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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     CMT 1H: FBLN5; 14q32     CMT 1I: POLR3B; 12q23     CMT1J: ITPR3; 6p21     CMT1: c1orf194; 1p13     CMT: ATP1A1; 1p13     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; 10q25   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         Child-Adult: 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 2FF: CADM3: 1q23     CMT 2GG: GBF1; 10q24     CMT 2HH: JAG1; 20p12     CMT 2II: SLC12A6; 15q14     CMT 2: TFG; 3q12     CMT 2: DGAT2; 11q13     CMT 2: MME; 3q25     CMT 2: DHX9; 1q25     CMT 2: 4p deletion     CMT2-like: BSCL2; 11q13     CFEOM3: TUBB3; 16q24     Giant axonal 2: DCAF8; 1q22     HMSN: BAG3; 10q25     HMSN: SLC12A6; 15q14     HMSN: SPTLC3; 20p12     HMSN: POLR3B; 12q23     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     HSMN + Ataxia: IFRD1; 7q31     HSAN I       SPTLC1: 9q22       SPTLC2: 14q24     PN: NOTCH2NLC; 1q21   Mitochondrial     MT-ATP6     mtRNAVal   Recessive     AR-CMT2       A (B1): Lamin A/C; 1q22       A2B: MFN2; 1p36       B (B2): PNKP; 19q13         PNKP: 19q13       EE: MPV17; 2p23       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       AHNAK2: 14q32       EGR2; 10q21       HSJ1/DNAJB2; 2q35       MCM3AP (GANP): 21q22       MYO9B: 19p13       NRG1: 8p12       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     Syndromes: HMSN+       Childhood onset       CNS         AR-CMT2: B4GALNT1; 12q13         ACCS: KCC3; 15q14       Deafness       Mitochondrial       Optic neuropathy (HMSN6)         HMSN6AR: MFN2; 1p36         HMSN6B: SLC25A46; 5q22         HMSN6C: PDXK; 21q22         HMSN ± Deaf   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

CMT + Intermediate NCV   Dominant     CMT-DIA: GBF1; 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-DI: SARS1; 1p13     CMT-X (Semi-dominant): GJB1     CMT 1C: LITAF; 16p13     CMT 2E: NEFL; 8p21     Hypomyelination: ARHGEF10; 8p23     PN: NOTCH2NLC; 1q21   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 PMP22: CMT1A GJB1: CMTX1 MPZ: CMT1B + Other MFN2: CMT2A2A + Other GDAP1: CMT2K + Other HINT1: NMAN SH3TC2: CMT4C Tissue & Functional involvement Demyelination Disorders: CMT I, III (Dejerine-Sottas), 4,   HNPP, Neuropathy with focally folded myelin sheaths,   Congenital hypomyelinating neuropathy Secondary axonal loss occurs Anatomical pattern: Distal > Proximal Functional consequence: Major cause of weakness Axonal: CMT type II; AR-CMT2; HMSN 5; HMSN 6 Genes producing either demyelinating or axonal neuropathies Connexin-32 (CMT-X) Male Demyelinating neuropathy Intermediate nerve conduction velocities Female Axonal neuropathy Near normal nerve conduction velocities P0: Specific mutations produce demyelinating or axonal disease GDAP1: CMT 4A (Demyelinating); Axonal CMT + Hoarseness Fibulin-5: Demyelinating; D-HMN + Macular degeneration & Cutis laxa

