Home
Index
Search
Links
Pathology
Molecules
Syndromes
  Muscle
NMJ
Nerve
Spinal
Ataxia
Antibody & Biopsy
Patient Information

HEREDITARY MOTOR SENSORY NEUROPATHIES (HMSN; CMT)

CMT & HMSN: Demyelinating
  Dominant
    CMT 1A: PMP-22; 17p12
    CMT 1B: P0 protein; 1q23
    CMT 1C: LITAF; 16p13
    CMT 1D: EGR2; 10q21
    CMT 1E (Deafness)
      PMP-22: 17p12
      P0 protein: 1q23
    CMT 1F: NEFL; 8p21
    CMT 1G: PMP2; 8q21
    CMT1: FBLN5; 14q32
    CMT1: c1orf194; 1p13
    CMT1: ITPR3; 6p21
    HNPP
      PMP-22 (Deletion or Point); 17p12
      KARS; 16q23
    HMSN 3 (Dejerine-Sottas)
        PMP-22; P0; 8q23; EGR2
    Thermosensitive
    PNS & CNS hypomyelin: SOX10; 22q13
    Sensory PN + Hearing loss: GJB3; 1p34
    Hypomyelination: ARHGEF10; 8p23
    CMT-DIF: GNB4; 3q26
    ATXPC: SAMD9L
    HMSN: HARS; 5q31
    HMSN: BAG3

  Recessive: Also AR-CMT1
    CMT 4A: GDAP1; 8q21
    CMT 4B1: MTMR2; 11q22
    CMT 4B2: SBF2; 11p15
    CMT 4B3: SBF1; 22q13
    CMT 4C: SH3TC2 (KIAA1985); 5q32
    CMT 4D (Lom): NDRG1; 8q24
    CMT 4E: EGR2; 10q21
    CMT 4F: Periaxin; 19q13
    HMSN-Russe (4G): HK1; 10q22
    CMT 4H: FGD4; 12q12
    CMT 4J: FIG4; 6q21
    CMT 4K: SURF1; 9q34
    HMSN 3 (Dejerine-Sottas)
        P0; PMP-22; EGR2; Periaxin
    HMSN + Juvenile glaucoma
    Cataracts (CCFDN): CTDP1; 18qter
    Cockayne's: 5
    Congenital hypomyelinating
        P0, PMP-22 & EGR-2
    Farber lipogranulomatosis: ASAH; 8p22
    CDG1a: PMM2; 16p13
    Krabbe: GALC; 14q31
    MLD: ARSA; 22q13
    PMP-22 point mutations
    Refsum's disease
        Childhood: PHYH; 10pter-p11.2
        Adolescent-Adult: PEX7; 6q22
        Infant: PEX1; 7q21
        PHARC: ABHD12; 20p11
        PBD8B: PEX16; 11p11
    HMSN +
      CNS: Heterogeneous
      Neurodegeneration: DNAJC3; 13q32

  X-linked
    CMTX1 (Males): GJB1 (CX32); Xq13
    CMTX3: Xq27
    Pyramidal signs
CMT & HMSN: Axonal
  Dominant
    CMT 2A2A: MFN2; 1p36
    ? CMT 2A1: KIF1B; 1p36
    CMT 2B: RAB7; 3q21
    CMT 2C: TRPV4; 12q24
    CMT 2D: GARS; 7p14
    CMT 2E: NEFL; 8p21
    CMT 2F/ Distal HMN: HSPB1; 7q11
    CMT 2G: See CMT 2P
    CMT 2I: P0; 1q22
    CMT 2J: P0; 1q22
    CMT 2K: GDAP1; 8q21
    CMT 2L: HSPB8; 12q24
    CMT 2M: DNM2; 19p13
    CMT 2N: AARS; 16q22
    CMT 2O: DYNC1H1; 14q32
    CMT 2P: LRSAM1; 9q33
    CMT 2Q: DHTKD1; 10p14
    CMT 2U: MARS; 12q13
    CMT 2V: NAGLU; 17q21
    CMT 2W: HARS; 5q31
    CMT 2Y: VCP; 9p13
    CMT 2Z: MORC2; 22q12
    CMT 2CC: NEFH; 22q12
    CMT 2DD: ATP1A1; 1p13
    CMT 2: TFG; 3q12
    CMT 2: DGAT2; 11q13
    CMT 2: MME; 3q25
    CMT 2: JAG1; 20p12
    CMT 2: GBF1; 10q24
    CMT2: CADM3: 1q23
    CMT2-like: BSCL2; 11q13
    Giant axonal 2: DCAF8; 1q22
    HMSN: BAG3
    HMSN + Deafness
      P0
      Connexin-31 (GJB3)
      Eye ± Ear dysfunction
    HMSN + Optic atrophy
      HMSN6A: MFN2; 1p36
    HMSN-Proximal: TFG; 3q12
    CMT2 + Pyramidal
      HMSN5: 4q34
      MFN2; 1p36
      KIF5A: 12q13
    HSMN + Ulcero-mutilation
    HMSN: SPTLC3; 20p12
    HSMN + Ataxia: IFRD1; 7q31
    CFEOM3: TUBB3; 16q24
    HSAN I
      SPTLC1: 9q22
      SPTLC2: 14q24

  X-linked
    Semi-Dominant
      1: GJB1 (CX32); Xq13
      6: PDK3; Xp22
    Recessive
      2: Xp22.2
      3: Xq27
      4 (Cowchock): AIFM1; Xq26
      5: PRPS1; Xq22
      Sensory PN + Deaf: Xq26

  Recessive
    AR-CMT2
      A (B1): Lamin A/C; 1q22
      B (B2): PNKP; 19q13
        PNKP: 19q13
      F/Distal HMN: HSPB1; 7q11
      H/Pyramidal signs: 8q21
      K/Hoarseness: GDAP1; 8q21
      P: LRSAM1; 9q33
      R: TRIM2; 4q31
      S: IGHMBP2; 11q13
      T: MME; 3q25
      X: SPG11; 15q21
      A2B: MFN2; 1p36
      EE: MPV17; 2p23
      AHNAK2: 14q32
      EGR2; 10q21
      HSJ1/DNAJB2; 2q35
      MCM3AP (GANP): 21q22
      PRPH: 12q13
      SACS: 13q12
      SORD; 15q21
    Acrodystrophy: ATSV; 2q37
    Andermann: KCC3; 15q14
    Ataxia + Neuropathy
      Cough + Sensory
      Hepato-Cerebellar: SCYL1; 11q13
      Neuropathy: Dystonin; 6p12
      SCAN
    Early onset
      CMT: SCO2; 22q13
      Lethal Neonatal
      NBIA2A: PLA2G6; 22q13
      Ouvrier
      Optic: MFN2; 1p36
      Respiratory failure
        REEP1: 2p11
        MFN2: 1p36
      Severe: NEFL; 8p21
    Episodic: SGPL1; 10q22
    Giant axonal: Gigaxonin; 16q23
    Neuromyotonia: HINT1; 5q31
    Optic neuropathy (HMSN6)
      HMSN6AR: MFN2; 1p36
      HMSN6B: SLC25A46; 5q22
      HMSN6C: PDXK; 21q22
      HMSN ± Deaf
      Mitochondrial
    Syndromes: HMSN+
      Childhood onset
      CNS
      Deafness

