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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     Adult: MORC2; 22q12     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: UBE3C; 7q36; Dom     2       A: HSPB8 (HSP22); 12q24; Dom       B: HSPB1 (HSP27); 7q11; Dom/Rec       C: HSPB3 (HSPL27); 5q11; Dom       D: FBXO38; 5p31; Dom/Rec     5: Upper limb predominance       A: GARS; 7p15; Dom       B: REEP1; 2p11.2; Dom       C: BSCL2; 11q13; Dom     6: IGHMBP2; 11q13; Rec     7: + Vocal cord paralysis       A: SLC5A7; 2q12; Dom       B: Dynactin 1 (DCTN1); 2p13; Dom     8: Congen, Legs: TRPV4; 12q24; Dom     9 dHMN: WARS1; 14q32; Dom     10 dHMN: EMELIN-1; 2p23; Dom     + Upper motor neuron           Senataxin; 9q34; Dom           4q34: Dom           HMN             J: 9p21; Rec             2B: HSPB1; 7q11; Dom             5C: BSCL2; 11q13; Dom             7B: Dynactin; 2p13; Dom           SPG + Motor neuropathy     HMN: 11p; Rec     HMN: 16p     HMN: KCC3; 15q14; Dom     HMN: SPTAN1; 9q34; Dom     HMN: MME; 3q25; Rec     HMN: SLC5A6; 2p23; Rec     HMN: COQ7; 16p12; Rec     CMT 2N: AARS; 16q22; Dom     CMT 2O: DYNC1H1; 14q32; Dom     Neuromyotonia: HINT1; 5q31; Rec     Child: BICD2; 9q22; Dom     Intellect Disability: TBCK; 4q24; Rec 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       6: REEP1; 2p11       dHMN: SIGMAR1: 9p13       dHMN: SYT2; 1q32       + Ataxia telangectasia: ATM; 11q22       + Encephalopathy: TBCE; 1q42       Lethal congenital contractures       MND, Distal: VRK1; 14q32       SORD: 15q21       NRCAM: 7q31     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     CONDSIAS: ADPRHL2; 1p34     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) ¹⁷⁸

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

SMN Genes: Different Splicing 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

Hoffman ~1891 From: Andrew Kornberg MD

Guido Werdnig Johann Hoffman

SMA 5q: Classification (without treatment)

• Inheritance: Recessive
• SMN1 mutations: Bi-Allelic

• History
  • SMA described independently by Guido Werdnig & Hoffmann in 1891
  • Werdnig
    • Described condition as "Neurogenic dystrophy"
  • Hoffmann
    • Established spinal nature of SMA
    • Coined term: "Spinale muskelatrophie"
• Epidemiology
  • Incidence of SMA disease: 1 in 6,000 to 20,000 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%
      • SMN1 copy numbers: Higher; 53% with 3 copies vs 6% with 3 in West
      • SMN2 copy numbers: Lower; 24% with none vs 8% in West
• 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
  • Genetics
    • SMN2 copies: 1
    • SMN1 copies: 0
  • 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
  • Course
    • Untreated: Death in 1st month
    • Treatment ¹⁸²
      • Prolonged survival
      • Motor
        • Respiratory insufficiency
        • GI: G-tube dependent for nutrition
        • Weakness: Severe; Some anti-gravity movement
      • Skin: Rash; Necrosis & Vasculopathy
      • Cardiac: Malformation
      • Bones: Fractures
• Clinical features: Werdnig-Hoffmann (Type 1)

  Onset Usually before 3 months Range 0 to 6 months Some with in utero decreased fetal movements Acute onset in occasional patient 13 Early weeks or months: Normal development After 1st few months New weakness No new motor milestones Motor neuron loss Clinical Weakness Diffuse; Proximal > Distal Severe Poor feeding Respiratory insufficiency: Paradoxical respirations Sparing of facial & oculomotor Hypotonia Fasciculations: Tongue Tendon reflexes: Reduced or absent Intellect: Normal; Alert faces Prognosis Untreated Respiratory failure Death 50% by 7 months 95% by 17 months Chronic course in 5% Treatment Better prognosis with: Earlier treatment Survival: Prolonged; 100% at 20 months Ventilator free: Often Motor: Improved strength & Milestones Feeding: Oral Hospitalizations: Reduced 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

  From: A Kornberg MD

• Clinical features: Kugelberg-Welander (Types II & III )
  

