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HEREDITARY MOTOR SYNDROMES (SMA, ALS + ...)

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

SMA: Clinical features   Congenital     Arthrogryoposis     SMA 0   Types: 1; 2; 3; 4   Lower motor neuron SMA: Clinical - Genetic correlations SMA: Gene testing SMA: Pathology SMN genes: SMN1; SMN2 SMN protein Other related & neighboring genes From: Andrew Kornberg MD

Hoffman ~1891

SMN1 mRNA 90% of pre-mRNA spliced to full length SMN SMN2 mRNA 80% of pre-mRNA spliced to SMN with no exon 7 SMN without exon 7 is unstable & rapidly degraded

• History
  • SMA described independently by Werdnig and Hoffmann in 1891
  • Werdnig described the condition as "neurogenic dystrophy"
  • Hoffmann
    • Established the spinal nature of the disease
    • Coined term: "spinale muskelatrophie"
• SMN1 (Telomeric SMN (SMN^T)) gene
  
  • Disease relations
    • SMA: Mutated in 95% of patients
    • ALS: Increased frequency (2x) of 1 or 3 gene copies
  • Contains 9 exons
  • Codes for protein containing 294 amino acids
  • Number of SMN1 gene copies⁸: Varies
    • 1 SMN1 copy on each chromosome
      • 82% to 96% of normal individuals
    • 2 SMN1 copies on one chromosome
      • 4% to 18% of normal individuals
    • Variability makes heterozygote testing complicated
  • SMN1 structure: Strongly homologous to SMN2
    • Exons 7 & 8 contain gene-specific nucleotide sequences
      • Some differences from SMN2
    • AG-rich exonic splice enhancer in SMN1 exon 7
      • Enhancer increases inclusion of exon 7 in protein
  • SMN1 gene chromosomal surrounding DNA
    • Composition: Large inverted duplication
    • Duplication has telomeric (t) & centromeric (c) copies
    • Each copy of duplication contains at least 4 genes
      • SMN
      • Other: p44; NAIP; H4F5
    • Repeated DNA unit features
      • Present on each chromosome
      • 0 to 4 copies
  • Telomeric (SMN1; SMN^T) gene mutations
    • Related to presence of SMA disease syndromes
• SMN2 gene (Centromeric SMN (SMN^C))
  • Disease relations
    • Number of Copies: More related to less severity of SMA
    • c.859G>C substitution: SMA less severe
  • Gene location: Centromeric to SMN 1 gene
  • Strong homology to SMN1: 5 nucleotide differences
    • Introns: One difference in 6; Two in 7
    • Exons: 2 Differences
      • Exon 7 (C to T): Translationally silent
      • Exon 8: 3' untranslated region
  • Nucleotide differences from SMN1 produce altered SMN splicing
    • Can produce identical amino acid sequences to SMN1
      • If fully translated
      • Quantitative: 10% of SMN1 gene
    • Often produces smaller SMN proteins than SMN1
      • SMN2 gene transcript often spliced at exon 5 or 7
      • 70% to 80% of SMA2 transcripts lack exon 5 and/or exon 7
    • Mechanism of altered splicing
      • Single-nucleotide change from SMN1 to SMN2 occurs in heptamer motif of the exon splicing enhancer
      • New nucleotide sequence (C to T)
        • Creates exonic splicing silencer: Inhibition is hnRNP A1 dependent³⁷
        • ? 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 number⁸: One or Multiple copies
    • Normals: No SMN2 copy 9%; 1 SMN2 copy 42%; 2 SMN2 copies 46%; 3 SMN2 copies 3%
    • SMA carriers: No SMN2 copy 1%; 1 SMN2 copy 18%; 2 SMN2 copies 47%; 3 SMN2 copies 31%; 4 SMN2 copies 3%
    • SMA patients
      • 2 or more SMN2 copies
      • Reduced SMN2 Gene number correlates with increased SMA severity
  • Homozygous SMN2 Deletions: Disease associations
    • More common in Lower motor neuron syndromes & MMN
    • Sporadic ALS: More common; Shorter survival
• Related or neighboring genes on chromosome 5q
  • SMN1 chromosomal locus: General
    • Complex 500 kb region of Chromosome 5q13
    • Contains large- and small-scale repetitive genetic elements
    • Locus of unusual genetic instability
    • Frequent spontaneous mutations
    • The 500 kb region contains 3 genes: SMN, NAIP, and p44
      • The 3 genes are located in a locus of duplicated and inverted DNA (6 genes)
      • Telomeric genes are functional genes
      • Centromeric genes represent dysfunctional copies
      • Genetic structure is unique to humans
  
  
  
  
  • Neuronal Apoptosis Inhibitory Protein (NAIP)
    • Females: Absence of NAIP strongly associated with severe phenotype
    • Males: No relation between NAIP deletion & phenotype
  • Basal transcription factor (Btf2-p44)
    • Deleted in 15% of SMA patients
  • C212/H4F5
    • C212: Multicopy microsatallite marker in an intron of H4F5
    • Reduction or absent alleles in
      • SMA type I: 94%
      • SMA type II: Frequency between type I and controls
      • SMA type III: Slightly more frequent than controls
    • Closest gene to SMN
    • Function unknown
  • Retrotransposon-like sequences
    • Transcribed into RNA
    • Reverse transcribed into cDNA
    • Reintegrated as cDNAs into the genome at a new location
• SMN protein: 38 kD or smaller splice variants
  • SMN Expression
    • From both SMN1 & SMN2 genes
    • Transcript splicing
      • SMN1 (SMN^T) proteins
        • 90% full length
        • 10% missing exon 5
        • AG-rich exonic splice enhancer in SMN exon 7
          • Increases inclusion of exon 7 in protein
      • SMN2 (SMN^C) proteins
        • Full length: 20% to 40%
        • Missing exon 5, or 7, or both: 60% to 80%
        • Most SMN2 spliced to generate short isoform of SMN protein without exon 7
          • Less stable: Short half-life
          • Poor self-oligomerization
    • Anatomical locations
      • High levels: Brain & spinal cord; Kidney; Liver
      • Moderate levels: Skeletal & cardiac muscle
    • Cell locations: Nuclear & cytoplasmic inclusions (gems)
      • Nucleus: 34kDa variant
        • Localized to gem bodies & nucleoli
        • Near nuclear membrane
      • Cytoplasm: 38kDa variant
        • Especially in motor neurons
        • Perikarya & proximal dendrites ± axons
        • Most cells: Not associated with organelles
        • Motor neurons: May be associated with cytoskeletal elements & mitochondrial membranes
    • 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 functions⁵¹
    • 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 maturation²³: Downregulation causes
        • Aberrant guidance of axons with excessive axonal branching
        • Reduced growth velocity
        • Reduced growth cone sizes
        • Anomalous calcium-channel clustering in growth cone
      • Axonogenesis: May be related to spluiced isoform of SMN protein
    • Muscle: SMN knockout produces myopathy
    • Disease correlations
      • SMN mutant proteins: Reduced RNA-binding activity
      • Less SMN protein & gem bodies in more severe SMA types
  • 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 myopathy²⁴
  • Splicing functions of SMN: Ubiquitous
    • Interacts with both RNA-binding proteins and RNA
    • RNA-binding element in exon 2a
    • Post-transcriptional nuclear RNA metabolism
      • During spliceosomal snRNP biogenesis and pre-mRNA splicing
      • Related to spliceosomes
    • Spliceosomal snRNPs: SMN-related proteins promote transport from cytoplasm to nucleus
    • Inhibition leads to
      • Reduced spliceosomal snRNP biogenesis
      • ? Reduced conversion of pre-mRNA (with introns) to mRNA (no introns)
• SMN: Clinical - Genetic correlations²
  • Epidemiology
    • Incidence of disease: 1 in 6,000 to 10,000 births²⁵
    • 2^nd most frequent autosomal recessive disease of childhood (After cystic fibrosis)
    • Carrier frequency of SMN1 mutations in general population: 2% to 3%
  • 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 offspring²⁵
      • 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 SMN2⁴⁷
    • 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 Deletions²⁰: 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
  • 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: Werdnig-Hoffmann (Type 1)

