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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): WARS1; 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 Protein mechanisms

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       SORD: 15q21     Dominant       Calf predominant: FBXO38; 5p31       Leg predominant       Distal Ulnar-Median       Childhood: BICD2; 9q22       + Macular Δ: FBLN5; 14q32       + Hearing loss: MYH14; 19q13       Scapuloperoneal: TRPV4; 12q24       SMAJ1: GARS1; 7p14       HMN: HARS; 5q31       HMN: GBF1; 10q24     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     Motor PN + Myopathy: VWA1; 1p36     MPAN: c19orf12; 9q12     Optic atrophy: c19orf12; 19q12     STAT5B: 17q21     TBX5: 12q24   Dominant     Cataracts & Skeletal abnormalities     DDPAC: MAPT; 17q21     HMN: EMELIN-1; 2p23     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   FOSMN   PLS, Juvenile: Alsin; 2q33; Recessive   Worster-Drought

Distal SMA From: Spiller

HMN: Protein mechanisms

dHMN: Spain ¹⁶⁷

• General
  • Prevalence: 2.3 per 100,000
  • Many sporadic
  • Onset age: Often in 1st decade
• Types
  • HSBP1 10.4%
  • GARS1 9.8%
  • BICD2 8.0%
  • DNAJB2 6.7%
  • SORD 3.1%

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

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 Treatments

Hoffman ~1891 From: Andrew Kornberg MD

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
  • SMN1 mutations ¹⁷²
    • Most (95% to 98%)
      • Deletion of SMN1 gene: Often deletion of entire gene
      • Homozygous in 93%
    • Few (4%): Deletion of exon 7; May be de novo
    • Rare
      • SMN1 point mutation (2%): Missense or In-frame deletion common; Also splice site & stop
      • Exon 8 deletion
      • Gene conversion of SMN1 to SMN2 (Exon 7 C>T)
      • Large deletion: SMN1 ± neighboring NAIP gene
  • Disease relations
    • SMA: Mutated in 95% of patients
    • ALS: Increased frequency (2x) of 1 or 3 gene copies
    • PMA: 2.7x increased frequency of SMN1 duplication ¹⁷⁵
  • Number of SMN1 gene copies ⁸: Varied
    • 1 SMN1 copy on each chromosome
      • 82% to 96% of normal individuals
    • 2 SMN1 copies on one chromosome (Duplication)
      • 4% to 18% of normal individuals
      • May have deletion on other chromosome
    • Variability makes heterozygote testing complicated
  • SMN1 gene structure: Strongly homologous to SMN2
    • Contains 9 exons
    • 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 (GTF2H2); 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: No clear effect
• 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 4 genes: SMN, NAIP, p44, H4F5 (SERF1a)
      • 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
  • GTF2H2 (Btf2-p44)
    • Deleted in 15% of SMA patients
  • SERF1A (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
  • 294 amino acids
  • 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
      • Assembles in the cytoplasm
      • Translocates to nucleus: Located in gems
      • Complex function: Cytoplasmic formation, nucleus import, & regeneration of spliceosomal snRNPs
    • 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)
  • Autoantibodies: Systemic sclerosis + Myopathy
• 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
    • Epidemiology: 3 patients described
    • Genetics
      • SMA type III patients
        • Have fewer SMN2 copies than expected
        • Have copies of mutated (G287R) SMN2 gene alone, or in combination with usual SMN2 gene
      • Normal population: Mutated SMN2 not common
    • SMN protein
      • More full length SMN protein produced
      • Mutation effect related to splicing modification
    • Clinical: SMA less severe than expected from SMN2 copy number
      • Proximal strength: Mildly to moderately reduced; Worst in hip flexors & knee extensors
      • Patients often SMA type III
    • 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)