  Mitochondrial
    MT-ATP6
    mtRNAVal
CMT + Intermediate NCV
  Dominant
    CMT-DIA: 10q24
    CMT-IB: DNM2; 19p13
    CMT-DIC: YARS; 1p35
    CMT-DID: P0; 1q22
    CMT-DIE: INF2; 14q32
    CMT-DIF: GNB4; 3q26
    CMT-DIG: NEFL; 8p21
    CMT-DI: c1orf194; 1p13
    CMT-DI: EBP50; 17q25.1
    CMT-X (Semi-dominant): GJB1
    CMT 1C: LITAF; 16p13
    CMT 2E: NEFL; 8p21
    Hypomyelination: ARHGEF10; 8p23

  Recessive
    CMT RIA: GDAP1; 8q21.1
    CMT RIB: KARS; 16q23
    CMT RIC: PLEKHG5; 1p36
    CMT RID: COX6A1; 12q24
    CMT XI: DRP2; Xq22


Other related names or disorders

  α-Methylacyl-CoA racemase (AMACR)
  Brachial plexopathy, Hereditary
  Childhood onset neuropathies
  CNS & Cranial nerve disorders
  Complex clinical syndromes
  Congenital Hypomyelinating
    EGR2: 10q21
    P0: 1q22
    PMP-22: 17p11
    ARHGEF10; 8p23
  Connective tissue: EMILIN1; 2p23
  Cowchock: AIFM1; Xq26
  Dejerine-Sottas (HMSN 3)
  Focally folded myelin sheaths
    CMT 4B: MTMR2; 11q23
    CMT 4B2: SBF2; 11p15
    CMT 4E: EGR2; 10q21
    CMT 4F: Periaxin; 19q13
    P0: 1q22
    Juvenile glaucoma
  Hereditary
    Motor neuropathies
      Distal (dHMN)
    Sensory neuropathies (HSN; HSAN)
  Metabolic abnormalities
  Minifascicles & Gonadal dysgenesis
    HSN: DHH; 12q12
  Myelin disorders; Recessive
  Recurrent
    Brachial plexopathy
    Pressure palsies (HNPP): PMP-22
    Neuropathy: 21q21
  SCA + Neuropathy
  SMARD
  SPG + Neuropathy
  Vertical talus: HOXD10; 2q31
Charcot-Marie-Tooth (CMT)
  Features
    Associated
    Childhood
    Childhood CMT
    Comparative
    General
    Molecules
    Pathology
  Myelin proteins
  External links
    Mutation database
    Mutations


Charcot (left) & Babinski
at the Salpêtrière clinic.


OVERVIEW 119

Prevalence
  • Hereditary neuropathies: 10 to 40 per 100,000
  • CMT Type 1: 15 per 100,000
  • CMT 1A
  • CMT 2: ? 7 per 100,000
  • Most common
Tissue & Functional involvement

Duchenne
CMT

R Baloh
Hereditary Neuropathies: Related Molecules

Pathology in hereditary neuropathies: Differential diagnosis 120
Other hereditary motor-sensory neuropathies
   
Bramwell 1907
Clinical CMT (HMSN): Differential Diagnosis & Associated Features 93

Neuropathy: CMT Genes & Drugs


HMSN types: Comparison of clinical features 36
Disorder Gene Locus Usual onset Early or distinct
symptoms
Tendon
Reflexes
NCVs
CMT1: Dominant; Demyelinating
CMT 1A PMP-22
Duplication
17p11 1st decade Distal weakness
Commonest form
Absent 15 to 20 M/s
CMT 1B P0 1q22 1st decade Distal weakness
More severe
Absent <20 M/s
CMT 1C LITAF 16p13 2nd decade Distal weakness Reduced 16 to 25 M/s
CMT 1D EGR2 10q21 2nd decade Distal weakness
Ptosis
Absent 26 to 42 M/s
CMT 1F NF-68 8p21 1 to 40 yrs Distal weakness
Ataxia
Reduced Axon loss
CMT 1 Fibulin-5 14q32 3rd to 6th decade Distal weakness Reduced Axon loss
CMT 1 PMP2 8q21 1st & 2nd decade Distal weakness Absent 15 to 22 M/s
CMT X (S-D*) GJB1 Xq13 2nd decade Distal weakness
Hearing loss
Encephalopathy
Absent distal 25 to 40 M/s
HNPP PMP-22
Deletion
17p11 3rd decade Focal episodic
weakness
Normal Entrapments
Dejerine-Sottas
  (HMSN 3)
PMP-22
8q23
EGR2
17p11
8q23
10q21
2 yrs Severe weakness Absent <10 m/s
CMT DIB DNM2 19p13 1st or 2nd
decade
Distal weakness
Neutropenia
Reduced
Distal
25 to 50 m/s
CMT DIE INF2 14q32 1st to 3rd
decade
Distal weakness
Renal (Proteinuria)
Reduced
Distal
23 to 45 m/s
CMT
  Intermediate
  NCV
10q24
YARS
P0
CMT-X
GNB4
10q24
1p35
1q22 
Xq13
3q26
1st to 5th
decade
Distal weakness   15 to 50 m/s
CMT2: Dominant; Axonal
CMT 2A MFN2 1p36 10 yrs Distal weakness
CNS
Hearing Δ
Absent distal > 38 M/s
CMT 2B RAB7 3q13 2nd decade Distal weakness
Sensory loss
Acromutilation
Absent distal Axon loss
CMT 2C TRPV4 12q24 1st decade Vocal cord &
Distal weakness
Absent > 50 M/s
CMT 2D GARS 7p15 16 to 30 yrs Distal weakness
  Arms > Legs
Reduced Axon loss
CMT 2E NF-68 8p21 1 to 40 yrs Distal weakness Reduced Axon loss
CMT 2F/
  Distal HMN
HSPB1 7q11 6 to 54 yrs Difficulty walking Reduced ankle Axon loss
CMT 2G   12q12 15 to 25 yrs Distal weakness Reduced 42 to 58 M/s
CMT 2K GDAP1 8q13 Infant Distal weakness
Vocal cord
Early disability
Reduced Axon loss
CMT 2L HSPB8 12q24 15 to 33 yrs Distal weakness Reduced Axon loss
CMT 2M DNM2 19p13 0 to 50 yrs Distal weakness
  Legs > Arms
Ophthalmoparesis
Reduced Axon loss
CMT 2N AARS 16q22 6 to 54 yrs Distal leg weak
Asymmetric
Reduced Axon loss
HMSN-P   3q13 17 to 50 yrs Proximal weakness
Cramps
Absent Axon loss
HSMN + Ataxia IFRD1 7q31 13 to 27 yrs Gait ataxia Absent Axon loss
CMT 2 P0 P0 1q22 37 to 61 yrs Leg weakness
Pupil or Hearing Δ
Reduced < 38 M/s to
Normal
AR-CMT2: Recessive; Axonal
AR-CMT2A Lamin A/C 1q22 2nd decade Distal weakness Reduced Axon loss
AR-CMT2B MED25 19q13 3rd & 4th
decade
Distal weakness Absent distal Axon loss
AR-CMT2 LRSAM1 9q33 2rd to 5th
decade
Distal weakness &
Sensory loss
Absent Axon loss
AR-CMT2
(CMT 2B5)
NEFL 8p21 < 2 years Severe
Distal weakness &
Sensory loss
Absent Axon loss
AR-CMT2 HSPB1 7q11 1st to 6th decade Distal weakness Reduced Axon loss
Andermann KCC3 15q13 1st decade Hypotonia Absent Mildly
reduced
Cowchock AIFM1 Xq26 1st decade Distal weakness
Retardation
Absent Axon loss
CMT X5 PRPS1 Xq22 8 to 13 yrs Legs
Hearing loss
Optic neuropathy
Reduced Axon loss
CMT4: Recessive; Demyelinating
CMT 4A GDAP1 8q13 Childhood Distal weakness
Vocal cord
Reduced Slow
CMT 4B MTMR2 11q22 2 to 4 yrs Distal & Proximal
weakness
Absent Slow
CMT 4B2 SBF2/
  MTMR13
11p15 1st 2 decades Distal weakness
Sensory loss
Glaucoma
Absent 15-30 m/s
CMT 4C SH3TC2 5q23 5 to 15 yrs Delayed walking Reduced 14 to 32 M/s
CMT 4D (Lom) NDRG1 8q24 1 to 10 yrs Gait disorder
Hearing Δ
Absent 10 to 20 M/s
CMT 4E EGR2 10q21 Birth Infant hypotonia
Arthrogryposis
Respiratory failure
Absent 9 to 20 M/s
CMT 4F Periaxin 19q13 1 to 3 yrs Motor delay
Sensory loss
Absent Absent
HMSN-Russe (4G) HK1 10q22 8 to 16 yrs Distal leg
weakness
  Moderately
reduced
CMT 4H FGD4 12q12 10 to 24 mo Walking delay
Severe; Scoliosis
Absent < 15 M/s
CMT 4J FIG4 6q21 Congenital
  to Adult
Asymmetric
Proximal &
Distal weakness
Absent 2 to 40 M/s
CMT 4 SURF1 9q34 Childhood Distal weakness &
  sensory loss
Absent 15 to 22 M/s
Dejerine-Sottas
  (HMSN 3)
P0
CMT 4F
1q22
19q13
2 yrs Severe weakness Absent <10 M/s
Congenital
  Hypomyelinating
  Neuropathy
P0
EGR2
PMP-22
1q22
10q21
17p11
Birth Severe weakness Absent <10 M/s
CCFDN CTDP1 18q23 1st or 2nd
decade
Distal leg weak
Cataracts
Retardation
Reduced 20 to 34 M/s
* Semi-Dominant