Duchenne CMT R Baloh CMT 2

Hereditary Neuropathies: Related Molecules Channels & Transporters TRPV4: CMT 2C; SMA ATP7A: SMAX3 SCN9A: HSN 2D GJB1: CMT X1 FLVCR1: AXPC1 Mitochondria GDAP1: CMT 4A; CMT 2K; AR-CMT2 MFN2: CMT 2A2 DHTKD1: CMT 2 HK1: CMT 4G MT-ATP6: CMT2 AIFM1: Cowchock PDK3: CMT X6 RAB7: CMT 2B SURF1: CMT 4 SLC25A46: Optic atrophy + HMSN Myelination & Schwann cell Myelin MPZ: CMT 1B; CMT 2I; CMT 2J PMP22: CMT 1A PMP2: HMSN Cytoskeleton INF2: CMT-DIE FGD4: CMT 2H PRX: CMT 4F FBLN5: CMT1 EGR2: CMT 1D GJB1: CMT 1X SOX10: PNS & CNS hypomyelination MME: AR-CMT2T, Adult-onset Proteasome LRSAM1: CMT 2P TRIM2: AR-CMT2 DNAJB2: DSMA5 PRNP: HSN + Diarrhea CCT5: HSN + Paraparesis RNF170: SNAX1 DCAF8: HMSN2 + Giant axons Chaperones HSPB1: CMT 2F HSPB3: HMN 2C HSPB8: CMT 2L Motor proteins & Axonal transport DCTN1: HMN 7B KIF21A: CFEOM1 HSPB1: CMT 2F NEFL: CMT 1F; CMT 2E BICD2: SMA LED2 DYNC1H1: SMA LED; CMT 2O KIF1A: HSN 2C KIF5A: SPG 10 MYH14: PNMHH Cytoskeleton (Cytoplasmic) NEFL: CMT 1F; CMT 2E TUBB3: CFEOM3 PLEKHG5 (GEF): DSMA4; CMT RIC RNA metabolism Aminoacyl-tRNA synthetases (ARS) AARS: CMT 2N; Epileptic encephalopathy (Recessive) GARS: CMT 2D HARS: Sensory-Motor PN KARS: HNPP; CMT Int + CNS MARS: Sensory-Motor PN NARS1: Encephalopathy + Neuropathy YARS: CMT DIC CTDP1: CCFDN HINT1: NMAN SETX: DHMN; ALS4; AOA2 IGHMBP2: DSMA1 MED25: AR-CMT2B Nuclear LMNA (Envelope): AR-CMT2A PRPS1 (Nucleotide synthesis): CMT X5 DNMT1 (DNA replication): HSN 1E Sphingolipid biosynthesis SPTLC1 SPTLC2 Membrane traffic ARHGEF10: Hypomyelination DNM2: CMT 2M LITAF (SIMPLE): CMT 1C MTMR2: CMT 4B MTMR13 (SBF2): CMT 4B2 RAB7: CMT 2B SH3TC2: CMT 4C TFG: HMSN-Proximal Endoplasmic reticulum & Golgi ATL1: HSN 1D; SPG3A BSCL2: HMN 5C DGAT2: CMT2 FAM134B: HSN 2B REEP1: HMN 5B; SPG31 TFG: HMSNP Endosomal sorting/ Cell signalling Schwann cell LITAF/SIMPLE: CMT 1C SH3TC2: CMT 4C MTMR2: CMT 4B1 MTMR13: CMT 4B2 SBF1: CMT 4B3 FIG4: CMT 4J; ALS 11 DNM2: CMT 2M; CMT D1B NDRG1: CMT 4D Axon RAB7: CMT 2B DNM2: CMT 2M; CMT D1B GNB4: CMT DIF WNK1: HSN 2A IKBKAP: HSN 3 NTRK1: HSN 4 NGF-β: HSN 5 Synaptic transmission DCTN1: HMN 7B SLC5A7: HMN 7A Connective tissue EMILIN1 Adhesion molecule CADM3

Pathology in hereditary neuropathies: Differential diagnosis 120 Myelin-related Onion bulbs, Large & Many (Schwann cell proliferation): PMP22; MPZ; SH3TC2 Folding of myelin lamellae (Tomaculae) Uncompacted & Outfoldings: MPZ (P0) Severe demyelination or absent myelin: EGR2 Anomalies of nodes of Ranvier (Paranodal loops): PRX Anomalies of cytoplasm of unmyelinated Schwann cells: SH3TC2 Schwann cell inclusions: ARSA; GLA; ABCD1; ASAH1 Axons Loss Myelinated axons: LMNA Unmyelinated axons: SH3TC2; INF2 Regeneration No regeneration: LMNA Axon clusters: GJB1 Morphology Axonal inclusions: NDRG1; GBE1 Actin filaments increased: INF2 Giant axons: NEFL; GAN Axonal mitochondrial pathology: MFN2; GADP1 Other hereditary motor-sensory neuropathies Often associated with complex clinical syndromes, or Specific metabolic abnormalities Also see: Distal motor neuropathies, Hereditary