  From: A Kornberg MD

  • 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
  • Clinical
    • Onset
      • Childhood or Juvenile
      • Cramps may be 1st symptom
        • EMG: Mild neurogenic changes
    • 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
    • Cognition: Normal ¹⁶⁹
• Clinical features: SMA 5q - Later onset (Type IV)
  • Onset ages: Juvenile or Adult
  • Weakness
    • Distribution
      • Proximal
      • Patchy: Psoas; Quadriceps > Hamstrings; Triceps
      • Symmetric or Asymmetric
    • Progression
      • Most: 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
  • Hydrocephalus ¹⁷³
    • 4x increased frequency
    • May be obstructive
• 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
• Treatments ¹⁶⁴
  • SMN2 pre-mRNA splicing
    • Modify: Increase full length SMN protein
    • Drugs
      • Nusinursen (Spinraza)
        • Drug type: Anti-sense oligonucleotide
        • Mechanism
          • Binds to intronic splice-silencing-site in intron 7 of SMN2
          • Inhibits action of other splice-factors
        • Treatment route: Intrathecal; Repeated treatments
        • Effects: Improved strength; Prolonged survival
        • Most effect: Youngest patients
      • Risdiplam
        • Drug type: Small molecule
        • Mechanism
          • Binds 2 sites on SMN2 pre-mRNA
          • Increases levels of full-length SMN mRNA & protein
        • Treatment route: Oral
        • Benefit: Improved survival & strength
  • SMN1 gene delivery: Onasemnogene abeparvovec (Zolgensma)
    • Non-replicating adeno-associated virus capsid (scAAV9)
      • Delivers wild-type SMN1 gene to motor neurons
    • Drug route: Intravenous; single treatment
    • Effects: Improved strength; Prolonged survival
    • Most effect: Youngest patients
  • Experimental treatments
    • Reldesemtiv (Tirasemtiv): Fast skeletal troponin inhibitor
    • Myostatin inhibitors: SRK 105 (Monoclonal antibody)
    • Olesoxime: Anti-apoptotic agent
    • 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
  • Care & Treatment
    • Respiratory support
    • Scoliosis care
    • Nutrition
• 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 protein Clinical features Clinical-genetic correlations Epidemiology Laboratory features Onset Pathogenic mechanisms Pathology	Bulbo-Spinal Muscular Atrophy Gynecomastia
Mouth in BSMA Attempted smile & At rest	Tongue in BSMA Wasted; Weak; Moves rapidly

• 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
  • General: Toxic gain of function → Neuronal degeneration
  • Large polyglutamine tract: Molecular effect
    • 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
    
    • 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
    • Fasciculation-like movements
    • Fasciculations
    • Atrophy: Especially face & tongue
    • Cramps: 50%
  • Tendon reflexes: Absent or reduced
  • Sensory: Often subclinical changes
    • Vibration: Reduced; Legs > Arms
    • Sensory Nerve Action Potentials (SNAPs): Small amplitude
  • Tremor
    • Hands
    • Postural & Action
    • Early disease manifestation: 4th decade
  • 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: Not typical fasciculations
        • Individual discharges: Large amplitude; Asymmetric; Repetitive (Grouped)
        • Frequency of discharges: Lower in BSMA (~3/min) than in ALS (~20/min)
        • Locations: Face (Especially lower), Tongue, Trunk & Limbs
        • Onset: Contraction evoked or Spontaneous
        • Electrodiagnostic: Grouped axon discharges (Multiple motor units in each discharge)
        • Not: Combined fasciculations, Myokymia or Neuromyotonia
      • Fasciculations
        • Location: Limbs
        • Pattern: Single motor units, Large amplitude potentials
      • Neuropathy: Chronic partial denervation with reinnervation
        • Fibrillations: Legs > Arms; Less common in arms than in ALS
        • 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
    • Grouped atrophy of muscle fibers
    • Small angular muscle fibers: Occasional
    • Muscle fiber hypertrophy
    • NO fiber type grouping
    • Internal nuclei
    • Type I muscle fiber predominance
  • CNS pathology
    • Lower motor neurons
      • Reduced number in spinal cord & brainstem
      • More loss of small motor neurons than ALS
    • 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

• 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

• 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

• 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, WARS1 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)

• 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)

• Epidemiology: 4 families
• Genetics
  • HSPB8 mutations: Missense; Lys141Asn, Lys141Glu
  • Allelic disorders
    • HMN 2A
    • CMT 2L
    • Motor neuropathy + Distal Myopathy
    • Limb-Girdle Myopathy with Myofibrillar pathology & Rimmed vacuoles
• HSPB8 protein
  • Heat shock protein
  • High expression in motor & sensory neurons of spinal cord
  • Interacts with HSPB1
  • 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.Lys141Glu); 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
• HSPB8 variant syndrome: Limb-Girdle Myopathy with Myofibrillar pathology & Rimmed vacuoles ¹⁶¹
  • Epidemiology: 8 families
  • Genetics
    • Mutations
      • Region: C-terminal
      • Type: Stop
      • c.577_580dupGTCA (p.Thr194Serfs*23); c.525_529del
    • Inheritance: de novo; Dominant
  • Clinical
    • Onset age: 19 to 37 years
    • Weakness
      • Legs > Arms
      • Proximal: Common; Distal in some
      • Symmetric
      • Respiratory: Some patients
    • Paraspinous: Muscle wasting
    • Tendon reflexes: Absent
    • Sensation: Normal
    • Contracture: Posterior neck
    • Course: Progressive
  • Laboratory
    • Serum CK: 600 to 1110
    • EMG: Fibrillations; Small motor unit potentials
    • Muscle imaging: Paraspinous fatty replacement
    • Muscle pathology
      • Rimmed vacuoles
      • Myofibrillar protein aggregates (Myotilin, Desmin, TIA1)
      • Lipid: Increase in type II fibers