External links

Hereditary Motor-Sensory Neuropathy (HMSN) Syndromes


CMT IA

  PMP 22 ; Chromosome 17p12; Dominant

PMP-22 mutation types
  Duplication
    Contiguous gene (YUHAL)
  Triplication
  Homozygous (Duplication)
  Point
  Recessive
CMT 1E (Deafness)
PMP-22
  Clinical-Gene relations
  Gene mutations
  Protein
Pathology

Also see: HNPP

CMT 1A
PMP-22 Duplication

Chaddock 1900

CMT IB + Other P0 Neuropathies 61

  Myelin Protein Zero (P0; MPZ) ; Chromosome 1q23.3; Dominant > de novo or Recessive

P0: Genetic features
P0 protein
P0 Clinical syndromes
Myelin Δ
  CMT 1B: Dominant
  CMT 1B (Roussy-Levy): Dominant
  CMT 1B: Dominant; Pupils; Early onset
  CMT 1E: Dominant; Hearing loss
  CMT: Semi-Dominant
  Dejerine-Sottas: Dominant or Recessive
  Steroid responsive, Late-onset
  Hypertrophic radiculopathy
  Entrapment + Focal-folding
  Increased P0 gene dosage: Dominant
  Congenital: Rec or Dom; Hypomyelin
Axonal
  CMT 2I: Dominant
  CMT 2J: Dominant; Pupil Δ; Hearing ↓
  Adult onset (Axonal)
Intermediate NCV
  CMT-DID: Dominant
P0 variant syndromes
P0

P0

CMT 1C 20

  Lipopolysaccharide-induced tumor necrosis factor-α factor (LITAF; SIMPLE; EET1; PIG7) ; Chromosome 16p13.13; Dominant

EGR2 mutations: CMT 1D & Other phenotypes

  EGR2 (Krox20) ; Chromosome 10q21.3; Dominant or Recessive

Hereditary Neuropathies (CMT 1 or D-HMN) ± Macular Degeneration & Hyperelastic Skin (HNARMD) 91

  Fibulin-5 (FBLN5) ; Chromosome 14q32.12 Dominant

CMT 1G 129

  Peripheral myelin protein 2 (PMP2) ; Chromosome 8q21.13; Dominant or Sporadic

CMT 1 150

  c1orf194 ; Chromosome 1p13.3; Dominant

CMT 1 170

  Inositol 1,4,5-Trisphosphate Receptor, Type 3 (ITPR3; IP3R3) ; Chromosome 6p21.31; Dominant or de novo

CMT: X-linked

Type 1: GJB1
  Variants
Type 2
Type 3
Type 4 (Cowchock): AIFM1
Type 5: PRPS1
Pyramidal signs


CMT 2

General features
CMT 2A: General

CMT 2A1
  Kinesin family member 1Bβ (KIF1B) ; Chromosome 1p36.22; Dominant
CMT 2A2A 172
  Mitofusin 2 (MFN2; KIAA0214) ; Chromosome 1p36.22; Dominant, Semi-Dominant or Recessive
  • Nosology: CMT 2A2; HMSN2A2
  • Epidemiology
    • Frequency: 8% to 33% of CMT2 probands
    • Most common CMT 2 type
    • More common in severe CMT2 population
  • MFN2 genetics
  • MFN2 protein 55
    • Mitochondrial: Transport & Fusion protein
    • Dynamin-related
    • Ubiquitously expressed: Present in spinal cord & peripheral nerve; Muscle; Heart
    • Cellular localization
    • Anchored to mitochondrial membrane by C-terminal domain
    • GTPase domain
      • N-terminal: Located in cytoplasm
      • High affinity for GTP
      • Lower GTPase activity than MFN1
    • May complex with: MFN1 ; Miro1 ; Miro2 : THG1L
    • Functions
      • Mitochondrial fusion
        • May participate in later stage of fusion than MFN1
        • May be associated with intermixing of mitochondria during cell fusion reaction
        • Regulates mitochondrial network architecture by mitochondrial fusion
      • Tethers ER to mitochondria: Required for efficient mitochondrial Ca++ uptake
      • Axon transport of mitochondria, bidirectional
    • Regulates OXPHOS expression
      • Loss-of-function
        • Inhibits pyruvate, glucose and fatty acid oxidation
        • Reduces mitochondrial membrane potential
        • Reduced expression of subunits in complexes I, II, III and V
      • Gain-of-function
        • Increased glucose oxidation
        • Increased mitochondrial membrane potential
      • Independent of effect on mitochondrial fusion
    • MFN2 deficient mice: Lower mitochondrial mobility
    • MFN2 mutant protein
      • May have dominant negative effect
      • May produce mitochondrial
        • Hypofusion (Arg94Gln, Thr105Met)
        • Hyperfusion (Leu76Pro, Arg364Trp)
  • Clinical 57
    • General
      • Similar to CMT 2A1, CMT 2E & CMT 2F
      • Severe phenotype more common: Early onset; More weakness
      • Some patients with mutations remain asymptomatic & without NCV changes
    • Onset
      • Age: Mean 12 to 15 years; Range 6 months to 5th decade
      • Gait disorder
      • Weakness: Distal legs
      • Childhood onset: More severe disease
    • Polyneuropathy
      • Weakness
        • Distal
        • Legs > Arms
        • Gait disorder
        • Course: Some need walking aids or lose ambulation
      • Sensory loss
        • Pansensory
        • Some: Small > Large fiber involvement
      • Tendon reflexes: Ankle absent; Knee reduced
      • Exacerbated by
        • Ethambutol: 1 patient
          • Onset: Months after treatment onset
          • Weakness: Increased
          • Vocal cord paralysis
          • Eye: Visual loss; Optic atrophy
          • Course after drug stopped: Improvement in vision
          • Ethambutol also exacerbates OPA1
        • ? INH
    • Optic atrophy (9%)
      • Associated with: More severe neuropathy phenotype; de novo mutations
      • Mutations: R94W; T206; Q276R; H361Y; R418X
      • Frequency with dominant MFN2 mutations: 7%
      • Onset: May be subacute visual loss with recovery
    • Other
      • Discomfort: Pain; Cramps
      • Tremor
      • Hearing loss
      • Macrocephaly
    • Course
      • Progressive: Wheelchair in 27%
      • Life span: Normal
  • Laboratory
    • Nerve conduction testing
      • Velocity: Slightly reduced
      • CMAP amplitude: Reduced, severe
      • SNAP amplitude: Reduced, severe
      • Axon loss: Progressive
      • Demyelinating features: Occasional patient
    • Nerve pathology 75
      • Myelinated axons: Loss; Especially large axons
      • Mitochondria: Degeneration or Small; Aggregation
      • Myelin: Thin
      • Onion bulbs: Occasional
      • Unmyelinated axons: Increased numbers