  From: A Kornberg MD

  • Onset
    • Usually before 3 months
    • Range
      • 0 to 6 months
      • Some with in utero decreased fetal movements
    • Acute onset in occasional patient¹³
      • Early weeks or months: Normal development
      • After 1st few months: New weakness; No new motor milestones
      • Motor neuron loss
  • Clinical
    • Weakness
      • Diffuse; Proximal > Distal
      • Severe
      • Poor feeding
      • Respiratory insufficiency: Paradoxical respirations
      • Sparing of facial & oculomotor
    • Hypotonia
    • Fasciculations: Tongue
    • Tendon reflexes: Reduced or absent
    • Intellect: Normal; Alert faces
    • Prognosis
      • Respiratory failure
      • Death: 50% by 7 months; 95% by 17 months
      • Chronic course in 5%
  • Pathology
    • Muscle
      • Large regions of grouped muscle fiber atrophy
      • Most larger fibers are type I
        
    • Spinal cord
      • Anterior horn: Motor neuron loss
    • Cell pathology
      • # of gem bodies in fibroblasts correlates with disease severity
      • SMA I spinal cords: 100-fold reduction in SMN protein
  • Variant: Facial weakness & Ophthalmoplegia
• Clinical features: Kugelberg-Welander (Types II & III )
  

  From: M Ryan MD

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

  SMA Spinal cord Anterior roots are atrophic

  • Genetics
    • SMN2 deletions: Increased incidence of homozygosity
      • Distal lower motor neuron syndromes (36% vs 5% in general population)
    • Occasional homozygous SMN1 deletions
  • Clinical
    • Distal > Proximal
    • Asymmetric
    • Progressive weakness
      • Slower with SMN^C than with SMN^T deletion
    • No family history
• Pathology
  • Muscle Pathology
    • Grouped atrophy
    • Large fibers: Mostly type 1; Hypertrophied
    • Small fibers mixed or type 2
    • Development: Muscle weakness & atrophy may precede loss of motor neurons
  • Spinal cord²⁶
    • Loss of motor neurons in anterior horn
      • Time period: 12 weeks of gestation to birth; Similar to period of normal cell death
      • Apoptosis: Increased only at 12 to 16 weeks, Not post-natal
    • Post-natal: Morphological changes in some motor neurons
      • Reduction in central Nissel
      • Peripheral displacemnet of nuclei
    • Anterior roots: Atrophic
• Gene testing
  • SMN deletions in > 95%: Exons 7 & 8 tested for deletions
  • Carrier testing
    • Quantitation of number of SMN1 genes
    • Does not detect carriers with more than 1 SMN1 gene on a chromosome
• Care & Treatment
  • Respiratory support
  • Scoliosis care
  • Nutrition
• Experimental treatments: Increase SMN2 expression
  • Histone deacetylase (HDAC) inhibitors: Non-specific increase
    • Phenylbutyrate
    • Valproate: 250 mg to 500 mg bid po
• Mouse models: Mice normally have no SMN2 gene
  • Absent SMN1 with transgenic SMN2 expression: More SMN2 expression ® Less severe disease
  • SMN1 heterozygotes with ~50% reduction of SMN protein: SMA Type 3 phenotype

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

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

• Androgen receptor 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
• CAG repeat length: Genetic-Clinical Correlations
  • Normal CAG repeats⁴⁶
    • 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: 40-65 CAG repeats
    • CAG repeat length effects
      • Longer
        • Earlier disease onset
        • ? More severe SBMA disease
        • Impaired spermatogenesis
        • 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
• Pathogenic mechanisms: Toxic gain of function ® Neuronal degeneration
  • Large polyglutamine tract ® Partial proteolysis due to abnormal folding of Androgen receptor
  • Truncated forms of androgen receptor may be produced
  • Aggregate location: Cytoplasm & Nucleus
  • Aggregates
    • May contain
      • Androgen receptor fragments: Only N-terminal epitopes
      • Proteasome components & ubiquitin; PA700 proteasome caps
      • Chaperones & Nuclear components with long polyglutamine tracts
      • Mitochondria
      • Other: Steroid receptor coactivator 1; NEDD8, Hsp70, Hsp90; HDJ-2/HSDJ; CREB binding protein
    • Formation suppressed by HDJ-2 chaperone
    • ? Toxic to cell
      • Nuclear location of aggregates may be necessary for toxicity
      • Truncated forms of AR with expanded repeat more toxic than full length protein
      • No correlation between frequency of aggregates & cytotoxicity
  • Proteins possibly involved in mechanism of CAG repeat toxicity
    • Caspases: May cleave androgen receptor
    • CREB binding protein (CBP) ⁴²
      • Polyglutamine-expanded androgen receptor: Interferes with CBP-mediated transcription of VEGF
      • VEGF: May rescue cultured cells with mutant androgen receptor
    • Sir2 pathway⁵⁰
      • 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
• 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
• Onset
  

  Mouth in BSMA Attempted smile & At rest

  • Age: Mean 27 years; Range 15 to 60 years
  • Early symptoms & signs: Adolescence³²
    • 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
• Clinical features
  • Weakness
    • Distribution
      • Proximal: Symmetric; Arms & Legs
      • Face: Upper & Lower
      • Tongue: Weakness; Atrophy; Fasciculations
    • Bulbar dysfunction
      • Dysphagia: Aspiration
      • Dysarthria
      • Masseter weakness
    • Symmetric
    • Slowly progressive: Over decades
  • Other muscle features
    • Fasciculations
      • Large
      • Face (Especially lower), Tongue, Trunk & Limbs
      • Contraction evoked or Spontaneous
    • Atrophy: Especially face & tongue
    • Cramps: 50%
  • Tendon reflexes: Absent or reduced
  • Sensory: Often subclinical changes
    • Vibration: Reduced; Legs > Arms
    • Small sensory nerve action potentials (SNAPs)
  • Tremor
    • Hands
    • Postural & Action
    • Early disease manifestation: 4th decade

      Tongue in BSMA Wasted; Weak; Moves rapidly

  • NO upper motor neuron signs
  • Androgen insensitivity related
    • Gynecomastia (50% to 70%)
    • Reduced fertility: Oligospermia
    • Testicular atrophy
    • Erectile dysfunction
  • Groin hernia: 33%
  • Other endocrine
    • Diabetes mellitus in some patients
    • Pituitary microadenoma: Rare
• Clinical manifestations: Heterozygous females
  • General: Mild manifestations later in life
  • Muscle cramps: 58%
  • Fasciculations: 20%
  • Tongue atrophy & fasciculations: 20% in 7th & 8th decade
  • Electrophysiology: Chronic denervation in 57%
• Laboratory
  • Electrodiagnostic
    • Twitching is grouped motor unit discharges, not fasciculations
    • Chronic partial denervation with reinnervation
    • CMAP amplitude: Reduced in 23% to 40%
    • SNAP amplitude: Reduced in 80% in sural
    • Cortical SSEPs: Absent or Prolonged latencies
  • Serum
    • CK: High; May be elevated early in disease course
    • Serum estradiol & gonadotropin: Elevated
    • Lipid disorders
      • Type II hyperlipoproteinemia
      • Type IV hyperlipoproteinemia
      • Hypobetalipoproteinemia
  • 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
  • Pathology
    • Lower motor neurons: Reduced number in spinal cord & brainstem
    • Sensory ganglion cells: Reduced number in dorsal root ganglia
    • Aggregates
      • In motor neurons, skin & other tissues expressing androgen receptor
      • Intranuclear & Cytoplasmic
• Eternal link: e-Medicine

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

• 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 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

Spinal Muscular Atrophy: Distal

Distal Hereditary Motor Neuropathies (Distal HMN): General features ⁴⁹

• Onset: Distal weakness of toe extensors
• Clinical
  • Weakness
    • Distribution: Distal arms & Legs
    • Course: Progressive
  • Sensory: Normal
  • Foot deformities
• Other features in some patients
  • Vocal cord paralysis
  • Diaphragm weakness
  • Pyramidal signs

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

• Onset: Juvenile to 40 years; ? Anticipation
• Clinical
  • Weakness & Atrophy
  • Distal
  • Symmetric
  • No bulbar or upper motor neuron involvement
  • Tendon reflexes: Reduced
  • Sensation: Normal
  • Progression: Slow
• Laboratory
  • Nerve conduction velocities: Normal
  • Muscle biopsy: Denervation atrophy

