness: Predominantly upper limbs & distal muscles
- Tendon reflexes: Reduced
- Contractures: Occasional; Mild; At knee and ankle
- Fingers: Fat
- Course
  - Common: Death or respiratory failure at < 3 months
Laboratory
- Serum CK: Normal
- Chest x-ray: Eventration of diaphragm
- Spinal cord pathology
  - Upper more severely affected than the lower
  - Small anterior roots
  - Remaining motor neurons show chromatolysis
- Nerve (Sural): Myelinated axon loss
- Muscle
  - Neurogenic atrophy without reinnervation
  - Large fibers: Type I
IGHMBP2 Variant: SMA, Later onset ⁶⁷
- Genetics
  - May have same mutation & family as severe disease
- Clinical
  - Onset: 2nd year
  - Weakness
    - Distal then Proximal
    - Dysphagia
  - Respiratory
    - Sleep hypoventilation
    - Vital capacity: Normal
  - Survival through childhood
IGHMBP2 Variant: AR-CMT2S ¹¹⁸
- Epidemiology
  - 12% of AR-CMT2
  - Asian, European, US
- IGHMBP2 Genetics
  - Inheritance: Recessive
  - Mutations: Heterozygous; Missense, Stop or Splice; Common p.Cys46*
- Clinical
  - Onset
    - Age: Childhood; 1 to 20 years
    - Gait disorder
    - Foot drop
  - Weakness
    - Distal
    - Arms & Legs
    - Proximal: Mild; Some patients
    - Symmetric
  - Sensory loss
    - Distal
    - Modalities: Large & Small fiber
  - Tendon reflexes: Absent
  - Tongue: Trombone shaped or Wasted
- Laboratory
  - NCV: Axon loss, Motor & Sensory
  - Nerve biopsy: Loss of large axons
Mouse model: Neuromuscular degeneration (nmd)
- Splice donor mutation
- Functional IGHMBP2 expression reduced to 20�25% of controls
- Life spans: 12 to 138 days
- Weakness & Muscle wasting
  - Progressive & Severe
  - Hind limbs then fore limbs
  - No phrenic nerve or diaphragm involvement
- Loss of motor neuron innervation
- Genetic disease modifier: On mouse chromosome 13
- Other tissues involved if IGHMBP2 expression replaced in nerve
  - Dilated cardiomyopathy: High serum CK & CK-MB
  - Skeletal muscle: Myopathy, mild
Differential diagnosis

Distal hereditary motor neuropathy, Jerash type (DSMA 2; HMNJ)

● Chromosome 9p21.1-p12; Recessive

Genetics
- Locus contains: SIGMAR1 gene
Clinical
- Onset age: 6 to 10 years
- Weakness
  - Distal
  - Legs, then Arms within 2 years
  - Muscle wasting: Hands & Feet
  - Steppage gait
- Tendon reflexes
  - Brisk at Knees; 6 to 25 years
  - Ankle: Absent
- Upgoing toes: Younger than 15 years
Laboratory
- Electrophysiology
  - Motor: Small CMAPs; Normal NCV
  - Sensory: Normal SNAPs
  - EMG: Chronic denervation
- Serum CK: Normal
- Biopsy: Sural Nerve
  - Mild reduction in number of myelinated axons
  - Occasional regeneration
- Biopsy: Muscle
  - Grouped atrophy
  - Target fibers
  - Type I predominance

Distal SMA, X-linked 3 (SMAX3) ⁴¹

● ATPase, Cu⁺⁺-transporting, alpha polypeptide (ATP7A)

; Chromosome Xq21.1; Recessive

Epidemiology: Brazilian, Australian & North American families
Genetics ⁷²
- Mutations
  - Missense
  - Locations: P1386S; T994I
- Allelic disorders
  - Menkes disease : Loss of function mutations
  - Occipital horn syndrome
ATP7A protein
- Copper-transporting P-type ATPase
- Normal copper: Localizes to trans Golgi network in basal copper concentrations
- Elevated copper: Relocates to small vesicles and plasma membrane
- Mutations
  - ATP7A protein levels: Normal
  - Functions: Impaired ATP7A trafficking in response to copper loading
Clinical
- Onset
  - Age: 1 to 61 years; Older in Australian family
  - Foot deformity
  - Gait disorder
- Weakness & Atrophy
  - Legs
    - Early in disease course
    - Distal
    - Tibioperoneal
  - Hands
    - Usual: With disease progression
    - Early in disease course: 1 patient
  - Proximal: Normal
  - Temperature sensitive: Occasional patients weaker in cold
  - Progression
    - Slow
    - Ambulation: Remains independent
- Tendon reflexes: Variable; Absent diffusely or in legs; May be normal
- Plantar response: Neutral
- Skeletal: Pes cavus
- Autonomic: Normal
- Hair: Normal
- Joints & Skin: Normal
- Heterozygous females: Normal
Laboratory
- Serum CK: Normal
- Electrophysiology
  - CMAP amplitudes: Reduced or Absent
  - NCV: Mildly reduced or normal
  - EMG: Chronic denervation
  - SNAPs: Normal
- Pathology
  - Nerve (Sural): Normal
  - Muscle: Denervation
- Normal
  - Catecholamine ratios in plasma
  - β-2-microglobulin in urine

Spinal muscular atrophy with respiratory failure (SMARD) 2, X-linked (SMAX) ¹¹¹

● Ribosomal biogenesis protein LAS1L (LAS1L)

; Chromosome Xq12; Recessive

Epidemiology: 1 patient
Genetics
- Mutation: S477N
LAS1L protein
- Function: Ribosomal biogenesis
- Coordinates processing of 45S rRNA at both ends of 2nd internal transcribed spacer
Clinical
- Onset age: Neonatal
- Weakness
  - Distal
  - Respiratory failure: Early onset; Diaphragm paralysis
- Fasciculations: Tongue
- Hypotonia
- Contractures: Mild; Toes & Fingers
- Tendon reflexes: Present
SMARD: Differential diagnosis
Laboratory
- Electrodiagnostic
  - CMAP amplitudes: Reduced in legs more than arms
  - SNAPs: Normal
  - EMG: Reduced recruitment, especially distal
- Brain MRI: Normal
- EEG: Normal
- CSF: Normal

Distal hereditary motor neuropathy ⁴⁵

● Chromosome 11p; Recessive

Epidemiology: Southern Italian family

Distal Hereditary Motor Neuropathy (HMN 2C) ⁷¹

● Heat-shock 27-kd protein 3 (HSPB3; HSPL27)

; Chromosome 5q11.2; Dominant

Epidemiology: 2 or 3 families
Genetics
- Mutations: Missense; Arg7Ser; R116P
- Other mutation with atypical syndrome: A33AfsX50
- Other: Small heat-shock protein disorders
  - HSPB8: HMN2A & CMT 2L
  - HSPB1: HMN2B & CMT 2F
  - αB-crystallin: Myofibrillar myopathy & Posterior polar cataracts
HSPB3 protein
- sHSP functions: Protein chaperones
- Expressed in ventral horn of spinal cord
- Interacts with HSPB2 & HSPB8
Clinical
- Onset
  - Age: 3rd decade
  - Weakness: Legs
- Weakness
  - Distal
  - Legs: Severe at ankles
  - Arms: Hands with wasting
  - Shoulder-girdle: Stop mutation, heterozygous
- Sensation: Normal
- Tendon reflexes: Reduced at ankles
Laboratory
- EMG: Denervation in distal legs & hands
- NCV: Normal velocities; Axon loss

Distal Hereditary Motor Neuropathy with Pyramidal features

● Chromosome 4q34.3-q35.2; Dominant

Epidemiology: Italian family
Clinical
- Onset
  - Age: 25 to 40 years
  - Gait Disorder: Spastic
- Weakness & Atrophy
  - Distal
  - Legs
- Upper motor neuron
  - Legs
  - Spasticity
  - Tendon reflexes: Brisk at knees; Reduced at ankles
- Sensation: Slight vibratory loss in feet
- Cognition & Bulbar: Normal
- Progression: Slow; Walking preserved
Laboratory
- Motor nerve conductions: Velocity normal; Amplitude reduced
- SNAPs: Normal

Spinal Muscular Atrophy: Other

Infantile Spinal Muscular Atrophy with Arthrogryposis (XL-SMA; SMAX2)

● Ubiquitin-activating enzyme 1 (UBE1)

; Xp11.23; Recessive

Mutations
- General location
  - Exon 15
  - Domain function: Interactions with gigaxonin
- Missense (Met539Ile; Ser547Gly)
- Synonymous (c.1731 C/T, Asn577Asn): Leads to
  - Reduced UBE1 expression
  - Altered methylation pattern of exon 15
UBE1 protein
- Ubiquitin-proteasome system
- E1 enzyme
- Initiates activation and conjugation of ubiquitin-like proteins
- Binds to gigaxonin
Clinical features
- Onset: Congenital or Infantile
- Weakness
  - Proximal: Similar to Werdnig-Hoffmann
  - Facial: Myopathic faces
- Skeletal
  - Contractures: Proximal & Fingers; Congenital
  - Fractures: Congenital
  - Facial dysmorphism
- Genital: Undescended testes
- Death
  - Usually < 2 years
  - Associated with respiratory insufficiency
- Family history: Miscarriages/spontaneous abortions
Pathology
- Muscle: Denervation
- Anterior horn cell loss
Rule out congenital 5q-linked SMA

Proximal SMA with dominant inheritance: Adult Onset (Finkel, Late adult type; SMAFK)

● VAPB

; Chromosome 20q13.32; Dominant

Epidemiology: Common in Brazil; 200 patients
Genetics
- Brazil & Portugal mutation: P56S
- Allelic disorder: ALS 8
Clinical
- Onset
  - Age: 30 to 60 years; Mean = 49 years
  - Legs
- Weakness & Atrophy
  - Proximal
  - Respiratory: Some patients
  - Gait: Waddling
- Fasciculations
- Tendon reflexes: Reduced (80%)
- Sensory & Bulbar: Normal
- Course: slow progression
Laboratory
- Serum CK high
- EMG: Neurogenic; Positive sharp waves, MUPs long duration & large amplitude
- NCV: Velocities normal; CMAP amplitudes reduced; SNAPs normal
- Muscle biopsy: Neurogenic

Hereditary motor neuropathy, distal 8 (HMN8): Spinal muscular atrophy, Congenital, non-progressive, of lower limbs

● TRPV4

; Chromosome 12q24.11; Dominant

Epidemiology: Multiple families
Genetics
- Allelic disorders
Clinical
- Onset age: Congenital
- Weakness
  - Legs only: Proximal & Distal
  - Non-progressive
  - Vocal cord paralysis: Some patients
- Contractures
  - Arthrogryposis
  - Knees & Ankles
Laboratory
- Serum CK: Mildly elevated
- Electrophysiology
  - EMG: Chronic denervation; Giant motor units
  - NCV: Normal motor & sensory
Differential diagnosis
- Distal SMA of lower limbs
- SMALED: DYNC1H1
- SMALED2: BICD2
- SMA Congenital, non-progressive, of lower limbs: TRPV4

Hereditary Motor Neuropathy, Distal 9 (HMN9; dHMN type I)

¹³⁹
● Tryptophanyl-tRNA synthetase (WARS)

; Chromosome 14q32.2; Dominant or Sporadic

Epidemiology: 5 families; 14 patients
Genetics
- Mutation: c.770A>G (p.His257Arg) (Recurrent); Phe138Tyr (de novo); Asp314Gly (Older onset)
WARS protein
- Function
  - Cytoplasmic Amino-acyl tRNA synthetase (ARS)
  - Catalyzes aminoacylation of tRNA^trp with tryptophan
- Mutation effect: Dominant negative
Clinical
- Onset
  - Age: 9 to 23 years
  - Weakness: Distal; Legs
  - Gait disorder
- Weakness & Wasting
  - Distal
  - Arms & Legs
  - Moderate to Severe
- Sensation: Normal
- Tendon reflexes: Ankles absent; Knees absent or normal
- Feet: High arches
- Course
  - Progressive
  - Most remain ambulant
  - 1 patient in wheelchair
Laboratory
- Electrodiagnostic
  - NCV: 35 to 63 M/s
  - CMAPs: Reduced amplitude
  - SNAPs: Normal amplitude
- Pathology
  - Sural nerve: Normal
  - Muscle: "Neurogenic atrophy"
- Muscle MRI: Distal atrophy

Early-onset spinal muscular atrophy with Contractures (SMALED2A)

^15, ⁹⁰
● Bicaudal D, drosophila, homolog of, 2 (BICD2)

; Chromosome 9q22.31; Dominant or Sporadic

Epidemiology: 19 families
Genetics
- Mutations
  - Hot spot: Ser107Leu
  - Other: Asn188Thr; Ile189Phe; Arg501Pro; Lys508Thr; Ala535Val; Thr703Met; Arg747Cys; Glu774Gly
  - Locations: Coiled-coil domains
- Allelic disorders
  - SMALED2
  - SPG
  - Arthrogryposis
  - Distal myopathy
BICD2 protein
- Golgin
- Adaptor protein
- Maintains Golgi structure
- Interacts with the dynein-dynactin motor complex: Axon transport
- Facilitates trafficking of cellular cargos involved in motor neuron development & maintenance
- Mutations: Increased microtubule stability; Abnormal collateral axon branching: Impaired NMJ development
- Dynein-related disorders, Other: SMA-LED; CMT 2O
Clinical
- Onset
  - Age: In utero, Congenital or few Young Adults
  - Fetal movements reduced
  - Walking: Late, Difficult or Slow
  - Contractures: Ankles
- Weakness
  - Legs > Arms
  - Legs: Proximal > Distal
  - Arms: Mild; Proximal & Hands
  - Respiratory: Sleep disordered breathing in some patients
  - Symmetric
  - Most patients ambulant
- Muscle wasting: Legs
- Skeletal
  - Feet: Pes planus or High arch ; Calcaneovalgus
  - Hip dislocation: Congenital or Early-onset
  - Spine
    - Scoliosis (50%): Not severe
    - Lordosis
  - Contractures
    - Common: Not all patients
    - Locations: Knees; Ankles (Pes equinovarus)
    - Onset: Congenital or 1st decade
  - Scapular winging: 40%
- Upper motor neuron
  - Spastic paraplegia: Some families; Later onset
- Tendon reflexes
  - More severe disease: Brisk in legs or arms
  - Reduced or absent in legs: Other patients
    - Especially at ankles
- Fasciculations: Arms in some patients
- Sensation: Usually normal; Occasional vibratory loss
- Cognitive: Normal
- Course
  - Slow progression or Stable
  - Many remain ambulatory to 5th decade
  - May need wheelchair
Laboratory
- MRI: Muscle
  - Involvement of vastus lateralis, intermedius; Sartorius > Rectus femoris
  - Sparing: Medial adductors & Semitendinosus
  - Similar to DYNC1H1-associated DCSMA
- Electrodiagnostic
  - EMG
    - Denervation with Reinnervation, Chronic
    - No fibrillations
  - NCV: Normal
- Serum CK: Usually normal; Up to 1100
- Spinal cord pathology
  - Motor neurons reduced: Lumbar more than cervical
  - Ventral roots: Atrophy
- Muscle
  - Chronic denervation
  - Type 1 predominance & hypertrophy
  - Groups of fast myosin negative muscle fibers
  - Fiber size: Varied
  - Pseudomyopathic
SMALED: Differential diagnosis
BICD2 variant syndrome: Spastic paraparesis (SPG)
- Epidemiology: 1 family, 4 patients
- Genetics
  - Inheritance: Recessive
  - Mutations: Especially coiled-coil domain 2; Missense; c.G1823A, p.S608L
  - Allelic with: SMALED2
- BICD2 protein
- Clinical
  - Onset age: 15 to 18 months
  - Spasticity: Gait disorder; Tendon reflexes brisk; Plantar reflex extensor
  - Amyotrophy (50%)
  - Sensation: Normal
  - Cognition: Normal
- Laboratory
  - Brain MRI: Normal
  - EMG/NCV: Normal
BICD2 variant syndrome: Arthrogryposis (SMALED2B) ¹³⁵
- Epidemiology: 7 sporadic patients
- Genetics
  - Inheritance: de novo; Dominant
  - Mutations: Gln194Arg, Cys542Trp; Arg694Cys
- Clinical
  - Fetal: Hypokinesia
  - Skeletal
    - Fractures, congenital
    - Hip dislocation
    - Micrognathia
    - Arthrogryposis
  - Hypotonia
  - Respiratory insufficiency
  - Microcephaly
  - Cognitive delay
  - Muscle: Atrophy
  - Course: Early death in some
- Laboratory
  - Brain imaging: Perisylvian polymicrogyria; Cerebellar vermis hypoplasia; Corpus callosum thin
  - Muscle: Neurogenic atrophy
  - EMG: Neurogenic
BICD2 variant syndrome: "Distal myopathy"
- Epidemiology: 3 families
- Genetics
  - Inheritance: Dominant
  - Mutations: Arg622Trp
- Clinical
  - Onset age
  - Weakness
    - Symmetric
    - Distal legs: Especially foot dorsiflexors
- Laboratory
  - Muscle MRI pathology: Thigh anterior & medial; Leg, Anterior > Posterior
  - Serum CK: Mildly high
  - EMG: Mixed myopathic & Neuropathic
  - NCV: Normal Motor & Sensory
  - Muscle pathology: Fiber size varied; Endomysial connective tissue increased

Spinal muscular atrophy with Lower limb predominance (SMA-LED)

⁷⁵
● Dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1)

Chromosome 14q32.31; Dominant

Epidemiology: 3 families
Genetics
- Mutations: Missense; I584L, K671E, Y970C; Tail domain
- Allelic disorders
DYNC1H1 protein
- Other dynein related disorder: Congenital SMA with contractures (SMALED2)
Clinical
- Onset
  - Age: Early childhood
  - Leg weakness
  - Late walking
- Weakness
  - Most severe: Quadriceps & Psoas; Hip abduction
  - Other: Distal legs; Mild
  - Arms: Normal
  - Symmetric
  - Functional disorders
    - Difficulty climbing stairs & rising from chair
    - Waddling gait
  - Course: Non-progressive
- Wasting: Quadriceps & Distal legs; Small hand muscles
- Tendon reflexes: Reduced at knees; Others normal
- Sensation: Normal
- Contractures: None
Laboratory
- Muscle MRI: Thigh
  - Early involvement: Vastus lateralis; Sartorius
  - Hypertrophy: Adductor longus; Semitendinosus
- Electrophysiology
  - EMG: Chronic denervation
    - Potentials: Large amplitude, long-duration
    - No spontaneous activity
    - Distribution: Proximal & Distal Legs; Not paraspinous
  - NCV: Normal velocities
- Muscle biopsy
  - Denervation: Small angular muscle fibers
  - Type 2 muscle fiber predominance
  - Focal inflammation: Perivascular
  - Chronic pathology: Muscle fibers small; Endomysium increased
Differential diagnosis

Hereditary Motor Sensory Neuropathy, Proximal (HMSN-P; CMT 2G)

⁹⁷
● Trk-fused Gene (TFG)