  • MFN2 variant: Cognitive impairment & Brain mitochondrial dysfunction + HMSN 73
    • Genetics
      • Mutation: R104W
      • inheritance: Dominant
    • Clinical
      • Spastic paraparesis
      • Polyneuropathy: Severe; Axonal or Demyelinating
      • Intrafamilial variability

  • MFN2 variant: Early onset stroke without neuropathy 72
    • Epidemiology: 1 Korean family
    • Genetics
      • Mutation: P456L
    • Clinical
      • Onset age: 12 & 47 years

  • MFN2 variant: Severe, Early Onset Axonal Neuropathy (SEOAN) 74
    • Genetics
      • Mutations: Homozygous or Compound heterozygous
      • Inheritance: Semi-Dominant
      • Parents: Asymptomatic or Mildly symptomatic
    • Clinical
      • Onset age: 2 to 3 years
      • Weakness: Diffuse; Distal > Proximal; Arms & Legs
      • Sensory loss: Distal; Arms & Legs
      • Disability: 2 to 32 years

  • MFN2 Variant syndrome: HMSN & Optic atrophy, Type VIA (HMSN 6A; HMSN VIA)
      Mitofusin 2 (MFN2) ; Chromosome 1p36.2; Dominant or Sporadic (New mutation)
    • Genetics 60
      • Mutation types: Missense & Nonsense
      • Mutations: R94W; T206I; Q276R; H361Y; R364W; R418X
      • Incomplete penetrance of visual loss: Q276R
      • Late onset visual loss: R94W
      • Allelic disorders
    • Optic atrophy
      • Onset
        • Time course
          • Adult: Hours to Weeks
          • Childhood: Progressive
        • Age: 5 to 50 years
      • Central scotoma
      • Color vision: Reduced
      • Course: Stable or Slow recovery of visual acuity (60%)
      • Optic disks: Pale
      • May be bilatersl
      • VEP: Prolonged
    • Neuropathy
      • Onset age: Mean 2 years; Range 1 to 10 years
      • Severe
      • Arms & Legs
      • Weakness
        • Distal > Proximal
        • Vocal cord involvement: Some patients
      • Sensory loss
        • Distal
        • Panmodal
        • Not disabling
      • Tendon reflexes: Reduced in legs or diffusely
      • Course: Progresses to gait disorder or wheelchair

  • MFN2 Variant syndrome: HMSN, Recessive Axonal (CMT2A2B) 92
    • Genetics
      • MFN2 Mutations
        • Missense (Phe216Ser; Thr362Met; Arg519Pro); Nonsense (Glu308X); Intragenic deletion
        • Common: Compound heterozygous
        • Homozygous
          • Adult onset: R632W
          • Severe childhood onset: Gly176Ser
        • Heterozygous carriers: Asymptomatic
      • Allelic disorders
    • Clinical
      • Onset
        • Age: Birth to 6th decade; Median 8 years
        • Foot drop
        • Hypotonia
      • Weakness
        • Arms & Legs
        • Distal
        • Knee & Elbow: Severe phenotypes
        • Diaphragm: Severe patient
        • Course: Progress to wheelchair
        • Severity: Variable among pedigrees
      • Sensory loss: Some patients; Pan-modal
      • CNS
        • Optic atrophy
          • Visual loss
          • 20% of recessive MFN2 mutations
        • Psychomotor delay: Severe patients
      • Skeletal
        • Scoliosis: Some patients
        • Contractures
        • Arthrogryposis: Severe cases
    • Laboratory
      • Nerve conduction studies
        • CMAPs & SNAPs: Absent or Reduced amplitude
        • Conduction velocities: Normal
      • Sural nerve: Axon loss; Abnormal mitochondria
      • Brain MRI: Spinal cord atrophy; White matter lesions

  • Variant Syndrome: HMSN + Pyramidal signs (HMSN5)

  • Variant Syndrome: Canine fetal-onset neuroaxonal dystrophy
    • Homozygous deletion


From: R Baloh MD

CMT 2A2

CMT 2A2

CMT 2B
  RAS-Associated protein RAB7 (RAB7; RAB7A) ; Chromosome 3q21.3; Dominant

CMT 2C (HMSN 2C) 27
  TRPV4 ; Chromosome 12q24.11: Dominant
CMT 2D
  Glycyl tRNA Synthetase (GARS) ; Chromosome 7p14.3; Dominant
CMT 1F 39
  Neurofilament light chain (NEFL) ; Chromosome 8p21.2; Dominant or Sporadic CMT 2E 4
  Neurofilament light chain (NEFL) ; Chromosome 8p21.2; Dominant AR-CMT (CMT 2B5): Severe, Early onset 78
  Neurofilament light chain (NEFL) ; Chromosome 8p21.2; Recessive
CMT 2F/ Distal HMN 19
  Heat-shock 27-kD protein 1 (HSPB1; HSP 27) ; Chromosome 7q11.23; Dominant or Recessive
CMT 2L 47
  Heat-shock 22-kD protein 8 (HSPB8) ; Chromosome 12q24.3; Dominant
CMT 2N 81
  Alanyl-tRNA Synthetase (AARS) ; Chromosome 16q22.1; Dominant
CMT 2O 96
  Dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) ; Chromosome 14q32.31; Dominant
CMT 2Q 108
  2-Oxoglutarate dehydrogenase E1 component DHKTD1, mitochondrial, Probable (DHTKD1) ; Chromosome 10p14; Dominant
CMT2/Distal HMN 169
  Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1 (GBF1) ; Chromosome 10q24.32; Dominant or de novo