Distal hereditary motor neuropathy (HMN 2B)

• Epidemiology: Families from UK, Croatia, Belgium, Austria
• Genetics
  • Missense mutations: R127W; S135F; T151I; P182L
  • Mutations in C-terminal domain
    • More severe phenotype
    • Onset age: 4 to 7 years
  • Allelic disorders
• 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

• Epidemiology: Belgian, Austrian & English families
• Genetics
  • Allelic disorders
    • 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)

• Epidemiology: Multiple ethnic origins
• Genetics
  • Allelic disorders
  • 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

• Nosology: Also called HMN 5A
• Epidemiology
  • European families
  • Most common D-HMN
• Genetics
  • Mutations
    • Missense
    • Exon 3
    • Common: 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
  • Lipid droplets: Synthesis & ER contacts
• Clinical
  • Onset
    • Age: Mean 15 to 24 years; Range 2 to 40 years; Childhood often
    • Weakness: Hands
  • 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
  • Muscle MRI: Thenar eminence, Soleus & Tibialis anterior most involved
• BSCL2 variant syndromes
  • CMT2-like ⁹⁹
    • Genetics
      • BSCL2 Mutation: S90W
      • Inheritance: 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
  • Also see
    • SPG 17 (Silver syndrome)

Hereditary Distal Ulnar-Median Muscular Atrophy ⁷

• ? 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)

• 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

• 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
    • Blockade of dynactin binding to dynein: Blocks vesicle motility along microtubules
    • 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
  • Onset
    • 3 years to Early adulthood
    • Respiratory difficulty due to vocal cord paralysis
  • Weakness
    • Face: Progressive
    • Vocal cord paralysis
    • Limbs: Distal; Hands then Feet
  • Sensory: Normal
  • Ankle contracture: With early onset
  • Tendon reflexes: May be brisk
  • Cognition: Normal
• Laboratory
  • NCV: Velocity normal, CMAPs small
  • EMG: MUPs large & long
• Variant syndrome: ALS or ALS susceptibility
  • Genetics
    • Inheritance: Dominant or Sporadic
    • Mutations: Missense; Thr1249Ile, Met571Thr, Arg785Trp, Arg1101Lys; R1275C
    • Incomplete penetrance
  • Clinical
    • Onset
      • Age: 46 to 64 years
      • Weakness: Arms, Legs, Posterior neck or Bulbar
    • Weakness
      • Arms, Legs or Bulbar
      • May be asymmetric
      • 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

• 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

• 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

• 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

• 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)

• 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)

• 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

• Epidemiology: Brazilian, Australian & North American families
• Genetics ⁷²
  • Mutations
    • Missense
    • Locations: P1386S; T994I
  • Allelic disorders
    • Menkes disease : Loss of function mutations
    • Occipital horn syndrome
    • Defects that allow residual copper transport
    • Often via leaky splice-junction mutations involving noncanonical bases
• 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

• 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

• Epidemiology: Southern Italian family

Distal Hereditary Motor Neuropathy (HMN 2C) ⁷¹

• Epidemiology: 4 families
• Genetics
  • Mutations: Missense; Arg7Ser; R116P; Y118H
  • Allelic disorder: Shoulder girdle weakness, p.L34Ffs*50 (A33AfsX50)
  • Other: Small heat-shock protein disorders
    • HSPB8: HMN2A & CMT 2L
    • HSPB1: HMN2B & CMT 2F
    • αB-crystallin: Myofibrillar myopathy & Posterior polar cataracts
    • HSF1 antibodies
• 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 or Mildly reduced
  • Tendon reflexes: Reduced at ankles
• Laboratory
  • EMG: Denervation in distal legs & hands
  • NCV: Normal velocities; Axon loss