; Chromosome 3q12.2; Dominant

Epidemiology: Okinawa, Japan families
Genetics
- Mutation: Pro285Leu
- Allelic disorders
  - SPG 57: Recessive
  - CMT2, Dominant
  - HMSN-P
  - Chondrosarcoma, extraskeletal myxoid
TFG protein
- Endoplasmic reticulum exit sites
- Vesicles: Trafficking & Biogenesis
- Inhibition: Slows protein secretion from endoplasmic reticulum (ER); Altered ER morphology
- Full length transcript: Predominantly expressed in neural tissues
Clinical
- Onset
  - Age: Weakness commonly in 5th decade; Range 17 to 50 years
  - Cramps: Painful; Onset in 3rd decade
  - Fasciculations
- Motor
  - Weakness
    - Proximal > Distal
    - Lower > Upper
    - Symmetric
  - Cramps
  - Fasciculations
  - Muscle atrophy
  - Course: Progression to severe disability & wheelchair
- Tendon reflexes: Absent
- Sensory
  - Loss: Vibration & Joint position > Pain
  - Dysesthesias: Distal
- Tremor
- Diabetes Mellitus: 40% with hyperglycemia
Lab
- Hyperlipidemia: 25%
- Hyperglycemia: 30%
- Serum CK: High; 200 to 500
- CNS MRI: Normal
- Electrodiagnostic testing
  - CMAP amplitude: Reduced
  - SNAP amplitude: Reduced or Absent
  - NCV: Velocity normal
  - EMG: Denervation: Fasciculations
- Pathology: Spinal cord
  - Decreased numbers of anterior horn cells
  - Marked loss of myelinated axons in the posterior columns
  - Neuronal cytoplasmic inclusions: TDP-43, TFG, Optineurin & ubiquitin
  - Golgi fragmentation
- Sural nerve
  - Myelinated axons: Reduced numbers
  - Ultrastructure: Aggregated ER; Mitochondria small
TFG variant disorder: SPG 57
- Epidemiology: 1 Indian family, 2 patients
- Genetics
  - Inheritance: Recessive
  - TFG mutation: Arg106Cys
  - Allelic disorders
- TFG protein
  - Mutation: Inability to self-assemble into oligomeric complex
- Clinical
  - Onset age: < 2 years
  - Spasticity
    - Legs > Arms
    - Gait: No independent walking
    - Tendon reflexes: Increased
  - Eye
    - Optic atrophy: Reduced visual acuity
  - Polyneuropathy
    - Distal wasting: Hands & Feet
  - Sensation: Normal
  - Cognitive: Normal
- Laboratory
  - NCV: Polyneuropathy
    - Axon loss
    - Demyelinating features: NCV reduced; Latencies increased
    - Sensory: SNAP amplitudes reduced
    - Motor: CMAPs reduced amplitude or Absent
  - Brain MRI: Normal
- Diferential diagnosis: SPOAN
TFG variant disorder: CMT2
- Epidemiology: Taiwan family
- Genetics
  - Mutation: Gly269Val
  - Inheritance: Dominant
- Clinical
  - Onset age: 28 to 40 years
  - Weakness: Distal; Arms & Legs
  - Sensory loss: Distal
  - Course: Progressive to need walking aids
- Laboratory
  - NCV: 44 to 61 M/s
  - Nerve pathology: Axon loss, Large myelinated

Spinal muscular atrophy, Prenatal onset, with Congenital bone fractures (SMABF)

¹²⁶
● SMABF1

: Thyroid hormone receptor interactor 4 (TRIP4; ASC1; ASC-1)

; Chromosome 15q22.31; Recessive
● SMABF2

: Activating signal cointegrator 1 complex, Subunit 1 (ASCC1; p50)

; Chromosome 10q22.1; Recessive

Epidemiology
- SMABF1: 3 families, 5 patients; Kosovo, Albania
- SMABF2: 1 family, 2 patients; Turkey
Genetics
- Mutations: Stop
- TRIP4 allelic variant: Congenital muscle disease
TRIP4 & ASCC1 proteins
- Expressed in embryos: Spinal cord, Brain, Paraspinal ganglia (Dorsal & Sympathetic), Thyroid & Submandibular glands
- ASC-1 transcriptional cointegrator complex
  - Subunits: TRIP4; ASCC1; ASCC2; ASCC3
  - Ribonucleoprotein complex
  - Participates in: Transcriptional coactivation, RNA processing events
  - ASC-1 binding protein: Cysteine and glycine rich protein 1 (CSRP1)
  - Role in late myogenesis
  - Expressed at low level in muscles, especially axial
- TRIP4 & ASCC1 location: Nucleus
Clinical
- Pregnancy: Reduced fetal movements
- Motor
  - Hypotonia
  - Respiratory difficulty
    - Diaphragm eventration
    - Pulmonary hypoplasia
  - Weakness
  - Muscle mass: Decreased
  - Tendon reflexes: Absent
  - CNS: Global developmental delay
- Bone
  - Generalized osteopenia
  - Congenital fractures: Multiple; Long bones
- Joints: Arthrogryposis
  - Multiple contractures: Proximal & Distal
- Congenital heart defects
  - Secundum atrial septal defect
  - Patent ductus arteriosus
  - Cardiomyopathy
- Other: Some patients
  - Face dysmorphism
    - Microretrognathia,
    - Hypertelorism
    - High-arched palate
  - Hypertrichosis
- Course: Death at 2 to 16 months
Laboratory
- EMG
  - Neurogenic
  - Muscle: No contraction to stimulation
- Pathology
  - Muscle
    - Fiber size: Atrophy; Variable
    - Type I fibers: Larger; Clustered
    - Fiber immaturity: Immature myosin (Developmental)
    - Western blot: TRIP4 with reduced size, Upregulation of splice isoform
  - Sural nerve: Loss of unmyelinated axons; Collagen pockets
  - Spinal cord
    - Anterior horn cells: Loss; Apoptosis
    - Astrogliosis
- Brain MRI: Cortical gyration abnormal

TRIP4 variant: Congenital muscle disease (MDCDC) ¹³²
- Nosology: Congenital muscular dystrophy, Davignon-Chauveau type
- Epidemiology: 1 French family, 4 patients
- Genetics
  - Inheritance: Recessive
  - Mutation: c.G950A, p.W297*
- Clinical
  - Onset age: Birth
  - Motor
    - Hypotonia: Neonatal; Axial
    - Respiratory failure
    - Feeding difficulties
    - Motor development: Delayed
    - Weakness: Severe; Especially proximal & Trunk
  - Skeletal: Some
    - Joint hyperlaxity
    - Scoliosis: May be severe
    - Rigid spine
    - Contractures: Mild or None
  - Skin
    - Hyperelasticity, mild
    - Dry with scratch lesions
    - Follicular hyperkeratosis
  - Course
    - Death in 1st years: Some
    - Late: Non-walking
- Laboratory
  - Serum CK: Normal or Mildly high
  - EMG: Myopathic
  - Muscle CT: Preservation of leg adductors
  - Muscle biopsy
    - Fiber size
      - Variable
      - Small angular fibers: Red stained on Gomori trichrome
    - Endomysial connective tissue: Mildly increased in some regions
    - Perimysium: Fat replacement
    - Muscle fibers
      - Minicores
      - Internal nuclei
      - Caps

Pontocerebellar hypoplasia with Spinal muscular atrophy (PCH1A)

● Vaccinia-related kinase 1 (VRK1)

; Chromosome 14q32.2; Recessive

Epidemiology: 3 families
Genetics
- Mutations: Nonsense or Missense ⁶⁸
- Allelic with: Motor Neuron Disease, Distal ± Sensory loss
VRK1 protein
- Serine/threonine kinase
- Phosphorylates p53 & CREB
- Localization: Nuclear + Some cytoplasm & cell membrane
- Role in: Nuclear envelope formation
- Expression: Ubiquitous including brain
Clinical
- Onset
  - Age: 1st decade
    - Severe cases: Prenatal or Birth; Death within months
    - Milder cases: < 6 months
  - Fetal movements: Reduced
  - Hypotonia
  - Feeding difficulty
- Motor
  - Hypotonia
  - Weakness
    - Early: Reduced movements
    - Diffuse
    - Feeding disorders
    - Progressive: Walking achieved in some then lost
  - Milestones: Delay & Decline
  - Polyneuropathy: Distal, Symmetric
- Tendon reflexes: Reduced or Increased
- CNS
  - Cerebellar: Ataxia; Nystagmus
  - Psychomotor retardation: Some patients
- Skeletal
  - Contractures: Variable;
    - Arthrogryposis: Severe cases
    - Mild: Later onset patients
  - Scoliosis
- Course: Survial ranges from months to 12 years
Laboratory
- Serum CK: Normal
- MRI
  - Cerebellar hypoplasia or absence, including vermis
  - Pontine hypoplasia: Severe cases
  - Microcephaly
- EMG: Neurogenic
- NCV: Axonal sensory-motor neuropathy
  - Motor & Sensory velocities: Normal or Mildly slowed
  - CMAP & SNAP amplitudes: Small
Pathology
- Muscle: Denervation; Fiber type grouping; Grouped atrophy
- Nerve: Loss of large myelinated & small unmyelinated axons in sural nerve
- CNS
  - Spinal cord: Motor neuron loss
  - Cerebellum: Hypotrophic; Absent dentate nucleus; Other structural defects
  - Brainstem: Hypotrophic; Posterior fossa cysts
  - Basal ganglia: Neuronal loss
  - Cortical atrophy
VRK1 variant syndrome: Motor Neuron Disease, Distal ± Sensory loss ¹²⁴
- Epidemiology: 3 patients
- Genetics
  - Inheritance: Recessive
  - Mutations
    - Missense
    - Compound heterozygous
    - p.H119R (c.356A>G); p.R321C (c.961C>T); R358*; G135R; L195V
- Clinical
  - Onset age: 3 to 27 years
  - Weakness
    - Distribution
      - Distal
      - Legs: Ankles & Toes
      - Arms
      - Legs > Arms
      - Symmetric
      - Respiratory
    - Gait disorder
    - Course: Slow progression over years
  - Muscle atrophy: Distal legs
  - Tendon reflexes: Brisk, except absent at ankles
  - Sensory loss: Small fiber modalities in legs
  - Skeletal: Pes cavus; Hammer toes
- Laboratory
  - Serum CK: Mildly high (347) or Normal
  - NCV
    - Motor: CMAPs small
    - Sensory: Normal
  - EMG
    - Distal legs: Active denervation (Fibrillations)
    - Arms & Proximal legs: Chronic denervation with reinnervation (Large motor units)
  - Muscle biopsy: Small angular muscle fibers; Nuclear clumps
  - Brain MRI: Normal

Pontocerebellar hypoplasia with Spinal muscular atrophy (PCH1B)

⁸⁹
● Exosome component 3 (EXOSC3)

; Chromosome 9p13.2; Recessive

Epidemiology: 50 patients; 31% of PCH1
Genetics
- Mutations: Missense (Most common); Deletion; Splice-site
- Common mutation: Asp132Ala; Homozygous associated with milder phenotype
- Altered reading frame mutations: More severe; Death in childhood
- No homozygous nulls reported
- Allelic with: Spastic paraplegia
EXOSC3 protein
- RNA exosome core component
- Cellular locations: Cytoplasm; Nucleus; Nucleolus
- Exosomes
  - EXOSC1�EXOSC3: Cap of exosomal ring for RNA recognition & binding
  - EXOSC4�EXOSC9: Form core, a hexamer channel through which RNA passes
- Exosome-related disorders
  - PCH1B: EXOSC3
  - SMA + Cerebellar hypoplasia (PCH1C) - EXOSC8
  - Cerebellar atrophy + Spinal Motor Neuropathy: EXOSC9
  - Spinal motor neuropathy: RBM7
  - Immune: PM/Scl (EXOSC9 & EXOSC10) autoantibodies
Clinical
- Onset: Congenital
- Motor neuron: Muscle wasting
- Contractures: Distal
- Cerebellar
- Oculomotor apraxia
- Microcephaly: Progressive
- Developmental delay: Global; Severe
Laboratory
- MRI: Cerebellar atrophy; Brainstem & Cortex small
- EMG: Neurogenic; Large motor units
- NCV
  - CMAP amplitude: Small
  - Sensory responses: Normal
- Autopsy
  - Cerebellum: Neuron loss (Purkinje & Granule)
  - Spinal cord: Motor neuron loss

Variant syndrome: Spastic paraplegia, Early onset & Complicated ¹⁰⁴
- Epidemiology: Bangladesh-Italian & Arab-Israel families
- Genetics
  - Inheritance: Recessive
  - EXOSC3 mutations: V80F; D132A; G191C
- Clinical
  - Onset age: 1 to 4 years
  - Spasticity
    - Legs > Arms
    - Gait disorder
    - Tendon reflexes: Brisk
    - Plantar response: Extensor
  - Cognitive impairment: Mild
    - Speech disorder
    - Learning dificulty
  - Cerebellar:
    - Dysarthria
    - Nystagmus
    - Intention tremor & Dysmetria
  - Motor: 1 family
    - Distal amyotrophy
    - Tongue atrophy
    - Fasciculations
  - Eye: Strabismus (50%)
  - Skeletal: Adducted thumbs, Talipes valgus; Short stature (50%); Normal head circumference
  - Course: May be progressive after 1st decade
- Laboratory
  - EMG: Distal denervation
  - Nerve conduction: Velocities normal
  - Brain MRI: Cerebellar atrophy
  - Muscle biopsy: Type 2 predominance; Varied muscle fiber size
  - SSEP: Delayed central conduction times

Cerebellar atrophy + Spinal Motor Neuropathy (PCH1D)

¹⁴⁹
● Exosome component 9 (EXOSC9)

; Chromosome 4q27; Recessive

Nosology: Ponto-Cerebellar Hypoplasia 1D
Epidemiology: 4 patients
Genetics
- Mutations: Stop; c.481C>T, c.41T>C (Milder phenotype)
EXOSC9 protein
- Exosome core protein
- Part of hexamer channel through which RNA passes
- PM/Scl antigen
- Other exosome disorders
Clinical
- Onset age: Prenatal or Congenital
- Prenatal: Reduced movements; Growth retardation
- Infant: Poor head control
- Motor
  - Delayed development
  - Hypotonia
  - Weakness: Generalized; Proximal & Distal; Respiratory
  - Fasciculations: Tongue; Limbs
- Sensation: Normal
- Tendon reflexes: Reduced or Present
- Skeletal
  - Joint contractures & Arthrogryposis
  - Neonatal fractures
  - Face: Dysmorphism
  - Growth delay
- Seizures: 1 patient
- Course: Progressive
Laboratory
- EMG: Motor neuropathy; Fasciculations
- NCV: Motor axon loss
- Muscle biopsy: Fiber type groups; Grouped atrophy; Type 1 fibers large
- Brain MRI: Cerebellar atrophy, progressive
- Serum CK: Borderline

Ponto-Cerebellar Hypoplasia + Spinal Motor Atrophy & Arthrogryposis (PCH)

¹⁵⁹
● Kinesin Family Member 26B (KIF26B)

; Chromosome 1q24; de novo

Epidemiology: 1 Indian patient
Genetics
- Mutation: Missense, Gly546Ser; Heterozygous
KIF26B protein
- Kinesin, Unconventional
- Intracellular motor protein
- Cell polarity of migrating endothelial cells during angiogenesis
Clinical
- Onset age: Congenital
- Face dysmorphism: Microcephaly
- Skeletal: Arthrogryposis; Camptodactyly; Dislocated joints
- Respiratory failure
- Course: Death at 7 months
Laboratory
- Brain MRI: Microcephaly; Ponto-Cerebellar Atrophy; Spinal cord thin; Atrophy, progressive
- Muscle biopsy: Atrophic fibers
- Nerve biopsy: Reduced numbers of myelinated axons
- EMG: Motor neuron loss

Lower motor neuron syndrome with childhood onset (DSMA4)

⁵⁷
● Pleckstrin homology domain-containing protein, Family G, Member 5 (PLEKHG5)

; Chromosome 1p36.31; Recessive

Epidemiology: African family from Mali, consanguinous
Genetics
- Mutation: Missense; Phe647Ser
- Allelic with: CMTRIC
PLEKHG5 protein
- Cytoplasmic
- Distribution: Ubiquitous; High in peripheral nerve (endoneurium), spinal cord & brain
- Function: Nuclear Factor κB�Activator
- Mutant protein: Reduced levels in cells; Loss of NFκB-activating function; Aggregates
- Proteins sharing PH or PH/RhoGEF domain: Dynamin 2; Alsin
- Other guanine nucleotide exchange factor (GEF) disorders
Clinical
- Onset
  - Age: 2 to 11 years
  - Weakness
- Weakness
  - Distribution: Generalized; Proximal & Distal
  - Respiratory: With disease progression
  - Scapular winging
  - Face & Cranial nerves (Bulbar): Normal
  - Course
    - Progressive over a decade to severe disability
    - Milder phenotype in some patients
- Tendon reflexes: Reduced or Absent
- Contractures: Hips; Elbows; Hands
- Spine: Hyperlordosis; Scoliosis
- Intelligence: Normal
- No upper motor neuron signs
Laboratory
- EMG: Denervation of muscle
- NCV: Normal motor & sensory
- Muscle biopsy: Denervation

Variant syndrome: Charcot-Marie-Tooth disease, Recessive Intermediate C (CMTRIC)
- Epidemiology: Korean, Portuguese & Moroccan families
- PLEKHG5 Genetics
  - Inheritance: Recessive
  - Mutations
    - Compound heterozygous or Homozygous
    - Deletion; Duplication (7 bp); Missense
  - Allelic with: DSMA4
- PLEKHG5 protein
- Clinical
  - Onset age: 1st to 5th decades
  - Weakness
    - Distal
    - Proximal With disease progression; Legs & Arms
    - Arms & Legs
    - Course: Progressive
  - Tendon reflexes: Reduced or Absent
  - Sensory loss: Distal; Large & Small axon modalities
  - Skeletal: Pes cavus; Spine deformity in 1 family
- Laboratory
  - Serum CK: May be mildly increased
  - NCV
    - Motor: Intermediate slowing (24 to 39 m/s in median nerve)
    - SNAPs: Absent or Reduced amplitude
  - EMG: Denervation, Distal
  - Muscle MRI: Fatty replacement, especially anterior & lateral distal legs
  - Normal: VER; BAER
  - Nerve biopsy
    - Axon loss: Large > Small; Severe
    - Regenerating axon clusters
    - Hypomyelination
    - PLEKHG5: Absent from axons; Present in Schwann cell nuclei
  - Muscle: Neurogenic

Distal Motor Neuropathy with Young Adult Onset (DSMA5; dHMN)

⁸⁷
● DNAJ/HSP40 Homolog, subfamily B, Member 2 (DNAJB2; HSJ1)