CMT2/Distal HMN 175
  Cell Adhesion Molecule 3 (CADM3) ; Chromosome 1q23.2; Dominant or de novo

Charcot-Marie-Tooth disease, Recessive Intermediate D (CMTRID) 123
  COX6A1 ; Chromosome 12q24.31; Recessive


HMSN-P

CMT 2-P0



Hereditary Sensory-Motor Neuropathy with Ataxia (SMNA) 26
  Interferon-related developmental regulator gene 1 (IFRD1) ; Chromosome 7q31.1; Dominant


CMT with Intermediate NCV (DI-CMT) 17



DI-CMT, Type A (CMTDIA)
  Chromosome 10q24.1-q25.1; Dominant


DI-CMT, Type B (CMTDIB)
  Dynamin 2 (DNM2) ; Chromosome 19p13.2; Dominant

DI-CMT, Type C (CMTDIC) 43
  Tyrosyl-tRNA synthetase (YARS) ; Chromosome 1p35.1; Dominant


DI-CMT, Type E (CMT-DIE): CMT, Intermediate with Glomerulopathy 101
  Inverted formin 2 (INF2; c14orf173) ; Chromosome 14q32.33; Dominant or Sporadic


DI-CMT, Type F (CMT-DIF) 113
  Guanine nucleotide-binding protein, β4 (GNB4) ; Chromosome 3q26.33; Dominant

DI-CMT 156
  Solute carrier family 9, Member 3, Regulator 1 (SLC9A3R1; EBP50; NHERF1) ; Chromosome 17q25.1; Dominant

Other CMT disorders with intermediate NCV

Recessive, Axonal CMT

AR-CMT2A: Lamin A/C; 1q22
AR-CMT2B: MED25; 19q13.3
AR-CMT2 + Hoarseness (CMT 2K): GDAP1; 8q21
AR-CMT2, Severe & Early onset: NEFL; 8p21
AR-CMT2/Distal HMN: HSPB1; 7q11-q21
AR-CMT2: LRSAM1; 9q33
AR-CMT2-Acrodystrophy
AR-CMT2-Ouvrier: Early childhood onset
AR-CMT2 + Neuromyotonia: HINT1; 5q31
Andermann (Corpus callosum Δ): 15q13
CMT X-linked
HMSN + CNS: Heterogeneous
Giant axonal neuropathy: Gigaxonin; 16q24
HMSN + Deafness
HMSN + Optic neuropathy ± Deafness
Lethal Neonatal
Neuroaxonal dystrophy




Axonal CMT (AR-CMT2A; CMT2B1) 1
  Lamin A/C ; Chromosome 1q22; Recessive
Axonal CMT (AR-CMT2B; CMT2B2) 12
  Polynucleotide Kinase 3' Phosphatase (PNKP) ; Chromosome 19q13.33; Recessive


CMT 2K 23
  Ganglioside-induced differentiation-associated protein 1 (GDAP1) ; Chromosome 8q21.11; Recessive or Dominant

GDAP1 CMT Variants
  Axonal
    Recessive (AR-CMT 2K)
    Recessive, Mild
    Dominant (CMT 2K)
  Intermediate
    Recessive, Type A (CMT RIA)
  Demyelinating
    Recessive, (CMT 4A)



Axonal CMT (AR-CMT): Ouvrier type
  Autosomal Recessive or Semi-Dominant


Axonal CMT with pyramidal involvement (AR-CMT2C; CMT4C2; CMT 2H) 14
  Chromosome 8q21.3; Recessive

HMSN with Intermediate NCV, X-linked (CMT XI) 128
  Dystrophin-related protein 2 (DRP2) ; Chromosome Xq22.1; Recessive

Hereditary Ulcero-mutilating Sensory > Motor Neuropathy, Recessive (HSAN IIC; HSN2C) 94
  Axonal transporter of synaptic vesicles (KIF1A; ATSV) ; Chromosome 2q37.3; Recessive

Axonal CMT (CMT2) with Acrodystrophy, Recessive
  Recessive 8

Axonal CMT (CMT2P), Recessive
  Leucine-rich repeat- and sterile alpha motif-containing 1 (LRSAM1) ; Chromosome 9q33.3; Recessive 90 or Dominant 99

Axonal CMT2, Recessive + Neuromyotonia (ARAN-NM; AR-CMT2 + Neuromyotonia; NMAN) 106
  Histidine triad nucleotide-binding protein 1 (HINT1) ; Chromosome 5q31.1; Recessive
  • Nosology
  • Epidemiology
    • 11% of AR-CMT2 families: > 60 families
    • Common in
      • Eastern Europe & Czech: Arg37Pro founder mutation; Carrier frequency up to 1/67
      • Portugal Roma & Italy: H112N
  • Genetics: Mutations
    • Missense
    • Loss of function
    • Glu34Lys; Arg37Pro; Q62X; C84R; G89V; G93D; H112N; W123X; c.148_149delAC
  • HINT1 protein
    • Histidine triad family
    • Subunit structure: Homodimer
    • Interacts with: CDK7
    • Subcellular location: Cytoplasm, Nucleus
    • Ubiquitously expressed
    • Purine phosphoramidase
      • Hydrolyzes adenosine 5'-monophosphoramidate substrates
      • Preferentially hydrolyses adenosine derivatives with a single phosphate, including phosphoramidates
    • Binds to lysyl-tRNA synthetase (KARS; LysRS)
    • Transcription factors regulated by HINT1
      • MITF , USF2 , Pontin (RUVBL1) , Reptin (RUVBL2)
      • Inhibits activator protein-1 (AP1; JUN) transcription factor by binding to POSH-JNK2 complex
    • Interacts with the μ-opioid receptor (MOR), major molecular target for morphine analgesia
  • Clinical
    • General: Motor > Sensory
    • Onset
      • Age: Often childhood; Range 3 to 28 years
      • Gait imbalance
    • Weakness
      • Distal
      • Legs > Hands (Finger extensors)
      • May be asymmetric
    • Muscle wasting: Distal; Legs & Hands
    • Neuromyotonia
      • Rest: Myokymia
      • Legs: Stiffness
      • Cramps & Fasciculations: Arms & Legs
      • Myotonia
        • Action, Not Percussion
        • Worse in Cold
        • Increased with action
        • Especially hands & grip
      • Frequency: 70% to 80%
      • Increased with nerve ischemia
    • Sensory loss: Some patients
    • Tendon reflexes: Reduced or Absent; Worse with disease progression
    • Joints
      • Hands: Flexion contractures with disease progression
      • Feet: Deformities
        • Pes cavus, equinovarus, cavovarus or Achilles tendon shortening
        • Toe contractures
      • Scoliosis (33%)
    • Course: Progressive; Most remain ambulatory > 60 years
  • Laboratory
    • Sensory nerve biopsy: Axon loss
    • EMG
      • Neuromyotonia
        • Spontaneous peripheral nerve discharges
          • Often increased by: Voluntary muscle contraction
        • Electrical activity
          • Enhanced by: Nerve ischaemia,
          • Not by: Mechanical or Rlectrical stimulation
      • Neurogenic changes: Distal > Proximal
    • NCV
      • Axon loss
        • Motor: 100%
        • Sensory: 65%
      • Conduction velocities: Normal
    • Serum CK: Normal to 1300; High in 33%
    • Sural nerve biopsy: Axon loss
  • Heterozygous carriers: Normal