  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

  From: M Ryan MD

  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 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 SMNC than with SMNT deletion No family history Pathology Muscle Pathology Grouped atrophy Large fibers: Mostly type 1; Hypertrophied Small fibers mixed or type 2 Development Weakness & Muscle atrophy: May precede motor neuron loss 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

  SMA Spinal cord Anterior roots are atrophic

• SMN 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 > 1 SMN1 gene on a chromosome

  SMA 5q: Treatments 164 SMN2 pre-mRNA splicing Modify: Increase full length SMN protein Drugs Nusinursen (Spinraza) Drug type: Anti-sense oligonucleotide Mechanism Binds to splice-silencing-site in SMN2 intron 7 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 Full-length SMN mRNA & protein: Levels ↑ 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 Most effect: Youngest patients Improved strength Prolonged survival SMN2 copies: Better with 3 than 2 CMAP amplitudes: Increased or Unchanged Experimental treatments Branaplam: SMN2 splicing Reldesemtiv (Tirasemtiv): Fast skeletal troponin inhibitors 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

  Spinal Muscular Atrophy: Treatments Features Drug   Nusinersen Risdiplam Onasemnogene Abeparvovec-xio Drug Type Oligonucleotide,   Antisense Small Virus (AAV)   Gene Delivery Mechanism More splicing of SMN2 gene to   full length SMN protein SMN transgene: Produces   full length SMN protein FDA: Ages All > 2 months < 2 years Pre-Rx Platelets Coagulation Urinalysis   Liver functions Platelets Troponin-I AAV9 antibodies Prednisolone Rx: 30 days Rx Intrathecal q 2 weeks x4,   then q 4 months Oral Daily Intravenous Single dose Limitations Lumbar puncture   needed Drug   interactions Pre-Rx serum   AAV9 antibodies Adverse   Events Thrombocytopenia Proteinuria LP problems Fever Diarrhea Skin rash Liver Δ   Acute; Transaminitis Thrombocytopenia Troponin ↑ Monitor Platelets Coagulation Urinalysis   Liver functions Platelets Troponin-I

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
  • Allelic disorders
    • Androgen insensitivity, Recessive
    • Androgen insensitivity, partial ± Breast cancer, Recessive
    • Hypospadias 1, X-linked Recessive
    • Spinal and bulbar muscular atrophy of Kennedy
    • Prostate cancer, susceptibility to, Somatic, Dominant
• Genetic-Clinical Correlations: CAG repeat length
  • 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
    • Cold temperatures: Increased weakness
    • 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
• Laboratory
  • Electrodiagnostic
    • NCV
      • CMAP amplitude: Reduced in 23% to 40%
      • SNAP amplitude: Reduced in 80% in sural
      • Distal latencies: Prolonged with cold exposure
    • 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
• 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%
• 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 Image 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) ⁵⁹

• Nosology
  • Juvenile ALS
  • Distal HMN
• Epidemiology: Australian family
• Genetics
  • Mutation
    • 1.35 Mb complex structural variation
    • Inserted sequence fragment contains
      • 4 protein-coding genes & their regulatory elements
        • MNX1(HB9)
        • NOM1
        • RNF32
        • LMBR1
      • Upstream regulatory elements & first 10 exons of ubiquitin-protein E3 ligase gene E3C
  • Allelic disorder: Angelman-like syndrome, Recessive ¹⁹¹
• UBE3C protein
  • Ubiquitin E3 protein ligase
  • HECT (homologous to E6-AP carboxyl 13 terminus) class of E3 ligases
  • Forms thioester complex with ubiquitin in presence of an E1 enzyme & E2 enzyme UBE2D1
  • Mutation causes: Duplicated copy of 1st 18 10 exons
• 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
  • Common cause of dHMN
  • 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)

