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

ALS: Hereditary & Familial

Spinal muscular atrophy (SMA): Types
  Recessive SMA
    SMA: SMN 5q13
      Congenital with arthrogryposis
      Werdnig-Hoffmann
      Kugelberg-Welander
    Spinal muscular atrophy 2 (SMA2)
    Spinal motor neuropathy: RBM7; 11q232
    SMA + Congenital fractures
      TRIP4; 15q22
      ASCC1: 10q22
    SMA + Encephalopathy: TBCD; 17q25
    SMA + Myoclonus Epilepsy: ASAH1; 8q22
    SMA + Pontocerebellar hypoplasia (PCH)
      PCH1A: VRK1; 14q32
      PCH1B: EXOSC3; 9p11
      Other: Motor + Cerebellar
        EXOSC8; 3q13
        EXOSC9; 4q27
    Mitochondrial
      DGUOK: 2p13
      SCO2: 22q13
      SLC25A21: 14q13
      TK2: 16q22
    Congenital contractures
  Dominant, Proximal
    Adult: VAPB; 20q13
    Adult + Cramps (SMAJ): CHCHD10; 22q11
    Bulbar
    Congenital + Legs weak: TRPV4; 12q24
    HMSN-P (Okinawa type): TFG; 3q12
    Respiratory & Proximal arms: MAPT; 17q21
    Scapuloperoneal syndromes
    SMALED
      1: Leg predominant; DYNC1H1; 14q32
      2: Early-onset; Contractures; BICD2; 9q22
  X-linked SMA (Recessive)
    Bulbospinal (Kennedy): AR; Xq12
    SMAX
      2: Infant + Arthrogryposis; UBE1; Xp11
      3: Distal; ATP7A; Xq21
HMN
    1: 7q34; Dominant
    2
      A: HSPB8 (HSP22); 12q24; Dominant
      B: HSPB1 (HSP27); 7q11; Dom or Rec
      C: HSPB3 (HSPL27); 5q11; Dominant
      D: FBXO38; 5p31; Dom or Rec
    5: Upper limb predominance
      A: GARS; 7p15; Dominant
      B: REEP1; 2p11.2; Dominant
      C: BSCL2; 11q13; Dominant
    6: IGHMBP2; 11q13; Recessive
    7: + Vocal cord paralysis, Dominant
      A: SLC5A7; 2q12
      B: Dynactin 1 (DCTN1); 2p13
    8: Congenital, Legs: TRPV4; 12q24
    9 (dHMN): WARS1; 14q32; Dominant
    + Upper motor neuron
          Senataxin; 9q34; Dominant
          4q34: Dominant
          HMN
            J: 9p21; Recessive
            2B: HSPB1; 7q11; Dominant
            5C: BSCL2; 11q13; Dominant
            7B: Dynactin; 2p13; Dominant
          SPG + Motor neuropathy
    HMN: 11p; Recessive
    HMN: 16p
    HMN: KCC3; 15q14; Dominant
    HMN: SPTAN1; 9q34; Dominant
    HMN: MME; 3q25; Recessive
    CMT 2N: AARS; 16q22; Dominant
    CMT 2O: DYNC1H1; 14q32; Dominant
    Neuromyotonia: HINT1; 5q31; Recessive
    Childhood: BICD2; 9q22
    Intellectual Disability: TBCK; 4q24

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

Distal SMA (DSMA; dHMN)
    Recessive
      1 (SMARD1): IGHMBP2; 11q13
      2 (HMN J): 9p21
      3: 11q13
      4: PLEKHG5; 1p36
      5: DNAJB2 (HSJ1); 2q35
      dHMN: SIGMAR1: 9p13
      dHMN: SYT2; 1q32
      + Ataxia telangectasia: ATM; 11q22
      + Encephalopathy: TBCE; 1q42
      Lethal congenital contractures
      MND, Distal: VRK1; 14q32
      SORD: 15q21
    Dominant
      Calf predominant: FBXO38; 5p31
      Leg predominant
      Distal Ulnar-Median
      Childhood: BICD2; 9q22
      + Macular Δ: FBLN5; 14q32
      + Hearing loss: MYH14; 19q13
      Scapuloperoneal: TRPV4; 12q24
      SMAJ1: GARS1; 7p14
      HMN: HARS; 5q31
      HMN: GBF1; 10q24
    X-linked
      dHMN: AIFM1; Xq26
      SMAX 3: ATP7A; Xq21
      SMARD2: LAS1L; Xq12
    Mitochondrial
      mtATP6 ± Episodic weakness
      mtATP8
    Sporadic: Hirayama
    Distal Motor Neuropathy or Myopathy
Multisystem disorders
  Recessive
    AAA syndrome: Aladin; 12q13
    ANE: RBM28; 7q31
    Chediak-Higashi: LYST; 1q42
    CONDCA: AGTPBP1; 9q21
    Hexosaminidase A: HEXA; 15q23
    Leukoencephalopathy: SCP2; 1p32
    MND + Dementia & Ophthalmoplegia
    Motor PN + Myopathy: VWA1; 1p36
    MPAN: c19orf12; 9q12
    Optic atrophy: c19orf12; 19q12
    STAT5B: 17q21
    TBX5: 12q24
  Dominant
    Cataracts & Skeletal abnormalities
    DDPAC: MAPT; 17q21
    HMN: EMELIN-1; 2p23
    Machado-Joseph: Ataxin-3; 14q32
    Myopathy + Paget: HNRNPA2B1; 7p15
  X-linked
    Cabezas: CUL4B; Xq23
    Neuroaxonal dystrophy 2
    Polyglucosan body: GBE1; 3p12
  Mitochondrial: SCO2
  Sporadic: Camera-Marugo-Cohen
  Spastic paraparesis
  Spastic paraparesis + Motor neuropathy