NMAN: Leg wasting, Distal


Axonal CMT2, Recessive, Early-onset 115
  Tripartite motif-containing protein 2 (TRIM2) ; Chromosome 4q31.3; Recessive

AR-CMT2T: Axonal CMT2, Recessive, Adult onset 133
  Membrane metalloendopeptidase (MME; CD10; CALLA; Neprilysin; NEP) ; Chromosome 3q25.2; Recessive

AR-CMT2 + Intellectual Disability (PNRIID) 138
  Minichromosome maintenance 3-associated protein (MCM3AP; GANP) ; Chromosome 21q22.3; Recessive

AR-CMT2 147
  AHNAK Nucleoprotein 2 (AHNAK2) ; Chromosome 14q32; Recessive

Episodic Axonal Neuropathy, Recessive 137
  Sphingosine 1-phosphate lyase (SGPL1) ; Chromosome 10q22.1; Recessive

Hefreditary Motor-Sensory or Motor Neuropathy (SORDDPN) 162
  Sorbitol Dehydrogenase (SORD) ; Chromosome 15q21.1; Recessive
  • Epidemiology
    • Common AR-CMT2 disorder
    • 45 individuals in 38 families
    • Estimated disease prevalence: 1/100,000
  • Genetics
    • Mutations
      • Nonsense (Common) or Missense
      • c.757delG (1 base pair deletion)
        • Most patients
          • Homozygous, or
          • Compound heterozygous +
              Another mutation
        • Carrrier frequency
          • General: 3/1,000
          • Amish: 3%
          • Africa & Asia: Rare
      • 69% of patients sporadic
      • Other mutations
        • Arg299X, R110P, R100X, A153D,
          V322I, L10F, c.316_425+165del
    • Allelic disorder: Cataract, congenital
  • SORD protein
    • Interconversion of polyols & their corresponding ketoses
    • Sorbitol pathway: Related to diabetic complications
  • Clinical
    • Onset
      • Age: Mean 17 years; Range 2 to 40 years
      • Gait disorder
    • Foot deformities (69%)
    • Weakness (100%)
      • Distal
      • Legs (98%): Mild to Severe
      • Arms (59%): Mild
    • Sensory loss
      • Vibration (43%)
      • Pin (33%)
    • Tremor: 20%
  • Laboratory
    • NCV
      • Common: Mildly reduced or Normal
      • Intermediate values in 9%
    • SNAP amplitudes: Normal or Reduced (65%)
    • SORD
      • Protein in tissue: Reduced
      • Sorbitol: Increased in Cells & Serum
      • Aldose reductase inhibitor effects
        • Reduce intracellular sorbitol levels



Normal nerve
SORD is present in scattered Endoneurial cells


HMSN III (Dejerine-Sottas) 32

General
Clinical
Types

Dejerine & Sottas 1893

Hereditary Liability to Pressure Palsies (HNPP)

PMP-22 mutations
  Clinical
  Genetics
    Biallelic deletions
  Laboratory
  Pathology
    Images
KARS mutations

HNPP: PMP-22 Genetics
  PMP-22 deletion; Chromosome 17p12; Dominant

HNPP-PMP22: Clinical features 44 HNPP: Laboratory features
Charcot-Marie-Tooth disease, Recessive Intermediate B (CMTRIB) 88
  Lysyl-tRNA Synthetase 1 (KARS1) ; Chromosome 16q23.1; Recessive or Dominant

CMT 4

General features
CMT 4A
  Ganglioside-induced differentiation-associated protein 1 (GDAP1) ; Chromosome 8q21.11; Recessive

HMSN + Focally-Folded Myelin Sheaths (CMT 4B)


  CMT 4B1
    Myotubularin-related protein-2 (MTMR2) ; Chromosome 11q21; Recessive
  • Epidemiology: Italian, Japanese & Saudi Arabian families
  • Genetics
    • Mutation Types: Nonsense; Frame shift; Exon skipping deletion
    • Mutation Effect: Reduced phosphatase activity
  • Myotubularin-related protein-2
    • High levels in
      • Neurons
      • Schwann cells: Myelinating & Non-myelinating
    • Dual specificity phosphatase: Family of 20 proteins
      • Characterized by protein/tyrosine phosphatase & SID domain
      • SID domain interactions
        • Proteins containing SET domain
          • Associate with chromatin
    • Enzyme action: Dephosphorylates
      • Phosphatidylinositol 3-phosphate
      • Phosphatidylinositol 3,5-bisphosphate
    • Myotubularin family disorders
    • Phosphinositide disorders
    • Interacts with: MTMR5 ; Dlg1
  • Clinical features
    • Onset: < 4 years; Mean 2 years
    • Weakness
      • Distal & Proximal lower extremity
      • Symmetric
      • Progressive: Adults often wheelchair bound
      • Facial: Some with synkinesis
      • Cause of death: Respiratory failure
    • Sensory loss: Panmodal; Distal
    • Tendon reflexes: Absent
    • Pes equinovarus
    • Prominent thick lips
  • Electrophysiology
    • Demyelination: NCV 9 to 20 M/s
    • Myelinated axon loss
  • Pathology
  • Variant syndrome: Mild, later-onset phenotype 118
    • MTMR2 mutation: c.1882–1885delAGAG; Near C-terminus
    • Clinical
      • Onset age: 13 years
      • Gait disorder
      • Weakness: Distal; Hands & Feet
      • Tendon reflexes: Reduced or Absent
      • Course: Slow progression
    • NCV
      • Motor: 21 to 27 M/s
      • Sensory: 31 to 36 M/s in arms
      • Sural SNAPs: Absent
    • Nerve biopsy
      • Myelin: Focally folded
      • Onion bulbs
      • Myelinated axons: Reduced numbers
  • Mouse models
    • Myelin folding: Abnormal
      • Paranodal: Distal nerves > Proximal
    • Nerve conducton velocities: Normal
    • Mutations
      • E276X mutation, homozygous
      • Conditional Knock-out
        • Schwann cell defects: Produce neuropathy
        • Neuronal defects: No neuropathy
CMT4B1 (AR-CMT-DM-MTMR2): Peripheral Nerve Ultrastructure
  Myelin: Remaining sheaths have many, aberrant myelin out-foldings
  Onion-bulbs: Irregular; Small
  Axon loss: Severe

From: JM Vallat & M Tazir

  CMT 4B2 2
    SET binding factor 2 (SBF2) (MTMR13) ; Chromosome 11p15.4; Recessive   HMSN + Focally folded myelin sheaths: With juvenile-onset Glaucoma 6
    SET binding factor 2 (SBF2) (MTMR13) ; Chromosome 11p15.4; Recessive
  CMT 4B3 with Focally folded myelin 117
    SET binding factor 1 (SBF1) (MTMR5) ; Chromosome 22q13.33; Recessive

  HMSN with focally folded myelin sheaths: Dominant
    P0 protein; Chromosome 1q23.3; Dominant
    Additional loci

  HMSN + Focally folded myelin sheaths: Additional locus
    Recessive



CMT 4C
  SH3 domain and tetratricopeptide repeat domain 2 (SH3TC2; KIAA1985) ; Chromosome 5q32; Recessive

