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

Hereditary & Familial ALS
Dominant
  ALS 1: SOD1; 21q
  ALS 3: 18q21
  ALS 4: Senataxin; 9q34
  ALS 6: FUS; 16p11
  ALS 7: 20p13
  ALS 8: VAPB; 20q13
  ALS 9: Angiogenin; 14q11
  ALS 10: TDP-43; 1p36
  ALS 11: FIG4; 6q21
  ALS-FTD 1: 9q21-q22
  ALS-FTD 2: 9p21
  Bulbar ALS
  Dynactin: 2p13
Recessive
  ALS 2: Alsin; 2q33
  ALS 5: 15q15
  ALS 6: FUS; 16p11
  ALS 6-21: 6p25, 21q22
X-linked
  ALS X: Xp11-q12
Other
  ALS-FTD-3: CHMP2B; 2p11; Sporadic
  Neurofilament, Heavy subunit: 22q12
  Peripherin: 12q12
  Western Pacific
    ALS-PD1
    ALS-PD2

Childhood-onset
  ALS2: Alsin; 2q33; Recessive
  ALS4: Senataxin; 9q34; Dominant
  ALS5: 15q15; Recessive
  ALS 6-21: 6p25, 21q22
  Distal HMN: 7q34; Dominant
  Other (Type 2)

Bulbar syndromes
  AAA syndrome: Aladin; 12q13; Recessive
  Brown-Vialetto-van Laere: Recessive
  BSMA: Dominant
  Bulbar ALS
  Fazio-Londe: Recessive or Dominant
  Kennedy's Syndrome (BSMA): Androgen Receptor; Xq12
  PLS, Juvenile: Alsin; 2q33; Recessive
  Worster-Drought

Multisystem disorders
  AAA syndrome: Aladin; 12q13; Recessive
  ANE: RBM28; 7q31
  Camera-Marugo-Cohen Syndrome
  Cataracts & skeletal abnormalities: Dominant
  DDPAC: MAPT; 17q21; Dominant
  Hexosaminidase A: β-Hexosaminidase A; 15q23; Recessive
  Machado-Joseph: Ataxin-3; 14q32; Dominant
  Mental retardation + Distal wasting: CUL4B; Xq23
  Mitochondrial: SCO2
  MND + Dementia & Ophthalmoplegia: Recessive
  Polyglucosan body disease: GBE1; 3p12; Recessive
  Spastic paraparesis
    + Motor neuropathy
Spinal muscular atrophy (SMA): Types
  SMA1: SMN 5q; Recessive
    Congenital with arthrogryposis
    Werdnig-Hoffmann
    Kugelberg-Welander
  Recessive SMA: Other
    Spinal muscular atrophy 2 (SMA2)
    SMA + Congenital fractures
    SMA + Pontocerebellar hypoplasia: VRK1; 14q32
    Mitochondrial
      SCO2: 22q13
      TK2: 16q22
  X-linked SMA (Recessive)
    Bulbo-SMA (Kennedy's): Androgen Receptor; Xq12
    Infantile SMA & Arthrogryposis (SMAX2): UBE1; Xp11
    Distal SMA, X-linked (SMAX 3): Xq13
  Dominant, Proximal SMA
    Adult onset: VAPB; 20q13
    Benign congenital with contractures
    Bulbo-SMA Autosomal Dominant
    Congenital with leg weakness: 12q23; Dominant
    HMSN-P (Okinawa type): 3q13; Dominant
    Scapuloperoneal syndromes: 12q24 & Other
  HMN & Distal SMA
    1: 7q34; Dominant
    2A: HSPB8 (HSP22); 12q24; Dominant
    2B: HSPB1 (HSP 27); 7q11; Dominant
    5: Upper limb predominance
      HMN 5A: GARS; 7p15; Dominant
      HMN 5B: BSCL2; 11q13; Dominant
    6: IGHMBP2; 11q13; Recessive
    7: + Vocal cord paralysis
      HMN 7A: 2q14; Dominant
      HMN 7B: Dynactin; 2p13; Dominant
    + Upper motor neuron: Senataxin; 9q34; Dominant
    HMN: 11p; Recessive
    HMN: 16p
  Distal SMA (DSMA)
    1: IGHMBP2; 11q13; Recessive
    2 (HMN J): 9p21.1-p12; Recessive
    3: 11q13; Recessive
    4 (Lower motor neuron syndrome): PLEKHG5; 1p36
    X-linked (SMAX 3): Xq13
    Leg predominant
    + Ataxia telangectasia: ATM; 11q22
    Childhood onset
      Dominant
      Recessive
    Distal Ulnar-Median: Dominant
  Lethal congenital contractures
  Scapuloperoneal