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

Distal SMA


From: Spiller

HMN: Protein mechanisms


dHMN: Spain 167


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

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

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

Hoffman ~1891

From: Andrew Kornberg MD

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


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


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

  Androgen Receptor (AR) (Increased CAG repeats) ; Xq12; Recessive

Androgen receptor protein
Clinical features
Clinical-genetic correlations
Epidemiology
Laboratory features
Onset
Pathogenic mechanisms
Pathology

Bulbo-Spinal Muscular Atrophy
Gynecomastia

Mouth in BSMA
Attempted smile & At rest
  

Tongue in BSMA
Wasted; Weak; Moves rapidly

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

  Autosomal Dominant

Spinal Motor Neuropathy 150

  RNA-binding motif protein 7 (RBM7) ; Chromosome 11q23.2; Recessive

Spinal Muscular Atrophy 2 5

  Autosomal Recessive (Not linked to SMA 5q)

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


Hereditary Motor Neuropathies: General features


J Nervous & Mental Disease 1894

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

  Chromosome 7q34-q36; Dominant 59

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

  Heat-shock 22-kD protein 8 (HSPB8; HSP22) ; Chromosome 12q24.23; Dominant

Distal hereditary motor neuropathy (HMN 2B)

  Heat-shock 27-kD protein 1 (HSPB1; HSP 27) ; Chromosome 7q11.23; Dominant or Recessive

Distal hereditary motor neuropathy with upper motor neuron signs 22

  Senataxin (SETX) ; Chromosome 9q34.13; Dominant

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

  Glycyl tRNA Synthetase 1 (GARS1) ; Chromosome 7p14.3; Dominant or de novo

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

BSCL2 gene (Seipin) ; Chromosome 11q12.3; Dominant

Hereditary Distal Ulnar-Median Muscular Atrophy 7

  Autosomal Dominant

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

  Solute carrier family 5 (Choline transporter), Member 7 (SLC5A7; CHT) ; Chromosome 2q12.3; Dominant

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

  Dynactin 1 (DCTN1) ; Chromosome 2p13.1; Dominant

Distal SMA: Calf predominant (HMN2D) 106

  F-box only protein 38 (FBXO38; MOKA) ; Chromosome 5p31.1; Dominant

Distal SMA: Leg predominant 19

  Dominant

Distal SMA 3 (DSMA 3) 21

  Chromosome 11q13.3; Recessive

Distal HMN: Childhood onset

  Autosomal Recessive

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

  Immunoglobulin μ-binding protein 2 (IGHMBP2) ; Chromosome 11q13.3; Recessive

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

  Chromosome 9p21.1-p12; Recessive

Distal SMA, X-linked 3 (SMAX3) 41

  ATPase, Cu++-transporting, alpha polypeptide (ATP7A) ; Chromosome Xq21.1; Recessive

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

  Ribosomal biogenesis protein LAS1L (LAS1L) ; Chromosome Xq12; Recessive

Distal hereditary motor neuropathy 45

  Chromosome 11p; Recessive

Distal Hereditary Motor Neuropathy (HMN 2C) 71

  Heat-shock 27-kd protein 3 (HSPB3; HSPL27) ; Chromosome 5q11.2; Dominant

Distal Hereditary Motor Neuropathy with Pyramidal features

  Chromosome 4q34.3-q35.2; Dominant

Spinal Muscular Atrophy: Other


Infantile Spinal Muscular Atrophy with Arthrogryposis (XL-SMA; SMAX2; AMCX1)
  Ubiquitin-activating enzyme 1 (UBE1; UBA1) ; Xp11.23; Recessive
Proximal SMA with Dominant inheritance: Adult Onset (Finkel, Late adult type; SMAFK)
  VAPB ; Chromosome 20q13.32; Dominant