• Epidemiology: Australian family
• Nosology
  • Juvenile ALS
  • Distal HMN
• Clinical
  • Onset
    • Age: Median 10 years; Range 3–40 years
    • Disordered walking & running
  • Weakness
    • Legs: Ankle extensors & Intrinsic foot muscles
    • Hands: Mild or None
  • 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)

• Genetics
  • HSPB8 mutations: Missense; Lys141Asn, Lys141Glu
  • Same gene mutated in: CMT2L
  • Similar locus to
    • Congenital lower limb SMA
    • Scapuloperoneal neuropathy
• HSPB8 protein
  • Heat shock protein
  • High expression in motor & sensory neurons of spinal cord
  • Interacts with HSBP1
  • Mutated protein promotes formation of intracellular aggregates
• 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

Distal hereditary motor neuropathy (HMN 2B)

• Epidemiology: Families from UK, Croatia, Belgium, Austria
• Genetics
  • Missense mutations: R127W; S135F; T151I; P182L
• Same gene mutated in: CMT 2F

Distal hereditary motor neuropathy with upper motor neuron signs²²

• Genetics
  • Allelic with
    • ALS4
    • AOA2
  • Similar locus to
    • SPG19
• Epidemiology: Belgian, Austrian & English families
• Onset
  • 4 to 49 years
• Clinical
  • 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

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

• Genetics
  • Allelic with CMT 2D
  • Mutations: Missense; G240R, L129P, G526R, E71G
• GARS protein
• Onset
  • Mean: 17 years
  • Weakness: Hands
• Clinical
  • Weakness
    • Thenar eminence & 1st Dorsal Interosseous
    • Lower extremities involved in 50% after 2 years
  • Rare pyramidal signs
  • Very slow progression

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

• Epidemiology
  • European families
  • Most common D-HMN
• Genetics
  • Mutations
    • Missense
    • Exon 3
    • Asn88Ser; Ser90Leu
    • Located at N-glycosylation site
  • Same gene mutated in
    • Berardinelli-Seip congenital lipodystrophy, Type 2: Null mutations
    • SPG 17 (Silver syndrome)
  • Mutation effects
    • Alters N-glycosylation site
    • Aggregate formation
• Seipin protein
  • Integral membrane protein: Endoplasmic reticulum
  • Glycosylated
• Onset
  • Age: Mean 15 years; Range 2 to 40 years
  • Weakness: Hands
  • Variant syndrome: Leg weakness early
• Clinical
  • Weakness
    • Hands
      • Early involvement
      • Thenar eminence > 1st Dorsal Interosseous
      • Asymmetric
    • Lower extremities
      • Peroneal weakness (60%)
      • Symmetric
      • Foot deformities (95%)
    • Proximal: Normal
  • Upper motor neuron
    • Tendon reflexes: Brisk
    • Tone: May be increased in legs
    • Plantar responses: Flexor
  • Sensory loss: Vibration reduced in legs
  • Hyperhidrosis (40%): Hands & Feet
  • Progression
    • Very slow over decades
    • No patients severely handicapped
• Electrophysiology
  • CMAPs: Small
  • Motor NCV: Normal or Mildly reduced
  • Sensory NCV: Mild reduction, especially older patients
  • EMG: Large MUPs; Reduced Recruitment
  • Central motor conduction times: Prolonged (60%)

Hereditary Distal Ulnar-Median Muscular Atrophy⁷

• ? 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) (Vocal cord involvement)

• Onset
  • Teens or younger
  • Voice or gait disorder
• Clinical
  • Distal weakness
    • Onset: Hands; Median distributaion
    • Progression to distal leg weakness
    • Wasting: Prominent distally
    • Usually symmetric but occcasional asymmetry
  • Vocal cord involvement
    • 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: Reduced distally in arms & legs with disease progression
  • Sensation: Normal
  • Course: Slow progression
• Electrodiagnostic
  • EMG: Distal denervation in feet & hands
  • NCV: Normal velocities; CMAPs small distally
• Not linked to CMT 2C

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

• Epidemiology: Single family
• Genetics
  • Mutation: Missense; G59S
  • Other DCTN1 mutations
    • May be associated with ALS susceptibility
    • Perry disease : Parkinsonism, Depression, Weight loss, Hypoventilation, TDP-43 immunostaining of brain
• Dynactin protein
  • Largest subunit of 10 million dalton dynactin complex
  • Binds to
    • Microtubules
    • Cytoplasmic dynein
    • 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
• Onset
  • Early adulthood
  • Respiratory difficulty due to vocal cord paralysis
• Clinical features
  • Facial weakness: Progressive
  • Vocal cord paralysis
  • Weakness: Distal; Hands then Feet
  • Sensory: Normal
• Variant syndrome: ALS or AS susceptibility
  • Genetics
    • Inheritance: Dominant or Sporadic
    • Mutations: Missense; Thr1249Ile, Met571Thr, Arg785Trp, Arg1101Lys
    • Incomplete penetrance
  • Clinical
    • Onset
      • Age: 48 to 64 years
      • Weakness: Arms, Legs, Posterior neck or Bulbar
    • Weakness
      • Arms, Legs or Bulbar
      • Progression: Slow; symptom duration = 4 to > 9 years
    • Upper motor neuron signs: Present
      • Tendon reflexes: Brisk
    • Fronto-Temporal Dementia
      • Some patients without motor neuron disease
      • 1 family
  • Laboratory
    • EMG: Widespread denervation
    • MRI: Normal

Distal HMN: Congenital¹⁵

• Clinical features
  • Onset: Congenital; Contractures
  • Weakness
    • Symmetric
    • Legs: Distal
    • Arms: Proximal & Hands
  • Tendon reflexes: Absent in legs
  • Progression: Very slow or None
• Laboratory
  • Serum CK: Normal
  • Nerve conduction studies: Normal velocities
  • Muscle biopsy: Type 1 predominance

Distal SMA: Leg predominant¹⁹

• 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

• Epidemiology
  • Lebanese & European families
  • Most patients probably from single ancestor
• Genetics: Normal IGHMBP2 gene
• Onset: Infancy to Early adult; Distal weakness
• Clinical
  • 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 (SMARD1; HMN 6)

• IGHMBP2 gene
  • Mutations: Missense; Nonsense; Frameshift deletion (exon 5) & Splice donor-site
• IGHMBP2 protein⁶⁶
  • Transcription factor: DNA binding protein
  • ATP-dependent 5' --> 3' helicase: Unwinds RNA & DNA duplices
  • Localization
    • Similar to SMN1 protein
    • Co-localizes with RNA-processing machinery in both cytoplasm and nucleus
    • Associates with 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
• Variant ⁶⁷
  • Genetics: May have same mutation & family as severe disease
  • Onset: 2nd year
  • Weakness
    • Distal then Proximal
    • Dysphagia
  • Respiratory
    • Sleep hypoventilation
    • Vital capacity: Normal
  • Survival through childhood
• 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

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

• Onset: 6 to 10 years
• Clinical
  • 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 (SMAX3)⁴¹

• Epidemiology: Brazilian & Australian families
• Onset
  • Age: 1 to 47 years; Older in Australian family
  • Foot deformity
  • Gait disorder
• Clinical
  • Weakness & Atrophy
    • Legs
      • Early in disease course
      • Distal, tibioperoneal
    • Hands: With disease progression
    • 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
  • Pes cavus
  • Heterozygous females: Normal
• Laboratory
  • Serum CK: Normal
  • Electrophysiology
    • CMAP amplitudes: Reduced or Absent
    • NCV: Mildly reduced
    • EMG: Chronic denervation
    • SNAPs: Normal
  • Pathology
    • Nerve (Sural): Normal
    • Muscle: Denervation

Distal hereditary motor neuropathy⁴⁵

• Epidemiology: Southern Italian family

Spinal Muscular Atrophy: Other

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

• Onset: Childhood to 40's
• Males more severely affected
• Slow progression
• Some families with vocal cord paralysis
  
  