Bramwell 1907

Neuropathy: CMT Genes & Drugs ¹⁹⁵

• Vincristine: May cause exacerbation of
  • CMT1A: PMP-22
  • EGR2: Neuropathy in previously asymptomatic patient
  • MORC2: CMT2Z
• Paclitaxel
  • Polymorphisms associated with neuropathy
    • Periaxin (PRX)
    • ARHGEF10
  • TRPV4
    • Experimental data: Inhibition prevents paclitaxel-induced neurotoxicity ¹⁴²
• Isoniazid (INH): May exacebate CMT2A
• Ethambutol: May exacebate CMT2A
• Thiopental anesthesia
  • CMT1A: PMP-22
    • Sensitive to low doses (Lower induction dose needed)
    • Especially with severe motor & sensory involvement

• GeneReviews
• Inherited Peripheral Neuropathies Mutation Database

Hereditary Motor-Sensory Neuropathy (HMSN) Syndromes

CMT IA

PMP-22   Gene mutations   Clinical-Gene relations     Duplication     Contiguous gene (YUHAL)     Triplication     Homozygous (Duplication)     Point   Allelic disorders     Recessive     CMT 1E (Deafness)   Protein   Pathology Also see: HNPP

CMT 1A PMP-22 Duplication

Chaddock 1900

• CMT 1A: Epidemiology
  • Prevalence: 10.5 per 100,000
  • 60% to 70% of Demyelinating CMT
  • 40% to 50% of all CMT
• Genetics
  • PMP-22 Gene mutation types
    • Duplication of one PMP-22 gene (3 total copies of PMP-22): Types
      • Segmental duplication in gene area
        • Due to unequal crossing over of chromosomes during meiosis
        • 
      • Duplication size
        • Varies among patients
        • Longer (Extended): 1%
        • Shorter: 2%
        • Trisomy of short arm on chromosome 17 (17p): Mosaic
    • Contiguous gene syndrome (YUHAL): Duplication of one PMP-22 gene & neighboring genes
    • Duplication of both PMP-22 genes (Homozygous) (4 copies)
    • Point mutation
      • Human
      • Mouse: Trembler (G150D)
    • Deletion: Most commonly associated with HNPP
    • Recessive
    • Nonrecurrent genomic rearrangements causing copy number variants ⁸²
      • Genomic deletions & duplications
      • Complex rearrangements
      • Exonic deletions: Small
  • PMP-22: Clinical-genetic correlations
    • Chromosomal duplication containing PMP-22
      • Identical to region deleted in HNPP
    • Homozygotic twins
      • Similar NCV but often dissimilar clinical severity
    • "Sporadic" cases: 18%
      • Paternal origin
        • Common: 89%
        • Due to unequal crossing over of homologous Chromosome 17 regions
        • Most breakpoints: 700 bp region in complex low copy repeat sequence (24,000 bp) that flanks gene
        • Also 'Mariner' insect transposon-like element (MITE) near break site
          • ? Promotes DNA cleavage by transposase
            
          • ? Cleavage leads to unequal cross-over
      • Maternal origin
        • Rare: 11%
        • Due to intrachromosomal rearrangement: Unequal sister chromatid exchange
        • Breakpoint location
          • Outside, but near, 700 bp interval containing most rearrangements of paternal origin
    • Disease modifiers
      • LITAF/SIMPLE 192V sequence variant ¹²⁶
        • Onset age
          • 13 years earlier in CMT1A & HNPP adult-onset
          • No difference in child onset patients with Ile92Val mutation
      • miR-149 SNP (n.86T>C, rs2292832) ¹⁴⁰
        • TC & CC genotypes: Associated with late onset & mild symptom in asian patients
      • SIPA1L2 (SPAR2) ¹⁴⁴
        • SNP clinical association: Foot dorsiflexion strength
          • SNPs: rs10910527, rs7536385, rs4649265, rs1547740
          • Minor alleles: More severe weakness
        • Expressed in peripheral nerve & growth cones
        • Part of a myelination-associated co-expressed network regulated by SOX10
        • Binding partners: MYH9; β-actin
      • Other possible loci of modifiers ¹⁴⁶
        • Difficulty with eating utensils: rs4713376, Chromosome 6
        • Hearing loss: rs7720606, Chromosome 5
        • Decreased ability to feel: rs17629990, Chromosome 4
        • CMT neuropathy score: rs12137595, Chromosome 1
  • Allelic disorders
    • CMT1A
    • Dejerine–Sottas-like
      • Recessive
      • Dominant
    • Congenital Hypomyelinating Neuropathy
    • HNPP
    • Sensory ataxia, Recessive
    • Davidenkow phenotype
    • Yuan-Harel-Lupski syndrome (YUHAL): Contiguous gene duplication
    • CMT 1E (Deafness)
      