Distal Hereditary Motor Neuropathy with Pyramidal features

• 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

• Epidemiology: 8 families
• Genetics
  • Mutations
    • General location
      • Exon 15
      • Domain function: Interactions with gigaxonin
    • Missense: Met539Ile (c.1617G>T; c.1617G>A); Ser547Gly; Glu557Val
    • Synonymous (c.1731 C/T, Asn577Asn): Leads to
      • Reduced UBE1 expression
      • Altered methylation pattern of exon 15
  • Allelic disorder (Somatic mutations)
    • VEXAS (Autoinflammmation): Met41Val; Met41Thr; Met41Leu
• UBE1 (UBA1) protein ¹⁶⁸
  • Expression: All tissues; High levels in motor neurons
  • Localization
    • Nuclear in normal motor neurons
    • Cytoplasmic SMN1-linked SMA motor neurons
  • Ubiquitin-proteasome system
  • Ubiquitin activating E1 enzyme
  • Initiates activation & conjugation of ubiquitin-like proteins
  • Binds to gigaxonin
  • Modification of proteins with ubiquitin or ubiquitin-like proteins
    • Controls many signaling networks
    • Requires
      • Ubiquitin activating enzyme (E1)
      • Ubiquitin conjugating enzyme (E2)
      • Ubiquitin protein ligase (E3)
  • Required for Atg7- & Atg3-independent autophagy
• Clinical features
  • Onset: Congenital or Infant
  • Weakness
    • Early: Hypotonia
    • Proximal > Distal: Similar to Werdnig-Hoffmann
    • Face: Myopathic faces
    • Bulbar
      • Speech: Nasal
      • Tongue: Fasciculations
  • Cramps: Some patients
  • Tendon reflexes: Reduced
  • Skeletal
    • Contractures: Proximal & Fingers; Congenital
    • Fractures: Congenital
    • Face: Dysmorphism
  • Genital: Undescended testes
  • Course
    • Severe disorders: Usually death < 2 years
    • Associated with respiratory insufficiency
    • Milder patients: Long lifespan
  • Family history: Miscarriages/spontaneous abortions
• Laboratory
  • Pathology
    • Muscle: Denervation
    • Anterior horn cell loss
  • Brain MRI: Normal
  • Serum CK: Mildly high
  • NCV: CMAP amplitudes reduced; Velocities normal
  • EMG: Fibrillations; Positive sharp waves
• Female carriers: No symptoms
• Rule out: Congenital 5q-linked SMA
  
  

• 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

• 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

• Epidemiology: 5 families; 14 patients
• Genetics
  • Mutation: c.770A>G (p.His257Arg) (Recurrent); Phe138Tyr (de novo); Asp314Gly (Older onset)
• WARS1 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

• Epidemiology: 23 families
• Genetics
  • Mutations
    • Hot spot: Ser107Leu
    • Other: Asn188Thr; Ile189Phe; Val485Gly; Arg501Pro; Lys508Thr;
        Ala535Val; Tyr557His; Ser681Leu; Thr703Met; Arg747Cys; Glu774Gly
    • Locations: Coiled-coil domains
  • Allelic disorders
    • SMALED2A
    • SPG
    • Arthrogryposis (SMALED2B)
    • 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 to Adult
    • 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
    • Pelvis: Gluteus medius & minimus
    • Thigh
      • Involved: Anterior; Vastus lateralis, intermedius; Sartorius > Rectus femoris
      • Spared: Medial adductors & Semitendinosus
    • Leg: Posterior calf (Gastrocnemius)
    • 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 pathology
    • 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