CMT 4D: HMSN (Demyelinating) & Hearing loss (Lom type)
  N-myc Downstream-Regulated Gene 1 (NDRG1) ; Chromosome 8q24.22; Recessive


CMT 4F 3
  Periaxin (PRX) ; Chromosome 19q13.2; Recessive


HMSN-Russe (HMSNR; CMT 4G) 5
  Hexokinase 1 (HK1) ; Chromosome 10q22.1; Recessive

CMT 4H 52
  frabin/FGD4 ; Chromosome 12p11.21; Recessive

CMT 4J 69
  FIG4 phosphoinositide 5-phosphatase (FIG4; SAC3) ; Chromosome 6q21; Recessive

HMSN + CNS or Cranial nerve involvement

Dominant, Axonal
Dominant, Demyelinating
Recessive, Axonal
Recessive, Demyelinating
X-linked, Demyelinating
Childhood onset


HMSN + CNS or Cranial nerve: Dominant, Demyelinating


HMSN + Systemic, CNS or Cranial nerve Disorders: Dominant, Axonal


HMSN + CNS or Cranial nerve: Recessive, Axonal neuropathy


HMSN + CNS or Cranial nerve: Recessive, Demyelinating


REFSUM SYNDROMES (Peroxisome Biogenesis Disorders; Zellweger syndromes)


HMSN + CNS or Cranial nerve: X-linked, Demyelinating

HMSN with pyramidal signs & cerebral white matter lesions 40
  Semi-Dominant

Hereditary Neuropathies - Other

α-Methylacyl-CoA racemase (AMACR) deficiency
  AMACR ; Chromosome 5p13.2; Recessive
HMSN with Minifascicle Formation & 46XY Pure Gonadal Dysgenesis 25
  desert hedgehog (DHH) ; Chromosome 12q13.12; Sporadic (Recessive)
HMSN + Congenital vertical talus 49
  HOXD10 ; Chromosome 2q31.1; Dominant
Hereditary Recurrent Neuropathy 122
  Chromosome 21q21.1–q21.3; Dominant
CMT 2W: Peripheral neuropathy, Hereditary 105
  Histidyl-tRNA synthetase 1 (HARS1) ; Chromosome 5q31.3; Dominant or Sporadic
CMT 2U: Peripheral neuropathy, Sensory-Motor 116
  Methionyl-tRNA synthetase (MARS) ; Chromosome 12q13.3; Dominant
CMT 2Z: Peripheral neuropathy, Sensory-Motor 131
  MORC family CW-type zinc finger protein 2 (MORC2) ; Chromosome 22q12.2; Dominant

CMT 2: Peripheral neuropathy, Early onset + Sensory Ataxia 132
  Diacylglycerol O-Acyltransferase 2 (DGAT2) ; Chromosome 11q13.5; Dominant
CMT 2: Polyneuropathy with Vocal Cord Involvement 155
  JAGGED 1 (JAG1) ; Chromosome 20p12.2; Dominant & de novo
CMT 2DD: Peripheral neuropathy, Motor + Sensory 139
  ATPase, Na+/K+ transporting, alpha-1 polypeptide (ATP1A1) ; Chromosome 1p13.1; Dominant
Also see: Childhood onset neuropathies
Patient information
Support groups