• Epidemiology: 1 family
• 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: 2 patients
• Genetics
  • Mutations: S477N, Splice (c. 846 G>C)
  • Allelic disorder: Wilson-Turner syndrome
• 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
    • Feeding difficulty
  • 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
  • Mutations: Missense; Arg269Cys (Also with CMT 2C & SPSMA)
  • Allelic disorders
• Clinical
  • Onset age: Congenital
  • Weakness
    • Developmental delay: Motor
    • Legs only: Proximal & Distal
    • Non-progressive
    • Vocal cord paralysis: Some patients
  • Tendon reflexes: Reduced in legs
  • Contractures
    • Arthrogryposis
    • Knees & Ankles
• Laboratory
  • Serum CK: Mildly elevated
  • Electrophysiology
    • EMG: Chronic (Giant motor units) & Active denervation
    • 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)
  • Allelic disorder: Microcephaly + Developmental delay & Brain anomalies, Recessive ¹⁸⁷
• 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: > 10 patients
• Genetics
  • Mutations: Missense; Arg251Cys, I584L, K671E, Y970C; Tail domain & other
  • 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
  • CNS: Learning difficulty in some patients
• 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: 16patients
  • SMABF2: 13 patients
• Genetics
  • Mutations: Stop; Often homozygous
  • TRIP4 allelic variant: Congenital muscle disease
  • ASCC1 variant: Congenital weakness, Developmental delay, Ulnar epiphysiolysis
• 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
  • Genetic correlations
    • ASCC1 mutations: More fractures; Shorter survival
  • 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 (especially posterior) > Arms: Ankles & Toes; Hands
        • Symmetric
        • Respiratory
      • Gait disorder
      • Course: Slow progression over years
    • Muscle atrophy: Distal legs, posterior
    • 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
    • Cerebellar
      • PCH: EXOSC1
      • PCH1B: EXOSC3
      • CABAC: EXOSC5
      • SMA + Cerebellar hypoplasia (PCH1C) - EXOSC8
      • Cerebellar atrophy + Spinal Motor Neuropathy: EXOSC9
    • Spinal motor neuropathy: RBM7
    • Immune: PM/Scl (EXOSC9 & EXOSC10) autoantibodies
• Clinical
  • Onset: Congenital
  • Motor neuron: Muscle wasting
  • Contractures: Distal
  • Cerebellar
  • Oculomotor apraxia
  • Microcephaly: Progressive
  • Developmental delay: Global; Severe
• Laboratory
  • MRI: Cerebellar atrophy; Brainstem & Cortex small
  • EMG: Neurogenic; Large motor units
  • NCV
    • CMAP amplitude: Small
    • Sensory responses: Normal
  • Autopsy
    • Cerebellum: Neuron loss (Purkinje & Granule)
    • Spinal cord: Motor neuron loss
• Variant syndrome: Spastic paraplegia, Early onset & Complicated ¹⁰⁴
  • Epidemiology: Bangladesh-Italian & Arab-Israel families
  • Genetics
    • Inheritance: Recessive
    • EXOSC3 mutations: V80F; D132A; G191C
  • Clinical
    • Onset age: 1 to 4 years
    • Spasticity
      • Legs > Arms
      • Gait disorder
      • Tendon reflexes: Brisk
      • Plantar response: Extensor
    • Cognitive impairment: Mild
      • Speech disorder
      • Learning dificulty
    • Cerebellar:
      • Dysarthria
      • Nystagmus
      • Intention tremor & Dysmetria
    • Motor: 1 family
      • Distal amyotrophy
      • Tongue atrophy
      • Fasciculations
    • Eye: Strabismus (50%)
    • Skeletal: Adducted thumbs, Talipes valgus; Short stature (50%); Normal head circumference
    • Course: May be progressive after 1st decade
  • Laboratory
    • EMG: Distal denervation
    • Nerve conduction: Velocities normal
    • Brain MRI: Cerebellar atrophy
    • Muscle biopsy: Type 2 predominance; Varied muscle fiber size
    • SSEP: Delayed central conduction times

• 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: 5 families
• Genetics
  • Mutations
    • Homozygous
    • Splice site (c.229+1G>A, c.352+1G>A); Deletion (c.310delC, 3.8-kb deletion); c184C>T;
  • 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
  • Muscle: May have rimmed vacuoles
• 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: 50 patients
• Genetics
  • Mutations
    • Types: Missense, Thr42Met, Thr42 Ala (Milder phenotype); Deletion, Small or whole gene
    • Homozygous
  • Allelic disorders
    • Farber Lipogranulomatosis: Very low ASASH1 levels
    • Progressive adult-onset brachydactyly due to osteolysis
    • SMA without epilepsy
• ASAH1 protein
  • Localization: Lysosome
  • Maintains intralysosomal ceramide homeostasis
  • Cleaves Ceramide into Sphingosine & free fatty acids at acid pH
• Clinical
  • Onset age: 1 to 30 years; Mean 6 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
  • NCV: CMAPS small; SNAPs normal
  • EEG
    • Epilepsy: Subcortical myoclonic epileptiform activity, sensitive to hyperventilation
    • May be normal
  • Serum CK: Normal
  • Muscle biopsy: Denervation & Reinnervation
• Variant syndrome: Farber Lipogranulomatosis
  • Genetics
    • ASAH1 mutations: Cause severe reduction in Acid ceramidase activity (< 10%)
    • Inheritance: Recessive
  • 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
  • Laboratory
    • 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; Homozygous
• 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