; Chromosome 2q35; Recessive

Epidemiology: 2 families
Genetics
- Mutations
  - Homozygous
  - Splice site; c.229+1G>A, c.352+1G>A
- Allelic with: CMT 2T
- Other DNAJ disorders
DNAJB2 (HSJ1) Protein
- Molecular co-chaperone
- HSP40/DNAJ family
- Cellular location: Nuclear & Cytoplasmic
- Isoforms
  - HSJ1b: Cytoplasmic face of endoplasmic reticulum (ER) by C-terminal prenylation; Perinuclear
  - HSJ1a: Cytosolic or Nuclear
- Expression: Strong in neurons; Post-synaptic NMJs in muscle
- Protects ubiquitylated clients against activity of ubiquitin hydrolases
- Has client-specific refolding activity
- May reduce aggregate formation
- Mutation: Causes truncated protein
Clinical
- Onset
  - Age: 16 to 23 years
  - Foot drop
  - Gait disorder
- Weakness
  - Distal: Severe in legs
  - Legs > Hands
  - Course: Progressive to wheelchair
- Sensory: Normal
- Tendon reflexes: Absent
- Edema: Legs
Laboratory
- Electrodiagnostic
  - CMAP amplitudes: Reduced, especially in legs
  - NCV: Normal velocity
  - SNAPs: Normal
  - EMG: Denervation, Distal legs

HSJ1 variant: AR-CMT 2 ¹¹⁷
- Epidemiology: Austrian family
- Genetics
  - Inheritance: Recessive
  - Mutation: Homozygous; Missense, Tyr5Cys
- Clinical
  - Onset age: 23 to 30 years
  - Weakness: Foot & toe dorsiflexion; Hip & knee flexors
  - Gait: Unstable
  - Sensory: Leg paresthesias
  - Tendon reflexes: Absent in legs
- Laboratory
  - NCV: Axonal motor & sensory length-dependent neuropathy
  - EMG: Denervation, Distal legs

Lower motor neuron syndrome with late-adult onset (SMAJ; LOSMoN)

⁷⁹
● CHCHD10

Chromosome 22q11.23; Dominant

Nosology: Spinal muscular atrophy, Jokela type
Epidemiology
- 17 Finnish families
- Eastern Finland (Northern Karelia) prevalence: 12:100,000
Genetics
- Mutation: G66V
- Allelic disorders
CHCHD10 protein: Mitochondrial
Clinical
- Onset
  - Age: 30 to 73 years
  - Weakness, Cramps or Fasciculations
- Weakness
  - Proximal > Distal + Abdomen
  - May be: Asymmetric or Distal
- Cramps: Proximal > Distal; Painful
- Fasciculations: Distal & Proximal
- Tendon reflexes: Absent diffusely or in legs
- Other occasional features
  - Myalgias (50%)
  - Drop attacks: Body or head
  - Tremor: Associated with hand fasciculations
  - Ataxia
  - Pes cavus: Mild
  - Vibration sense reduction (50%): Distal legs; Asymmetric
- Course
  - Progression: Slow
  - Most retain some ambulation
Laboratory
- Serum CK: Normal to 8x High
- NCV
  - Normal velocities
  - CMAP amplitudes: Normal or Reduced
  - SNAPs: Normal or Mildly small
- EMG: Denervation, Distal & Proximal
  - Motor unit potentials: Long duration; Large amplitude
  - Fibrillations
  - Fasciculations
  - Complex repetitive discharges
  - Recruitment: Reduced
- MRI
  - Posterior lower leg muscles abnormal
  - Especially medial gastrocnemius
- Muscle biopsy ¹²⁸
  - Fiber type grouping
  - Grouped atrophy
  - Pyknotic nuclear clumps
  - Type 2 fibers: Small
  - Largest muscle fibers: Hypertrophy
  - Neonatal myosin heavy chain (MHCn): 3%-50% (median 15%) of muscle fibers
  - Vacuoles
    - Frequency: 60% of biopsies
    - Fibers also stain for LC3, p62, SMI-31 & TDP-43
    - More common with longer disease duration

Proximal Spinal Muscular Atrophy with Progressive Myoclonic Epilepsy (SMA-PME; SMAPME)

⁹¹
● N-Acylsphingosine Amidohydrolase 1 (ASAH1; Acid ceramidase)

; Chromosome 8p22; Recessive

Epidemiology: 4 families, Turkish & Italian
Genetics
- Mutations
  - Types: Missense, Thr42Met, Thr42 Ala (Milder phenotype); Whole gene deletion
  - Homozygous
- Allelic with: Farber Lipogranulomatosis
Clinical
- Onset age: 3 to 30 years
- Weakness
  - Proximal
  - Legs, then Arms; Face, mild
  - Respiratory: Later in disease course
- Tongue fasciculations
- Tendon reflexes: Absent or Present
- Tremor: Postural
- Seizures
  - Myoclonus epilepsy
  - With more severe phenotypes
- No contractures
- Skin: Normal
- Course
  - Progressive: To severe disability
  - Death: Some patients in 2nd decade
Laboratory
- EMG: Chronic denervation
- EEG
  - Epilepsy: Subcortical myoclonic epileptiform activity, sensitive to hyperventilation
  - May be normal
- Serum CK: Normal
- Muscle biopsy: Denervation & Reinnervation
Variant syndrome: Farber Lipogranulomatosis
- ASAH1 mutations: Cause severe reduction in Acid ceramidase activity (< 10%)
- Clinical
  - Skin: Lipogranulomata, subcutaneous; Periarticular subcutaneous nodules
  - Joints: Contractures; Pains
  - Hoarse voice
  - CNS: Mental retardation; Progressive deterioration
  - Lower motor neuron involvement (15%)
    - Hypotonia
    - Muscle atrophy
    - Respiratory insufficiency
    - EMG: Denervation
  - Systemic
    - Hepatomegaly
    - Splenomegaly
  - Eyes: Macular cherry red spots
  - Death: < 2 years
- NCV: Slowing in some patients
- Nerve pathology
  - Schwann cells, myelinating: Banana bodies

Spinal Muscular Atrophy with Hypomyelination & Cerebellar Hypoplasia (PCH1C)

¹¹⁴
● Exosome component 8 (EXOSC8)

; Chromosome 13q13.3; Recessive

Epidemiology: 3 families & 22 patients, Hungarian & Arab-Palestinian
Genetics
- Mutations: Missense; Ala2Val, Ser272Thr
- Other exosome disorder: PCH1B - EXOSC3
EXOSC8 protein
- Exosome component
  - Multi-protein complex
  - Functions
    - 3'->5' exoribonuclease activity
    - Participates in many cellular RNA processing & degradation events
    - Degradation of AU-rich element (ARE) containing mRNAs
  - Immune disorders: Exosome = PM/Scl target of autoantibodies
  - EXOSC8
    - Part of central hexamer channel of exome
    - Non-catalytic component
- Cell location: Nucleus & Cytoplasm
Clinical
- Onset age: Infant; 2 to 4 months
- Failure to thrive
- Weakness: Severe
- Spasticity
- Psychomotor retardation
- Vision: Impaired
- Hearing: Impaired
- Deterioration: Triggered by inter-current infections
- Death: Respiratory failure < 20 months
Laboratory

CNS
- Cerebellar hypoplasia
- Hypomyelination: Especially lateral descending tracts
Muscle
- Fiber size: Varied
- Cytochrome oxidase: Some negative fibers
- Mitochondrial oxidative enzymes: Complex I & IV reduced
Peripheral nerve: Normal myelin

Encephalopathy with Distal Spinal Muscular Atrophy, Early-onset, Progressive (PEAMO)

¹³⁴
● Tubulin-specific chaperone E (TBCE)

; Chromosome 1q42.3; Recessive or Simplex

Epidemiology: 4 families, 6 patients
Genetics
- Mutations: c.463Tgt;A (p.Ile155Asn) homozygous or + Stop
- Allelic disorders
  - Kenny-Caffey syndrome
  - Sanjad-Sakati syndrome
  - Clinical features
    - Congenital hypoparathyroidism
    - Mental retardation
    - Face dysmorphism
    - Growth failure
TBCE protein function
- Tubulin-specific chaperones
- Folding of α-tubulin
- Formation of α-β-tubulin heterodimers
- Heterodimer polymerization into microtubules
- See: SMA + TBCD mutations
Clinical
- Onset age: Neonatal to 14 months
- Hypotonia
- Developmental delay
  - Speech: Absent or Dysarthria
  - Cognition: Moderate to Severe involvement
- Weakness & Wasting
  - Distal
  - Legs & Arms
- Spasticity: Tetraparesis
- Ataxia (60%)
- Optic atrophy (40%)
- Scoliosis
- Course: Progressive
Laboratory
- Brain MRI
  - Cerebellar atrophy
  - Corpus callosum hypoplastic
  - Similar to NBIA
- Muscle pathology: Small angular fibers; Fiber type grouping
- EMG: Motor units large; Distal fibrillations; No fasciculations
- NCV: CMAP amplitudes reduced; Conduction velocities normal
- VEPs & BAERs: Delayed
- Calcium/Phosphate metabolism: Normal
Mouse model: pmn
- Genetics
  - TBCE Mutation: Trp524Gly
  - Gene location: Mouse chromosome 13
- Loss of motor neurons & myelinated axons
- CNS
  - Tracts - Fasciculus gracilis; Rubrospinal; Reticulospinal
  - Normal: Corticospinal tract
  - Pathological pattern: Dying back
- Death: 6 weeks

Spinal Muscular Atrophy, Early-onset with Neurodegeneration ¹³⁶
● Tubulin-specific chaperone D (TBCD)

; Chromosome 17q25.3; Recessive

Epidemiology: 1 family 2 patients
Genetics
- Mutation: Homozygous; R942Q
- Allelic disorder
  - Encephalopathy, progressive, early-onset, with Brain atrophy & Thin corpus callosum : Has motor neuron loss
TBCD protein
- Microtubule assembly
- Peripheral nerve: Axon & Dendrite maintenance
- See: dHMN + TBCE mutations
Clinical
- Hypotonia
- Developmental disorder
- Weakness: Diffuse; Prfoximal > Distal; Face; Respiratory
- Fasciculations: Tongue
- Microcephaly
- Seizures
- Psychomotor retardation
- Vision loss: Optic atrophy
Laboratory
- Serum CK: Normal
- Brain MRI: Cerebral atrophy
- NCV: CMAP amplitudes reduced; Velocities reduced
- Muscle: Grouped atrophy; Hypertrophy of largets muscle fibers
- Sural nerve: Normal

Motor Neuropathy & Intellectual Disability (TBCK Encephaloneuronopathy)

¹⁴³
● TBC1 Domain-containing kinase K (TBCK)

; Chromosome 4q24 Recessive

Epidemiology: 9 patients; Common Puerto Rican children of Boricua descent
Genetics
- Mutations: c.1652T>C (p.L551P); R126X
- Allelic with: Hypotonia, infantile, with psychomotor retardation and characteristic facies 3
TBCK protein
- Protein kinase
- Associates with mitotic apparatus
- Regulates: Cell size, Cell proliferation, MTOR signaling
Clinical
- Onset age: Child
- Hypotonia
- Weakness
  - Diffuse: Distal > Proximal
  - Respiratory insufficiency by teenage years
  - Rarely sit
- Tendon reflexes: Absent
- Face
  - Ptosis
  - Hypotelorism
  - Coarse
  - Macroglossia
- CNS
  - Autism
  - Speech & Cognitive delay
  - Seizures: Focal & Generalized
  - ? Exacerbation by ketogenic diet
  - Course: Progressive
- Systemic
  - Osteoporosis
  - Renal: Calculi; Urinary retention
  - Hypothermia: Intermittent to 33°C
Laboratory
- Motor axon loss
- Dyslipidemia: HIgh cholesterol or triglycerides
- TBCK- fibroblasts: Increased LC3+ autophagosomes
- Urine: Free oligosaccharide profiles
- Brain MRI: Leukoencephalopathy; Atrophy
- NCV: Motor neuronopathy
  - CMAPs: Small amplitude
  - SNAPs: Generally preserved
  - Velocities: Normal
- EMG: Chronic partial denervation; Myokymia in 1 patient; Some myopsthy in teenage years
- Muscle ultrasound: Atrophic; Dense; Fasciculating movements
- Muscle & Nerve biopsies: Non-diagnostic

Spinal Muscular Atrophy-like disorder ¹⁵¹
● Solute carrier family 25 (Mitochondrial oxodicarboxylate carrier), Member 21 (SLC25A21)

; Chromosome 14q13.3 Recessive

Epidemiology: 1 Pakistani patient
Genetice
- Mutation: Lys232Arg; Hpmozygous
SLC25A21 protein
- Mitochondrial
- Oxodicarboxylate carrier
Clinical
- Onset age: 3 years
- Weakness
  - Distal then Proximal
  - Arms & Legs
  - Face: Mild
  - Respiratory
  - Gait disorder
  - Muscle atrophy
  - Exacerbations: Associated with fever
- Tendon reflexes: Brisk
- Scoliosis
- Course: Progressive
Laboratory
- Anemia: Microcytic
- NCV: Motor axon loss
- Nerve: Axon loss
- Muscle
  - Groups of
    - Atrophic & Hypertrophied muscle fibers
    - Fiber types
  - Type 1 predominance
  - Mitochondrial
    - COX- muscle fibers
    - Complex I & IV activities: Reduced
    - mtDNA depletion
- Brain MRI: Normal

SMA: Severe infantile
● Recessive

Scapuloperoneal syndromes (? Dominant; Sporadic)

ALS: Hereditary

Inheritance
Dominant
ALS 1: SOD1; 21q
ALS 4: Senataxin; 9q34
ALS 6: FUS; 16p11
ALS 7: 20p13
ALS 8: VAPB; 20q13
ALS 9: Angiogenin; 14q11
ALS 10: TDP-43; 1p36
ALS 11: FIG4; 6q21
ALS 12: OPTN; 10p15
ALS 13: Ataxin-2: 12q24
ALS 14: VCP; 9p13
ALS 17: CHMP2B; 3p11
ALS 18: PFN1; 17p13
ALS 19: ErbB4; 2q34
ALS 20: HNRNPA1; 12q13
ALS 21: Matr3; 5q31
ALS 22: TUBA4A; 2q35
ALS 23: ANXA11; 10q22
ALS 24: NEK1; 4q33
ALS 25: KIF5A; 12q13
ALS: DAO; 12q24
ALS: GLE1; 9q34
ALS: SS18L1; 20q13
ALS: GLT8D1; 3p21
FTDALS1: c9orf72; 9p21
FTDALS2: CHCHD10; 22q11
FTDALS3: SQSTM1 (p62); 5q35
FTDALS4: TBK1; 12q14
ALS-FTD: CCNF; 16p13
ALS-FTD: 16p12
ALS-FTD: GRN; 17q21
ALS-FTD: TIA1; 2p13
SPG17: BSCL2; 11q13
Dynactin: 2p13
hnRNPA2B1: 7p15
Bulbar ALS

Recessive
ALS 2: Alsin; 2q33
ALS 5: Spatacsin; 15q21
ALS 6: FUS; 16p11
ALS 12: OPTN; 10p15
ALS 16: SIGMAR1; 9p13
ALS 6-21: 6p25, 21q22
ALS: ATP13A2; 1p36
ALS-PD2: DJ1, 1p36
ALS-Slow: ERLIN1; 10q24
ALS-Slow: CACNA1H; 16p13
MPAN: c19orf12; 9q12
MND, Distal: VRK1; 14q32
SPG39: PNPLA6; 19p13

X-linked, Dominant
ALS 15: UBQLN2; Xp11

Other (Sporadic)
ALS 1: SOD1; 21q
ALS 6: FUS; 16p11
FTDALS1: c9orf72; 9p21
FTDALS2: CHMP2B; 3p11
ALS: NEFH; 22q12
EWSR1: 22q12
Peripherin: 12q12
SQSTM1 (p62): 5q35
TAF15: 17q12
ALS-PD1 (West Pacific)

Onset age
Adult onset
ALS 1: SOD1; 21q
ALS 6: FUS; 16p11
ALS 7: 20p13
ALS 8: VAPB; 20q13
ALS 9: Angiogenin; 14q11
ALS 10: TDP-43; 1p36
ALS 11: FIG4; 6q21
ALS 12: OPTN; 10p15
ALS 13: Ataxin-2: 12q24
ALS 14: VCP; 9p13
ALS 17: CHMP2B; 3p11
ALS 18: PFN1; 17p13
ALS 19: ErbB4; 2q34
ALS 20: HNRNPA1; 12q13
ALS 21: Matr3; 5q31
ALS 22: TUBA4A; 2q35
ALS 23: ANXA11; 10q22
ALS 24: NEK1; 4q33
ALS 25: KIF5A; 12q13
ALS: DAO; 12q24
ALS: SS18L1; 20q13
ALS: GLT8D1; 3p21
ALS-Slow: CACNA1H; 16p13
ALS X: UBQLN2; Xp11
ALS Other: Heterogeneous
FTDALS1: c9orf72; 9p21
FTDALS2: CHMP2B; 3p11
FTDALS3: SQSTM1 (p62); 5q35
FTDALS4: TBK1; 12q14
FTDALS: 16p12
FTDALS: GRN; 17q21
Bulbar ALS
ALS: NEFH; 22q12
Dynactin: 2p13
Western Pacific

Childhood onset (Juvenile)
ALS 2: 2q33; Recessive
ALS 4: Senataxin; 9q34; Dominant
ALS 5: Spatacsin; 15q21; Recessive
ALS 6: FUS; 16p11; Sporadic
ALS 6-21: 6p25, 21q22
ALS 16: SIGMAR1; 9p13
ALS-Slow: ERLIN1; Recessive
Distal HMN 1: 7q34; Dominant
Other (Type 2)

Also see
ALS
Hereditary vs Sporadic
Dominant
Recessive
Sporadic
Aggregate composition
Susceptibility loci
Motor syndromes, Hereditary
Mouse models
PLS
External link: ALS mutations

General: Hereditary vs Sporadic ALS

Feature	Hereditary ALS	Sporadic ALS
Males:Females	1:1	1.7:1
Disease Duration	Bimodal < 2 & > 5 years	Unimodal 3 to 4 years
% of ALS cases	5% to 15%	~90%
Onset
Age distribution	More younger	More older
Mean age	46 years	56 to 63 years
Juvenile	ALS 2, 4, 5, 6	Rare
Bulbar features	25% c9orf72 40% ALS1 10%	15%
Legs	Common	Occasional
LMN predominant	ALS 1, 6, 17	PMA

ALS SYNDROMES: DOMINANT

ALS 1

● Superoxide Dismutase 1 (SOD1)

; Chromosome 21q22.11; Usually Dominant

Clinical features
General
Specific syndromes
Mutations
Location
Functional aspects
Specific correlations
Pathology
Population statistics
SOD1 other
SOD1 protein
Variants
Canine disorder
SOD1 deficiency