Hereditary motor neuropathy, distal 8 (HMN8): Spinal muscular atrophy, Congenital, non-progressive, of lower limbs
  TRPV4 ; Chromosome 12q24.11; Dominant
Hereditary Motor Neuropathy, Distal 9 (HMN9; dHMN type I) 139
  Tryptophanyl-tRNA synthetase 1 (WARS1) ; Chromosome 14q32.2; Dominant or Sporadic

Early-onset spinal muscular atrophy with Contractures (SMALED2A) 15, 90
  Bicaudal D, drosophila, homolog of, 2 (BICD2) ; Chromosome 9q22.31; Dominant or Sporadic


Spinal muscular atrophy with Lower limb predominance (SMA-LED) 75
  Dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) Chromosome 14q32.31; Dominant
Hereditary Motor Sensory Neuropathy, Proximal (HMSNO; HMSN-P; CMT 2G) 97
  Trk-fused Gene (TFG) ; Chromosome 3q12.2; Dominant


Spinal muscular atrophy, Prenatal onset, with Congenital bone fractures (SMABF) 126
  SMABF1 : Thyroid hormone receptor interactor 4 (TRIP4; ASC1; ASC-1) ; Chromosome 15q22.31; Recessive
  SMABF2 : Activating signal cointegrator 1 complex, Subunit 1 (ASCC1; p50) ; Chromosome 10q22.1; Recessive

Pontocerebellar hypoplasia with Spinal muscular atrophy (PCH1A)
  Vaccinia-related kinase 1 (VRK1) ; Chromosome 14q32.2; Recessive
Pontocerebellar hypoplasia with Spinal muscular atrophy (PCH1B) 89
  Exosome component 3 (EXOSC3) ; Chromosome 9p13.2; Recessive
Cerebellar atrophy + Spinal Motor Neuropathy (PCH1D) 149
  Exosome component 9 (EXOSC9) ; Chromosome 4q27; Recessive

Ponto-Cerebellar Hypoplasia + Spinal Motor Atrophy & Arthrogryposis (PCH) 159
  Kinesin Family Member 26B (KIF26B) ; Chromosome 1q24; de novo

Lower motor neuron syndrome, Childhood onset (DSMA4) 57
  Pleckstrin homology domain-containing protein, Family G, Member 5 (PLEKHG5) ; Chromosome 1p36.31; Recessive


Distal Motor Neuropathy with Young Adult Onset (DSMA5; dHMN) 87
  DNAJ/HSP40 Homolog, subfamily B, Member 2 (DNAJB2; HSJ1) ; Chromosome 2q35; Recessive


Lower motor neuron syndrome with late-adult onset (SMAJ; LOSMoN) 79
  CHCHD10 Chromosome 22q11.23; Dominant


Proximal Spinal Muscular Atrophy with Progressive Myoclonic Epilepsy (SMA-PME; SMAPME) 91
  N-Acylsphingosine Amidohydrolase 1 (ASAH1; Acid ceramidase) ; Chromosome 8p22; Recessive


Spinal Muscular Atrophy with Hypomyelination & Cerebellar Hypoplasia (PCH1C) 114
  Exosome component 8 (EXOSC8) ; Chromosome 13q13.3; Recessive

Encephalopathy with Distal Spinal Muscular Atrophy, Early-onset, Progressive (PEAMO) 134
  Tubulin-specific chaperone E (TBCE) ; Chromosome 1q42.3; Recessive or Simplex
Spinal Muscular Atrophy, Early-onset with Neurodegeneration 136
  Tubulin-specific chaperone D (TBCD) ; Chromosome 17q25.3; Recessive
Motor Neuropathy & Intellectual Disability (TBCK Encephaloneuronopathy) 143
  TBC1 Domain-containing kinase K (TBCK) ; Chromosome 4q24 Recessive
MTDPS18: Spinal Muscular Atrophy-like disorder 151
  Solute carrier family 25 (Mitochondrial oxodicarboxylate carrier), Member 21 (SLC25A21) ; Chromosome 14q13.3 Recessive

SMA: Severe infantile
  Recessive



Scapuloperoneal syndromes (? Dominant; Sporadic)