• Clinical
  • Onset: > 40 years; Mean = 49 years
  • Proximal weakness & atrophy
  • Tendon reflexes reduced
  • Sensory & Bulbar: Normal
• Laboratory
  • Serum CK high
  • EMG: Neurogenic changes
  • Muscle biopsy: Neurogenic
• Allelic with: ALS 8

• Epidemiology: Netherlands family
• Onset: Congenital
• Clinical
  • Weakness
    • Legs only: Proximal & Distal
    • Non-progressive
  • Contractures
    • Arthrogryposis
    • Knees & Ankles
• Laboratory
  • Serum CK: Mildly elevated
  • Electrophysiology
    • EMG: Chronic denervation; Giant motor units
    • NCV: Normal motor & sensory
• Other
  • Similar locus to Distal HMN II
  • Also see: Distal SMA of lower limbs

• Onset: Childhood with late walking
• Weakness
  • Legs: Proximal & Distal
  • Non-progressive
  • Selectively involves lower extremities
• Contractures: Knees; Pes equinovarus
• Electrodiagnostic
  • EMG: Chronic denervation with reinnervation
  • NCV: Normal

• Epidemiology: Okinawa, Japan
• Clinical
  • Onset: 17 to 50 years; Cramps
  • Motor
    • Weakness
      • Proximal > Distal
      • Lower > Upper
      • Symmetric
    • Cramps
    • Fasciculations
    • Muscle atrophy
    • Course: Progression to severe disability
  • Tendon reflexes: Absent
  • Sensory
    • Loss: Vibration & Joint position > Pain
    • Dysethesias: Distal
  • Tremor
  • Diabetes Mellitus: 40% with hyperglycemia
• Lab
  • Hyperlipidemia: 30%
  • Serum CK: High; 200 to 500
  • CNS MRI: Normal
• Electrodiagnostic testing
  • CMAP amplitude: Reduced
  • SNAP amplitude: Reduced or Absent
  • EMG: Denervation: Fasciculations
• Pathology: Spinal cord
  • Decreased numbers of anterior horn cells
  • Marked loss of myelinated axons in the posterior columns

• Genetics: Normal SMN
• Clinical
  • Motor
    • Hypotonia
    • Respiratory difficulty
    • Muscle mass: Decreased
    • Course: Death in infancy
  • Bone
    • Generalized osteopenia
    • Congenital fractures
  • Other in some patients
    • Joints: Multiple contractures
    • Congenital heart defect
    • Hypertrichosis
• EMG: Neurogenic
• Pathology
  • Muscle: Atrophy; Denervation; Large fibers type I
  • Spinal cord: Anterior horn cell loss; Astrogliosis

• Mutation: Homozygous; Nonsense⁶⁸
• VRK1 protein
  • Serine/threonine kinase
  • Phosphorylates p53 & CREB
  • Localization: Nuclear + Some cytoplasm & cell membrane
  • Role in nuclear envelope formation
  • Expression: Ubiquitous including brain
• Onset
  • Severe cases: Prenatal or Birth; Death within months
  • Milder cases: < 6 months
  • Fetal movements: Reduced
  • Hypotonia
  • Feeding difficulty
• Clinical
  • Motor
    • Hypotonia
    • Weakness
      • Early: Reduced movements
      • Diffuse
      • Feeding disorders
      • Progressive: Walking achieved in some then lost
    • Milestones: Delay & Decline
  • Tendon reflexes: Reduced or Increased
  • Cerebellar: Ataxia; Nystagmus
  • Psychomotor retardation
  • Contractures: Variable; Arthrogryposis in severe cases; Mild in later onset patients
  • Course: Survial ranges from months to 12 years
• Laboratory
  • Serum CK: Normal
  • MRI: Cerebellar hypoplasia or absence, including vermis; Pontine hypoplasia in severe cases
  • EMG: Neurogenic
  • NCV: Normal or mildly slowed motor & sensory velocities; Small CMAP & SNAP amplitudes
• Pathology
  • Muscle: Denervation; Fiber type grouping; Grouped atrophy
  • Nerve: Loss of large myelinated axons in sural nerve in some patients
  • 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

• Genetics
  • Mutation: Missense; Phe647Ser
• Epidemiology: African family from Mali, consanguinous
• PLEKHG5 protein
  • Function: Nuclear Factor κB–Activator
  • Distribution: Ubiquitous; High in peripheral nerve, spinal cord & brain
  • Mutant protein: Reduced levels in cells; Loss of NFκB-activating function; Aggregates
  • Proteins sharing PH or PH/RhoGEF domain: Dynamin 2; Alsin
  • PLEKHG4 mutations: SCA4
• Onset
  • Age: 2 to 11 years
  • Weakness
• Clinical
  • Weakness
    • Distribution: Generalized; Proximal & Distal
    • Respiratory: With disease progression
    • Scapular winging
    • Face & Cranial nerves (Bulbar): Normal
    • Course
      • Progressive over a decade to severe disability
      • Milder phenotype in some patients
  • Tendon reflexes: Reduced or Absent
  • Contractures: Hips; Elbows; Hands
  • Spine: Hyperlordosis; Scoliosis
  • Intelligence: Normal
  • No upper motor neuron signs
• Laboratory
  • EMG: Denervation of muscle
  • NCV: Normal motor & sensory
  • Muscle biopsy: Denervation

Hereditary ALS

General: Hereditary vs Sporadic ALS

• ALS 1
  l Superoxide Dismutase 1 (SOD1) ; Chromosome 21q22.1; Usually Dominant
  
  

  Clinical features   General   Specific syndromes Mutations   Location   Functional aspects   Specific correlations Pathology Population statistics SOD other SOD protein

  
  
  • Population statistics
    • Frequency of SOD mutations in ALS syndromes
      • 10% to 20% of Familial ALS
        • Usually Dominant: May skip a generation
        • Occasional Recessive: D90A
        • New sporadic mutation identified: H80A; Rapidly progressive disease³¹
      • 1% to 3% of Sporadic ALS
      • 1% to 3% of all ALS
    • Penetrance: Overall 85% by age 85
  • Mutations: Location & character
    • More than 140 different disease related mutations identified
    • 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
      • Hot spots: A4; C6; N86; G93; D101; L126; N139;L144
    • Common features
      • Heterozygous missense point mutations
      • Dominant inheritance with complete penetrance
        A4V; G37R; L38V; G41S; H43R; H46R; D76V; L84F; L84V;
        N86K; E100G; D101F; I104F; G108V; C111Y; I112M; G114A;
        L126X; G127X; G141E; L144F; V148G; V148I
    • Other types
      • Stop codon: Exon 5 not needed for toxic action of mutated SOD
        • Nonsense mutations produce polypeptide length of 121 tp 156 aa (Normal 153)
        • 17 nonsense mutations identified
      • Intron: IVS4AS, A-G, -11 (11 bases upstream from intron-junction of exon 5)
      • Deletion
      • Intronic: Altered splice site; 3' untranslated region
      • Recessive
        • D90A; ? D96N
        • Dose effect (Homozygous more severe): L84F, N86S, L126S
      • Incomplete penetrance
        A4T; L8Q; V14G; G16S; N19S; E21G; ΔG27/P28; N65S; G72S; D76Y;
        N86S; A89V; D90A hetero; G93S; A95T; 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: E40G; L84F; Asp90Ala; G93A & G93D; D109Y
    • Protein stability
      • Unstable: L126X; G127X
      • Normally stable: A89V; D90A
    • Correlation between ratio of mutant:normal SOD1 in RBC⁵³
      • 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
  • SOD 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
    • Other SOD molecules
      • SOD2: Mitochondrial; Manganese
      • SOD3: Extracellular; Copper-Zinc
  • Clinical: General features of hereditary SOD1 ALS
    • Clinically similar to sporadic ALS
      • Onset with monomelic leg weakness suggests familial ALS
    • Most mutations with variable clinical features among patients
    • Homozygosity
      • Often causes more severe phenotype than heterozygous state: Asn86Ser; Asp90Ala
    • Some patients may have mainly lower motor neuron signs
    • Onset
      • Mean age = 46
        • 10 years younger than sporadic ALS
        • 3.5 years younger than non-SOD FALS
        • 90% penetrance by age 70
      • No anticipation
      • Preparetic phase: Some with myalgias, leg cramps & painful paresthesias
      • Weakness: Asymmetric limb
    • Duration (Mean for all FALS) = 3.4 to 5.6 yrs
      • Similar for SOD & non-SOD FALS
    • Lower motor neuron signs
      • Common
      • Especially predominant in rapidly progressive cases
    • Upper motor neuron signs
      • May be more common with slowly progressive course
      • Reported with Asp76Tyr & Homozygous Asp90Ala mutations
      • Dominant upper motor neuron signs: Not reported
    • Bulbar onset
      • Unusual
      • Later onset age
      • Reported with some mutations
    • Cramps: G12R; G37R; D90A; E100G
    • Other Neural features
      • Sensory neuropathy: A89V; D90A
      • Extra-motor system symptoms: ? More frequent
      • Dementia: Rare; A4T; G41S; I113T; L144F; ? More common in non-SOD group
      • Autonomic failure: D90A; Val118Leu; 1 patient³
      • Supranuclear EOM paresis: May occur late in disease course; H80R; I104F
      • Bladder dysfunction: G41S; Asp90Ala (Homozygous)