    • Sub-Acute polyneuropathy
    • Mouse disorders
      • Trembler (DSS-like)
      • Trembler-J (CMT 1E-like)
• PMP-22 protein
  • 2 transcripts: Different 5' ends
    • 1 predominantly expressed in Schwann cells
      • Over expression → Reduced Schwann cell proliferation
    • 2nd (GAS3) regulated in growth-dependent fashion in fibroblasts
      • Over expression → Growth arrest & Apoptosis
  • Synthetic pathways
    • Most wild type PMP-22 is retained in endoplasmic reticulum & degraded
    • Some PMP-22: Transported to Golgi, Glycosylated & Incorporated into myelin
  • Abundance: 2% to 5% of PNS myelin protein
  • Location: Compact myelin
  • Functions
    • Structural: Myelination
    • Mediates cholesterol trafficking (efflux) in Schwann cells ¹⁶⁵
      • CRAC domain in 4th transmembrane domain
      • PMP22 KO mice: Elevated cholesterol in perinuclear area; No myelin
      • PMP22 overexpression: Cholesterol sequestered in lysosomes
    • Regulation of cell growth/differentiation
  • Protein Family & Structure
    • Immunoglobulin superfamily
    • Membrane topology: 4 Hydrophobic transmembrane domains (4-TM)
    • Other homologous neural 4-TM proteins
      • Proteolipid protein : CNS
      • Connexin-32
      • Plasmolipin
      • Myelin vesicular protein (MVP17)
  • PMP-22 protein expression altered in nerves in CMT1A & HNPP
    • PMP-22 Duplication
      • Increased PMP-22 protein Expression: At early disease stages
      • Abnormal Schwann cell differentiation
    • PMP-22 Point mutations & Deletions (HNPP)
      • Reduced PMP-22 protein Expression
      • Several PMP-22 mutations
        • Some accumulation in Schwann cell cytoplasm: Adaxonal; Endoplasmic reticulum
        • Reduced degradation
        • Reduced Insertion into compact myelin
      • Gly107Val: Strong staining of PMP-22 in onion bulbs
      • Leu105Arg mutation: No PMP-22 staining in nerve; More severe disease
• Duplication of PMP-22 gene
  • Epidemiology
    • Male: Female 1:1
      • Sex: No effect on disabilty
    • Family history +: 60%
    • Most common CMT 1 type
      • Range: 37.5% (Umea, Sweden) to 84% (Turku, Finland)
  • Mutation
    • Segmental duplication in area containing PMP-22 gene on 1 chromosome 17
    • Occurs with abnormal alignment during meiotic crossing over
    • Leads to total of 3 copies of PMP-22 gene
    • 
    • Extra gene produces: Overexpression of PMP-22 protein
  • Neuropathy: Clinical features
    • Neuropathy: Onset
      • Onset age: 1st decade in 75%; 2nd decade in 10%; Rare asymptomatic in 30's
      • Initial symptoms: Gait disorder; Foot deformity
      • Initial signs: 1st decade ³⁴
        • Leg areflexia (100%)
        • Disordered heel walking (66%)
        • Foot muscle atrophy (50%)
        • Nerve enlargement (50%)
        • Pes cavus (33%)
        • Short Achilles tendon (25%)
      • Severity: Similar or worse in males compared to females
    • Weakness
      • Related to degree of axon loss ⁵¹
      • Distal muscles: Most patients
        • Especially intrinsic muscles of Feet & Hands
        • Most common muscles: Big toe & foot dorsiflexion
      • May be normal at wrist, knee & more proximal muscles
      • Proximal
        • Rare at onset
        • ~10% in late teens
        • Leg weakness: Hips & thighs; Eventually in ~40%
        • Arm weakness: Eventually in ~20%
      • Rarely: Diaphragm or Bulbar
      • Focal nerve lesions: 10%
      • ? More disability in females
    • Muscle size
      • Wasting (Most common): Hands & Distal legs
      • Calf hypertrophy: Occasional families
    • Sensory loss
      • Mild; Pansensory
      • Occcasional patients with normal sensory exam
    • No paresthesias or autonomic disorders
    • Tendon reflexes: Reduced or absent
    • Enlarged nerves: ~20% clinically; 100% by ultrasound
    • Cramps ¹⁰⁰
      • Location: Calf muscles