ALS: Hereditary

Inheritance
Dominant
  ALS 1: SOD1; 21q
  ALS 4: Senataxin; 9q34
  ALS 6: FUS; 16p11
  ALS 7: 20p13
  ALS 8: VAPB; 20q13
  ALS 9: Angiogenin; 14q11
  ALS 10: TDP-43; 1p36
  ALS 11: FIG4; 6q21
  ALS 12: OPTN; 10p15
  ALS 13: Ataxin-2: 12q24
  ALS 14: VCP; 9p13
  ALS 17: CHMP2B; 3p11
  ALS 18: PFN1; 17p13
  ALS 19: ErbB4; 2q34
  ALS 20: HNRNPA1; 12q13
  ALS 21: Matr3; 5q31
  ALS 22: TUBA4A; 2q35
  ALS 23: ANXA11; 10q22
  ALS 24: NEK1; 4q33
  ALS 25: KIF5A; 12q13
  ALS 26: TIA1; 2p13
  ALS: DAO; 12q24
  ALS: GLE1; 9q34
  ALS: SS18L1; 20q13
  ALS: GLT8D1; 3p21
  ALS: SPTLC1; 9q22
  FTDALS1: c9orf72; 9p21
  FTDALS2: CHCHD10; 22q11
  FTDALS3: SQSTM1 (p62); 5q35
  FTDALS4: TBK1; 12q14
  FTDALS5: CCNF; 16p13
  FTDALS6: VCP; 9p13
  FTDALS7: CHMP2B; 3p11
  FTDALS8: CYLD; 16q12
  ALS-FTD: GRN; 17q21
  ALS-FTD: TIA1; 2p13
  ALS-FTD: HTT; 4p16
  SPG17: BSCL2; 11q13
  Dynactin (DCTN1): 2p13
  hnRNPA2B1: 7p15
  ERLIN2: 8p12
  HSPB1: 7q11
  Bulbar ALS

Recessive
  ALS 2: Alsin; 2q33
  ALS 5: Spatacsin; 15q21
  ALS 6: FUS; 16p11
  ALS 12: OPTN; 10p15
  ALS 16: SIGMAR1; 9p13
  ALS 6-21: 6p25, 21q22
  ALS: ATP13A2; 1p36
  ALS-PD2: DJ1, 1p36
  ALS-Slow: ERLIN1; 10q24
  ALS-Slow: CACNA1H; 16p13
  ALS + Ataxia: SYNE1; 6q25
  MPAN: c19orf12; 9q12
  MND, Distal: VRK1; 14q32
  SPG39: PNPLA6; 19p13
  ERLIN2: 8p12

X-linked, Dominant
  ALS 15: UBQLN2; Xp11

Other (Sporadic)
  ALS 1: SOD1; 21q
  ALS 6: FUS; 16p11
  ALS: SPTLC1; 9q22
  FTDALS1: c9orf72; 9p21
  FTDALS2: CHMP2B; 3p11
  ALS: NEFH; 22q12
  EWSR1: 22q12
  Peripherin: 12q12
  SQSTM1 (p62): 5q35
  TAF15: 17q12
  ALS-PD1 (West Pacific)
Onset age
Adult onset
  ALS 1: SOD1; 21q
  ALS 6: FUS; 16p11
  ALS 7: 20p13
  ALS 8: VAPB; 20q13
  ALS 9: Angiogenin; 14q11
  ALS 10: TDP-43; 1p36
  ALS 11: FIG4; 6q21
  ALS 12: OPTN; 10p15
  ALS 13: Ataxin-2: 12q24
  ALS 14: VCP; 9p13
  ALS 17: CHMP2B; 3p11
  ALS 18: PFN1; 17p13
  ALS 19: ErbB4; 2q34
  ALS 20: HNRNPA1; 12q13
  ALS 21: Matr3; 5q31
  ALS 22: TUBA4A; 2q35
  ALS 23: ANXA11; 10q22
  ALS 24: NEK1; 4q33
  ALS 25: KIF5A; 12q13
  ALS 26: TIA1; 2p13
  ALS: DAO; 12q24
  ALS: SS18L1; 20q13
  ALS: GLT8D1; 3p21
  ALS-Slow: CACNA1H; 16p13
  ALS X: UBQLN2; Xp11
  ALS Other: Heterogeneous
  FTDALS1: c9orf72; 9p21
  FTDALS2: CHMP2B; 3p11
  FTDALS3: SQSTM1 (p62); 5q35
  FTDALS4: TBK1; 12q14
  FTDALS5: CCNF; 16p13
  FTDALS6: VCP; 9p13
  FTDALS7: CHMP2B; 3p11
  FTDALS8: CYLD; 16q12
  FTDALS: 16p12
  FTDALS: GRN; 17q21
  Bulbar ALS
  ALS: NEFH; 22q12
  Dynactin: 2p13
  Western Pacific