ALS syndromes: Correlations with specific SOD mutations

l Exon 1; Ala4Val   Most common mutation   Rapid onset & progression (1.0 yrs)   Frequently only lower motor neuron signs l Exon 2; His46Arg   @ Cu binding site of SOD   Onset late; in legs   Bulbar unusual   Slow progression (17 yrs) l Exon 2; 6 bp deletion(ΔG27/P28) 65   Mutation reduces transcription   Low levels of mutant SOD1 protein   Philipino founder   Low penetrance   Disease duration: 4.3 years l Exon 4; Leu84Val   Lower motor neuron only   Rapid progression (1.5 yrs)   ?Earlier onset in males l Exon 4; Asp90Ala   Onset: 20 to 94 yrs; Legs; Preparetic phase     Leg cramps; Myalgia; Painful paresthesia   Bladder dysfunction   Progression: Slow; Legs ® Arms   Inheritance     Recessive: Finnish (2.5% carriers)     Dominant: Other patients l Exon 4; Ile104Phe   Variable intrafamilial clinical features     Age of Onset: 6 yrs - asymptomatic     Course: 2 to 14 yrs until bulbar signs     Limb onset: arms or legs l Exon 4; Ile113Thr   Reported in Sporadic ALS patients   Relatively common; Low penetrance   Late Onset: Mean 59 years   Course: Variable; 2 to 20 years l Exon 5; Codon 126   2 base pair deletion   Rapid Progression Mutant protein not detectable in brain

l General syndrome features Lower motor neuron predominant A4V; G72C; Leu84Val; Gly93Cys; E100K; D101N; S134N Slow progression Gly37Arg (18 yrs); Gly41Asp (11 yrs); Leu144Ser; Leu144Phe (9 yrs); Gly93Cys (13 yrs); Gly93Ser Rapid progression Ala4Thr (1.5 yrs); A4V; C6G; C6F V7E; L8Q; G10V; G41S; H43R; H48Q Asn86Ser Homozygous (5 mo); D101G; D101H; D101Y; Leu106Val (1.2 yrs); I112T; R115G; D125H; 126 2bp del; S134N; 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; Val148Ile; I149T; Ile151Thr Onset in legs G10V; H46R; L84F; D90A; Gly93Cys; Gly93Ser SOD Mutations in "sporadic" ALS Most common: Asp90Ala; Ile113Thr Other: V14G; G16S; E21K; G72S; D101N; V118InsAAAAC; E133delGAA Incomplete penetrance

• Genetic variants: Other features
  • Ala4Val
    • Folding of mutated SOD protein less stable than normal³⁰
    • Clinical: Rapidly progressive disease
  • Phe20Cys⁶⁰
    • 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 factor²⁹: 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 models¹⁸
    • 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
• 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


• ALS X
  l Chromosome Xp11-q12; Dominant
  • Adult onset
  • Specific clinical information not avaliable in literature
  • Unreported family: X-linked; Semidominant
    • Onset
      • Age: Adult; 2nd to 5th decade
      • Bulbar dysfunction
    • Bulbar & Pseudobulbar dysfunction
      • Prominent
      • Dysarthria
      • Dysphagia
    • Progression: Slow
  
  
• ALS 3 ¹⁷
  l Chromosome 18q21; Dominant
  • Epidemiology: Large European (French) family
  • Onset: Legs; Mean age 45
  • Clinical
    • Upper motor neuron signs: Common
    • Lower motor neuron signs: Common
    • Weakness: Limbs & Bulbar
    • Other CNS systems not involved: No Pain, Sensory loss, Dementia or Cerebellar disorders
    • Progression: Mean 5 years
  • Laboratory
    • EMG: Diffuse denervation
  
  
• ALS 6³⁶
  l Fusion, derived from 12-16 translocation, malignant liposarcoma (FUS; FUS/TLS) ; Chromosome 16p11.2; Dominant or Recessive
  • Epidemiology
    • Multiple families in Europe & US
    • Familial ALS: Frequency 4% to 5%
    • Sporadic ALS: Frequency 0.5% to 0.7%; G507D, R521C, Exon 6
  • Genetics: Mutations
    • Missense, or In-frame deletion or insertion
    • Hot spot: Exon 15; R521
    • Other mutations in Exons 3, 5, 6 & 14
    • Recessive mutation: H517Q
    • R521C: Associated with symmetric, proximal arm, neck & axial weakness
  • FUS protein
    • Cellular localization
      • Normal: Nuclear
      • Disease: Cytoplasmic protein accumulation
    • Functions
      • DNA & RNA metabolism
        • RNA-interacting domains: Located in the mid-region of protein
      • Implicated in tumorigenesis & RNA metabolism
      • FUS deficient neurons: Decreased spine arborization with abnormal morphology
        • Hippocampal neuronal slice cultures: FUS is in RNA granules that are transported to dendritic spines
        • Local RNA translation in response to metabotropic glutamate receptor (mGluR5) stimulation
    • Knockout mice: Perinatal mortality; Male sterility; Radiation sensitivity
  • Clinical
    • Onset age
      • Mean 38 to 67 years; Range 29 to > 70 years
      • Limbs or Bulbar
      • Variable penetrance at 70 years: 39% to 83%
    • Lower motor neuron signs
      • Common
      • Weakness: Distribution
        • Limbs & Bulbar
        • May be symmetric
        • Early: Proximal in some patients; Upper or Lower extremities
    • Upper motor neuron signs: Common
    • Progression: Variable among families: Range 0.5 to 20 years
  • Autopsy
    • 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
  • Variant syndrome: Recessive inheritance
    • Cape Verdean family
    • Mutation: Homozygous H517Q
    • Onset: Proximal upper extremities
    • Spread: To lower extremities; Not bulbar region
    • Progression: Slow; Up to 14 years
  
  
• ALS 7³⁸
  l Chromosome 20p13; Dominant
  • Linkage security: Probable
  • Epidemiology: 1 family
  • Onset age: Mean = 57 years
  • Clinical: El Escorial criteria
  • Course: Mean = 3 years
  
  
• ALS 8⁴³
  l Vesicle-associated membrane protein B (VAPB) ; Chromosome 20q13.33; 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
    • Mutant protein: Intracellular aggregates not associated with membranes
  • Onset
    • Age: 25 to 55 years
    • Cramps
    • Fasciculations
    • Weakness: Few patients
  • Clinical: 3 variant syndromes
    • 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
  l Angiogenin (ANG) ; Chromosome 14q11; 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
    • K17I mutation identified in healthy male
  • 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
  • Onset
    • Age: 27 to 76
    • Bulbar onset: 50%
  • Clinical
    • "Typical ALS"
    • Course: 0.8 to 10 year survival
  