      • Age: Onset in childhood (32%)
      • More with: Increasing age; Stronger ankle; Hand tremor
    • Sleep apnea ¹⁵
      • With more severe neuropathy
      • ? Related to pharyngeal involvement
    • Progression
      • Slow: Over decades
      • Occasional exacerbations in pregnancy: Especially with earlier onset disease
      • Penetrance: Nearly complete by 20 years; Earlier if nerve conductions performed
      • Motor disability: Mild increase with concomitant diabetes
    • Clinical variants
      • More severe generalized weakness; Earlier onset
      • Roussy-Levy Syndrome
        • Neuropathy + Ataxia + Tremor
        • Original RLS family has MPZ mutation
      • Occasional: Transient recurrent palsies
    • Drug interactions
      • Vincristine: Produces severe exacerbation of neuropathy
      • Thiopental anesthesia
        • Sensitive to low doses: Lower induction dose needed
        • Especially with severe motor & sensory involvement
  • CNS ¹⁰⁹
    • Cognitive impairment: 70% by neuropsychological assessment
    • White matter
      • Volume reduced in 70%
      • Creatine level: reduced in 28%
      • Hypomyelination sparing U-fibers
    • Brainstem auditory evoked potentials: Delayed wave I
  • Electrophysiology ¹⁷⁶
    • NCV: Demyelinating Neuropathy + Axonal loss
      • Conduction velocities
        • Uniformly slow in all nerves
        • Mean 17 to 21 M/s
        • Range 5 to 34 M/s
      • Time course of NCV slowing
        • Clearly present by 2 years
        • Onset before clinical signs appear
        • Slower in earlier onset patients
        • Stable after age 5 years
      • Conduction block: Rare
      • Compound motor action potential (CMAP): Small
        • Due to axonal loss
        • Degree of reduction: Correlates with
          • Disease severity
          • Slowing of NCV
          • Nerve length
        • May be progressively reduced over time
      • Distal latency: Prolonged, Even in 1st months of life
      • F-wave responses: Prolonged
      • Sensory potentials
        • Amplitude: Often absent or small
        • Velocity: Slow
    • EMG: Denervation, Distal > Proxiomal
  • Laboratory
    • CSF protein: High, Less in duplication patients
    • Ultrasound: Nerve size enlarged, especially median & ulnar
  • Pathology: Early excess myelin production
    • Onion bulbs
      • Small to moderate size & frequency
      • Many develop > 6 years of age
      • More prominent in nerves with less severe axon loss
    • Myelinated axons
      • Early: Myelin sheaths thicker than normal
      • Late: Thinly myelinated axons
      • Number: Large reduction, Especially with disease progression
      • Tomaculae: Occasional patient
    • Transgenic animals with PMP-22 overexpression: Hypomyelination
• PMP-22: Triplications ¹²¹
  • Genetics
    • Triplication origin
      • de novo from maternally transmitted duplications
      • Nonallelic homologous recombination (NAHR): Especially intrachromosomal
      • Mutatation rate from duplication: 1:550
    • Inheritance: Dominant
  • Clinical: Polyneuropathy
    • Onset
      • Age: Early childhood
      • Gait: Waddling
    • Weakness
      • Distal
      • Hands & Feet
      • Symmetric
      • More severe than: Other family members with duplication
    • Muscle atrophy: Severe; Distal > Proximal
    • Sensory loss: Distal; Feet & Hands
    • Tendon reflexes: Absent
    • Skeletal
      • Pes cavus
      • Kyphoscoliosis
      • Finger flexion contractures: Onset 3rd decade
  • Laboratory
    • NCV: 8 to 16 m/S
    • CMAP amplitude: Reduced or absent
    • SNAP amplitudes: Reduced or absent
    • EMG: Denervation, distal or diffuse
• PMP-22: Small mutations : Point & Other
  • Genetics
    • Point mutations usually inherited as: Dominant
    • Recessive: Arg157Trp
    • Recessive or Dominant PMP-22: Thr118Met ¹⁹²
      • Present in controls: 1:75 in Europe; 1:120 general population