• 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

• Epidemiology: Okinawa, Japan, Brazil, Taiwan (CMT2), Korea 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 posterior columns
    • Neuronal cytoplasmic inclusions: TDP-43, TFG, Optineurin & ubiquitin
    • Golgi fragmentation
  • Sural nerve
    • Myelinated axons: Reduced numbers
    • Ultrastructure: Aggregated ER; Mitochondria small
  • Muscle
    • Fiber size variability
    • Internal nucle
    • Fiber splitting
    • Core-like or targetoid structures
    • Grouped atrophy
    • Fiber type groups
    • Aggregates: TFG, TDP-43, p62
• TFG variant disorder: SPG 57
  • Epidemiology: Sudan, Indian & Italian families
  • Genetics
    • Inheritance: Recessive
    • TFG mutations: Arg22Trp, Ile66Thr, Arg106Cys, R106H
    • Allelic disorders
  • TFG protein
    • Mutation
      • Inability to self-assemble into oligomeric complex
      • Abnormal secretion from ER
      • Impaired axon fasciculation after neuronal differentiation
  • 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
    • Nerve pathology: INAD
    • CNS: Length dependent corticospinal tract axonopathy
  • Diferential diagnosis: SPOAN
• TFG variant disorder: CMT2 ¹⁶⁰
  • Epidemiology: Taiwan, Iranian & Italian families
  • Genetics
    • Mutation: Gly269Val
    • Inheritance: Dominant
  • Clinical
    • Onset age: 28 to 40 years
    • Weakness
      • Distal
      • Arms ≥ Legs
    • Cramps
    • Sensory
      • Loss: Distal; Arms & Legs; Panmodal
      • Paresthesias
      • Gait ataxia
      • Pain: Allodynia; Face
    • Tendon reflexes: Reduced in legs
    • Course: Progressive; May need walking aids
  • Laboratory
    • NCV: 44 to 61 M/s; Motor sensory axon loss
    • EMG: Chronic denervation
    • Nerve pathology: Axon loss, Large myelinated

• Epidemiology
  • SMABF1: 7 families, 10 patients
  • SMABF2: 6 families, 11 patients
• 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: 6 families
  • Genetics
    • Inheritance: Recessive
    • Mutations: c.G950A, p.W297*; Stop, Splice, Missense (Milder phenotype)
  • Clinical
    • Onset ages: Birth to adult
    • 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
      • Dysmorphic: Flat face; Thick neck
    • Skin
      • Hyperelasticity
      • Dry with scratch lesions
      • Follicular hyperkeratosis
      • Xerosis
    • Cardiac: Dilated; Some patients
    • Ophthalmoplegia: 2 patients
    • Course
      • Death in 1st years: Some
      • Late: Non-walking
      • Often stable
  • Laboratory
    • Serum CK: Normal or Mildly high
    • EMG: Myopathic
    • Muscle CT: Preservation of leg adductors
    • Muscle MRI: Posterior thigh involvement with semi-tendinosus sparing
    • 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
        • Rods
        • Cytoplasmic bodies
        • Type 1 predominance

• 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: 7 patients
  • Genetics
    • Inheritance: Recessive
    • Mutations
      • Missense
      • Compound heterozygous
      • V236M; p.H119R (c.356A>G); p.R321C (c.961C>T); R358*; G135R; L195V
  • Clinical
    • Onset age: 3 to 31 years
      • Distribution
        • Distal
        • Legs > Arms: Ankles & Toes; Hands
        • 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: High (347 to 3,400) 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

• 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
    • PCH: EXOSC1
    • 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

• 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

• 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

• Epidemiology: Several families
• Genetics
  • Mutations
    • Location: C-terminal region common
    • Pro630His; Pro27Ter; Val455Gly; Gln550X; Met557Leu; Phe647Se; c.2057delT, c.2752_2753delGG; Thr686Met; Pro707His
  • Allelic with: CMT-RIC
  • Same mutations may produce DSMA4, CMT-RIC or Overlap phenotype
• 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
    • Small GTPase signalling pathways: Dysregulation
    • Autophagy disturbed
  • Proteins sharing PH or PH/RhoGEF domain: Dynamin 2; Alsin
  • Other guanine nucleotide exchange factor (GEF) disorders
• Clinical
  • Onset
    • Age: 2 to 25 years
    • Weakness
  • Weakness
    • Distribution: Generalized; Proximal ≥ Distal; Symmetric
    • 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
  • Sensory: Normal or Mild loss
  • No upper motor neuron signs
• Laboratory
  • EMG: Denervation; Motor units large
  • NCV
    • Motor: Normal or Slow velocities; CMAPs may become small
    • Sensory: Normal or Mildly slow
  • Serum CK: Mildly high
  • Muscle biopsy: Denervation
  • Muscle MRI: Fatty replacement in glutei & thighs > legs
• Variant syndrome: Charcot-Marie-Tooth disease, Recessive Intermediate C (CMTRIC)
  • Epidemiology: Korean, Portuguese & Moroccan families
  • PLEKHG5 Genetics
    • Inheritance: Recessive
    • Mutations
      • Compound heterozygous or Homozygous
      • Stop; 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
      • Legs > Arms
      • Modalities: Large & Small axon
      • Varied severity
    • 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