  
• ALS 4: Juvenile onset
  l Senataxin ; Chromosome 9q34; Dominant
  • Genetics⁴⁴
    • Mutations
      • Missense
      • Locations: L389S; R2136H; T3I
      • Differ from stop or truncation mutations in senataxin in AOA2
    • Allelic with
      • Distal HMN with upper motor neuron signs
      • AOA2 (Recessive)
    • Similar locus to
      • SPG19
  • Epidemiology: England; Southern Maryland
  • Onset: 2nd decade; Mean = < 6 to 21 years
  • Clinical
    • Early: Gait disorder
    • Weakness: Distal in hands & feet; Later also proximal; Distal wasting
    • Bulbar disorders: Infrequent
    • Upper motor neuron signs: Hyperreflexia 86%; Upgoing toes 17%
    • Sensory: Normal or minor changes in few older patients
    • Variable degrees of severity
  • Course
    • Slowly progressive over decades
    • 5th & 6th decades: Wheelchair; Loss of hand function
    • Milder phenotype: Mild gait disorder
  • Electrophysiology: Chronic motor neuropathy
    • EMG: Denervation, Distal > Proximal
    • NCV: Reduced CMAP amplitude; Normal NCV; Normal sensory
  • Pathology
    • Reduced number of Anterior horn cells, especially lumbar
    • Sensory pathways: Posterior column fiber loss; Loss of DRG neurons
    • Axonal swellings: Roots, Spinal gray, Dentate, Cranial nerves 3 & 4
    • Spinal cord atrophy
  
  
• ALS-FTD 1⁹ : ALS + Frontotemporal Dementia
    l Chromosome 9q21-q22; Dominant or Sporadic
  • Clinical
    • Onset: Adult, mean 54 years
    • Amyotrophic lateral sclerosis
      • Corticospinal signs
      • Lower motor neuron signs
    • Dementia
      • Fronto-Temporal: Impulsive behavior; Reduced Ability to perform daily tasks
      • Frontal release signs
      • Onset often at same time as ALS
      • Frequency: 75% of ALS patients in family
    • Posterior column: Axonal loss
    • Disease course: Most < 4 years; Mean 3.8 years; 15 years in 1 patient
  • Laboratory
    • Imaging: Frontotemporal brain atrophy
    • Pathology: Frontortemporal atrophy & gliosis; No neurofibrillary tangles
  
  
• ALS-FTD 2⁵⁴ : ALS + Frontotemporal Dementia
    l Chromosome 9p21.3-p13.2; Dominant
  • Epidemiology
    • English, French & Scandinavian families
    • Frequency: 60% of hereditary ALS-FTD
  • Onset
    • Age
      • Range: 39 to 84 years
      • Mean 58
      • Older than non-linked ALS-FTD families
    • Clinical
      • Motor features before Dementia (30%)
      • Dementia (FTD) before Motor (32%)
  • Clinical
    • Motor neuron disease
      • Upper motor neuron
        • Tendon reflexes: Brisk
        • Plantar response: Upgoing in some patients
      • Lower motor neuron
        • Weakness
        • Fasciculations
      • Regions involved: Bulbar (100%); Arms; Legs
    • Dementia
      • Psychiatric symptoms: 50%
      • Apathetic
      • Cognitively impaired
      • Socially isolated
      • May occur in some patients without motor neuron disease
    • Survival: 1 to 8 years; Mean 3.6
  • Laboratory
    • EMG: Denervation
    • Muscle: Neurogenic atrophy
    • MRI
      • Frontotemporal atrophy: Bilateral
      • Hypoperfusion: Frontal & Temporal; bilateral
    • CNS
      • Inclusions
        • Ubiquitinated in anterior horn cells, Bunina bodies or Hirano bodies
        • TDP-43-positive neuronal cytoplasmic: Cortex & SSpinal cord
        • Not tau positive
      • Frontoparietal atrophy
  
  
• ALS-FTD 3⁵⁸: ALS-like disorder ± Frontotemporal Dementia
    l Chromatin-modifying protein (CHMP2B) ; Chromosome 2p11.2; Sporadic
  • Epidemiology: Case reports
  • Genetics
    • Mutations: Missense
    • Other mutations cause: Fronto-Temporal Dementia
  • Protein
    • Nosology: Charged multivesicular body protein 2B
    • Component of vesicle sorting complex
      • Other mutations in vesicle sorting complex proteins: ALS2; ALS8
  • Clinical
    • Onset
      • Age: 7th & 8th decade
      • Bulbar dysfunction
    • Q206H mutation: Lower motor neuron syndrome
      • Clinical
        • Weakness: Bulbar (Tongue); Hands; Respiratory
        • Fasciculations
        • Tendon reflexes: Reduced
        • Progression: Respiratory failure over 15 months
      • EMG: Diffuse denervation
    • I29V mutation: Fronto-temporal dementia syndrome
      • May be benign variation or pathogenic mutation
      • Onset: Dementia
      • Clinical
        • Spastic dysarthria & dysphagia
        • Weakness: 1 arm & both legs
        • Tendon reflexes: Brisk
  • Pathology
    • Motor neurons: Ubiquitylated inclusions
    • p62 antibodies (sequestosome 1): Oligodendroglial inclusions in motor cortex
  
  
• Parkinsonism-Dementia-Amyotrophic Lateral Sclerosis Complex 2
  l DJ-1 (PARK7) ; Chromosome 1p36; Recessive
  • Epidemiology: Southern Italian family
  • Clinical
    • Parkinsonism: Early onset; Some families with only PD
    • Weakness: Arms & Legs
    • Tendon reflexes: Brisk
    • Cognitive impairment
  • Laboratory
    • EMG: Denervation
    • CSF: Normal
  
  
• ALS with Bulbar onset, Benign course & Bunina bodies¹⁰
  l Autosomal Dominant
  • Epidemiology: Japanese family
  • Onset: Bulbar dysfunction; 5th & 6th decade
  • Clinical
    • 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: Neurofilament heavy chain (NF-H) with variant alleles
    l Chromosome 22q12.1-q13.1; ? Dominant or Sporadic
  • Mutations
    • 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
  • Clinical-Genetic associations
    • Sporadic ALS: Mutations in 1% of patients
      • Role in disease: ? Risk factor rather than causative effect
      • Reduced expression of NFL in sporadic ALS patients without SOD1 or NF mutations
    • Hereditary ALS: Scandinavian pedigree
      • ALS in 4 members of 2 generations
      • Deletion in the NF-H tail: Nucleotides 1989-2030
      • Clinical features: Variable
        • Dementia
        • Dysphagia
        • Monomelic ALS
  
  
• ALS 10: TDP-43 mutations ⁶²
    l Tar DNA-binding protein (TDP-43; TARDBP) ; Chromosome 1p36.22; Dominant or Sporadic
  • Epidemiology
    • Families: American, Canadian, English & French
    • Sporadic ALS patients: Frequency ~1 in 200; 8 patients described
  • Genetics: Mutations
    • Missense
    • Often exon 6: G287S; Gly290Ala; Gly294Ala; Gly298; Ala315Thr; Glu331Lys; Met337Val; G348C; R361S; A382T; N390D; N390S
    • Other: D169G (Exon 4)
  • TDP-43 protein
    • Expression: Ubiquitous
    • Subcellular distribution: Nucleus & Cytoplasm
    • Binds DNA and RNA: Regulates transcription & splicing
    • May be involved in microRNA biogenesis, apoptosis & cell division
    • Phosphorylated TDP-43 present in neuronal aggregates in ALS & Fronto-temporal dementia
    • Mutation locations: C-terminal in region involved in protein-protein interactions
  • Clinical
    • Onset
      • Age: 5th to 8th decade
      • Weakness
        • Legs: Most common
        • Bulbar & Arms: Some patients
    • Weakness
      • Legs before Arms: 80%
      • Distal + Proximal
      • Respiratory
    • Tendon reflexes: Brisk
    • Spasticity: Mild or None
    • Bulbar: Few patients
    • Cognition: Usually normal
    • Course
      • Slowly progressive (5 to 10 years) in most
      • Rapid (1 to 2 years) in some families (Gly290Ala; Gly298Ser)
  • 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: Upper & lower motor neurons + elsewhere in CNS
  
  
• ALS: Peripherin mutations ⁴⁸
    l Peripherin ; Chromosome 12q12-q13; Sporadic
  • Mutations: 2 identified
    • Nucleotide insertion in intron 8
    • 1-bp deletion in exon 1: Frameshift
  • 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
  • Clinical: 1 patient
  • Course: 5 years
  • Onset: Asymmetric leg weakness
  