From: M Weiss

ALS-SOD1 (A4V): Tongue atrophy

Population statistics
- Frequency of SOD mutations in ALS syndromes
  - 12% to 23% of Familial ALS
    - Usually Dominant: May skip a generation
    - Occasional Recessive: D90A
    - New sporadic mutation identified: H80A; Rapidly progressive disease ³¹
  - 1% to 3% of Sporadic ALS
  - 1% to 3% of all ALS
- Penetrance: Overall 85% by age 85
Mutations: Location & character
- 153 different disease related mutations identified
- 55 likely pathogenic: Based on linkage, population studies, or hotspot location
- Locations
  - Usually in exons 1, 2, 4 & 5
  - Few in exon 3: 6 exon 3 mutations identified
  - 6 different mutations identified at codon 93 (Gly93) in exon 4
  - Most common mutations: D90A; A4V; I113T; L144F; G41D; E100K
  - Hot spots: A4; C6; N86; G93; D101; L126; N139;L144
- Common features
  - Heterozygous missense point mutations
  - Dominant inheritance with complete penetrance
- Other types
  - Stop codon: Exon 5 not needed for toxic action of mutated SOD
    - Nonsense mutations produce polypeptide length of 121 tp 156 aa (Normal 153)
    - 17 nonsense mutations identified
  - Intron: IVS4AS, A-G, -11 (11 bases upstream from intron-junction of exon 5)
  - Deletion
  - Intronic: Altered splice site; 3' untranslated region
  - Recessive
    - D90A; ? D96N
    - Dose effect (Homozygous more severe): L84F, N86S, L126S
  - Incomplete penetrance ⁷⁶
    - Unaffected patients more often female
- External link: ALS mutation database
Mutations: Functional aspects
- Most mutations affect subunit protein folding or dimer contact.
- Mutations may alter some Cu binding sites
- Mutant SOD enzyme activities vary.
  - Inactive: H46R & Gly85Arg
  - Normal: C6S; E40G; L84F; Asp90Ala; G93A & G93D; D109Y
- Protein stability
  - Unstable: L126X; G127X
  - Normally stable: A89V; D90A
- Correlation between ratio of mutant:normal SOD1 in RBC ⁵³
  - Lower ratio: Shorter disease duration
- No correlation between duration of disease and SOD mutant peptide ...
  - Ability to scavenge superoxide
  - Half-life
  - Solubility
  - Resistance to proteolytic digestion
  - Propensity to aggregate spontaneously into sedimentable structures
  - Relative affinity for Cu
- Stop mutations all in exons 4 & 5: Active site in exon 3 preserved
Allelic disorders\
- SOD1 deficiency
- Animal variant: Myelopathy
SOD1 protein
- Abundant: 1% of cytosolic protein
- Structure: Homodimer
- Each subunit contains Cu⁺⁺ & Zn⁺⁺ in cave-like active site
- Subcellular location: Cytoplasmic & mitochondrial
- Function
  - Detoxifies O₂^- to H₂O₂
  - Prevents oxidative damage
  - Associated enzymes preventing oxidative damage: Catalase; Glutathione peroxidase
  - Zn⁺⁺ maintains pH stability of dismutase reaction
- Misfolded SOD1: Binds to VDAC1 ⁷⁸
- Other SOD molecules
  - SOD2: Mitochondrial; Manganese
  - SOD3: Extracellular; Copper-Zinc
Clinical: General features of hereditary SOD1 ALS
- Clinically vs Sporadic ALS
  - Fewer upper motor neuron signs
  - Onset with monomelic leg weakness suggests familial ALS
- Most mutations with variable clinical features among patients
- Homozygosity
  - Often causes more severe phenotype than heterozygous state: Asn86Ser; Asp90Ala
- Some patients may have mainly lower motor neuron signs
- Onset
  - Mean age = 46
    - 10 years younger than sporadic ALS
    - 3.5 years younger than non-SOD FALS
    - 90% penetrance by age 70
  - No anticipation
  - Preparetic phase: Some with myalgias, leg cramps & painful paresthesias
  - Weakness: Asymmetric limb
- Duration (Mean for all FALS) = 3.4 to 5.6 yrs
  - Similar for SOD & non-SOD FALS
- Lower motor neuron signs
  - Common
  - Especially predominant in rapidly progressive cases
- Upper motor neuron signs
  - May be more common with slowly progressive course
  - Reported with Asp76Tyr & Homozygous Asp90Ala mutations
  - Dominant upper motor neuron signs: Not reported
- Bulbar onset
  - Unusual
  - Later onset age
  - Reported with some mutations
- Cramps: G12R; G37R; D90A; E100G
- Other Neural features
  - Sensory neuropathy: A89V; D90A
  - Extra-motor system symptoms: ? More frequent
  - Dementia: Rare; A4T; G41S; I113T; L144F; ? More common in non-SOD group
  - Autonomic failure: D90A; Val118Leu; 1 patient ³
  - Vocal cord dysfunction: A4V; I113F; Gly147Ser; I149T
  - Supranuclear EOM paresis: May occur late in disease course; H80R; I104F
  - Bladder dysfunction: G41S; Asp90Ala (Homozygous)

ALS syndromes: Correlations with some SOD1 mutations
Specific SOD1 mutations l Exon 1; Ala4Val Most common mutation Rapid onset & progression (1.0 yrs) Frequently only lower motor neuron signs l Exon 2; His46Arg @ Cu binding site of SOD Onset: Late; Legs Bulbar unusual Slow progression (17 yrs) l Exon 2; 6 bp deletion(ΔG27/P28) ⁶⁵ Mutation reduces transcription Low levels of mutant SOD1 protein Philipino founder Low penetrance Disease duration: 4.3 years l Exon 4; Leu84Val Lower motor neuron only Rapid progression (1.5 yrs) ?Earlier onset in males l Exon 4; Asp90Ala Onset: 20 to 94 yrs; Legs; Preparetic phase Leg cramps; Myalgia; Painful paresthesia Bladder dysfunction Progression: Slow; Legs ® Arms Inheritance Recessive: Finnish (2.5% carriers) Dominant: Clinically variable Incomplete penetrance l Exon 4; Ile104Phe Variable intrafamilial clinical features Age of Onset: 6 yrs - asymptomatic Course: 2 to 14 yrs until bulbar signs Limb onset: arms or legs l Exon 4; Ile113Thr Reported in Sporadic ALS patients Relatively common; Low penetrance Late Onset: Mean 59 years Course: Variable; 2 to 20 years l Exon 5; Codon 126 2 base pair deletion Rapid Progression Mutant protein not detectable in brain	ALS clinical features Lower motor neuron predominant A4V; G72C; Leu84Val; Gly93Cys; E100K; D101N; S134N Slow progression C6S; Asp11Tyr; G12R; V31A; Gly37Arg (18 yrs); Gly41Asp (11 yrs); F45C; H46R¹³¹; D76V; Gly93Cys (13 yrs); Gly93Ser; Leu144Ser; Leu144Phe (9 yrs) Rapid progression Ala4Thr (1.5 yrs); A4V; C6G; C6F V7E; L8Q; G10V; G41S; H43R; H48Q Asn86Ser Homozygous (5 mo); D101>G,H,N,Y; Leu106Val (1.2 yrs); I112T; I113F; R115G; D125H; 126 2bp del; S134N; Gly147Ser; Val148Gly (2 yrs); V148G Late onset His46Arg; Gly85Arg (55 yrs); D90A; I113T; Ala140Gly; Leu144Phe Early onset Gly37Arg; Leu38Val; A89V; L104F (6 yrs); ?Leu106Val More common in females Gly41Asp Bulbar onset Cys6Gly; L8Q; His48Gln; Asp76Tyr; Asp90Ala (Homozygous); D101Y; I112M; T116R; Cys146Arg; Gly147Ser; Val148Ile; I149T; Ile151Thr Onset in legs G10V; H46R; L84F; D90A; Gly93Cys; Gly93Ser SOD Mutations in "sporadic" ALS Most common: Asp90Ala; Ile113Thr Other: Asp11Tyr; V14G; G16S; E21K; G72S; D101N; V118InsAAAAC; E133delGAA Incomplete penetrance

ALS syndromes: Correlations with some SOD1 mutations

Specific SOD1 mutations

l Exon 1; Ala4Val
Most common mutation
Rapid onset & progression (1.0 yrs)
Frequently only lower motor neuron signs

l Exon 2; His46Arg
@ Cu binding site of SOD
Onset: Late; Legs
Bulbar unusual
Slow progression (17 yrs)

l Exon 2; 6 bp deletion(ΔG27/P28) ⁶⁵
Mutation reduces transcription
Low levels of mutant SOD1 protein
Philipino founder
Low penetrance
Disease duration: 4.3 years

l Exon 4; Leu84Val
Lower motor neuron only
Rapid progression (1.5 yrs)
?Earlier onset in males

l Exon 4; Asp90Ala
Onset: 20 to 94 yrs; Legs; Preparetic phase
Leg cramps; Myalgia; Painful paresthesia
Bladder dysfunction
Progression: Slow; Legs ® Arms
Inheritance
Recessive: Finnish (2.5% carriers)
Dominant: Clinically variable
Incomplete penetrance

l Exon 4; Ile104Phe
Variable intrafamilial clinical features
Age of Onset: 6 yrs - asymptomatic
Course: 2 to 14 yrs until bulbar signs
Limb onset: arms or legs

l Exon 4; Ile113Thr
Reported in Sporadic ALS patients
Relatively common; Low penetrance
Late Onset: Mean 59 years
Course: Variable; 2 to 20 years

l Exon 5; Codon 126
2 base pair deletion
Rapid Progression

Mutant protein not detectable in brain

ALS clinical features

Lower motor neuron predominant
- A4V; G72C; Leu84Val; Gly93Cys;
  E100K; D101N; S134N
Slow progression
- C6S; Asp11Tyr; G12R; V31A;
  Gly37Arg (18 yrs); Gly41Asp (11 yrs); F45C;
  H46R¹³¹; D76V; Gly93Cys (13 yrs); Gly93Ser;
  Leu144Ser; Leu144Phe (9 yrs)
Rapid progression
- Ala4Thr (1.5 yrs); A4V; C6G; C6F
  V7E; L8Q; G10V; G41S; H43R; H48Q
  Asn86Ser Homozygous (5 mo);
  D101>G,H,N,Y; Leu106Val (1.2 yrs);
  I112T; I113F; R115G; D125H; 126 2bp del;
  S134N; Gly147Ser; Val148Gly (2 yrs); V148G
Late onset
- His46Arg; Gly85Arg (55 yrs); D90A;
  I113T; Ala140Gly; Leu144Phe
Early onset
- Gly37Arg; Leu38Val; A89V;
  L104F (6 yrs); ?Leu106Val
More common in females
- Gly41Asp
Bulbar onset
- Cys6Gly; L8Q; His48Gln; Asp76Tyr;
  Asp90Ala (Homozygous);
  D101Y; I112M; T116R; Cys146Arg;
  Gly147Ser; Val148Ile; I149T; Ile151Thr
Onset in legs
- G10V; H46R; L84F; D90A;
  Gly93Cys; Gly93Ser
SOD Mutations in "sporadic" ALS
- Most common: Asp90Ala; Ile113Thr
- Other: Asp11Tyr; V14G; G16S; E21K; G72S;
  D101N; V118InsAAAAC; E133delGAA
- Incomplete penetrance

Genetic variants: Other features
- Ala4Val ¹⁴⁷
  - Epidemiology
    - Common among North American SOD1 ALS patients: 36% to 50%
    - Unusual in China
  - SOD1 protein: Folding of mutated SOD1 protein less stable than normal ³⁰
  - Clinical
    - Onset age: Mean 50 years
    - Course
      - Rapidly progressive
      - Mean survival: 1.4 years; 50% of other SOD1 mutations
    - Lower motor neuron predominant
- Phe20Cys ⁶⁰
  - Onset
    - Legs
    - Weakness or Fasciculations
    - Later in Females
  - Course: Mean 1.9 years
  - Bulbar signs present late
- Gly85Arg (Transgenic mouse pathology)
  - Rapid clinical course; Normal SOD1 activity
  - Astrocytic inclusions: Contain SOD1 & ubiquitin; Increased with disease progression
  - Aggregates in motor neurons: Contain SOD1
  - Reduced Glial glutamate transporter with disease progression
  - ? 1° disease in astrocytes
- Asp90Ala
  - Finnish population
    - Recessive inheritance: Heterozygotes asymptomatic
    - Genes derived from single founder: D90A 20,000 years ago; Recessive allele 1,500 years ago
    - Linked protective factor ²⁹: In SOD1 regulatory region; ? Reduces mutant SOD transcription
    - Clinical: Slow progression in homozygotes
  - Other geographic locales
    - Dominant inheritance
    - Progression in heterozygotes: Typical ALS course
  - SOD1 activity: Normal
- Rat SOD models ¹⁸
  - G93A high expression
    - Onset: 110 days
    - Rapid disease progression (8 days)
    - Motor neuron degeneration
    - Vacuolar pathology
  - H46R-4 high expression
    - Onset: 140 days
    - Slower progression (24 days)
    - Motor neuron pathology
    - Protein deposition & aggregation
- Other transgenic mice
  - Mitochondrial vacuoles, or
  - Neurofilament accumulation
SOD1 MND Laboratory
- CSF protein: Often high, atypical for other ALS
Pathology of SOD1-ALS: May vary with different mutations
- Common features: Some different from sporadic ALS
  - Cell loss: Corticospinal tract neurons & Anterior horn
    - Relatively normal corticospinal tract & brainstem motor nuclei: Gly93Cys
  - Posterior column changes
    - Especially fasciculus cuneatus (Middle root zone) at cervical level
    - Mutations: A4V; A4T; Gly93Cys; Gly93Ser; I113T; Not H48Q
  - Spinocerebellar tract pallor
  - Mouse models
    - Activation of non-neuronal cell types: Astroglia & Microglia
    - Sequential activation of Caspase-1 and -3
- Hyaline conglomerate inclusions (HCI) ²⁷
  
  Hyaline conglomerate
  inclusion
  - Cells: Surviving motor neurons
  - Subcellular location: Intracytoplasmic
  - Contain SOD, neurofilaments, peripherin ± ubiquitin
  - No correlation between frequency of aggregates & cell death
  - Mutations: Ala4Val, A4T, H48Q, D101N, I112T, I113T, 126 bp deletion
  - Have specificity for SOD1 FALS mutations
- E100G: ALS-dementia type
  - Dentate granule inclusions
  - Frontal lobe gliosis
Animal variant: Canine Degenerative Myelopathy, Recessive SOD1 ⁹²
- Dog breeds (115): Pembroke Welsh corgi, Boxer, Rhodesian ridgeback, German Shepherd dog & Chesapeake Bay retriever
- SOD1 mutations
  - Homozygous missense: E40K
  - Most same mutation; Also Thr18Ser
  - Wire Fox Terrier: High frequency of E40K allele; Low frequency of disease
- Clinical
  - Onset age: ≥ 8 years
  - Spastic paraparesis
  - Gait ataxia
  - Flaccid tetraparesis: Late
  - Course: Progressive over 2 to 3 years
- Pathology: Spinal cord
  - Lateral white matter: Myelin & axon loss
  - Neuronal cytoplasmic inclusions: Contain SOD1
  - No motor neuron cell body loss
SOD1 variant: SOD1 deficiency ¹⁵⁵
- Nosology: Spastic Tetraplegia & Axial Hypotonia, Progressive (STAHP)
- Epidemiology: 1 Afghan family
- Genetics
  - Mutation: Homozygous; Truncating; c.335dupG
  - Inheritance: Recessive
  - Heterozygous carriers: No phenotype
- Clinical
  - Onset age: 9 months
  - Developmental delay: Cognition imp[aired
  - Dysmorphism: Low set ears; Overlapping toes
  - Spasticity: Tetraparesis; Legs & Arms; Tendon reflexes brisk
  - Hyperekplexia
- Laboratory
  - Brain MRI: Cerebellar atrophy
  - Blood manganese: Low
  - SOD1 activity: Undetectable
  - Muscle
    - Fiber sizes: Varied
    - α-dystroglycan: Focally reduced
  - Muscle ultrasound & EMG: Fasciculations
  - NCV: Normal