• Epidemiology: 1 Turkish family, 2 patients
• Genetics
  • Mutation: Ser134Pro
  • Allelic disorder: Neurodevelopmental disorder with Developmental delay, Hypotonia, Spasticity
• NRCAM protein
  • Location: Neurons & Glial cells in Ventral midline
  • Adhesion molecule
  • Immunoglobulin (Ig)-CAM
    • L1 subgroup
    • Neural specific
  • Nervous system development
    • Axon pathfinding
• Clinical
  • Onset age: 2nd decade
  • Weakness
    • Distal
    • Legs > Arms
  • Skeletal: Scoliosis; Pes cavus; Hammer toes
• Laboratory
  • EMG: Denervation, distal; Myopathic, proximal
  • NCV: CMAPs small; SNAPs normal
  • Serum CK: 2x to 3x high
• NRCAM variant: Neurodevelopmental disorder with Developmental delay, Hypotonia, Spasticity (NEDNMS)
  • Epidemiology: 8 patients
  • Genetics
    • Mutations: Missense & Stop
    • Inheritance: Recessive
  • Clinical
    • Onset age: Birth
    • Developmental delay
    • Cognitive disorder
    • Hypotonia (50%)
    • Spasticity (50%)
    • Ataxia
    • Skeletal: Dysmorphism; Microcephaly; Scoliosis; Hip dislocation
    • Cryptorchidism
    • Respiratory: O₂ supplementation
    • Eye: Strabisums (30%); Optic atrophy
    • Hearing loss
  • Laboratory
    • Brain imaging: Ventricles large; Myelination Δ
    • NCV: Polyneuropathy

ALS: Hereditary

General: Hereditary vs Sporadic ALS

• Amyotrophic Lateral Sclerosis 1 (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 (59%)
    • Penetrance: Overall 85% by age 85
  • Genetics
    • Inheritance: Dominant; de novo; Recessive
    • Mutations: Location & Character
      • > 200 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
      • Mutations: Common features
        • Heterozygous
        • Missense
        • Point
        • 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
        • China ¹⁸¹: V47A, H46R, C111Y, G147D
        • Finland: D90A
        • Dominant de novo ¹⁷⁹: Gly38Arg (Slow progression); Ala90Thr; Asp91Val; Asp102Asn (Rapid progression)
      • Other types
        • Stop codon ¹⁸³
          • 17 nonsense mutations identified
          • Nonsense mutations producing disease
            • Locations: Outside AA 50 to 100
            • Escape nonsense mediated decay
            • Produce polypeptide length of 121 tp 156 aa (Normal 153)
          • Exon 5 not needed for toxic action of mutated SOD
        • 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
    • Clinical 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
    • Patients often have mainly lower motor neuron signs
    • Onset
      • Mean age
        • General: 46 years
          • US: 50 years
          • China: 44 to 46 years
        • 10 years younger than sporadic ALS
        • 3.5 years younger than non-SOD FALS
        • 90% penetrance by age 70
      • Juvenile (< 25 years) onset: Few patients
        • SOD1 Mutations: de novo; G16S, P66S, H80A
        • Onset age: 18 to 24 years
        • Course: Rapid progression
      • 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
      • Survival
        • Male > Female
        • 5 years: 31% to 55%
        • Varies strongly with specific mutations
    • 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)
    • Treatment
      • SOD1 Antisense oligonucleotide ¹⁸⁴