• Epidemiology: 4 families
• Genetics
  • Mutations
    • Homozygous
    • Splice site (c.229+1G>A, c.352+1G>A) & Deletion (c.310delC, 3.8-kb deletion)
  • Allelic with: CMT 2
  • 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: 1st to 4th decade
    • Foot drop
    • Gait disorder
  • Weakness
    • Distal: Severe in legs
    • Legs > Hands
    • Bulbar & Respiratory: Later in course
    • Course: Progressive to wheelchair
  • Sensory: Normal early; Loss later in course
  • Tendon reflexes: Absent
  • CNS: Parkinson disease in some patients
  • Edema: Legs
• Laboratory
  • Electrodiagnostic
    • CMAP amplitudes: Reduced, especially in legs
    • NCV: Normal velocity
    • SNAPs: Normal
    • EMG: Denervation, Distal legs
• DNAJB2 (HSJ1) variant: AR-CMT 2 ¹¹⁷
  • Epidemiology: 3 families
  • Genetics
    • Inheritance: Recessive
    • Mutation: Homozygous; Tyr5Cys, c.310delC, c.619-1G>A
  • 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

• 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

• 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

• 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

• 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

• 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

• 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

• Epidemiology: 1 Pakistani patient
• Genetics
  • 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; Wheelchair at 15 years
• 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
  • CSF: Lactate mildly high
  • Urine: Excretion of 3-Hydroxyisovaleric & Glutaric acid

ALS: Hereditary

General: Hereditary vs Sporadic ALS

• 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
      • China: Most common F-ALS gene
    • 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
        A4V; G37R; L38V; G41S; H43R; H46R; D76V; L84F; L84V;
        N86K; E100G; D101F; I104F; G108V; C111Y; I112M; G114A;
        L126X; G127X; G141E; L144F; V148G; V148I
    • 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
        A4T; C6S; L8Q; V14G; G16S; N19S; E21G; ΔG27/P28; N65S; G72S; D76Y;
        N86S; A89V; D90A hetero; G93S; A95T; E100K; D101N; S105L;
        I113T; V118L; V118KTGPX; L126S; N139H
        • 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

• 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
  • Muscle
• 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 (Juvenile) ALS, Familial or Sporadic
    • Sporadic ALS
      • Frequency
        • General ALS: 0.5% to 0.7%
        • Juvenile onset: 7% to 50%
      • Mutations: Exon 6; G507D, R518G, R521C, R521H
  • 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 ¹⁷⁷
    • Cellular localization
      • Normal: Nuclear; Synapses (Pre- & Post-synaptic)
      • Disease
        • Cytoplasm accumulation
        • Present in: Anterior horn cell aggregates in sporadic & hereditary ALS except SOD1
    • Protein groups
      • hnRNP
      • TET: EWSR1, TAF15
    • Functions
      • DNA & RNA metabolism
        • DNA-/RNA-binding
        • DNA repair
        • RNA-interacting domains: Located in the mid-region of protein
        • RNA processing: Regulation of splicing & transcription of synaptic mRNAs
      • Interactions
        • Syntaphilin (SNPH) : Mitochondrial tethering protein
        • Mitochondrial proteins
        • GluA1 (GRIA1)
        • U7 snRNA/snRNP: Regulates expression of histone genes
      • Implicated in
        • Tumorigenesis
        • RNA metabolism
        • Stress granule formation
        • FUS aggregates: 10% of FTD
      • 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
    • 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
    • Lipid-droplet-ER contact
    • 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 ¹⁵⁹
  ● Senataxin ; Chromosome 9q34.13; Dominant
  • Epidemiology: England; Southern Maryland
  • Genetics ⁴⁴
    • Mutations
      • Missense
      • Locations: T3I, Glu385Lys, Leu389Ser, R2136H
      • 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: Later also proximal
      • Hands & Feet
      • Usually symmetric
      • Bulbar disorders: Infrequent, Dysphagia
    • Muscle wasting: Distal
    • Upper motor neuron signs
      • Hyperreflexia 86%
      • Upgoing toes 17%
    • Sensory: Normal or Mild changes in some (30%) older patients
    • CNS: Ataxia in arms in up to 50%
    • Severity: Variable degrees
    • Course
      • Slowly progressive over decades
      • 5th & 6th decades: Wheelchair; Loss of hand function
      • Milder phenotype: Mild gait disorder
  • Laboratory
    • Electrophysiology: Motor neuropathy, Chronic
      • EMG: Denervation, Distal > Proximal, Chronic
      • NCV
        • CMAP amplitude: Reduced
        • Distal latencies: Long
        • Temporal dispersion: Some patients
        • Conduction block: some patients
        • NCV: Normal
        • Sensory: Normal
    • Pathology
      • Reduced number of Anterior horn cells, especially lumbar
      • Sensory pathways: Posterior column fiber loss; Loss of DRG neurons
      • Axon swellings: Roots, Spinal gray, Dentate, Cranial nerves 3 & 4
      • Spinal cord atrophy
    • Muscle MRI: Fat increased in legs
    • Serum CK: Normal or Mildly high
    • Colon polyps (25%)
  