ALS 15 ⁸²
● Ubiquilin 2 (UBQLN2; PLIC2; CHAP1) ; Chromosome Xp11.21; Dominant or Semi-Dominant
- Epidemiology
  - Frequency: 5 families; ~1% of ALS
  - Male vs Female
    - Progression: Similar disease duration
    - Onset age: Males younger; 34 vs 47 years
- Genetics
  - Mutation locationss
    - Missense in Proline: Pro497His, Pro497Ser, P506T, P509S, P525S
    - In or near PXX (Proline/Glycine repeats) domain
    - Sporadic patients: Outside PXX domain
  - Gene subjected to X-inactivation
  - Penetrance: 90% by age 71
  - Variant syndrome: Spastic paraparesis
  - Female carriers: Usually asymptomatic
- UBQLN2 protein
  - Ubiquitin-like protein family: Bind to subunits of proteasome
  - Regulates: Protein degradation pathways
    - Ubiquitin-proteasome system (UPS)
    - Endoplasmic reticulum�associated protein degradation pathway: Interacts with UBXD8 & HERPUD1
    - Macroautophagy
  - Interacts with: TDP-43; HSP70 (HSPA1A)
  - Mutations: May impair autophagy
- Clinical
  - General phenotypes: ALS, ALS + FTD, Juvenile-onset ALS, Madras
  - Onset
    - Age: 10 to 71 years; Older in females
    - Bulbar dysfunction
    - Dementia: Some patients
  - Upper motor neuron
    - Spasticity: Legs > Arms; Gait disorder
    - Tendon reflexes: Brisk
    - Bulbar & Pseudobulbar dysfunction
      - Prominent
      - Dysarthria
      - Dysphagia
  - Lower motor neuron: Often not prominent
    - Weakness: Plantar foot flexion; Hands in some patients
    - Fasciculations: Some patients
    - Wasting: Occasional
  - Dementia
    - Some patients
    - Fronto-Temporal, then Global
    - May precede motor signs
  - Sensory: Normal
  - Progression
    - Slow
    - Death after 2 to 17 years
- Laboratory
  - CNS pathology
    - Motor neurons: Skein-like inclusions
      - Contain Ubiquilin-2, Ubiquitin, p62, TDP43, FUS, Optineurin
      - No SOD1
    - Spinal cord
      - Axon loss: Corticospinal tract
      - Anterior horn: Loss of anterior horn cells; Astrocytosis
    - Hippocampus: Ubiquillin-2 pathology in ALS/FTD with & without UBQLN2 mutations
- Variant phenotype: Madras motor neuron syndrome
ALS 6 ³⁶
● Fusion, derived from 12-16 translocation, malignant liposarcoma (FUS; FUS/TLS) ; Chromosome 16p11.2; Dominant, Recessive or de novo (Sporadic)
- Epidemiology
  - Multiple families in Europe & US
  - Familial ALS: Frequency 4% to 5%
  - Common in: Early-onset familial ALS
  - Sporadic ALS: Frequency 0.5% to 0.7%; G507D, R518G, R521C, R521H, Exon 6
- Genetics
  - Mutations
    - Missense, In-frame deletion or insertion, or Frameshift
    - Hot spots: Exon 15; Arg521; Pro525
    - Other mutations: > 30; In Exons 3, 5, 6 & 14
    - Recessive mutation: H517Q
    - R514S & R521C: Associated with Symmetric, Proximal arm, neck & axial weakness
    - Pro525Leu & Pro525Arg ¹⁴⁴
      - Onset age: Very young (<30 years)
      - Bulbar presentation
      - Disease duration: Short, Rapid progression
      - Cytoplasmic inclusions: Stress granule�like
      - Pro525Leu: German patients
    - Arg521: Less bulbar involvement
    - Y526C: Young onset; Rapid progression
    - Basophilic inclusions: P525L; c.1554-1557delACAG
    - C-terminal nuclear localization truncation mutations: More aggressive disease
    - de novo mutations: Described in early onset (11 to 34 years) ALS syndromes
  - Incomplete penetrance: Common
  - Allelic disorders
    - Essential tremor 4 ⁹⁶
      - Epidemiology: Rare families
      - Mutations: Gln290X; Arg216Cys; Met392Ile; Pro431Leu
      - FUS mutant proteins: Degraded by nonsense-mediated-decay pathway
      - No symptoms of ALS
    - Frontotemporal dementia
    - ALS/Parkinson disease
    - Juvenile-onset ALS (< 25 years)
    - fALS, Recessive
    - ALS6, Dominant
    - ALS3: ALS family with gene originally localized to 18q21 ¹⁷
- FUS protein
  - Cellular localization
    - Normal: Nuclear
    - Disease
      - Cytoplasmic protein accumulation
      - Present in anterior horn cell aggregates in sporadic & hereditary ALS except SOD1
  - Functions
    - DNA & RNA metabolism
      - DNA-/RNA-binding
      - DNA repair
      - RNA-interacting domains: Located in the mid-region of protein
    - Implicated in tumorigenesis & RNA metabolism
    - FUS deficient neurons: Decreased spine arborization with abnormal morphology
      - Hippocampal neuronal slice cultures: FUS is in RNA granules that are transported to dendritic spines
      - Local RNA translation in response to metabotropic glutamate receptor (mGluR5) stimulation
    - Stress granule formation
  - Protein groups
    - hnRNP
    - TET: EWSR1, TAF15
  - Knockout mice: Perinatal mortality; Male sterility; Chromosomal instability; Radiation sensitivity
- Clinical: Predominantly lower motor neuron syndromes ⁷⁸
  - Onset
    - Age
      - Mean 44 years; Range 29 to > 70 years
      - Variable penetrance at 70 years: 39% to 83%
      - Earlier & shorter survival than SOD1 & TDP43 FALS
    - Limbs or Bulbar: Bulbar more frequent than SOD1 FALS
  - Lower motor neuron signs
    - Common
    - Weakness: Distribution
      - Limbs
      - Bulbar: May be present at onset
      - Early: Proximal or bulbar in some patients; Upper or Lower extremities
      - May be symmetric or asymmetric
      - Posterior neck
  - Upper motor neuron signs: Common
  - Other CNS
    - Cognition: Usually normal; Defecits in few patients
    - Extrapyramidal: Parkinsonism in few patients
  - Progression
    - Variable among families: Range 0.5 to 20 years; Mean 3.4 years
    - Slower progression: Later onset age
    - More rapid than SOD1 ALS: 89% die in < 4 years
  - Neoplasm association: None
- Pathology
  - Loss of motor neurons: Anterior horn of spinal cord & hypoglossal nucleus
  - Myelin pallor in anterior corticospinal tracts
  - Macrophages surrounding shrunken Betz cells in motor cortex (neuronophagia)
  - Increased lipofuscin staining in neurons
- FUS Variant syndrome: Recessive inheritance
  - Epidemiology: Cape Verdean family
  - FUS mutation: Homozygous H517Q
  - Clinical
    - Onset: Proximal upper extremities
    - Spread: To lower extremities; Not bulbar region
    - Progression: Slow; Up to 14 years
- Variant syndrome: Juvenile ALS with basophilic inclusions ⁷⁷
  - Family history: None
  - FUS mutations
    - C-terminal region
    - P525L (c.1554-1557delACAG); Y526C
  - Clinical
    - Onset age: 17 to 22 years
    - Weakness
      - Asymmetric
      - Arms & Legs
      - Bulbar: Relatively spared; Tongue wasting
      - Respiratory failure
    - Progression
      - Rapid: More than other juvenile ALS (ALS 2, 4, 5)
      - Death < 1 year
    - Upper motor neuron signs: Mild or Absent
    - No dementia
  - Laboratory
    - Pathology
      - CNS: Loss of axons in motor roots & corticospinal tracts
      - Basophilic inclusions
        
        In motor & non-motor neurons
        
        Stain for p62, PABP & FUS
        
        Tubulofilamentous structures
        
        Associated with electron-dense granules
        
        ? Origin from endoplasmic reticulum
    - EMG: Diffuse denervation
ALS 7 ³⁸
● Chromosome 20p13; Dominant
- Epidemiology: 1 family
- Genetics
  - Linkage security: Probable
- Clinical
  - Onset age: Mean = 57 years
  - Clinical: ALS = El Escorial criteria
  - Course: Progressive; Mean = 3 years
ALS 8 ⁴³
● Vesicle-associated membrane protein B (VAPB) ; Chromosome 20q13.32; Dominant
- Epidemiology
  - 7 Brazilian families
  - Rare in other populations
- Genetics
  - Same missense mutation in all families: Pro56Ser
  - Allelic with: Proximal SMA, Adult onset
- VAPB protein
  - Location: Associated with ER & Golgi membranes
  - Regulates membrane delivery into dendrites.
  - Mutant protein: Intracellular aggregates not associated with membranes
- Clinical: 3 variant syndromes
  - Onset
    - Age: 25 to 55 years
    - Cramps
    - Fasciculations
    - Weakness: Few patients
  - Heterogeneity: Inter- & Intra-familial
  - Atypical ALS
    - Onset: 25 to 44 years
    - Bulbar signs: Dysphagia (73%)
    - Lower motor neuron
      - Weakness: Arms & Legs; Trunk & Tongue in some patients
      - Cramps: Long-standing; Painful; Easily precipitated
      - Fasciculations
    - Upper motor neuron: Few patients
    - Tendon reflexes: Reduced
    - Postural tremor
    - Sensory loss: Few patients
    - Course
      - Slowly progressive
      - 1 patient with respiratory failure
  - ALS, Rapidly progressive
    - Survival: < 5 years
    - Lower motor neuron signs
    - Pyramidal signs
    - Occurs in same kindreds as atypical ALS syndrome
  - Spinal muscular atrophy, Late onset
    - Onset 35 to 55 years
    - Weakness: Predominantly proximal
    - Fasciculations
    - Cramps
    - Tendon reflexes: Reduced or Absent
    - No bulbar or pyramidal involvement
- Laboratory
  - Serum CK: Normal or Mildly elevated
  - EMG: Denervation, proximal, distal & tongue; Giant motor unit potentials
  - NCV: Normal motor & Sensory
  - Muscle biopsy: Neurogenic
    - Groups of large & small angulated fibres
    - Fiber type grouping
ALS 9 ⁵⁵
● Angiogenin (ANG) ; Chromosome 14q11.2; Dominant or Sporadic
- Epidemiology
  - Most identified in Irish & Scottish populations
  - Uncommon in US
  - Mutations found in some patients with no family history of ALS
- Genetics
  - Missense mutations: Q12L; K17I; K17E; R31K; C39W; K40I; I46V; V113I
  - Similar mutations occur in some Parkinson patients
  - Some missense mutations found in healthy controls: I46V; K17I
- Angiogenin protein
  - Mediator of blood vessel formation
    - Promotes endothelial invasiveness needed for blood vessel formation
    - Induces vascularization of normal and malignant tissues
      - Required for VEGF activity
    - Ribonuclease family: Abolishes protein synthesis by hydrolyzing cellular tRNAs
    - Induced by hypoxia
    - Transported to nucleus after uptake by endothelial cells
  - Present in wide spectrum of cells: Especially liver
  - Cell localization
    - Contains nuclear localization signal
    - Secreted protein
  - Mutation effects: Loss of function
- Clinical
  - Onset
    - Age range: 27 to 76; Similar to ALS or PD without mutation
    - Bulbar onset: 50%
    - Spinal onset: 50%
  - Pattern: "Typical ALS"; No specific phenotype
    - Upper motor neuron
    - Lower motor neuron
  - Course: 0.8 to 10 year survival
  - Parkinson disease
    - Often occurs with no ALS
    - Some ALS syndrome patients have Parkinson signs
ALS 4: Juvenile onset
● Senataxin ; Chromosome 9q34.13; Dominant
- Epidemiology: England; Southern Maryland
- Genetics ⁴⁴
  - Mutations
    - Missense
    - Locations: L389S; R2136H; T3I
    - Differ from stop or truncation mutations in senataxin in AOA2
  - Allelic with
    - Distal HMN with upper motor neuron signs
    - AOA2 (Recessive)
  - Similar locus to
    - SPG19
- Senataxin protein
- Clinical
  - Onset age: 2nd decade; Mean = < 6 to 21 years
  - Early: Gait disorder
  - Weakness: Distal in hands & feet; Later also proximal; Distal wasting
  - Bulbar disorders: Infrequent
  - Upper motor neuron signs: Hyperreflexia 86%; Upgoing toes 17%
  - Sensory: Normal or minor changes in few older patients
  - Variable degrees of severity
- Course
  - Slowly progressive over decades
  - 5th & 6th decades: Wheelchair; Loss of hand function
  - Milder phenotype: Mild gait disorder
- Electrophysiology: Chronic motor neuropathy
  - EMG: Denervation, Distal > Proximal
  - NCV: Reduced CMAP amplitude; Normal NCV; Normal sensory
- Pathology
  - Reduced number of Anterior horn cells, especially lumbar
  - Sensory pathways: Posterior column fiber loss; Loss of DRG neurons
  - Axonal swellings: Roots, Spinal gray, Dentate, Cranial nerves 3 & 4
  - Spinal cord atrophy
ALS-FTD 1 : ALS + Frontotemporal Dementia ⁹
● Chromosome 9q21-q22; Dominant or Sporadic
- Probably same as: ALS-FTD with c9orf72 mutations
ALS-FTD : ALS + Frontotemporal Dementia 1 (FTDALS1) ^54, ⁸³
● C9orf72 ; Chromosome 9p21.2; Dominant or Sporadic
- Epidemiology
  - European & North American families
  - Frequency
    - 60% of hereditary ALS-FTD
    - 27% to 38% of familial ALS patients
    - High frequency
      - Finnish ALS patients: 50% of familial; 21% of sporadic
      - Sweden
      - Jewish ¹⁴⁵
        
        Ashkenazi
        
        Present in up to 80% of fALS
        
        More common in bulbar onset sALS
        Have nucleotide repeat expansion on common, unstable risk haplotype
        
        North African Jews
        Other Jewish fALS Association: OPTN
    - Low frequency: Germany
    - Not present: Native Americans; Asia; Pacific Islands
    - Sporadic (Simplex) patient frequency
      - ALS: 0% to 21%; High in Finland
      - FTLD: Sporadic 7% to 10%
    - C9orf72 expansion in UK population: 1 in 700
    - FTLD familial: 19%
    - Lifetime risk of C9orf72-associated FTLD or ALS: 1 in 2,000
  - Sex: Male = Female
- Genetics
  - Mutation: GGGGCC (G₄C₂) hexanucleotide repeat expansion
    - Location
      - 1st intron & promoter
      - Non-coding region between non-coding exons 1a & 1b
    - Hexanucleotide repeat numbers
      - Controls
        
        Range ¹⁵³
        
        Control populations: 2 to 45; Rarely as high as 70
        
        2 or 3: Most common
        Other peak lengths: 5 & 8
        Intermediate length: 7 to 45
        
        Finland: Repeat lengths > 20 more common
        
        Repeat type: Uninterrupted
        Most common repeat size: ≤ 3
        Linkage disequilibrium between repeat length & neighboring SNP rs3849942
        Intergenerational repeat change
        
        Rate: 0.29%
        
        Intergenerational changes (Sequence instability)
        
        Usually occur from starting repeat length ≥ 8
        
        No expansion into disease range
        
        All occurred on rs3849942A haplotype
      - Patients
        
        Range: 700 to 4,400
        Somatic instability
        
        Present
        
        Different expansion size in varying brain & tissue areas
        
        No recent shared ancestry
      - 70 repeat expansions
        
        Increased C9orf72 expression
        
        On typical 200-kb risk haplotype
        
        May increase to pathogenic size range (~1,750 repeats) across generation
  - Associated genetics
    - Associated with SNPs: rs2477521; rs3849942 allele A
    - Finnish founder risk haplotype: All cases with GGGGCC repeat expansion
    - Hypermethylation of CpG island near & 5' of G₄C₂ repeat ¹⁰³
      - Associated & segregates with G₄C₂ expansion
      - Higher degree of methylation: Shorter disease duration
      - No methylation for normal or intermediate alleles (up to 43 repeats)
  - Penetrance ¹⁴²
    - Younger ages: Low; Rare < 35 years
    - 58 years: 50% penetrance
    - Older ages
      - 83 years: 75% to 99% penetrance
      - Females 2 years older than Males
      - Female + Bulbar onset: 3 years older
    - ALS: Mildly earlier onset age than FTD
    - Spinal onset: 2 years earlier than Bulbar
  - Genotype-Phenotype correlations & modifiers
    - c9orf72 expansion size
      - Greater size in blood
        
        Correlates with: Older age at clinical onset
        
        No relation to: Clinical syndrome diagnosis
      - Size of repeat in brain: Similar in most patients
    - Frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP)
      - c9orf72 mutations are most common cause
      - TMEM106B homozygous minor rs3173615 allele (GG; p.T185S) ¹⁰⁸
        
        Protects (OR 0.26) c9orf72 mutation carriers from developing FTD
        No protection from MND
        
        Also protective (OR 0.12) of FTLD-TDP caused by GRN mutations
    - TMEM106B A rs1990622 allele: Later age onset
    - ATXN2 intermediary polyQ expansions ¹¹⁶
      - Associated with development of clinical signs of both FTD & ALS
      - Predispose to: Expression of motor neuron disease within phenotype
      - Frequency in c9orf72 carriers: 3%
  - c9orf72 expansions can also occur with clinical diagnoses of
    - Alzheimer disease (1.2%)
    - Sporadic Creutzfeldt-Jakob disease (0.2%)
    - Huntington disease-like syndrome (1.7%)
    - Nonspecific neurodegenerative disease syndromes (2%)
    - Ataxia
    - Corticobasal syndromes
    - Controls (0.15%)
  - Possible disease mechanisms
    - C9orf72 protein haploinsufficiency (Down regulation)
    - Nuclear RNA foci: Sense (G₄C₂) & Antisense (C4G2)
    - Dipeptide repeat (poly-GA, -GP, -GR, -PA, -PR) inclusions or toxicity
- C9orf72 expression ¹⁰⁷
  - Subcellular: Probably nuclear
  - Cellular: Neurons > > Astrocytes or Microglia
  - Gray matter > White matter
  - Mutation
    - Reduced expression of isoform a
    - Associated with formation of nuclear RNA foci
  - Disease mechanism: ? Toxic RNA
- Clinical ¹⁵⁷
  - Onset
    - Age
      - Range: 34 to 84 years
      - Mean: 6th decade; 55 to 59 years
      - Median: 58 years
      - Similar for: ALS & FTD presentations
      - Same mean age as: Sporadic ALS
      - Young onset (< 45 years): Less than singleton ALS
      - Anticipation: 2 to 3 years younger onset per generation ¹³⁷
      - Later onset: More G₄C₂ repeats
    - Clinical
      - Weakness
        
        Limb: 50% to 67%
        Bulbar: Frequency 33% to 43%; More common than sporadic ALS
        Motor features before Dementia (30%)
      - Cognitive
        
        Dementia (FTD) before Motor (32%)
        Psychosis
        Paranoid, deluded or irrational thinking
  - Motor neuron disease
    - Occurs in patients without FTD (> 50%)
    - Upper motor neuron (95%)
      - Tendon reflexes: Brisk (95%)
      - Spasticity (46%)
      - Plantar response: Upgoing in 20%
      - Bulbar dysfunction
    - Lower motor neuron
      - Weakness
      - Fasciculations
    - Course
      - Survival: Median 30 to 37 months
      - Monthly change: -1.4% (sVC) to -1.8% (ALS-FRS)
      - vs sporadic ALS: Fewer slowly progressive patients
      - No corrrelationi with repeat size
    - Clinical variants ¹⁰⁹
      - No dementia: 50%
      - Primarily upper or lower motor neuron involvement: Rare
      - Spastic paraparesis: Rare
  - Dementia (FTD)
    - Frontotemporal lobar degeneration (FTLD)
    - Frequency
      - Patients: 30% to 35%
      - Families: 50%
    - Type
      - Behavioral (64%)
      - Progressive nonfluent aphasia (27%)
      - Semantic dementia (9%)
    - Psychiatric symptoms: 50%
    - Cortical
      - Cognitively impaired
      - Limb apraxia
      - Cortical sensory loss
      - Aphasia: Non-fluent
    - May occur in some patients without motor neuron disease
  - Extrapyramidal
    - Increased tone, Some patients
    - Huntington disease phenotype (2%)
      - Onset age: Younger than other c9orf72 syndromes; May be pediatric
      - Signs: Dystonia, Chorea, Myoclonus, Tremor, Rigidity
  - Epilepsy: Myoclonic ¹⁴⁶
    - Epidemiology: 1 family
    - Genetics
      - Mutation: c9orf72 repeat expansion
      - Other family members with psychiatric or neurodegenerative disorders
    - Onset age: 15 years
  - Disease duration
    - ALS
      - Mean 3.6 years; Range 1�6 years
      - Long survival: Less frequent than singleton ALS
    - FTD: Mean 5 years; Range 1�12 years
- Laboratory
  - EMG: Denervation
  - Muscle: Neurogenic atrophy
  - MRI
    - Atrophy
      - Frontotemporal: Bilateral
      - Thalamus
    - Fusiform, Thalamic, Supramarginal, Broca & Orbitofrontal regions: Involved in c9orf72, but not sporadic, ALS
    - Hypoperfusion: Frontal & Temporal; bilateral
    - White matter: Corpus callosum, Superior motor tracts, Corticospinal & Cerebellar pathways
  - CNS pathology
    - Brain atrophy: Especially frontal
    - Corticospinal tracts: Reduced myelin staining
    - LMN: Loss of from brainstem & spinal cord
    - Inclusions
      - Staining
        
        Ubiquitin, p62 or TDP-43: Vary in different brain locations
        Ubiquitinated in anterior horn cells, Bunina bodies or Hirano bodies
        
        TDP-43-positive neuronal cytoplasmic: Cortex & Spinal cord
        Not tau positive
      - Locations
        
        Neocortex
        
        Hippocampal dentate granule cells
        
        Cerebellar granule layer
      - Intranuclear inclusions
        
        Transcribed GGGGCC repeat: Forms nuclear RNA foci in cortex & spinal cord
        Proteins: None described
ALS 17 (ALS-FTD 3 ) ⁵⁸: ALS-like disorder ± Frontotemporal Dementia
● Chromatin-modifying protein (CHMP2B) ; Chromosome 3p11.2; Sporadic
- Epidemiology
  - Sporadic ALS
  - ALS: 1%
  - Lower motor neuron predominant ALS (PMA): 10%
- Genetics
  - Mutations
    - Missense
    - Ile29Val; Thr104Asn; Gln206His
  - Other mutations cause: Fronto-Temporal Dementia
- Protein
  - Nosology: Charged multivesicular body protein 2B
  - Component of vesicle sorting complex (ESCRTIII)
    - Other mutations in vesicle sorting complex proteins: ALS2; ALS8
  - Expressed in all areas of brain
  - Mutations: Reduced protein stability
- Clinical
  - Onset
    - Age: 7th & 8th decade
    - Bulbar dysfunction
  - Lower motor neuron syndrome: (Ile29Val; Thr104Asn; Gln206His)
    - Clinical
      - Weakness
        