      • Mutated protein
        • Folding: Less stable; Similar configuration to Wild type
        • Reduced traffic to cell surface: 4% to 6% vs normal of 20%
        • Less likely to form large intracellular aggregates vs other disease mutants
      • Heterozygous phenotypes
        • Normal
        • Neuropathy, Mild: Conduction velocities Normal or Mildly reduced
        • HNPP, Mild
        • Carpal tunnel syndromes: Chronic or Repeated
      • Homozygous mutation: Axonal neuropathy, Severe
      • Thr118Met/Null: More severe than WT/Null patients
    • Locations
      • Common: Transmembrane domain of PMP-22 protein, especially TM2
      • Other: 1st extracellular loop; Asp37Val
    • Missense or single base pair deletion occurs in
      • Human CMT 1A
      • Mouse models
        • Trembler (G150D)
        • Trembler-J (Leu16Pro mutation): Abnormal folding & Mis-assembly of PMP-22
    • Cellular features
      • Accumulate in swollen & fragmented ER + Golgi apparatus; Aggregate; Little reaches plasma membrans
        • His12Gln, Leu16Pro (DSS phenotype); Ser72Leu, Ser79Cys, Leu105Arg, Leu147Arg
      • Mistraffic to cell surface without aggregation: Thr118Met
  • Clinical features
    • Variable
      • Often more severe than duplication
      • Mild subclinical forms: Some patients
      • Variability within some families
      • Axonal neuropathy: Few dominant or recessive point mutations
    • Deafness ³⁷ (CMT 1E )
      • Clinical: Early onset; Severe
      • Mutations
        • Locations
          • Base of first extracellular loop
          • Transmembrane domains (1-3)
        • Specific mutations
          • Missense: Thr23Arg; Thr28Gln; Val65Phe; Ala67Pro (Severe phenotype); Leu71Pro;
              Ser72Leu (Sporadic); Ser76Ile (Sporadic); Ser112Arg
          • Inframe deletion: del 115-118 (Later onset hearing loss)
    • Sensory loss: Distal
    • Weakness: Distal
    • Vocal cord dysfunction: Some patients
    • PMP22 point mutation: R159C ⁸⁹
      • Inheritance: Dominant
      • Late onset: 5th decade
      • Sensory loss: Distal; Trophic changes
      • Weakness: Distal; Onset after sensory loss
      • Tendon reflexes: Reduced, especially at ankles
      • NCV: Axon loss
      • Pathology: Axon loss; No demyelination; Mildly thin myelin sheaths
    • PMP22 point mutation: Gly94fsX222 ⁹⁸
      • Inheritance: Dominant
      • Clinical
        • Fixed distal weakness: Legs & Arms
        • Episodes: Distal leg sensory
      • NCV
        • Demyelinating neuropathy
        • Focal changes at entrapment sites
      • Nerve pathology
        • Tomaculae
        • Demyelinating neuropathy
    • Also see: CMT1A Recessive
  • Electrophysiology (Demyelinating types)
    • Demyelinating Neuropathy
      • More severe than duplication
      • Slow NCV
      • Long Distal latency
      • Very slow NCV (15 to 20 m/sec): Asp37Val mutation
  • Pathology: Early reduced myelin production
    • Onion bulbs
      • Large & on most axons
      • Most develop < 6 y.o.
    • Myelin sheaths thinner than normal
    • Myelin uncompaction: Asp37Val
      • Widening of intraperiod line
      • Splitting of major dense line
    • Tomaculae: Asp37Val; Gly94fsX222
      • Teased fiber
      • Ultrastructure
      • External link
• Homozygotes for PMP-22 gene duplication
    ● PMP-22 duplication (4 copies); Chromosome 17p11.2-p12
  • Clinical features
    • Most severe weakness
    • Earlier onset < 1 year
  • Electrophysiology: Very slow NCV
• Autosomal Recessive CMT1A
    ● PMP-22 point mutations: Thr118Met; Arg157G; Arg157Trp
  • Mutant protein properties
    • Aggregation tendency: Low
    • Cellular transport: Reach cell surface
  • Clinical: Dejerine-Sottas phenotype
    • Onset: Infant
    • Weakness: Distal
    • Sensory loss
    • Ataxia
  • Also see: Sensory ataxia
    ● PMP-22 deletions
  