  
  
• ALS-FTD 1 : ALS + Frontotemporal Dementia 1 (FTDALS1) ^{9, 54, 83}
    ● C9orf72 ; Chromosome 9p21.2; Dominant or Sporadic
  • Epidemiology
    • Frequency
      • High frequency
        • Europe & America
          • 60% of hereditary ALS-FTD
          • 27% to 50% of familial ALS patients
        • 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
    • Transmission from females: 1.4x higher
  • 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
            • Unaffected individuals: 2 to 19
            • 2 or 3: Most common repeat sizes
            • Other peak lengths: 5 & 8
            • Intermediate lengths: 7 to 45
            • Finland: Repeat lengths > 20 more common
          • Repeat type: Uninterrupted
          • 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, General: 250 to 4,400
          • Symptoms reported with 20 to 22 repeats
          • 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
      • Psychiatric disorders: Suicide may be common ¹⁶³
      • 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
        • General
          • Range: 34 to 84 years
          • Mean: 6th decade; 55 to 59 years
          • Median: 58 years
        • Similar for: ALS & FTD presentations
        • Same, or earlier, mean age as: Sporadic ALS
        • Young onset (< 45 years): Less than singleton ALS
        • Anticipation: 2 to 3 years younger onset per generation ¹³⁷
        • Earlier onset: Sporadic cases ¹⁶³
        • Later onset: More G₄C₂ repeats
      • Clinical
        • Weakness
          • Limb
            • Frequency: 50% to 67%
            • Legs: More common
            • Arms: Less common
          • Bulbar
            • Frequency 33% to 43%
            • More common than sporadic ALS
            • Clustered in some families
          • 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%
      • Apathetic
      • Socially isolated
      • Delusion
      • Working memory: Impairment
      • Less eating dysregulation than FTD non-carriers
      • 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
        • FTD patients: May have presymptomatic cortical thinning
      • 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 (FTDALS7) (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: 3 families; 7 patients
    • Genetics
      • Inheritance: Dominant
      • Mutations: Frameshift (Stop) in 3' UTR or C-terminus 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
      • Muscle MRI: Sparing of gracilis & biceps, short head in thigh
  