        Bulbar (Tongue)
        
        Dysarthria
        
        Weakness
        
        Wasting
        
        Hands or Legs
        
        Respiratory
      - Fasciculations: Tongue & Limbs
      - Tendon reflexes: Reduced or Normal
      - No UMN signs
      - No FTD
      - Progression: Respiratory failure over 15 months
    - EMG: Diffuse denervation
  - I29V mutation: Fronto-temporal dementia syndrome (FTD-3)
    - May be benign variation or pathogenic mutation
    - Clinical
      - Onset: Dementia
      - Spastic dysarthria & dysphagia
      - Weakness: 1 arm & both legs
      - Tendon reflexes: Brisk
- Pathology ¹²³
  - Motor neurons
    - Loss
    - Ubiquitylated inclusions
  - p62 antibodies (sequestosome 1): Oligodendroglial inclusions in motor cortex
  - Neuronal Pathology: Frontal cortex
    - Lysosomal: Autofluorescent aggregates
Parkinsonism-Dementia-Amyotrophic Lateral Sclerosis Complex 2 ¹²⁷
● Oncogene DJ-1 (PARK7; DJ1) ; Chromosome 1p36.23; Recessive
- Epidemiology: Southern Italian & Turkish families
- Genetics
  - Mutations: Q45X; E163K & g.168_185dup
  - Allelic disorder: Parkinson disease 7, Autosomal recessive, Early-onset
- Clinical
  - Onset age: 3rd & 4th decades
  - Parkinsonism
    - Early onset
    - Bradykinesia
    - Tremor
    - Asymmetric
    - Levodopa responsive
    - Some families with only PD
  - Motor system
    - Weakness: Arms & Legs
    - Hand atrophy
    - Tendon reflexes: Brisk
    - Plantar response: Extensor
    - Cognitive impairment
- Laboratory
  - EMG: Fibrillations; Fasciculations
  - NCV: SNAPs normal
  - CSF: Normal
ALS with Bulbar onset, Benign course & Bunina bodies ¹⁰
● Autosomal Dominant
- Epidemiology: Japanese family
- Clinical
  - Onset
    - Bulbar dysfunction
    - Age: 5th & 6th decade
  - Cranial nerves: Atrophy of facial muscles & tongue; Dysarthria
  - Weakness: Arms ± Legs; Respiratory
  - Tendon reflexes increased
  - Normal: Sensation; Intellect; Bladder
  - Course: Progressive over 10 years
- Pathology
  - Reduced numbers of Upper & Lower motor neurons
  - Bunina bodies: In lower motor neurons
  - Normal: posterior columns
ALS: NEFH
● Neurofilament heavy chain (NEFH) ; Chromosome 22q12.2; ? Dominant or Sporadic
- Genetics
  - Mutation type: Inframe deletion or insertion
  - Mutation location
    - Large NFH side arm domain
    - Hypervariable C-terminus
      - Amino acids Lys-Ser-Pro (KSP)
      - KSP sequences in normal neurofilament heavy chain
        
        Repeated > 40 times
        Located in hypervariable region
        Commonly phosphorylated
        
        Sites for proline-directed serine/threonine protein kinases
        
        Located in sidearm projection that cross links neurofilaments
  - Mouse mutants
    - Over expression of neurofilaments: Associated with motor neuron disease
    - Neurofilament subunit knock-out: Reduced axon caliber
  - Allelic disorder: CMT, Axonal
- Neurofilaments
- Clinical (Genetic associations)
  - Sporadic ALS: Mutations in 1% of patients
    - Role in disease: ? Risk factor rather than causative effect
    - Reduced expression of NFL in sporadic ALS patients without SOD1 or NF mutations
  - Hereditary ALS: Scandinavian pedigree
    - ALS in 4 members of 2 generations
    - Deletion in the NF-H tail: Nucleotides 1989-2030
    - Clinical features: Variable
      - Dementia
      - Dysphagia
      - Monomelic ALS
- NEFH variant syndrome: CMT 2CC, Axonal ¹²⁹
  - Epidemiology: 2 families; 5 patients
  - Genetics
    - Inheritance: Dominant
    - Mutations: Frameshift (Stop) in 3' UTR of NEFH
    - Mutation effects
      - Translation of cryptic amyloidogenic elements (CAEs) encoded by 3' UTR
      - NEFH protein with 40 additional amino acids
      - Aggregation-prone NEFH molecule
  - Clinical
    - Onset age: 2 to 38 years
    - Weakness: Distal then Proximal; Legs > Arms
    - Muscle wasting: Distal
    - Sensory loss: Panmodal; Distal; Legs > Arms
    - Tendon reflexes: Reduced in legs
    - Course: Slow progression
  - Laboratory
    - Serum CK: Normal to 1,288
    - Brain & Spinal cord MRI: Normal
    - Muscle biopsy
      - Denervation: Grouped atrophy; Fiber type grouping
      - Internal nuclei
      - Rimmed vacuoles: Few fibers
      - Mitochondrial oxidative enzymes: Reduced complexes I, II+III & IV
    - NCV: Axon loss, Legs > Arms; CMAP & SNAP amplitudes reduced
    - EMG: Chronic denervation, Distal & Proximal; Proximal myopathic changes
    - CSF: Normal
ALS 10: TDP-43 ⁶²
● Tar DNA-binding protein (TDP-43; TARDBP) ; Chromosome 1p36.22; Dominant, Sporadic, or Recessive
- Epidemiology
  - Families: American, Canadian, English, French, Chinese
  - More common in Southern (Sardinia) than Northern European populations
    - 33% of ALS in Sardinia (A382T mutation)
  - Familial ALS: 3% to 6%
  - Sporadic ALS patients: Frequency ~1 in 200; 8 patients described
  - 18% with TDP43 mutations sporadic
- Genetics: Mutations
  - Missense
  - Locations
    - Often exon 6
      - Contains glycine rich domain
      - C-terminal
      - Interacts with splicing proteins (hnRNPs)
      - G287S; Gly290Ala; Ser292Asn; Gly294Ala; Gly298; Ala315Thr;
        Glu331Lys; Met337Val; G348C; R361S; A382T; N390D; N390S
    - Other mutation: D169G (Exon 4)
    - Clinical Correlations
      - Shortest survival: G298S
      - Long survival & Late onset: A315T; M337V
      - Frequent mutations: G348C; A382T
  - Allelic with: Frontotemporal lobar degeneration with tdp43 inclusions, TARDBP-related
- TDP-43 protein
  - Expression: Ubiquitous
  - Subcellular distribution
    - Nucleus & Cytoplasm
    - Reduced in nucleus in cells with TDP-43 cytoplasmic aggregates
  - Binds DNA and RNA: Regulates transcription & splicing
  - May be involved in microRNA biogenesis, apoptosis & cell division
  - Contains: Prion-like domain
  - Tendency to self associate & form aggregates
    - Sequestered into polyglutamine inclusions
    - Phosphorylated TDP-43: Present in neuronal aggregates in ALS & Fronto-temporal dementia
  - Mutation locations: C-terminal in region involved in protein-protein interactions
  - hnRNP protein: Similarity to hnRNPs
  - Stress granule related proteins (hnRNP): ALS related
- Clinical
  - General: Onset age earlier; Disease duration longer
  - Onset
    - Age
      - 4th to 8th decade
      - Younger than sporadic ALS
    - Weakness
      - Arms: 50%; More than SOD1 ALS
      - Legs: 20%
      - Bulbar: Common in Asians
  - Weakness
    - Arms before Legs: 60%
    - Distal + Proximal
    - Respiratory
    - Bulbar: Few patients
  - Upper motor neuron
    - Tendon reflexes: Brisk
    - Spasticity: Mild or None
  - Cognition
    - Usually normal
    - FTD-ALS syndromes: Occasional patient
    - FTD may be presenting syndrome
    - Other family members may have pure ALS with normal cognition
    - More involved in Sardinia
  - Extrapyramidal: Parkinsonism in few patients
    - Tremor, resting
    - Rigidity
    - Akinesia
  - Course
    - Slowly progressive (5 to 10 years) in most
    - Rapid (1 to 2 years) in some families (Gly290Ala; Gly298Ser)
    - Mean: Longer survival than sporadic ALS
- Laboratory
  - Nerve conduction testing: Normal
  - EMG: Denervation, proximal & distal; Fasciculations
  - CNS pathology
    - Anterior horns of spinal cord: Neuronal loss, Gliosis, and Bunina bodies
    - Corticospinal tracts: Pallor
    - Betz cell loss in primary motor cortex
    - TDP-43 inclusions
      - Locations: Upper & lower motor neurons + elsewhere in CNS
      - Often ubiquitinated
- Variant: Homozygous A382T missense mutation ⁸⁰
  - Epidemiology: 1 Sardinian patient
  - Genetics: A382T missense mutation
    - Incomplete penetrance
  - Clinical
    - Onset age: 49
    - Amyotrophic lateral sclerosis
      - Bulbar: Dysarthria & Dysphagia
      - Spasticity: Arms & Legs
      - Tendon reflexes: Increased
      - Plantar reflex: Extensor
    - Parkinsonism: Rigidity; Bradykinesia
    - Dystonia
    - Tics: Motor & Vocal; Childhood onset
    - Dementia: Frontotemporal
  - Laboratory
    - EMG: Distal denervation in arms & legs
    - NCV: Reduced CMAP amplitude
  - Parents: Heterozygous; Normal or Dementia
- Other TDP-43 variant syndromes
  - ALS + Extrapyramidal symptoms
  - ALS + Supranuclear palsy
  - Supranuclear palsy
  - FTD without motor neuron disease
ALS: Peripherin mutations ⁴⁸
● Peripherin (PRPH) ; Chromosome 12q13.12; Sporadic
- Genetics
  - Mutations: 4 identified
    - Nucleotide insertion in intron 8
    - 1-bp deletion in exon 1: Frameshift
    - Missense: R133P; D141Y
  - Allelic disorder: Axonal neuropathy
- Peripherin protein
  - Intermediate filament (type III)
  - Location: Peripheral nervous system; Lower levels in motor neurons
  - Increased levels after neuronal injury
  - Overexpression in mice: Motor neuron disease
  - Mutations disrupt neurofilament assembly
  - Associated with ubiquitinated inclusions
    - Round & Lewy body-like inclusions
    - Hyaline conglomerate inclusions
    - Axonal spheroids: Occur in proximal axons of diseased motor neurons
- Clinical: 4 patients
- PRPH variant disorder: Sensory-Motor neuropathy ¹⁵⁴
  - Epidemiology: Icelandic population
  - Genetics
    - Inheritance: Recessive
    - Mutation: Splice-donor variant; c.996+1G>A; Loss-of-function
  - Clinical
    - Neuropathy (50%)
      - Onset age: 20 years
      - Sensory
        
        Pain & Vibration loss
        
        Subjective: Foot numbness
      - Weakness: Toe extensors
  - Laboratory
    - Sural NCV
      - SNAP Amplitude: Smsll
      - Conduction velocity: Normal
      - Heterozygotes: Partial reduction in sural SNAP amplitude
ALS 11 ⁶³
● FIG4 Chromosome 6q21; Dominant or Sporadic
- Epidemiology
  - 10 patients of European ancestry
  - Frequency: 1% to 2% of ALS patients
- ALS
  - Mutations
    - Heterozygous
    - Missense or Termination
    - No patient with Ile41Thr mutation common in CMT 4J
  - Allelic disorders
- FIG4 protein
- Clinical patterns
  - Onset age: Mean 56 years; Range 29 to 77 years
  - ALS or PLS
  - Onset site: Bulbar, Legs or Arms
  - Brisk tendon reflexes
  - Personality change: Mild; 2 patients
  - Disease progression
    - Slow to Rapid
    - Disease duration: Mean 9 years; Range 1 to 29 years
  - ALS + FTD: 1 patient
- Laboratory
  - EMG: Normal to Moderate denervation
  - SSEP: Normal in 1 patient
  - Muscle biopsy: Rare atrophic muscle fibers
  - Autopsy: Lower motor neuron loss
- Animal model: 'pale tremor' (plt) mouse
ALS 18 ⁹⁵
● Profilin-1 (PFN1) Chromosome 17p13.2; Dominant
- Epidemiology
  - < 30 patients
  - 3% of FALS
  - 0.2% of SALS
- Genetics
  - Mutations: C71G; M114T; E117G; G118V
  - 2 singleton patients with no family history
- PFN1 protein
  - Converts monomeric G-actin to filamentous F-actin
  - Axonal integrity & Axonal transport
  - Mutant proteins: May form ubiquitinated aggregates; Alter growth cone morphology
- Clinical
  - Onset age: 4th to 7th decade
  - Limb onset: All patients
  - Bulbar onset: No patients
ALS 19 ¹⁰⁵
● V-erb-B2 Avian erythroblastic leukemia viral oncogene homolog 4 (ErbB4; HER4) ; Chromosome 2q34; Dominant
- Epidemiology: Japanese & Canadians
- Genetics
  - Mutations: Missense; Arg927Gln, Arg1275Trp
- ErbB4 protein
- Clinical
  - Onset
    - Age: Adult; 45 to 70 years
    - Arm involvement
  - Lower motor neuron
    - Weakness: Limbs
    - Respiratory insufficiency
  - Upper motor neuron
  - Cognitive: Normal or ALS + FTD in 1 patient
  - Progression
    - Slow
    - Death: After 4 to 9 years
ALS ⁷³
● D-amino acid oxidase (DAO) Chromosome 12q24.11; Dominant
- Epidemiology: 1 family
- Genetics
  - Mutation: R199W
  - May be schizophrenia locus
- DAO protein
  - Tissues: Liver, Kidney, Brain (Neurons & Astrocytes)
  - Peroxisomes
  - Homodimer
  - Flavoenzyme
  - Oxidizes: D-serine, D-alanine, D-proline
  - Mutation effect: ? Dominant negative
- Clinical
  - Onset: Hand weakness & wasting
  - Upper motor neuron features
  - Lower motor neuron involvement
  - Bulbar signs
  - Disease progression: Rapid; 1 to 2 years
  - Age at death: Mean 44 years; Early 40's in 75%; Range 42 to 73 years
- Pathology in obligate carrier
  - Motor neuron loss: Cervical & Lumbar spinal cord
  - Lateral corticospinal tract pathology
  - Frontal & temporal lobes: Preserved
  - TDP-43 in motor neurons: Localized to nuclei; No inclusions
  - DAO activity in spinal cord: Reduced
ALS ⁸⁶
● TAF15 RNA Polymerase II, TATA Box-binding protein-associated factor, 68-kD (TAF15) Chromosome 17q12; Sporadic
- Epidemiology: 6 sporadic patients; 0.5% of sporadic ALS
- Genetics
  - Mutations
    - Type: Missense;
    - Location: Exons 13-16; M368T, G391E, R408C, G452E, G473E
  - Allelic with: Chondrosarcoma, extraskeletal myxoid
- TAF15 protein
  - Contains: Prion-like domain
  - RNA recognition motif (RRM)-containing
  - Location: Nucleus & Cytoplasm
  - TET proteins (translated-in-liposarcoma, Ewing�s & TAF15)
    - TAF15
    - FUS
    - EWS
  - Mutant protein: Cytoplasmic foci
- Clinical: ALS, Adult onset
  - Onset age: 5th to 7th decade
  - Weakness: Distal & Proximal; Bulbar; Asymmetric
  - Tendon reflexes: Brisk
  - Sensation: Normal
  - ALS + FTD: 1 patient
- EMG: Denervation
ALS ⁸⁸
● Ewing sarcoma Breakpoint 1 (EWSR1) Chromosome 22q12.2; Sporadic
- Epidemiology: 3 sporadic ALS patients
- EWSR1 protein
  - Location: Nucleus; Cytoplasm, punctate or granular, in ALS neurons
  - Contains: Prion-like domain
  - Aggregation prone: Like FUS, TDP-43, TAF15
- Genetics
  - Mutations: Missense; G511A, P552L
- Clinical: ALS
  - Onset ages: 35 & 50 years
ALS 22: ALS ± Dementia ¹¹⁹
● Tubulin α-4A (TUBA4A) ; Chromosome 2q35; Dominant
- Epidemiology: 12 patients
- Genetics
  - Mutations: Val7Ile; G34V; T145P; R215C; R320C; R320H; The349Ser; A383T; W407X; Asp438Asn; K430N
- TUBA4A protein
  - Expression: Ubiquitous; High in brain
  - Component of Microtubules
  - See
    - Axon transport
    - Tubulin disorders
  - Mutations
    - Destabilize microtubule network
    - Reduced repolymerization capability
- Clinical: ALS
  - Onset ages: 48 to 71 years
  - Spinal-onset
  - Upper & Lower motor neuron signs
  - Frontal dementia: 3 patients & 1 1st degree relative
  - Disease duration: 1 to 7 years
FTDALS 4 ¹²⁰
● TANK-Binding Kinase 1 (TBK1) ; Chromosome 12q14.2; Dominant or Sporadic
- Epidemiology: 1% to 3% of ALS & ALS/FTD; > 30 families
- Genetics
  - Mutations
    - Types: Loss-of-function & Missense
    - Effects: Loss of function; ? Dominant gain of function
    - Heterozygous
  - Penetrance
    - Incomplete
    - Family history: Often negative
  - Allelic disorders
    - Increased TBK1 copy number: Glaucoma (Primary open angle; Normal tension)
    - PLS/Dementia
- TBK1 protein
  - IKK-kinase family
  - Autophagy
    - Efficient cargo recruitment in autophagy
    - Degradation of protein aggregates
  - Co-localizes with OPTN & SQSTM1 in autophagosomes
  - NF-κB pathway
- Clinical
  - ALS syndrome
    - Onset
      - Age: Mean 60 years; Oldest 80 years
      - Common: Legs or Arms
      - Bulbar in 15% to 40%
    - Bulbar involvement: 87%
    - Tendon reflexes: Brisk
  - Fronto-Temporal dementia
    - Cognitive impairment in 50%
    - Language impairment (Aphasia)
    - Presenting feature in 60%
  - Course
    - Survival: Mean 42 months; Range 1 to 9 years
    - Age at death: Mean 65 years; Range 50 to 77 years
- Laboratory
  - EMG: Active & chronic denervation
  - Pathology
    - TDP-43 & p62 inclusions: Neurons & Glia
- TBK1 variant: PLS/Dementia ¹⁴⁰
  - Epidemiology: 1 Spanish family, 6 patients
  - Genetics
    - Inheritance: Dominant
    - Mutation: Arg573Gly
  - Clinical
    - Onset age: 60 to 66 years
    - Dementia: 67%
      - Behavioral changes
      - Aphasia, Non-fluent
      - Memory deficits
    - PLS syndrome: 33%
      - Distribution: Bulbar ± Spinal
      - Course: Slow progression
      - May occur without dementia
      - EMG: No denervation
ALS-FTD ¹³⁰
● Cyclin F (CCNF) ; Chromosome 16p13.3; Dominant & Sporadic
- Epidemiology: 6 families; 19 sporadic patients; Diverse geography
- Genetics
  - Mutations: Missense; S3G, K97R, T181I, S195R, R392T, S509P, T543I, S621G (Segregates), E624K, I772T
  - Similar locus to: ALS-FTD 16p12
- CCNF protein
  - Component of E3 ubiquitin�protein ligase complex (SCFCyclin F)
- Clinical
  - Onset age: Mean 55 years; Range 42 to 66 years
  - Syndromes
    - ALS alone
      - Most common presentation
      - Limb or Bulbar onset
      - UMN + LMN signs
      - Asymmetric
    - PLS syndrome: 1 patient
    - FTD-ALS syndrome: 1 patient
    - Disease duration: 3 to 4 years
- Laboratory
  - TDP 43 brain pathology: 1 patient
ALS-FTD ¹⁰¹
● Chromosome 16p12.1�q12.2; Dominant
- Epidemiology: 2 families
- Genetics
  - Possible gene variants: CYLD; RPGRIP1L
  - Similar locus to: ALS-FTD CCNF
- Clinical
  - Onset age: 30 to 62 years
  - ALS
    - Weakness: Flaccid paralysis
    - Bulbar
      - Dysarthria
      - Dysphagia
      - Jaw jerk: Present
      - Tongue: Wasting; Fasciculations
    - Sensory: Normal
  - Dementia: Memory loss; Behavior problems
  - Course: Death 5 to 12 years after onset
  - Other occasional: Parkinson disease; Paget
- Pathology
  - Fronto-Temporal atrophy
  - Tauopathy: Cytoplasmic neuronal reactivity
  - phospho-TDP-43 Cytoplasmic neuronal inclusions
  - Hippocampal neurofibrillary tangles
ALS ¹²¹
● SS18-like gene 1 (SS18L1; CREST) ; Chromosome 20q13.33; Dominant
- Epidemiology: 2 patients
- Genetics
  - Possible Mutations: Q388X; I123M; c.660_668del, p.Gln222_Ser224del; c.790G>A, p.Ala264Thr
- SS18L1 protein
  - Location: Nucleus
  - Calcium regulated transcriptional activator
  - Subunit of neuron-specific chromatin remodeling complex (nBAF)
  - Neural outgrowth
  - Interacts with: FUS
- Clinical
  - Onset age: Adult to 8th decade
  - ALS syndrome
ALS 23 ¹⁴¹
● Annexin A11 (ANXA11) ; Chromosome 10q22.3; Dominant
- Epidemiology: 20 patients; 1% of FALS, 1.7% of SALS
- Genetics
  - Mutations: Missense; P36R, G38R, D40G (Common European founder), G175R, G189E, R235Q,R346C, G491R
  - Penetrance: Incomplete
  - Mutations found in sporadic ALS patients
  - ? Related to sarcoidosis susceptibility (SS3)
  - Allelic disorders: R230C polymorphism associates with Autoimmune disorders & Sarcoidosis
- ANXA11 protein
  - Calcium binding
  - Subcellular location: Nucleus & cytoplasm (vesicle-like structures)
  - Binds to: Calcyclin; Phospholipids, RNA granules, Lysosomes
  - Roles
    - Intracellular trafficking
    - Vesicle transport
    - RNA: Granules & Transport, Long distance with interaction with lysosomes
  - Breast cancer & other malignancies: Increased expression
  - 56-kD antigen recognized by sera from patients with autoimmune diseases
- Clinical: ALS
  - Onset
    - Age: Late; Mean 67 years; RAnge 37 to 71 years
    - Bulbar (80%)
  - Weakness
    - Bulbar: Dysarthria; Dysphagia
    - Limbs
  - Age at death (D40G mutation): 71 to 85 years
  - Cognitive impairment: Some patients
- Laboratory
  - Brain
    - Neurons: Inclusions
      - Cytoplasmic ANXA11, Phospho-TDP-43 & p62
      - Morphology: Skein-like, Tubular-shaped, Filamentous & Complex basket-like
      - Brain locations: Motor cortex; Occipital lobe
    - Astrocytes: Increased calcyclin
  - EMG: Denervation
ALS ¹⁵⁸
● Glycosyltransferase 8 domain-containing protein 1 (GLT8D1) ; Chromosome 3p21.1; Dominant or Sporadic
- Epidemiology: 14 patients
- Genetics
  - Mutations: Exon 4; R92C (Common; Short survival), I70T (Long survival), G78W (Long survival), A82E, I87N
  - Additional ARPP21 mutation (P529L): Shorter survival
- GLT8D1 protein
  - Glycosyltransferase
  - Widely expressed: Neurons; Golgi localization signal
  - Mutated proteins: Reduced glycosyltransferase activity
- Clinical
  - Onset ages: 33 to 66 years; Average 49 years
  - Weakness: Limb or Bulbar
  - Disease duration: 6 to 101 months
ALS: Hereditary, Other
- Heterogeneous category of: Non-SOD linked; Adult onset; Hereditary ALS syndromes
- Comprises 30% to 50% of dominant ALS syndromes
? Western Pacific ALS