ALS syndromes: Correlations with some SOD1 mutations

Specific SOD1 mutations Exon 1; Ala4Val   Most common mutation   Rapid onset & progression (1.0 yrs)   Frequently only lower motor neuron signs Exon 2; His46Arg   @ Cu binding site of SOD   Onset: Late; Legs   Bulbar unusual   Slow progression (17 yrs) 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 Exon 4; Leu84Val   Lower motor neuron only   Rapid progression (1.5 yrs)   ?Earlier onset in males 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 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 Exon 4; Ile113Thr   Reported in Sporadic ALS patients   Relatively common; Low penetrance   Late Onset: Mean 59 years   Course: Variable; 2 to 20 years 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; Arg115; 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, Markiesje & 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
    • Dyskinesia
    • 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: More common in Asia
    • Familial ALS: Frequency 3% to 5%
    • Common in: Early-onset (Juvenile) ALS, Familial or Sporadic
    • Sporadic ALS
      • Frequency
        • General ALS: 0.3% to 0.7%
        • Juvenile onset
          • 7% to 50%
          • More in Japan & China
          • Most common gene with fALS onset < 25 years
      • 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
          • Processing: Regulation of splicing & transcription of synaptic mRNAs
          • RNA binding: Introns, evolutionary conserved
      • Interactions
        • Syntaphilin (SNPH) : Mitochondrial tethering protein
        • Mitochondrial proteins
        • GluA1 (GRIA1)
        • U7 snRNA/snRNP: Regulates expression of histone genes
        • snRNP70
          • Gene spicing variants
            • Alternative 3'UTR selection
            • Associated with ALS subtype: Increased oxidative & proteotoxic stress
        • U1 snRNA & U1 snRNP
      • 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
    • Mutations: Often have abnormal cytoplasm localization
    • Knockout mice: Perinatal mortality; Male sterility; Chromosomal instability; Radiation sensitivity
  • Clinical ⁷⁸
    • Onset
      • Age
        • Mean 37 to 44 years; Range Teens to > 70 years
        • Variable penetrance at 70 years: 39% to 83%
        • Earlier & shorter survival than SOD1 & TDP43 FALS
      • Upper cervical & neck
      • Limbs or Bulbar: Bulbar more frequent than SOD1 FALS
    • General phenotypes: Predominantly lower motor neuron syndromes
      • Axial & arm weakness: Dropped head; Mid to late adult onset
      • Benign: Slow progression; Late onset
      • Juvenile: Bulbar onset; Cognitive Δ
    • Genotype-Phenotype correlations: Mutation locations
      • Last 2 amino acids in NLS domain: Aggressive phenotype; Bulbar onset; Cognitive Δ
      • Missense at 510 to 521 (K510R, H517Y, Q519E, R521H): Mild; Slow progression; Flail leg
      • Missense in C-terminal (Common): Proximal arm; LMN phenotype
      • P525L & Y526L: Juvenile
    • 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
      • Tremor
      • 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 (SETX) ; 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 disorders
      • 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%)
    • Knock in mice: CD8 cell clonal increase
  
  
  
• 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
        • C9orf72 expansion in UK population: 1 in 700
      • Low frequency: Germany
      • Rare: Native Americans; Iran; Asia; Pacific Islands
      • Sporadic (Simplex) ALS patient frequency
        • ALS
          • General: 0% to 21%
          • High in Finland
          • China: 0.8%
        • FTLD: Sporadic 7% to 10%
      • 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 c9orf72 mutation patients
        • Sporadic ALS ¹⁸⁹
          • c9orf72 repeat length ≤ 2: Longer survival
          • c9orf72 repeat length longer in normal range: Shorter survival with bulbar onset
      • 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
      • Tetranucleotide repeat: TTTA in intron ¹⁹⁰
        • Repeat range: 6 to 15
        • 9 TTTA allele: sALS risk reduced; Spinal onset ALS
        • 10 TTTA allele; 2.7 yr later onset vs othe sALS
    • 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: 15 families
    • Genetics
      • Inheritance: Dominant
      • Mutations: Frameshift (Stop) in 3' UTR or C-terminus of NEFH; 1 missense
      • 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 64 years
      • Weakness
        • Distal or Proximal
        • Legs > Arms
        • Triceps; Quadriceps
      • Muscle wasting: Distal
      • Sensory loss
        • Varied degrees
        • Panmodal
        • Distal
        • Legs > Arms
      • Tendon reflexes: Reduced in legs
      • Upper motor neuron: Some patients
      • Course: Slow progression
    • Laboratory
      • Serum CK: Normal to 1,288
      • Brain & Spinal cord MRI: Normal
      • Muscle pathology
        • Denervation: Grouped atrophy; Fiber type grouping
        • Internal nuclei
        • Rimmed vacuoles: Few fibers
        • Mitochondrial oxidative enzymes: Reduced complexes I, II+III & IV
      • Nerve pathology
        • Axon loss
      • 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
    • Type: 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
      • Southern China: Gly298Ser
    • Mutation effects: May increase sTDP-43 isoform
    • Allelic with: Frontotemporal lobar degeneration with TDP-43 inclusions, TARDBP-related
  • TDP-43 protein
    • Expression
      • Ubiquitous
      • Short isoform (sTDP-43): More prominent in
        • Motor neurons
        • Cytoplasm
    • 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 & FTD
    • 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
      • Actin binding region
      • A20T; C71G; ?T109M; M114T; M114V; E117G (also in controls); G118V; R136W; Q139L
    • 2 singleton patients with no family history
  • PFN1 protein
    • Converts monomeric G-actin to filamentous F-actin
      • Formin dependent
    • Axonal integrity & Axon transport
    • Nucleotide exchange factor
    • Binds ATXN2 & VCP
    • Mutant proteins
      • May form ubiquitinated aggregates: Increased p62 & ubiquitin in neurons
      • Alter growth cone morphology
      • Altered actin polymerization into filaments
      • Altered autophagy & mitochondrial distribution
  • Clinical: Similar to SOD1
    • Onset age: 4th to 7th decade; Mean > 50 years
    • Onset region
      • Limbs: All patients, Especially distal legs
      • Bulbar: No patients
    • Lower motor neuron: Most defecits
    • Upper motor neuron: Few deficits; Tendon reflexes in arms may be brisk
    • Respiratory: Late in disese course
    • Independent walking: Often lost in 1st 2 years
    • Cognitive: Normal
    • Course: Progressive; Death < 3 years
  • Brain pathology
    • Motor neurons: Loss; TDP43 & p62 inclusions
    • NO PFN1 inclusions
    • Corticospinal tracts: Moderate myelinated axon loss
  