Return to Polyneuropathy Index
Return to Neuromuscular home page


References
1. Am J Hum Genet 1999;65:722-727, Neuromuscular Disorders 2003;13:60–67, Brain 2007 Mar 8
2. Genomics 1999;62:344-349, Human Molecular Genetics 2003;12:349–356
3. Am J Hum Genet 2001;68:325-333
4. Am J Hum Genet 2000;67, Brain 2007;130:394–403, JAMA Neurol 2014; Online Sep
5. Am J Hum Genet 2000;67:664-671, Ann Neurol 2001; Online Aug 7, European Journal of Human Genetics 2009; Online June
6. Neurology 2000;55:392-397, Am J Hum Genet 2003;72 Online April3
7. Neuromuscular Disorders 2000;10:497-502
8. J Neurol 1999;246:107-112
9. JNNP 2000;69:806-811, Brain 2003;126:134-151
10. JNNP 2000;69:799-805, J Clin Neurosci 2020;75:228-231
11. Neurology 2000;55:1552-1557
12. Am J Hum Genet 2001;68:269-274, Neuromuscular Disorders 2004;14:301–306. Neurogenetics 2018;19:215-225
13. Neurology 2001;56:100-103
14. Neuromuscular Disorders 2001;11:27-34
15. Lancet 2001;357:267-272
16. Hum Mol Genet 2001;10:947-952
17. Neurology 2001;56:A315, Neuromuscular Disorders 1998;8:392–393, Am J Hum Genet 2001;69:000–000
18. Neuromuscular Disorders 2001;11:400-403, J Neuromuscul Dis 2020 Jun 12
19. Eur J Hum Genet 2001;9:646-650, Neurology 2008; Online October, J Neurol Sci 2020 Mar 27;413:116809
20. Am J Hum Genet 2002;70:244-250, Neurology 2003;60:22-26, Eur J Neurol 2017;24:530-538
21. Neurology 2001;57:1906-1908
22. Nature Genet 2002;30:21-22, Neurology 2002;59:1865–1872
23. Nature Genet 2002;30:22-24, Arch Neurol 2003;60:598-604, Brain 2003;126: August, Brain 2007 Mar 8
24. JNNP 2002;72:396-399
25. Ann Neurol 2002;51:385–388
26. Am J Hum Genet 2002; On-Line April
27. Neuromuscular Disorders 2002;12:399–404, J Neurol Neurosurg Psychiatry 2002;73:762–765, Neurology 2003;60:1151–1156
28. Neurology 2002;58:1769–1773
29. Neuromuscular Disorders 2002;12:386-391
30. Ann Neurol 2002;52:429–434, Pediatr Neurol 2008;38:293-295
31. J Neurol 2002;249:1298-1302
32. Muscle Nerve 2002;26:608–621
33. J Cell Sci 2002;115:4937-4946
34. Muscle Nerve 2003; Online December 2002
35. Am J Hum Genet 2003; On-Line January
36. J Neurol 2002;249:1629-1650, Semin Neurol 2010;30:373-386
37. Neurology 2003;60:506–508
38. Pediatr Neurol 2003;28:115-118
39. Brain 2003;126:590-597, J Neurol Neurosurg Psychiatry 2017 May 13
40. Muscle Nerve 2003;28: 623–625
41. Am J Hum Genet 2003;73:1106–1119, PNAS 2009; Online September 29, N Engl J Med 2010 Mar 10, Hum Mol Genet 2010;19:1009-1018
42. Neurology 2003;61:1154-1155
43. Am J Hum Genet 2003; Online November
44. Muscle Nerve 2004;29:205-210, Acta Neurol Scand 2003;108:352-358, Neuromuscul Disord. 2003;13:827-829
45. Neurology 2003;61:1457-1458
46. J Med Genet 2004;41:193–197
47. Human Genet 2004;114:527–533, Human Genet 2004; Online November
48. J Peripher Nerv Syst. 2004;9:124
49. Am J Hum Genet 2004; Online May
50. J Neuropath Exp Neurol 2004;63:1167-1172
51. J Neurol 2004;251:1491-1497
52. Hum Mol Genet 2005; Online March, Am J Hum Genet 2007; Online March, Neurology 2009;72:617–620
53. Ann Neurol 2005;57:749–754
54. Neurology 2005;64:1964–1967
55. J Cell Sci 2005 Jun 28, Hum Mol Genet 2005;14:1405-1415
56. JNNP 2005;76:1109-1114
57. Neurology. 2005;65:197-204, Neurology. 2005;65:496-497
58. Neuromuscul Disord 2005 On line Sep 27, Neurogenetics 2007 Aug 24
59. Nature Genetics 2005; Online Jan 22
60. Ann Neurol 2005;59:276–281
61. J Neurol Sci 2005; Online
62. JNNP 2006;77:963-966, J Comp Neurol 2006;498:252-265, Neuromuscul Disord 2006;16:308-310
63. Neurology 2006;67;2016-2021, Neurogenetics 2008;9:191-195, Muscle Nerve 2012; Online Nov, PLoS Genet 2016 Jul;12(7):e1006177, Neurology 2018 Apr 6
64. Neurology 2006;67;2250-2252
65. Ann Neurol 2006;59:358–364
66. Otol Neurotol 2005;26:405-414
67. Neurology 2007;68:849–855
68. Neuromuscul Disord. 2007 Apr 10
69. Nature 2007; Online June 17, Brain 2008;131:1990-2001, Ann Neurol 2018 Mar 8
70. Neuromuscul Disord 2008;18:334-338, Neurology 2007;69:291-295
71. Neurology 2009;72:20-27, Am J Hum Genet 2010 Online August
72. Neurology 2008;70:2010-2011
73. Neurology 2008;71:1959–1966
74. Neurology 2008;71:1678–1681
75. J Neuropathol Exp Neurol 2008;67:1097-1102
76. Neurogenetics 2009 Mar 17
77. Am J Human Genet 2009; Online April 30
78. Journal of Human Genetics 2009;54:94–97, Ann Neurol 2009; Online May
79. Neuromuscular Disorders 2009; Online November
80. Nature Genetics 2009; Online Dec A, B, C
81. Am J Hum Genet 2009; Online Dec
82. Am J Med Genet 2010; Online May
83. PLoS One 2010;5:e11258
84. J Human Genetics 2010; Online August
85. J Obes 2011;2011. pii: 482021. Epub 2010 Sep 1
86. Surv Ophthalmol. 2010 Sep 16
87. Neurology 2010;75:1300-1302, Eur J Neurol 2020 Oct 12
88. American Journal of Human Genetics 2010;87:560–566
89. Muscle Nerve 2011; Online February
90. PLoS Genet 2010 Aug 26;6
91. Brain 2011; On-Line May
92. Neurology 2011;77:168–173
93. Neuromuscul Disord 2011;Jul 6
94. Am J Human Genet 2011; Online Aug
95. Genome Research 2011;21:658–664
96. Am J Human Genet 2011; Online Aug, Hum Mutat 2014 Dec 16
97. Neuromuscular Disorders 2011; Online Sept
98. J Peripher Nerv Syst 2011;16:113-118
99. Human Molec Genet 2011; online October
100. Neurology 2011; Online November
101. NEJM 2011; 365:2377-2388
102. Neurogenetics 2012; On line Jan
103. Ann Neurol 2012;71:84–92
104. Neurology 2012;78:1644–1649
105. Hum Mutat 2012 Aug 28, Brain 2015 Jun 13
106. Nature Genetics 2012; Online September, Brain 2016 Dec 21
107. Neuromuscular Disord 2012;22:806-807, Hum Molec Genet 2103;22:1404-1416
108. Am J Human Genet 2012; Online November
109. JNNP 2012; Online December
110. Muscle Nerve 2012;45:135-138
111. Neurol Sci 2012; Online Dec 4
112. J Peripher Nerv Syst 2012;17:391-398
113. Am J Human Genet 2013; Online Feb, Eur J Med Genet 2017 Jun 19
114. Neurogenetics 2013; Mar 3
115. Human Molecular Genetics 2013; Online April, Hum Genet 2015 Apr 17
116. JNNP 2013; Online June
117. Neurology 2013:81 Online June
118. J Neurol Sci 2013; Online August
119. Nat Rev Neurol 2013; Online Sep, GeneReviews 2019
120. Clin Neuropathol 2012;31:7–23
121. Am J Hum Genet 2014; Online Feb
122. Neuromuscular Disorders 2014; Online May
123. Am J Human Genet 2014; Online August
124. Ann Neurol 2014;76:134-139
125. Eur J Pediatr 2014 Oct 7
126. Neurogenetics 2014: Online Oct
127. Am J Human Genet 2014; Online Nov
128. Neuromuscular Disorders 2015, Neurology Genetics 2018;4:e220
129. Cell Rep. 2015;12:1169-1183, PLoS Genet. 2016;12:e1005829
130. Hum Mutat 2015 Oct 14, Neurobiol Dis 2020 Jan 21
131. Brain 2015; Online Oct, Ann Neurol 2015; Online December
132. Hum Mutat 2016 Jan 20
133. Ann Neurol 2016; Online March, J Med Genet 2018 Nov 10, Neurology 2020 Nov 3
134. Sci Signal 2016;9(439):ra77
135. Neurology Genetics 2016;2:e94
136. Am J Hum Genet 2016;99:607-623
137. Neurology 2017 Jan 11
138. Brain 2017 Online June
139. Am J Hum Genet 2018;102:505-514
140. Neuromuscular Disorders 2018; April
141. Eur J Neurol 2015;22:1548-1555
142. Exp Neurol 2018 Apr 28
143. Amyotroph Lateral Scler Frontotemporal Degener 2019 Jan 20:1-3
144. Ann Neurol 2019; Jan
145. Muscle Nerve 2019; March
146. J Neuromuscul Dis 2019 Apr 3
147. Neurogenetics 2019 Apr 22
148. Hum Mutat 2019 May 22
149. Neurology Genetics 2019;5:e565
150. Brain 2019; Online June
151. Ann Neurol 2019; Online July
152. Cerebellum Ataxias 2019 Jul 15;6:9
153. Ann Clin Transl Neurol 2019 Aug 20
154. Nat Commun 2019;10:5045
155. J Clin Invest 2020 Feb 17
156. Glia 2020 Feb 20
157. Hum Mutat 2016;37:1202-1208
158. Front Genet 2020;11:61
159. Parkinsonism Relat Disord 2020;74:6-11
160. Hum Mutat 2020 Apr 25
161. Neurol Genet 2020;6(2):e407
162. Nat Genet 2020 May 4
163. Ann Clin Transl Neurol 2020;7:15-25
164. J Peripher Nerv Syst 2020 May 15
165. Glia 2020 Jun 8
166. Am J Hum Genet 2020 Jul 15
167. Neuromuscul Disord 2016;26:837-840
168. Cells 2020;9:E1832
169. Am J Hum Genet 2020 Sep 10
170. Ann Clin Transl Neurol 2020 Sep 19
171. Ann Clin Transl Neurol 2021 Jan 6
172. Brain 2020;143:3589-3602
173. J Peripher Nerv Syst 2021 Apr 12
174. Neurol Clin Pract 2021 Apr;11(2):e129-e134
175. Brain 2021 Apr 23
176. Eur J Neurol 2016;23:1566-71

Illustration by J. Kwon, MD

6/18/2021