  • Deletion mutations
    • Mutations: HNPP type + Exon 2 & 3 Deletion
  • Clinical features: Severe phenotype
    • HNPP: HNPP phenotype in parents
    • CMT1A
    • Dejerine-Sottas
    ● Hemizygous mutation for PMP-22: Point mutation & Deletion
• Contiguous PMP-22 gene duplication: Yuan-Harel-Lupski syndrome (YUHAL)
  • Epidemiology: 23 patients
  • Genetics
    • Genomic rearrangement
    • Genes duplicated: PMP-22 & RAI1
    • Inheritance: Sporadic (Non-recurrent)
    • RAI1 duplication syndrome: Potocki-Lupski syndrome (PTLS)
  • Clinical: Variable features
    • Onset age: Infancy
    • Hypotonia
    • Failure to thrive
    • Global developmental delay: Walking, Speech delay, Behavior difficulties
    • Dysmorphic features (50%)
      • Face: Triangular
      • Palpebral fissures: Downslanted
      • Nose: Broad; Philtrum smooth or broad
      • Upper lip: Thin
      • Ears: Abnormal
    • Polyneuropathy
      • Onset age: Less than 5 to 10; Earlier than typical CMT-IA
      • Weakness & Atrophy: Distal arms & legs
      • Sensory loss: Distal arms & legs
      • Tendon reflexes: Reduced at ankles
    • Constipation
    • Skeletal
      • Foot deformities: Equinovarus; Pes planus or cavus
      • Joint laxity
    • Congenital heart disorder
  • Laboratory
    • Nerve conduction: Velocity reduced (15 to 24 M/s)
    • Spine MRI: Syringmyelia (Some patients), Thoracic or Cervical
    • Renal defects: Structural
• PMP-22 variant: Sensory Ataxia, Early onset ¹⁶⁴
  • Epidemiology: 1 patient
  • Genetics
    • Mutations
      • Homozygous
      • c.483A>G; p.[*161Trpext*10]),
      • Sequence change: Loss of termination codon
    • Inheritance: Recessive
  • PMP-22 protein
    • Mutant protein: 9 amino acids larger
  • Clinical
    • Onset age: < 1 year
    • Locomotor delay: Walking at 3 years
    • Sensory ataxia: Gait ataxia; Pseudo-athetosis
    • Strength: Near normal
    • Tendon reflexes: Reduced; Absent in Legs
    • Skeletal: Varus posture in feet
  • Laboratory
    • NCV
      • Patient: 2 to 3 m/Sec; SNAPs absent
      • Parents: HNPP-like features
    • CSF protein: Very high
    • Brain MRI: Normal
• PMP-22 variant: Congenital Hypomyelinating Neuropathy
  • Genetics
    • Inheritance: de novo Dominant > Recessive
    • Mutations: Missense; Gain-of-function; Location in transmembrane domains
  • Clinical
    • Onset: Early infantile
    • Weakness: Distal + Proximal
    • Sensory: Pan-modal loss; Ataxia
    • Cranial nerve involvement
    • Disability: Severe
    • Skeletal deformities
  • Laboratory
    • NCV: < 12 M/s
    • Nerve pathology
      • Axon loss
      • Myelin sheaths: Thin or Absent
      • BLOBs
      • Endoneurial collagen: Surrounds axon