  
• ALS 11 ⁶³
    l 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 with: CMT 4J
  • FIG4 protein
  • Onset age: Mean 56 years; Range 29 to 77 years
  • Clinical patterns
    • 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
  • 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: Hereditary, Other
  • Heterogeneous category of: Non-SOD linked; Adult onset; Hereditary ALS syndromes
  • Comprises 80% of dominant ALS syndromes
  
  
• ? Western Pacific ALS

• ALS 2: Childhood-onset ALS: Long survival; Usually Recessive
  l Alsin ; Chromosome 2q33; Recessive
  • Genetics¹⁶
    • Mutations
      • Disease related: Carboxyl-terminal
      • ALS2: Deletions in exon 3 or 4
      • Disrupt reading frame
    • Allelic with
      • Juvenile PLS: Caused by different mutation in same gene
      • SPG, Infantile onset
  • Protein⁴⁰
    • Contains 3 guanine-nucleotide exchange factor (GEF) domains for GTPases
    • Localization
      • Cytoplasmic face of endosomal membranes
      • Requires amino-terminal "RCC1 (regulator of chromatin condensation)-like"" GEF domain
    • Possible functions
      • ? Involved in membrane-proximity activities of small GTPases
      • ? Related to vesicle transport & intracellular trafficking
    • Tissue Expression
      • Neurons in brain & spinal cord
      • Low abundance in all tissues
    • Mutants
      • All have short half-life
      • Rapidly degraded by proteasomes
  • Onset: Mean 6.5 years; Most often < 10 years; Occasional 3rd decade
  • Clinical features (Type 3)
    • Spasticity: Face; Limbs (Paraplegia)
    • Pseudobulbar affect
    • Amyotrophy: Mild; Distal; Legs > Arms; Increases with age
    • Sensory & Bladder: Normal
    • Progression: Very slow; Reduced Walking after age 40
  • Laboratory
    • CSF protein: Normal
    • Nerve conduction velocities: Normal
    • Nerve biopsy: Mild Reduction in number of large & small axons
  
  
• ALS 5: Childhood-onset ALS
  l Chromosome 15q15.1-q21.1; Recessive (Type 1)
  • Most common form of recessive ALS
  • Onset: Teens
  • Clinical Syndrome: Weakness, Arm atrophy & Spasticity in all limbs (Type 1)
    • Lower motor neuron: Predominant
      • Distal > Proximal
      • Arms > Legs
    • Bulbar: Late; Not pseudobulbar
    • Spasticity: Less than ALS2
  • Laboratory
    • CSF protein: Normal
    • Sural nerve: Reduced number of Myelinated axons
  
  
• ALS: Childhood-onset, recessive ⁶⁴
  l Chromosome 6p25, 21q22; Recessive
  • Epidemiology: 1 Utah family, 4 patients
  • Clinical
    • Onset age: 4 to 10 years
    • Ptosis: Mild
    • Weakness & Atrophy
      • Distal
      • Arms & Legs
      • Symmetric
      • Respiratory failure: Late in course, 1 patient
    • Bulbar & Cranial
      • Speech: Dysarthric; Spastic
      • Dysphagia
      • Face weakness, mild
    • Upper motor neuron
      • Spasticity: Legs > Arms
      • Tendon reflexes: Brisk in legs ± arms
      • Plantar response: Upgoing or absent
    • Sensory loss: Mild; Distal; Vibration
    • Gynecomastia: 1 patient
    • Progression: Slow; Loss of ambulation after decade
  • Laboratory
    • NCV
      • Normal velocities
      • CMAPs: Reduced amplitude in legs
      • SNAPS: Reduced amplitude
    • EMG: Denervation, Distal
    • Nerve biopsy: Minimal loss of sensory axons
    • Muscle biopsy: Grouped atrophy; Fiber type grouping
  
  
• Recessive ALS: Other types
  • Clinical syndrome: Weakness & severe spasticity, esp. in legs (Type 2)
    • Symptoms in lower limbs
    • ? form of familial spastic paraplegia

BULBAR MOTOR NEURON SYNDROMES: Hereditary & Other

• Definition
  • Progressive bulbar palsy of childhood
  • Disorder of bulbar motor neurons
• Clinical features
  • Onset: 1 to 12 years
  • Cranial nerves
    • Ptosis
    • Facial weakness
    • Dysphagia
    • Normal hearing
  • Respiratory stridor
  • Hyperreflexia
• Subtypes
  • Dominant: Rare
  • Recessive: Early onset
    • Respiratory failure
    • Rapid progression: Death < 2 years from onset
  • Recessive: Later onset
    • Less respiratory involvement
    • Bulbar: Dysarthria; Dysphagia
    • Facial weakness
    • Slow progression
• Laboratory
  • CSF: Normal
  • Serum CK: Normal
  • EMG: Denervation; Large amplitude Motor unit potentials
  • Neuropathology
    • Loss of neurons from motor cranial nerve nuclei
    • Occasional: Anterior horn cell loss; Cerebelar involvement

• Epidemiology
  • 50% of patients sporadic cases
  • Most familial cases female
• Clinical features
  • Onset
    • Most 2nd decade; 25% 1st decade
    • Early development normal
  • Cranial nerves
    • Deafness: Bilateral; Sensory-Neural
    • Weakness: Especially 7, 9,and 12
      • Facial: Bilateral
      • Bulbar
        • Tongue: Wasting & Fasciculations
        • Dysphagia
    • Normal eye movements
  • Motor
    • Weakness
      • Especially upper extremities, neck & trunk
      • Respiratory failure
    • Tone: Reduced
    • Muscle wasting
  • Tendon reflexes: Normal or Reduced
  • Sensory examination: Normal
  • CNS: Normal intelligence
  • Skeletal: Contractures, distal; Scoliosis
  • Disease course
    • Irregularly progressive
    • Death in more severe patients: Respiratory failure
• Laboratory
  • Brainstem auditory responses: Absent
  • EMG: Denervation changes
  • NCV: Normal motor velocities; Reduced or absent SNAPs

• Epidemiology
  • Common in South India
  • Family history of similar disorder: 2%
  • Male = Female
• Onset
  • Age: Juvenile; Range 2nd & 3rd decade; Mean 16 years
  • Hearing loss: 53%
  • Arm weakness: 38%
• Clinical
  • Weakness
    • Limbs
    • Asymmetric
  • Cranial nerve
    • Facial weakness
    • Deafness: Sensorineural (30% to 80%)
    • Bulbar involvement (40%): Dysphagia; Dysarthria
    • Tongue: Weakness; Fasciculations
  • Motor
    • Lower motor neuron signs (85%): Arms > Legs
    • Pyramidal signs (80%)
    • Wasting
    • Fasciculations
    • Most remain ambulatory
  • Reflexes
    • Tendon reflexes: May be brisk in legs
    • Plantar: May be extensor (50%)
  • Sensory: Normal
• Course: Slowly progressive
• Pathology: 1 patient
  • Anterior horn cells: Reduced
  • Ventrolateral column: Axonal loss
  • Other cranial nerve nuclei involved: 3, 5, 6, 7, 10
  • Cochlear nuclei: Neuronal loss
  • Other tracts involved: Spinocerebellar & Spinothalamic
  • Other regions of CNS also involved
  • Cellular: Microglial reaction; No cytoskeletal pathology
• Differential diagnosis: Similar to Brown-Vialetto-van Laere
• Variant: CNS features (13%)³³
  • Bulbar dysfunction (100%)
  • Optic atrophy
  • Cerebellar disorder: Ataxic gait
  • Pyramidal signs
  • Minipolymyoclonus
  • Family history positive: 29%

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

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

Multisystem disorders

• Hexosaminidase A: GM2 Gangliosidosis, Late Onset (Tay-Sachs)
    l β-Hexosaminidase A (HEXA) ; Chromosome 15q23-q24; Recessive
  
  • Genetic features
    • Gly269Ser substitution in α chain
      • Most common mutation in adult form
        
      • Usually in compound heterozygosity with null mutation
    • Other mutations with milder disease
      • Missense: Arg499His; Arg499Cys; Arg504His; Arg504Cys
      • Splice site: IVS7-7G
    • Other mutations (null): More severe disease
      • Exon 11: 4-bp insertion
        