  
• ALS 19 ¹⁰⁵
    ● V-erb-B2 Avian erythroblastic leukemia viral oncogene homolog 4 (ErbB4; HER4) ; Chromosome 2q34; Dominant or de novo
  • Epidemiology: Japanese, Chinese (0.67% of sALS; 1.2% of fALS) & Canadians
  • Genetics
    • Mutations: Missense; Arg927Gln, Arg1275Trp
    • Allelic disorders
      • sALS with Respiratory onset ¹⁸⁶
        • Insertion in ERBB4 gene: More common (71%) than in controls (25%) or other sALS (46%)
      • Tumor drivers: Missense mutations
  • ErbB4 protein
    • sALS: ERBB4 immunoreactivity reduced in spinal cord
  • Clinical
    • Onset
      • Age: Adult; 45 to 70 years
      • Arm involvement
      • Bulbar: 2 patients
    • Lower motor neuron
      • Weakness: Limbs
      • Respiratory insufficiency
    • Upper motor neuron
    • Cognitive: Normal or ALS + FTD in 1 patient
    • Progression
      • Slow, usually
      • Death: After 1.5 to 20 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), D40Y, G175R, G189E, R235Q,R346C, G491R
    • Penetrance: Incomplete
    • Mutations also found in sporadic ALS patients
    • Allelic disorders
      • R230C polymorphism associates with Autoimmune disorders & Sarcoidosis
      • Multisystem proteinopathy 6 (MSP6; IBMWMA)
      • ? Sarcoidosis susceptibility (SS3)
  • 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
    • Nosology: Inclusion body myopathy + Brain white matter abnormalities (IBMWMA)
    • Epidemiology: Brazilian & Greek families, 18 patients
    • Genetics
      • Inheritance: Dominant
      • Mutation: D40Y (Also found in ALS patient)
    • Clinical
      • Onset age: Usually 5th or 6th decade
      • Weakness
        • Asymmetric
        • Legs > Arms
        • Proximal
        • Axial: Head ptosis; Abdominal; Scapular winging
        • Gastrocnemius: Medial
        • Face: Ptosis, mild
        • Gait disorder
        • Course: Slow progression
      • ALS: 2 patients
        • Spinal onset
        • Course: Rapid progression
      • Fronto-Temporal Dementia (20%)
      • No Paget disease of bone
    • Laboratory
      • Muscle pathology
        • Rimmed vacuoles
        • Aggregates: Annexin A11, TDP-43, p62, Myotilin
        • No inflammation
        • Ultrastructure: Myofibrillar Δ Autophagic material
      • EMG
        • Myopathic ± Chronic denervation: May be presymptomatic
        • Fasciculations: ALS syndrome patients
      • Muscle MRI
        • Arms: Anterior (Biceps) involvement
        • Thigh: Adductors; Posterior (Semitendinosus, Semimembranosus)
        • Leg: Gastrocnemius, medial
        • 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