Also see
  External link: ALS mutation databases
  Monomelic amyotrophy (Hirayama): Sporadic
  Mouse models


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

  l Survival Motor Neuron 1 (SMN1) protein ; Chromosome 5q12.2-q13; Recessive

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

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

  l Increased CAG repeats in Androgen Receptor ; Xq12; Recessive

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

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

  l Autosomal Dominant

Spinal Muscular Atrophy 2 5

l Autosomal Recessive (Not linked to SMA 5q)

Spinal Muscular Atrophy: Distal

HMN & Distal SMA
  1: 7q34; Dominant
  2A: HSPB8 (HSP22); 12q24; Dominant
  2B: HSPB1 (HSP 27); 7q11; Dominant
  5: Upper limb predominance
    HMN 5A: GARS; 7p15; Dominant
    HMN 5B: BSCL2; 11q13; Dominant
  6: IGHMBP2; 11q13; Recessive
  7: + Vocal cord paralysis
    HMN 7A: 2q14; Dominant
    HMN 7B: Dynactin; 2p13; Dominant
  + Upper motor neuron: SETX; 9q34; Dominant
  HMN: 11p; Recessive
  HMN: 16p
Distal SMA (DSMA)
  1: IGHMBP2; 11q13; Recessive
  2 (HMN J): 9p21.1-p12; Recessive
  3: 11q13; Recessive
  4 (LMN syndrome): PLEKHG5; 1p36
  X-linked (SMAX 3): Xq13
  Leg predominant
  + Ataxia telangectasia: ATM; 11q22
  Childhood onset
    Dominant
    Recessive
  Ulnar-Median: Dominant

Scapuloperoneal
Also see
  Congenital SMA (12q23)
  Hirayama
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



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




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

l Autosomal Dominant   l Chromosome 7q34-q36; Dominant 59


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

  l HSPB8 (HSP22) ; Chromosome 12q24-qter; Dominant


Distal hereditary motor neuropathy (HMN 2B)

  l HSPB1 (HSP 27) ; Chromosome 7q11.23; Dominant or Recessive

Distal hereditary motor neuropathy with upper motor neuron signs22

  l Senataxin (SETX) ; Chromosome 9q34; Dominant


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

  l Glycyl tRNA Synthetase ; Chromosome 7p15; Dominant


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

l BSCL2 gene (Seipin) ; Chromosome 11q13; Dominant


Hereditary Distal Ulnar-Median Muscular Atrophy7

  l Autosomal Dominant


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

  l Chromosome 2q14; Dominant


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

  l Dynactin (DCTN1) ; Chromosome 2p13; Dominant


Distal HMN: Congenital15

  l Autosomal Dominant


Distal SMA: Leg predominant19

  l Dominant


Distal SMA 3 (DSMA 3)21

  l Chromosome 11q13.3; Recessive


Distal HMN: Childhood onset

  l Autosomal Recessive


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

  l Immunoglobulin μ-binding protein 2 (IGHMBP2) ; Chromosome 11q13.2–q13.4; Recessive


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

  l Chromosome 9p21.1-p12; Recessive


Distal SMA, X-linked (SMAX3)41

  l Chromosome Xq13.1–q21; Recessive


Distal hereditary motor neuropathy45

  l Chromosome 11p; Recessive

Spinal Muscular Atrophy: Other



Infantile Spinal Muscular Atrophy with Arthrogryposis (XL-SMA; SMAX2)
  l Ubiquitin-activating enzyme 1 (UBE1) ; Xp11.23; Recessive

Proximal SMA with dominant inheritance
  l Autosomal Dominant: Child-Adult Onset

Proximal SMA with dominant inheritance: Adult Onset (Finkel, Late adult type)
  l VAPB; Chromosome 20q13.3; Dominant

Spinal muscular atrophy: Congenital, non-progressive, of lower limbs
  l Chromosome 12q23-q24 + Other locus; Dominant

Benign congenital spinal muscular atrophy with contractures
  l Dominant; Some, but not all, families Chromosome 12q23-q24

Hereditary Motor Sensory Neuropathy, Proximal (HMSN-P; CMT 2G)
  l Chromosome 3q13.1; Dominant