      • Exon 12: G to C mutation in splice junction
        
      • Exon 1: A to T in initiation codon
  • HEXA protein
    • Location: Lysosome enzyme
    • Function: Breakdown of gangliosides
    • Disease syndromes: < 10% of normal Hex A activity
    • Later-onset syndromes: Higher Hex A activity
  • Clinical features
    • Onset: Cramping in legs
    • Weakness
      • Proximal > Distal; Symmetric
        
      • May be only sign, or present with CNS features
    • Sensory: Unusual¹⁴
      • Paresthesias: Distal; 2nd decade onset
      • Loss: Mild; Pansensory
    • Tendon reflexes: Normal or Brisk
    • Cerebellar: Gait Ataxia; Nystagmus
    • Cortical function
      • Dementia
      • Manic-Depressive-like disorder
      • May be normal
    • Movement disorder: Dystonia & Choreoathetosis
  • Lab
    • MRI with cerebellar atrophy in many, but not all, patients
    • Nerve biopsy: Sensory-Motor axonal neuropathy
    • EMG: Large motor units; Fibrillations
  • Lower motor neuron phenotype also with Sandhoff disease
  
  
• Machado-Joseph (esp Type I)
    l CAG triplet repeats; Chromosome 14q32.1; Dominant
  • Clinical features
    • Type I = Earlier onset (20 to 30 yrs) with longer CAG repeats
      
    • Dystonia; Facial & Lingual Fasciculations; Bulging Eyes
    • Cerebellar signs with distal amyotrophy in later onset (Types II & III)
    • Allelic with Spino-Cerebellar Ataxia (SCA) III
      
      
• Polyglucosan body disease : Adult-onset
  l Glycogen branching enzyme (GBE1) ; Chromosome 3p12; Recessive
  
  • Epidemiology
    • Mostly in Ashkenazi Jewish patients
    • Non Ashkenazi Jewish patients: German, Italian
  • Genetics: Missense mutations
    • Ashkenazi Jewish patients: Tyr329Ser
    • German & Italian: Arg515His & Arg524Gln
  • GBE1 protein
    • Converts amylose into amylopectin
  • Clinical features: CNS + Polyneuropathy³⁹
    • Course
      • Onset
        • Adult: > 40 yrs
        • Other forms in childhood with myopathy & hepatic disease
      • Slowly progressive
    • Polyneuropathy
      • Legs > Arms
      • Motor: Weakness, Distal
      • Sensory loss: Large fiber modalities
    • Myelopathy
      • Spasticity: Legs
      • Neurogenic bladder
      • Tendon reflexes: Brisk in legs
      • Extensor plantar responses
    • Dementia (67%): Cortical & Subcortical
  • Laboratory
    • MRI
      • Cortical atrophy
      • White-matter changes: Periventricular; Subcortical
      • Distribution: Bilateral; Symmetric
      • Non-enhancing
      • Diffuse atrophy: Brain & Spinal cord
    • Nerve conduction studies: Neuropathy
      • Axonal loss
      • Sensory & Motor involvement
  • Pathology
    • Dx by sural nerve or axillary skin biopsy
    • Polyglucosan bodies: CNS & PNS
    • Perivascular inflammation: Occasional
  l ALS with polyglucosan bodies
  
  
• Motor neuronopathy with cataracts and skeletal abnormalities
  l Chromosome 10q23.3-q24.2; Dominant with anticipation
  • See SPG 9
  • Clinical features
    • Onset: 1 to 37 years
    • Cataracts
    • Weakness
      • Distal arms & proximal legs
        
      • Exacerbation during pregnancy; remission afterwards
    • Upper motor neuron signs
    • Skeletal
      • Short stature; Dysplastic skull base; Small carpal bones
  
  
• Disinhibition-dementia-Parkinsonism-amyotrophy complex (DDPAC; Fronto-Temporal dementia)
  l Microtubule-associated protein tau (MAPT) ; Chromosome 17q21.1; Dominant
  • Allelic with
    • Frontotemporal dementia with parkinsonism
    • Frontotemporal dementia with motor neuron disease (K317M mutation)
    • Progressive supranuclear palsy
    • Tauopathy and respiratory failure (Ser352Leu)
    • Pick disease
  • Clinical
    • Onset: Mean age 45 years; Alcoholism or Depression
    • Dementia: Behavior & judgement > Language & praxis; Kluever-Bucy syndrome
    • Disinhibition: Alcoholism; Hyperreligiosity; Excessive eating, sexual behavior
    • Parkinsonism
    • Amyotrophy
    • Variability of symptoms among patients
  • Pathology
    • Superficial cortex: Spongiform changes
    • Spinal cord: Motor neuron loss
  
  
• Motor neuron disease with dementia & ophthalmoplegia
  l Autosomal Recessive
  • Epidemiology: 1 patient
  • Clinical
    • Weakness: Bulbar; Arms; Respiratory failure
    • Ophthalmoplegia: Reduced gaze excursion, especially up; Supranuclear
    • Progression: Over 1 year
  • Laboratory
    • EEG: Diffuse slowing
    • CT: Atrophy of frontal lobe & midbrain
    • Brain: Abnormal anterior horn & corticospinal tracts; Bunina bodies
  
  
• Alopecia, Neurological Defects & Endocrinopathy (ANE)
  l RBM28 ; Chromosome 7q31.32-7q32; Recessive
  • Epidemiology: Arab Moslem kindred
  • Genetics
    • Mutation: Missense; Leu351Pro
  • RBM28 protein
    • Component of snRNP complexes
    • Ubiquitous expression
    • Regulates ribosome biogenesis
    • Mutant: Ribosome depletion; Structural abnormalities of rough endoplasmic reticulum
  • Clinical
    • Skin
      • Hair loss
        • Widely varying severity
        • Skin biopsy: Absence of mature hair follicles; Reduced β-catenin
      • Pigment
        • Flexural reticulate hyperpigmentation
        • Facial pigmented nevi: Multiple
      • Subcutaneous fat: Loss
    • Motor
      • Progressive decline
      • Combined upper & lower motor dysfunction
      • Onset: 2nd decade
    • CNS
      • Mental retardation: Moderate to severe
    • Endocrine: Central hypogonadotropic hypogonadism
      • Delayed or absent puberty
      • Central adrenal insufficiency
      • Gynecomastia
    • Skeletal
      • Short stature
      • Microcephaly
      • Hypodontia
      • Kyphoscoliosis
      • Ulnar deviation of hands
  • MRI
    • Hypoplastic pituitary gland with preserved hypothalamus
    • Normal basal ganglia & white-matter

Motor Neuron Disease: Mouse models

• Wobbler ⁵²
  l Vacuolar protein sorting protein 54 (Vps54)
  • Mutation: Missense L967Q
  • Motor neuron disease
  • Spermiogenesis defect
• Neuromuscular degeneration (nmd): SMARD1
• Muscle deficient: Mouse chromosome19
  • Onset: Hindlimb weakness
  • Peripheral nerve: Axonal degeneration
  • Neurons: Ventral horn & Brainstem motor; Vacuolar degeneration
  • Death: 8 months
• Progressive motor neuronopathy (PMN)²⁸
  l Tubulin-specific chaperone E (TBCE) ; Mouse chromosome 13
  • Mutation: Trp524Gly
  • TBCE protein function: Folding of α-tubulin; Formation of α-β-tubulin heterodimers
  • Loss of motor neurons & myelinated axons
  • CNS
    • Tracts - Fasciculus gracilis; Rubrospinal; Reticulospinal
    • Normal: Corticospinal tract
    • Pathological pattern: Dying back
  • Death: 6 weeks
  • TBCE: Human disease
    • Kenny-Caffey syndrome
    • Sanjad-Sakati syndrome :
    • Clinical features
      • Congenital hypoparathyroidism
      • Mental retardation
      • Face dysmorphism
      • Growth failure
• CNTF knockout: Mouse chromosome 19
• SOD transgenic
• Neurofilament heavy chain : Overexpression
• PQBP-1 transgenic³⁵
  • PQBP-1
    • Transcription and/or mRNA processing factor
    • Interacts with polyglutamine disease gene products
  • Clinical: Progressive weakness with increasing age
  • Pathology: Neuronal loss in spinal anterior horn; Loss of motor axons