ALS SYNDROMES: RECESSIVE

ALS 2: Childhood-onset ALS: Long survival; Usually Recessive
● Alsin ; Chromosome 2q33.1; Recessive
- Genetics ¹⁶
  - Mutations
    - Disease related: Carboxyl-terminal
    - ALS2: Deletions in exon 3 or 4
    - Disrupt reading frame
  - Allelic with
    - Juvenile PLS: Caused by different mutation in same gene
    - SPG, Infantile onset
    - Juvenile ALS + Dystonia
- Protein ⁴⁰
  - Contains 3 guanine-nucleotide exchange factor (GEF) domains for GTPases
  - Localization
    - Cytoplasmic face of endosomal membranes
    - Requires amino-terminal "RCC1 (regulator of chromatin condensation)-like"" GEF domain
  - Possible functions
    - ? Involved in membrane-proximity activities of small GTPases
    - ? Related to vesicle transport & intracellular trafficking
  - Tissue Expression
    - Neurons in brain & spinal cord
    - Low abundance in all tissues
  - Mutants
    - All have short half-life
    - Rapidly degraded by proteasomes
- Clinical features (Type 3)
  - Onset age: Mean 6.5 years; Most often < 10 years; Occasional 3rd decade
  - Spasticity: Face; Limbs (Paraplegia)
  - Pseudobulbar affect
  - Amyotrophy: Mild; Distal; Legs > Arms; Increases with age
  - Sensory & Bladder: Normal
  - Progression: Very slow; Reduced Walking after age 40
- Laboratory
  - CSF protein: Normal
  - Nerve conduction velocities: Normal
  - Nerve biopsy: Mild Reduction in number of large & small axons
- ALS2 variant syndrome: Juvenile ALS + Dystonia ¹¹⁰
  - Epidemiology: 8 patients, 3 families
  - Genetics
    - Inheritance: Recessive
    - Mutations: Nonsense; Fameshift; Splice
  - Clinical
    - Onset age: 1 to 3 years
    - UMN
      - Spastic diplegia
      - Dysarthria
      - Gait disorder
      - Tendon reflexes: Brisk; ankle clonus
    - Cortical
      - Developmental delay
      - Emotional lability
    - Weakness: Generalized
    - Muscle wasting: Legs > Arms; Distal > Proximal
    - Dystonia: Generalized
    - Skeletal: Microcephaly; Scoliosis; Limb contractures
    - Other
      - Ataxia
      - Anarthria
    - Course: Bedbound at 5 to 19 years
    - Normal: Hearing; Eye movements
  - Laboratory
    - Muscle pathology
      - Small angular muscle fibers
      - Fiber type grouping
    - NCV: Normal
ALS 5: Childhood-onset
● Spatacsin ; Chromosome 15q21.1; Recessive
- Epidemiology
  - 10 families
  - ? Most common form of recessive ALS
- Genetics ⁷⁰
  - Spatacsin mutations
    - Multiple
    - Missense common; Some frameshift
    - Many other families linked to similar locus
  - Consanguinous families
  - Allelic disorders
- Spatacsin protein
- Clinical: Weakness, Arm atrophy & Spasticity in all limbs (Type 1)
  - Onset age: Range 7 to 23 years; Mean 16
  - Spasticity
    - Limbs
    - Face & Jaw
    - Bulbar
    - Hyperreflexia
    - Plantar responses: Extensor
    - Gait
  - Amyotrophy & Weakness: Occasionally predominant
    - Distal
    - Hands & Feet
    - Tongue
    - Fasciculations
  - Course
    - Slowly progressive
    - Survival: Duration 27 to 40 years
  - Cognition: Normal
  - Bladder: Normal
- Laboratory
  - EMG: Denervation
    - Positive sharp waves
    - Fibrillations
    - Fasciculations
  - Nerve conduction
    - CMAP amplitudes: Small
    - SNAP amplitudes: Normal
    - NCV: Normal
  - Pathology
    - Pyramidal tracts: Small
    - Anterior horn cell loss
    - Sural nerve: Reduced number of Myelinated axons
    - Corpus callosum: Normal
  - CSF protein: Normal

ALS 12: Adult-onset ⁷⁴
● Optineurin (OPTN) ; Chromosome 10p13; Dominant or Recessive
- Epidemiology
  - Japanese consanguinous, German, Italian & Dutch families
  - 1% to 4% of FALS
  - SALS: < 1%
- Genetics
  - Mutations
    - Japanese: Recessive or Dominant; Exon 5 homozygous deletion, Q398X homozygous, E478G heterozygous
    - Other: All Dominant; Misense, Nonsense, Intronic
  - Allelic with: Primary open-angle glaucoma
- OPTN protein
  - Interacts with: Huntingtin ; Transcription factor IIIA; RAB8
  - Colocalises with SOD1- and TDP-43-positive inclusions in ALS
  - Binds to ubiquitinated receptor-interacting protein
  - Negatively regulates TNF-α induced activation of NF-κB
- Clinical
  - Onset
    - Age range: 24 to 83 years
    - Weakness: Legs > Bulbar, Arms
  - Weakness
    - Arms
    - Legs
    - Asymmetric
    - Respiratory: Late in course
    - Bulbar
      - Some patients
      - Dysphagia; Dysarthria; Tongue fasciculations
  - Tendon reflexes: Normal or Increased
  - Spasticity: Prominent in 70%
  - Progression: Variable
    - Range: 0.75 to 25 years
    - Rapid progression: Q165X; Q454E; K557T; p.Lys440Asnfs*8
  - Fronto-Temporal Dementia: Few patients
  - No glaucoma
- Laboratory
  - EMG: Diffuse denervation
- Pathology
  - Spinal cord: Loss of myelin & Axons
  - OPTN cytoplasmic inclusions
ALS 16: Childhood-onset ⁸¹
● Sigma-1 Receptor (SIGMAR1; σ₁R) ; Chromosome 9p13.3; Recessive
- Epidemiology: Eastern Saudi Arabian family
- Genetics
  - Mutation: Homozygous; Missense; E102Q
  - Allelic disorders
    - Distal HMN (dHMN)
    - ? FTD-MND
    - Similar locus to: Distal SMA2 (Jerash type, DSMA 2; HMNJ)
- SIGMAR-1 protein
  - Endoplasmic reticulum (ER) chaperone
  - Expression: Ubiquitous, High in Motor neurons
  - Sub-cellular: Post-synaptic cholinergic densities (C-terminals)
  - Ligand: Neurosteroids, Psychostimulants, Dextrobenzomorphans, Dimethyltryptamine
  - Functions
    - Ion channel modulation: Through interaction with K⁺ channels & Inositol 1,3,5-triphosphate receptors (IP3Rs)
    - Lipid transport
    - Neuronal cell differentiation
    - ER stress response
    - Regulates: Axon elongation; Tau phosphorylation
  - Mutation effect: Abnormal subcellular distribution of SIGMAR-1
- Clinical
  - Onset
    - Age: 1 to 2 years
    - Spasticity: Legs
  - Spasticity
    - Legs > Arms
    - Tendon reflexes: Brisk
  - Weakness
    - Hand & Forearm muscles: Especially extensors & triceps
  - Normal: Sensation; Cognition; Bladder
  - Progression: Often to wheelchair by 3rd decade
- Laboratory
  - EMG: Denervation in limb muscles; Motor units large
  - NCV: Normal velocities
  - Brain MRI: Normal
- SIGMAR1 Variant syndrome, Possible: Frontotemporal lobar degeneration-Motor neuron disease
  - Inheritance: Dominant
  - Epidemiology: Australian families
  - Genetics
    - 3' UTR point mutations: Some may be polymorphisms, also occur in normals
    - Some patients & familes: Pathogenic mutation may be another gene, c9orf72 expansion
- SIGMAR1 Variant syndrome: Distal hereditary motor neuropathy (dHMN; DSMA2) ¹²²
  - Epidemiology: Chinese (3 patients), Portugal & Afghan families
  - Genetics
    - Inheritance: Recessive
    - Mutations: Deletion or Splice
      - c.151+1G>T: Produces shortened protein (σ₁R^31_51del); Homozygous
      - c.561_576del (Exon 4)
      - Exon 4 deletion
    - Similar locus to: Distal SMA2 (Jerash type, DSMA 2; HMNJ)
  - Clinical
    - Onset age: 9 to 12 years
    - Muscle
      - Weakness: Distal; Legs > Arms; Foot drop; Symmetric
      - Wasting: Distal; Legs > Arms
    - Tendon reflexes
      - Ankles: Absent
      - Knees: Increased or Reduced
    - Plantar reflex: Extensor
    - Feet: Pes equinovarus; Hammer toes
    - Sensory: Normal
    - Course: Slow progression, more rapid during adolescence
  - Laboratory
    - NCV
      - CMAPs: Amplitudes reduced; Velocities borderline (32 to 52 M/s)
      - SNAPs: Normal
    - EMG: Distal denervation, large motor units
    - Sural nerve: Normal
    - Brain MRI: Normal
ALS: Childhood-onset ⁶⁴
● Chromosome 6p25, 21q22; Recessive
- Epidemiology: 1 Utah family, 4 patients
- Clinical
  - Onset age: 4 to 10 years
  - Ptosis: Mild
  - Weakness & Atrophy
    - Distal
    - Arms & Legs
    - Symmetric
    - Respiratory failure: Late in course, 1 patient
  - Bulbar & Cranial
    - Speech: Dysarthric; Spastic
    - Dysphagia
    - Face weakness, mild
  - Upper motor neuron
    - Spasticity: Legs > Arms
    - Tendon reflexes: Brisk in legs ± arms
    - Plantar response: Upgoing or absent
  - Sensory loss: Mild; Distal; Vibration
  - Gynecomastia: 1 patient
  - Progression: Slow; Loss of ambulation after decade
- Laboratory
  - NCV
    - Normal velocities
    - CMAPs: Reduced amplitude in legs
    - SNAPS: Reduced amplitude
  - EMG: Denervation, Distal
  - Nerve biopsy: Minimal loss of sensory axons
  - Muscle biopsy: Grouped atrophy; Fiber type grouping
Recessive ALS: Other types
- Clinical syndrome: Weakness & severe spasticity, esp. in legs (Type 2)
  - Symptoms in lower limbs
  - ? form of familial spastic paraplegia

BULBAR MOTOR NEURON SYNDROMES: Hereditary & Other

Brown-Vialetto-van Laere
1: SLC52A3; 20p13; Recessive
2: SLC52A2; 8q24; Recessive
3: UBQLN1; 9q21; Dominant
Bulbar ALS
Fazio-Londe: SLC52A3; 20p13; Recessive
Kennedy's Syndrome: Androgen Receptor ; Xq12; Recessive
Madras motor neuron disease: Sporadic
Spino-bulbar muscular atrophy: Dominant
Worster-Drought

Fazio-Londe

¹²
● SLC52A3 (RFT2; c20orf54)

; Chromosome 20p13; Recessive

Definition
- Progressive bulbar palsy of childhood
- Disorder of bulbar motor neurons
Genetics
- Allelic with: Brown-Vialetto-van Laere 1 (BVVLS1)
Clinical features
- Onset: 1 to 12 years
- Cranial nerves
  - Ptosis
  - Facial weakness
  - Dysphagia
  - Normal hearing
- Respiratory stridor
- Hyperreflexia
Subtypes
- Dominant: Rare
- Recessive: Early onset
  - Respiratory failure
  - Rapid progression: Death < 2 years from onset
- Recessive: Later onset
  - Less respiratory involvement
  - Bulbar: Dysarthria; Dysphagia
  - Facial weakness
  - Slow progression
Laboratory
- CSF: Normal
- Serum CK: Normal
- EMG: Denervation; Large amplitude Motor unit potentials
- Neuropathology
  - Loss of neurons from motor cranial nerve nuclei
  - Occasional: Anterior horn cell loss; Cerebelar involvement
Similar to: Brown-Vialetto-van Laere
- But no hearing loss

Brown-Vialetto-van Laere 1 (BVVLS1)

⁴
● SLC52A3 (RFT2; c20orf54)

; Chromosome 20p13; Recessive

J Nerv Ment Dis 1894;19:707�716

J Nerv Ment Dis 1894;19:707�716

Nosology: Progressive Bulbar Palsy with Sensorineural Deafness
Epidemiology
- 50% of patients: Sporadic
- Sex associations
  - Female predominant 60% to 75%
  - Familial cases: Many female
  - Males: Often have more severe course
- Family origin: Arabic; European; Pakistani
Genetics
- Mutation types: Deletion; Missense; Stop
- c.1325_1326delTC; P28T; E36K; G54R; E71X; E71K;
  I75T;R132W; Y213X; F224L; V413A; L442RfsX35; F457L
- Allelic with: Fazio-Londe
SLC52A3 (c20orf54) protein
- Transmembrane
- Riboflavin transporter
Clinical features
- Onset
  - Age
    - Common: 1st or 2nd decade; Often < 8 years
    - Range: Infancy to early 3rd decade
    - May be variable within families
  - Early development: Normal
  - Hearing loss: Often precedes motor syndrome
  - Gait disorder
  - May follow episode of viral infection
- Cranial nerves
  - Deafness (100%)
    - Bilateral
    - Sensory-Neural
  - Weakness: Especially 7, 9,and 12
    - Facial: Bilateral
    - Bulbar
      - Tongue: Wasting & Fasciculations
      - Dysphagia
  - Eye
    - Optic atrophy (90%)
    - Most: Normal eye movements
    - External ophthalmoplegia: 1 patient
- Motor
  - Weakness
    - Especially: Arms & Hands, Neck (Extension) & Trunk
    - Respiratory failure: More severe cases
    - Gait disorder
    - Dysphagia: Some patients
  - Tone: Reduced
  - Muscle wasting
- Tendon reflexes: Normal or Reduced
- Sensory examination: ?
- CNS
  - Truncal ataxia: Some patients
  - Normal intelligence
- Skeletal: Contractures, distal; Scoliosis
- Other: Occasional features
  - Congenital heart disease
- Disease course
  - Irregularly progressive
  - Early onset: More rapid course (6 to 18 mo)
  - Death
    - Death in more severe patients: Respiratory failure; 1 to 2 years
    - Some patients live through 6th decade
  - Treatment: Riboflavin replacement, High dose (100mg to 500 mg per day)
Laboratory
- Brainstem auditory responses: Absent
- EMG: Denervation
- NCV: Motor velocities: Normal SNAP amplitudes: Reduced or absent
- Acyl carnitine profiles: Abnormal; Similar to MADD deficiency