Childhood onset (Juvenile) 165
  ALS 2: 2q33; Recessive
  ALS 4: Senataxin; 9q34; Dominant
  ALS 5: Spatacsin; 15q21; Recessive
  ALS 6: FUS; 16p11; Sporadic
  ALS 6-21: 6p25, 21q22
  ALS 16: SIGMAR1; 9p13
  ALS: SPTLC1; 9q22
  ALS-Slow: ERLIN1; Recessive
  ALS + Ataxia: SYNE1; 6q25
  Distal HMN 1: 7q34; Dominant
  Other (Type 2)

Also see
  ALS
    Hereditary vs Sporadic
    Dominant
    Recessive
    Sporadic
    Aggregate composition
    Susceptibility loci
  Motor syndromes, Hereditary
  Mouse models
  PLS
  External link: ALS mutations
Protein Pathways
Protein Quality
  SOD1
  VCP
  OPTN
  TBK1
  UBQLN2
  p62
  NEK1
  FIG4
  CCNF
  CYLD
Cytoskeletal
  PFN1
  DCTN1
  TUBA4A
  EPHA4
  KIF5A
  ANXA11
  PRPH
RNA pathology
  c9orf72
  TDP43
  FUS
  TAF15
  ELP3
  ANG
  NEK1
  TIA1
  ATXN2
Vesicles
  Alsin
  CHMP2B
  VAPB
Lipids
  SPTLC1


General: Hereditary vs Sporadic ALS

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

ALS SYNDROMES: DOMINANT

ALS syndromes: Correlations with some SOD1 mutations
Specific SOD1 mutations

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

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

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

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

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

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

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

l Exon 5; Codon 126
  2 base pair deletion
  Rapid Progression
Mutant protein not detectable in brain

ALS clinical features
  • Lower motor neuron predominant
    • A4V; G72C; Leu84Val; Gly93Cys;
      E100K; D101N; S134N

  • Slow progression
    • C6S; Asp11Tyr; G12R; V31A;
      Gly37Arg (18 yrs); Gly41Asp (11 yrs); F45C;
      H46R131; D76V; Gly93Cys (13 yrs); Gly93Ser;
      Leu144Ser; Leu144Phe (9 yrs)

  • Rapid progression
    • Ala4Thr (1.5 yrs); A4V; C6G; C6F
      V7E; L8Q; G10V; G41S; H43R; H48Q
      Asn86Ser Homozygous (5 mo);
      D101>G,H,N,Y; Leu106Val (1.2 yrs);
      I112T; I113F; R115G; D125H; 126 2bp del;
      S134N; Gly147Ser; Val148Gly (2 yrs); V148G

  • Late onset
    • His46Arg; Gly85Arg (55 yrs); D90A;
      I113T; Ala140Gly; Leu144Phe

  • Early onset
    • Gly37Arg; Leu38Val; A89V;
      L104F (6 yrs); ?Leu106Val

  • More common in females
    • Gly41Asp

  • Bulbar onset
    • Cys6Gly; L8Q; His48Gln; Asp76Tyr;
      Asp90Ala (Homozygous);
      D101Y; I112M; T116R; Cys146Arg;
      Gly147Ser; Val148Ile; I149T; Ile151Thr

  • Onset in legs
    • G10V; H46R; L84F; D90A;
      Gly93Cys; Gly93Ser

  • SOD Mutations in "sporadic" ALS
    • Most common: Asp90Ala; Ile113Thr
    • Other: Asp11Tyr; V14G; G16S; E21K; G72S;
      D101N; V118InsAAAAC; E133delGAA
    • Incomplete penetrance

ALS SYNDROMES: RECESSIVE


BULBAR MOTOR NEURON SYNDROMES: Hereditary & Other

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



Fazio-Londe 12
  SLC52A3 (RFT2; c20orf54) ; Chromosome 20p13; Recessive
Brown-Vialetto-van Laere 1 (BVVLS1) 4
  SLC52A3 (RFT2; c20orf54) ; Chromosome 20p13; Recessive
Brown-Vialetto-van Laere 2 (BVVLS2) 93
  SLC52A2 (RFT3; GPR172A; RFVT2) ; Chromosome 8q24.3; Recessive
Brown-Vialetto-van Laere 3 (BVVLS3) 94
  Ubiquilin 1 (UBQLN1) ; Chromosome 9q21.32; Dominant
Madras Motor Neuron Disease 61
  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
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