  
• 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
    • > 60 identified
    • 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
      • TDP-43
      • hnRNPA2B1
      • hnRNPA1
      • FUS
    • Sporadic ALS: TDP-43 cytoplasmic aggregates common
  • 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 ¹⁷⁶
      • 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
  • Onset age: 57 years
  • Course: 5 years
  • Onset: Asymmetric leg weakness
  • ALS diagnosis
  • 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 & Axon 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
    • Frequency: 1% to 3% of ALS & ALS/FTD; > 40 families
    • Common in Belgium
  • Genetics
    • Mutations
      • Types
        • Loss-of-function
        • Missense: Less clear pathogenicity
      • Effects: Loss of function; ? Dominant gain of function
      • Heterozygous
    • Penetrance
      • Incomplete
      • Family history: Often negative
    • Allelic disorders: Different syndromes in same family
      • Increased TBK1 copy number: Glaucoma (Primary open angle; Normal tension)
      • PLS/Dementia
      • Primary progressive aphasia
      • Parkinsonism, atypical: Cortico-basal syndrome
      • Encephalopathy, acute, infection-induced (herpes-specific), susceptibility to, 8 (IIAE8)
  • TBK1 protein
    • Kinase family
      • Serine/Threonine
      • IKK (IκB)
    • Autophagy
      • Efficient cargo recruitment in autophagy
      • Degradation of protein aggregates
    • Co-localizes with & phosphorylates OPTN & SQSTM1 in autophagosomes
    • NF-κB pathway
  • Clinical
    • ALS syndrome
      • Onset
        • Age: Mean 60 years; Oldest 80 years; 9 years later than c9orf72
        • Common: Legs or Arms
        • Bulbar in 15% to 40%
      • Bulbar involvement: 87%; Dysarthria; dysphagia
      • Upper motor neuron
        • Tendon reflexes: Brisk
        • Spasticity: May be asymmetric
      • Lower motor neuron
        • Fasciculations
        • Muscle atrophy
    • Fronto-Temporal dementia
      • Cognitive impairment in 50%
      • Language impairment (Aphasia)
      • Presenting feature in 60%
    • Extrapyramidal features: Hypokinesia; Tremor; Rigidity
    • Course
      • Survival: Mean 42 months; Range 1 to 9 years
      • Age at death: Mean 65 years; Range 50 to 77 years
  • Laboratory
    • EMG
      • Denervation, Active & Chronic
      • May be normal
    • Brain MRI: Atrophy, often temporal & asymmetric
    • FDG-PET: Asymmetric hypoperfusion or glucose hypometabolism
    • Pathology
      • Brain atrophy: Frontal & Temporal
      • TDP-43 & p62 inclusions: Neurons & Glia
      • Motor neuron loss
  • 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 5 (FTDALS5) 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 8 (FTDALS8) ^{101, 162}
    ● CYLD Lysine-63 Deubiquitinase (CYLD) ; Chromosome 16q12.1; Dominant
  • Epidemiology: European Australian family,
  • Genetics
    • Mutation: Missense; c.2155A>G, p.M719V
    • Allelic disorders
      • Brooke-Spiegler syndrome
      • Cylindromatosis, familial
      • Trichoepithelioma, multiple familial, 1
  • CYLD protein
    • Deubiquitinating enzyme
    • Removes lys63-linked ubiquitin chains
    • Acts as negative regulator of NF-κ-B signaling
    • Deubiquitinates NF-κ-B receptors
      • TRAF2
      • TRAF6
      • NEMO (IKBKG)
      • BCL3
  • 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
    • Glial CYLD-immunoreactivity in white matter
  
  

  ALS-FTD 166   ● Huntingtin (HTT) ; Chromosome 4p16.3; Dominant Epidemiology: 10 patients, 8 families Genetics Mutation: CAG repeat Expansion sizes: 40 to 64 copies Somatic instability Allelic disorders Huntington disease Lopes-Maciel-Rodan syndrome HTT protein Transcription regulator Expression: Ubiquitous Clinical Onset ages Range: 19 to 76 years Earlier with larger repeat Cognitive Present at disease onset Behavioral & Language disorders Personality change ALS features Upper motor neuron Spasticity Tendon reflexes: Brisk in legs Lower motor neuron Weakness: Asymmetric Dysarthria Other CNS: Some patients Oculomotor disorders Course: Progressive; Several > 1 decade Laboratory Brain MRI: Normal or Brainstem atrophy Pathology Axon degeneration Descending corticospinal tracts Inclusions HTT: In frontal cortex TDP43: In motor neurons p62: May be intranuclear

  HTT (PolyQ) aggregates   Not in nuclei; Motor cortex From: R Bucelli; R Hickman (Columbia, NY)

  
  
• 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
      • Multisystem proteinopathy (MSP)
  • 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 (FTD): 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
  • ANXA11 variant syndrome: Multisystem proteinopathy 6 ¹⁷⁴
    • Epidemiology: 3 Brazilian families, 11 patients
    • Genetics
      • Inheritance: Dominant
      • Mutation: D40Y
    • Clinical
      • Onset age: Usually 5th or 6th decade
      • Weakness
        • Legs > Arms
        • Proximal
        • Axial: Head ptosis; Abdominal
        • Gastrocnemius: Medial
        • Face: Ptosis
        • Gait disorder
        • Course: Slow progression
      • ALS: 2 patients
        • Spinal onset
        • Course: Rapid progression
      • Fronto-Temporal Dementia (20%)
    • Laboratory
      • Muscle pathology
        • Rimmed vacuoles
        • Aggregates: Annexin A11, TDP-43, p62
        • No inflammation
      • EMG
        • Myopathic ± Chronic denervation: May be presymptomatic
        • Fasciculations: ALS syndrome patients
      • Muscle MRI
        • Arms: Anterior (Biceps) involvement
        • Legs: Posterior (Semitendinosus, Semimembranosus)
        • Paraspinous
      • Brain imaging
        • White matter damage: Corticospinal tracts; Frontal subcortical
  
  
• 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