Spinal muscular atrophy, type I, with congenital bone fractures
  l Autosomal Recessive or Sporadic

Pontocerebellar hypoplasia with Spinal muscular atrophy (PCH1)
  l Vaccinia-related kinase 1 (VRK1) ; Chromosome 14q32; Recessive

Lower motor neuron syndrome with childhood onset (DSMA4)57
  l PLEKHG5 ; Chromosome 1p36; Recessive


SMA: Severe infantile
  l Recessive



Scapuloperoneal syndromes (?Dominant; Sporadic)


Hereditary ALS

Inheritance
Dominant
  ALS 1: SOD1; 21q
  ALS 3: 18q21
  ALS 4: Senataxin; 9q34
  ALS 6: FUS; 16p11
  ALS 7: 20p
  ALS 8: VAPB; 20q13
  ALS: TDP-43; 1p36
  ALS 9: Angiogenin; 14q11
  ALS 11: FIG4; 6q21
  ALS-FTD 1: 9q21-q22
  ALS-FTD 2: 9p21
  Bulbar ALS
  Dynactin: 2p13
Recessive
  ALS 2: Alsin; 2q33
  ALS 5: 15q15
X-linked
  ALS X: Xp11-q12
Uncertain inheritance
  Neurofilament heavy chain: 22q12
  Peripherin: 12q12
  Western Pacific
Onset age
Adult onset
  ALS 1: SOD1; 21q
  ALS 3: 18q21
  ALS 6: FUS; 16p11
  ALS 7: 20p13
  ALS 8: VAPB; 20q13
  ALS: TDP-43; 1p36
  ALS 9: Angiogenin; 14q11
  ALS X: Xp11-q12
  ALS Other: Heterogeneous group
  ALS-FTD 1: 9q21-q22
  ALS-FTD 2: 9p21
  ALS-FTD-3: CHMP2B; 2p11
  Bulbar ALS
  Neurofilament heavy chain: 22q12
  Dynactin: 2p13
  Western Pacific
Childhood onset (Juvenile)
  ALS 2: 2q33; Recessive
  ALS 4: Senataxin; 9q34; Dominant
  ALS 5: 15q15; Recessive
  Other (Type 2)
External link: ALS mutation databases



General: Hereditary vs Sporadic ALS

Feature Hereditary ALS Sporadic ALS
Males:Females 1:1 1.7:1
Disease Duration Bimodal
  < 2 & > 5 years
Unimodal
  3 to 4 years
% of ALS cases 10% 90%
Onset
  Age distribution More younger More older
  Mean age 46 years 56 to 63 years
  Juvenile ALS 2, 4, 5 Rare
  Bulbar features 20% to 30% Unusual
  Legs Common Occasional




l ALS SYNDROMES: DOMINANT

ALS 1: SOD1; 21q
ALS 3: 18q21
ALS 4: Senataxin; 9q34
ALS 6: FUS; 16p11
ALS 7: 20p13
ALS 8: VAPB; 20q13
ALS 9: Angiogenin; 14q11
ALS 10: TDP-43; 1p36
ALS 11: FIG4; 6q21
ALS-FTD 1: 9q21-q22
ALS-FTD 2: 9p21
ALS X: Xp11-q12
Bulbar ALS
Dynactin: 2p13
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

l ALS SYNDROMES: RECESSIVE

ALS2: 2q33
ALS5: 15q15
ALS 6: FUS; 16p11
ALS 6-21: 6p25, 21q22

BULBAR MOTOR NEURON SYNDROMES: Hereditary & Other

Brown-Vialetto-van Laere
Bulbar ALS
Fazio-Londe
Kennedy's Syndrome
Madras motor neuron disease
Spino-bulbar muscular atrophy: Dominant
Worster-Drought

Fazio-Londe12
  l Autosomal; Recessive or Dominant
Brown-Vialetto-van Laere: Progressive bulbar palsy with deafness 4
  l Autosomal Recessive or Dominant + many Sporadic cases
Madras Motor Neuron Disease61
  l Sporadic; Occasional recessive inheritance
Worster-Drought syndrome: Congenital suprabulbar paralysis 11

Cortical Suprabulbar palsy

Multisystem disorders


Motor Neuron Disease: Mouse models



Patient resources
Patient information: Spinal muscular atrophy


Return to Neuromuscular Home Page
Return to Motor Syndromes
Return to Polyneuropathy Index

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