Brown-Vialetto-van Laere 2 (BVVLS2)

⁹³
● SLC52A2 (RFT3; GPR172A; RFVT2)

; Chromosome 8q24.3; Recessive

Nosology
- Progressive Bulbar Palsy with Sensorineural Deafness
- Childhood Neuronopathy
Epidemiology: 3 families, Scottish, Italian & Lebanese
SLC52A2 genetics
- Mutations: Gly306Arg, Homozygous; Ser52Phe, Gly419Ser; Leu123Pro, Leu339Pro
- Allelic disorder: SCAR3 (SCABD2)
SLC52A2 protein
- Riboflavin transporter
- Brain: High expression
Clinical
- Onset
  - Age: 2 years
  - Motor: Gait disorder; Exercise intolerance; Dysphonia
  - Hearing loss: 2 to 6 years
- Hearing loss: Sensorineural
- Weakness
  - Bulbar
  - Arms & Hands > Legs
  - Axial: Neck weakness; Hypotonia
  - Tongue fasciculations
  - Respiratory failure: 2nd decade
- Tendon reflexes: Absent
- Sleep: Hypoventilation
- Optic atrophy: Reduced visual acuity
- Scoliosis
- Hypermetabolic syndrome
- Course: Progressive; Early death in some patients
- Treatment: Riboflavin replacement, High dose (100mg to 500 mg per day)
Laboratory
- Polyneuropathy: Axonal; Sensory & Motor
- BAER & VER: Abnormal
- Acyl carnitine profiles: Abnormal; Similar to MADD deficiency
- Carnitine deficiency

Brown-Vialetto-van Laere 3 (BVVLS3) ⁹⁴
● Ubiquilin 1 (UBQLN1)

; Chromosome 9q21.32; Dominant

Epidemiology: 1 Italian female singleton patient
Mutated UBQLN1 protein
- Induces cytosolic mislocalization of TDP-43
- In aggregate forms that co-localize with the UBQLN1
Genetics
- Mutation: Missense, E54D; Heterozygous
- Other disease association: Intronic variant (UBQ-8i) related to Alzheimer disease
Clinical
- Onset: Juvenile
- Motor neuron disease: Bulbar palsy
- Hearing loss: Sensorineural

Madras Motor Neuron Disease ⁶¹
● Sporadic; Occasional recessive inheritance

Epidemiology
- Common in South India
- Family history of similar disorder: 2%
- Male = Female
Genetics
- A8302G mutation in mt-tRNA^Lys ¹⁰⁰
  - Homoplasmic in 7% of Madras patients
  - High levels (82%) also in some unaffected family members
- No mutations in: SLC52A1, SLC52A2, SLC52A3, c9orf72
Clinical
- Onset
  - Age: Juvenile; Mean 16 years, Range 1st to 5th decade
  - Hearing loss: 53%
  - Arm weakness: 38%
- Cranial nerve
  - VII: Facial diplegia, Lower > Upper
  - VIII: Deafness, Sensorineural (30% to 80%)
  - IX to XII: Bulbar involvement (40%)
    - Dysphagia
    - Dysarthria (Hoarseness)
  - Tongue: Weakness; Fasciculations
- Lower motor neuron signs (85%)
  - Weakness
    - Limbs: Arms > Legs
    - Asymmetric
    - Diffuse: Distal > Proximal
  - Wasting
  - Fasciculations: Limbs & Face
- Pyramidal signs (80%)
- Reflexes
  - Tendon reflexes: May be brisk in legs
  - Plantar: May be extensor (50%)
- Sensory: Normal
- Other: ? Minipolymyoclonus related to fasciculations
- Course
  - Slowly progressive
  - Most remain ambulatory
Laboratory
- Electrodiagnostic
  - EMG: Active & Chronic denervation in cranial, proximal & distal muscles
  - CMAPs: Small amplitude
  - SNAPs: Normal
- Pathology: 1 patient
  - Anterior horn cells: Reduced
  - Ventrolateral column: Axonal loss
  - Other cranial nerve nuclei involved: 3, 5, 6, 7, 10
  - Cochlear nuclei: Neuronal loss
  - Other tracts involved: Spinocerebellar & Spinothalamic
  - Other regions of CNS also involved
  - Cellular: Microglial reaction; No cytoskeletal pathology
Differential diagnosis: Similar to
Variant: Madras MND + CNS features (13%) ³³
- Epidemiology: India
- Family history
  - Positive: 29%, More frequent than typical MMND
- Clinical
  - Onset age: Younger than typical Madras MND
  - Bulbar dysfunction (100%): More common than typical Madras MND
  - Optic atrophy (100%)
  - Cerebellar disorder: Ataxic gait
  - Pyramidal signs
  - Minipolymyoclonus

Worster-Drought syndrome: Congenital suprabulbar paralysis

¹¹

Inheritance patterns
- X-linked
- Autosomal dominant with reduced penetrance
Clinical
- Course
  - Onset: Congenital
  - Age at diagnosis: 6 years
  - Non-progressive
  - Male > Female: 3:1
  - Familial cses: 6% to 21%
- Bulbar paralysis
  - Abnormal tongue & lip movement (98%)
  - Brisk jaw jerk (90%)
  - Airway obstruction: Especially neonatal presentation
  - GI: Dribbling; Poor nutrition; Aspiration; G-E reflux
  - Speech: Dysarthric
- Spastic tetraparesis (91%): Mild
- Cortical
  - Language disorder: Expressive > Receptive
  - Learning difficulties (81%)
  - Neuropsychiatric disorders (41%)
  - Epilepsy (28%): Neonatal; Febrile; epilepsy
- Congenital defects (61%)
  - Contractures: Jaw & Other
  - Palatal
  - Micrognathia
  - Fused teeth
- Eye movements: Abnormal (13%)
Laboratory
- CNS Imaging
  - Abnormal in 32%
  - Perisylvian polymicrogyria: Unilateral or Bilateral
- Swallowing studies: Abnormal, especially in oral & pharyngeal phases

Cortical Suprabulbar palsy

Foix-Chavany-Marie syndrome: Faciopharyngoglossomasticatory diplegia
Loss of voluntary control: Preserved automatic function
Anatomy: Bilateral persylvian lesions

Multisystem disorders

Hexosaminidase A: GM2 Gangliosidosis, Late Onset
● β-Hexosaminidase A (HEXA) ; Chromosome 15q23; Recessive
- Nosology: Tay-Sachs, Late onset (LOTS)
- Genetic features
  - Gly269Ser substitution in α chain
    - Most common mutation in adult form
    - Usually in compound heterozygosity with null mutation
  - Other mutations with milder disease
    - Missense: Arg499His; Arg499Cys; Arg504His; Arg504Cys
    - Splice site: IVS7-7G
    - General: Chilhood + Adult mutations
  - Other mutations (null): More severe disease
    - Exon 11: 4-bp insertion
    - Exon 12: G to C mutation in splice junction
    - Exon 1: A to T in initiation codon
  - Misdiagnosis
    - Pseudo-deficiency alleles: Arg247Trp; Arg249Trp
    - False negative: B1 variant; Abnormal reactivity to GM2 but not artificial substrate
- HEXA protein
  - Location: Lysosome enzyme
  - Function
    - Breakdown of gangliosides
    - Hydrolyzes GM2 ganglioside to GM3
  - Disease syndromes: < 10% of normal Hex A activity
  - Later-onset syndromes: Higher Hex A activity
- Clinical features
  - Onset: Cramping in legs
  - Weakness
    - Proximal > Distal
    - Selective: Triceps; Quadriceps
    - Symmetric
    - May be only sign, or present with CNS features
  - Spontaneous activity
    - Cramps
    - Fasciculations
  - Cerebellar
    - Gait Ataxia
    - Dysarthria
    - Nystagmus
    - Tremor
  - Cortical function
    - Dementia
    - Manic-Depressive-like disorder
    - Easy startle
    - More common with neuropsychometric testing: Subcortical
      - Deficits: Attention, Processing speed, Executive function, Memory
    - May be normal
  - Sensory: Unusual ¹⁴
    - Paresthesias: Distal; 2nd decade onset
    - Loss: Mild; Pansensory; Distal legs
  - Tendon reflexes: Normal, Reduced in legs, or Brisk
  - Corticospinal: Some patients
    - Spasticity
    - Bladder dysfunction
  - Movement disorder: Dystonia & Choreoathetosis
  - Cranial nerves: Spared
  - Exacerbating drugs: Psychotropic medications (Haloperidol, Chlorpromazine, Risperidone)
- Lab
  - MRI: Cerebellar atrophy common
  - Nerve biopsy: Axon loss, Sensory & Motor
  - Muscle biopsy: Denervation, Grouped atrophy, Pyknotic nuclear clumps
  - NCV: Small amplitude CMAPs & SNAPs
  - EMG: Large motor units; Fibrillations; CRDs
  - Autonomic pathology: Membranous cytoplasmic bodies (MCBs) in neurons
- Experimental treatments
  - Hematopoetic stem cell transplant ¹⁴⁸
  - Not helpful in clinical trials
    - Pyrimethamine 50 mg/day ¹¹³
    - Miglustat
- Lower motor neuron phenotype also with Sandhoff disease
Machado-Joseph (esp Type I)
● CAG triplet repeats; Chromosome 14q32.12; Dominant
- Clinical features
  - Type I = Earlier onset (20 to 30 yrs) with longer CAG repeats
  - Dystonia; Facial & Lingual Fasciculations; Bulging Eyes
  - Cerebellar signs with distal amyotrophy in later onset (Types II & III)
  - Allelic with Spino-Cerebellar Ataxia (SCA) III
Polyglucosan body disease : Adult-onset
● Glycogen branching enzyme (GBE1) ; Chromosome 3p12.2; Recessive
- Epidemiology
  - Ashkenazi Jewish patients: Increased fequency
  - Non Ashkenazi Jewish: German, Italian, Latin American, Pacific Islander, Caucasian & Cambodian
- Genetics
  - Mutations: Missense
    - Ashkenazi Jewish patients: Tyr329Ser
    - German & Italian: Arg515His & Arg524Gln
  - Also see: GSD 4
- GBE1 protein
  - Converts amylose into amylopectin
- Clinical features: CNS + Polyneuropathy ³⁹
  - Course
    - Onset
      - Adult: > 40 yrs; Mean 51 years
      - Other forms in childhood with myopathy & hepatic disease
    - Slow progression
  - Polyneuropathy
    - Legs > Arms
    - Motor: Weakness, Distal
    - Sensory loss: Large fiber modalities (Vibration)
    - Impotence
  - Myelopathy
    - Spasticity
      - Legs > Arms
      - Gait disorder
      - Tendon reflexes: Brisk in legs
      - Plantar responses: Extensor
    - Neurogenic bladder
  - Dementia (50% to 67%)
    - Cortical & Subcortical
    - Attention & Memory defecits
  - Survival: Mildly reduced; Mean 70 years
- Laboratory
  - MRI
    - Cortical atrophy
    - White-matter changes: Periventricular; Subcortical
    - Distribution: Bilateral; Symmetric
    - Non-enhancing
    - Diffuse atrophy: Brain & Spinal cord
  - Nerve conduction studies: Neuropathy
    - Axonal loss
    - Sensory & Motor involvement
- Pathology
  - Dx by sural nerve or axillary skin biopsy
  - Polyglucosan bodies
    - Locations: CNS & PNS
    - Cell location: Astrocyte processes
  - Perivascular inflammation: Occasional
● ALS with polyglucosan bodies
Motor Neuronopathy with Cataracts & Skeletal abnormalities
● ALDH18A1 (P5CS) ; Chromosome 10q24.1; Dominant
- See SPG 9A (ALDH18A1)
- Clinical features
  - Onset: 1 to 37 years
  - Cataracts
  - Weakness
    - Distal arms & proximal legs
    - Exacerbation during pregnancy; remission afterwards
  - Upper motor neuron signs
  - Skeletal
    - Short stature; Dysplastic skull base; Small carpal bones
Disinhibition-Dementia-Parkinsonism-Amyotrophy complex (DDPAC; Fronto-Temporal dementia)
● Microtubule-associated protein tau (MAPT) ; Chromosome 17q21.31; Dominant
- Allelic with
  - Frontotemporal dementia with parkinsonism
  - Frontotemporal dementia with motor neuron disease
  - Progressive supranuclear palsy
  - Tauopathy + Respiratory failure (Recessive)
  - Pick disease
  - Lower motor neuron disorder
- Clinical
  - Onset: Mean age 45 years; Alcoholism or Depression
  - Dementia: Behavior & judgement > Language & praxis; Kluever-Bucy syndrome
  - Disinhibition: Alcoholism; Hyperreligiosity; Excessive eating, sexual behavior
  - Parkinsonism
  - Amyotrophy
  - Variability of symptoms among patients
- Pathology
  - Superficial cortex: Spongiform changes
  - Spinal cord: Motor neuron loss
- MAPT variant syndrome: Lower motor neuron syndrome ¹¹²
  - Epidemiology: 1 family, 5 patients
  - Genetics
    - MAPT mutation: D348G
    - Inheritance: Dominant
  - Clinical
    - Onset age: 6th & 7th decade
    - Weakness
      - Proximal: Arms
      - Respiratory
    - Tendon reflexes: Reduced
    - Leg cramps
    - Fatigue
    - No: Frontotemporal lobar degeneration; Semantic dementia; UMN features
  - Pathology
    - α-motoneurons
      - Loss
      - Phosphorylated tau: Accumulation in surviving motor neurons
    - Spinal anterior horns: Atrophy
- MAPT variant syndrome: FTD + Motor neuron syndrome
  - Genetics
    - Mutation: L317M
    - Inheritance: Dominant
  - Clinical
    - Dysarthria
    - Tremor
    - Amyotrophy
    - Frontal signs
    - Levodopa-resistant parkinsonism
    - Supranuclear palsy
    - Corticobasal degeneration
  - Pathology
    - Spinal motor neurons: Loss
    - Tau inclusions
- MAPT variant syndrome: Tauopathy + Respiratory failure
  - Epidemiology: 1 family, 2 patients
  - Genetics
    - Mutation: Homozygous; Ser352Leu
    - Inheritance: Recessive
  - Clinical
    - Onset age: 3rd decade
    - Respiratory failure, Acute
    - Learning difficulty: Early onset; 1 patient
  - Pathology
    - Tau accumulation: In some neuron cell bodies
Motor neuropathy & Growth retardation
● Signal transducer and activator of transcription 5B (STAT5B) ; Chromosome 17q21.2; Recessive
- Epidemiology: 2 patients, 1 family
- Genetics
  - Mutation: Glu315Ala
- STAT5B protein
  - Signal transduction
  - Transcription activator
- Clinical
  - Growth retardation: Short stature
  - Dysmorphic face: Ptosis
  - Motor neuropathy
Motor neuron disease with dementia & ophthalmoplegia
● Autosomal Recessive
- Epidemiology: 1 patient
- Clinical
  - Weakness: Bulbar; Arms; Respiratory failure
  - Ophthalmoplegia: Reduced gaze excursion, especially up; Supranuclear
  - Progression: Over 1 year
- Laboratory
  - EEG: Diffuse slowing
  - CT: Atrophy of frontal lobe & midbrain
  - Brain: Abnormal anterior horn & corticospinal tracts; Bunina bodies
Alopecia, Neurological Defects & Endocrinopathy (ANE)
● RBM28 ; Chromosome 7q32.1; Recessive
- Epidemiology: Arab Moslem kindred
- Genetics
  - Mutation: Missense; Leu351Pro
- RBM28 protein
  - Component of snRNP complexes
  - Ubiquitous expression
  - Regulates ribosome biogenesis
  - Mutant: Ribosome depletion; Structural abnormalities of rough endoplasmic reticulum
- Clinical
  - Skin
    - Hair loss
      - Widely varying severity
      - Skin biopsy: Absence of mature hair follicles; Reduced β-catenin
    - Pigment
      - Flexural reticulate hyperpigmentation
      - Facial pigmented nevi: Multiple
    - Subcutaneous fat: Loss
  - Motor
    - Progressive decline
    - Combined upper & lower motor dysfunction
    - Onset: 2nd decade
  - CNS
    - Mental retardation: Moderate to severe
  - Endocrine: Central hypogonadotropic hypogonadism
    - Delayed or absent puberty
    - Central adrenal insufficiency
    - Gynecomastia
  - Skeletal
    - Short stature
    - Microcephaly
    - Hypodontia
    - Kyphoscoliosis
    - Ulnar deviation of hands
- MRI
  - Hypoplastic pituitary gland with preserved hypothalamus
  - Normal basal ganglia & white-matter
Dravet syndrome with Motor Neuropathy
● SCN1A ; Chromosome 2q24.3; Recessive
- Nosology: Epileptic encephalopathy, early infantile, 6 (EIEE6)
- Epidemiology: Rare epilepsy syndrome
- Genetics
- SCN1A protein
- Clinical
  - Ataxia: Gait
  - Seizures: Severe; Onset 2 to 6 months; Pharmacoresistant
  - Psychomotor delay: Moderate to severe
  - Orthopedic
    - Misalignment
    - Knee hyperextension
    - Foot: Pes valgus
  - Crouching
  - Movement disorders
    - Onset age: Adulthood
    - Lingual dyskinesia
    - Rigidity
    - Dystonic gait
    - Treatable with levodopa
  - Tendon reflexes: Reduced (30%)
- Laboratory
  - EEG: Normal then Generalized spike-wave activity
  - NCV: Normal
  - EMG: Motor neuronopathy ¹³⁰
    - Chronic denervation, especially > 4 years
    - Motor units: Prolonged; High amplitude; Polyphasic

Motor Neuron Disease: Mouse models

Wobbler ⁵²
● Vacuolar protein sorting protein 54 (Vps54)
- Mutation: Missense L967Q
- Motor neuron disease
- Spermiogenesis defect
Neuromuscular degeneration (nmd): SMARD1
Muscle deficient: Mouse chromosome19
- Onset: Hindlimb weakness
- Peripheral nerve: Axonal degeneration
- Neurons: Ventral horn & Brainstem motor; Vacuolar degeneration
- Death: 8 months
Progressive motor neuronopathy (PMN) ²⁸
CNTF knockout: Mouse chromosome 19
SOD transgenic
Neurofilament heavy chain : Overexpression
PQBP-1 transgenic ³⁵
- PQBP-1
  - Transcription and/or mRNA processing factor
  - Interacts with polyglutamine disease gene products
- Clinical: Progressive weakness with increasing age
- Pathology: Neuronal loss in spinal anterior horn; Loss of motor axons

Patient resources
Patient information: Spinal muscular atrophy