CMT IB + Other P₀ Neuropathies ⁶¹

P0: Genetic features   Clinical-Gene correlations 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     Congenital: Rec or Dom; Hypomyelin     Dejerine-Sottas: Dominant or Recessive     Entrapment + Focal-folding     Hypertrophic radiculopathy     Increased P0 gene dosage: Dominant     Roussy-Levy     Steroid responsive, Late-onset   Axonal     CMT 2I: Dominant     CMT 2J: Dominant; Pupil Δ; Hearing ↓     Adult onset (Axonal)   Intermediate NCV     CMT-DID: Dominant   P0 variant syndromes Nerve pathology

P0

• Epidemiology
  • Prevalence: P0 mutations in 5% to 8% of CMT I patients
• Genetic features
  • Different mutations identified: > 300
  • Regions
    • Exon 1: Signal sequence
    • Exons 2 & 3: Extracellular domain; Immunoglobulin-like
    • Exon 4: transmembrane domain
    • Exons 5 & 6: Cytoplasmic domain
  • Disease
    • Mostly point mutations
    • Exons 2 & 3 most common
      • Corresponds to immunoglobulin-like extracellular domain
    • 2 mutations in exon 4: Margins of transmembrane domain
    • Mutations in transmembrane domain: Point or small tandem duplication
      • Pathology with severely hypomyelinated axons
    • Roussy-Levy (Original family)
    • P₀ autoantibodies: NOD.Aire^GW/+ mice
  • Allelic disorders
  • Clinical-genetic correlations ¹⁸⁶
    • Many mutations cause specific phenotypes
      • Individuals in same family: Similar phenotype & NCV
      • Onset age: May vary
    • CMT 1B demyelinating neuropathy mutations
      • Loss of function
        • Mutations ¹⁸⁵
          • Null: Ser34 deletion
          • Other: Tyr53; Tyr68, Asp104
        • Clinical
          • Phenotype: Less severe neuropathy; Sensory > Motor; Tendon reflexes absent
          • Exception: Ser233Argfs*18 with severe, early onset disease
      • Missense mutations
        • Mechanisms
          • Disturb structure and function of MPZ
          • Cause intracellular MPZ folding problems
          • Mislocalize MPZ
          • Asp35Tyr, Ile62Phe, Ser63del, Tyr68Cys, Gly93Glu, Arg98Cys, Val146Phe
      • Mutations in single amino acids in extracellular domain
        • Usual clinical: Typical CMT clinical syndrome
        • Truncation mutations: Gly74frameshift; Tyr125stop; Tyr152stop
        • Severe CMT; Ser34Cys; D61N; Arg69Cys; Trp72Cys
    • Dejerine-Sottas & other severe demyelinating neuropathy mutations
      • Mutations producing aberrant protein
        • Ser34Cys leads to free thiol group & disulfide aggregates
          
        • ? Acts as dominant negative
      • Homozygosity for P₀ mutation
        • Gly74frameshift; Phe35del
        • Heterozygotes have typical CMT
      • Mutations in cytoplasmic & transmembrane domain
        • Transmembrane (DJS): Leu145frameshift; Ala192frameshift
        • Transmembrane: Gln186stop (Congenital hypomyelination); Val203frameshift (Severe CMT)
    • Axonal CMT2-P₀
      • Mutations
      • Adult onset more common
    • Other mutations
      • Asn131Lys: CMT1B + Postural tremor in arms & ataxia.
      • Ile135Arg & Lys138Glu: Optic atrophy; Severe phenotype
      • Arg98Cys: Sensory > Motor
      • Thr124Met: Pain; Pupil Δ; Hearing loss; Motor syndrome
    • Same mutations may produce demyelinating or axonal neuropathies
      • Mutations: Ser78Leu, Arg98Cys, Arg98His
• P₀ Protein ¹⁶⁸
  • Size
    • 28 kD
    • Myelin protein: 219 amino acids
  • Cells
    • Myelinating Schwann cells
    • Büngner band Schwann cells
  • Most abundant protein in peripheral nerve myelin
    • 50% of total peripheral myelin protein
    • Present in myelin around most axons
  • Myelin location
    • Compact myelin: Around Large & small myelinated axons
    • Associated proteins: PMP-22 & Myelin basic protein
    • Absent from: CNS myelin
  • Necessary for
    • Normal myelin: Structure & Function
    • Formation of intraperiod line
  • Extracellular fold
    • Domain similar to immunoglobulin variable chain
    • Glycosylated: On extracellular domain
    • Homophilic: Extracellular adhesion with similar P₀ domains
      • In same membrane: Interacts in cis to form homotetramers
      • With apposing membranes
        • Tetramers interact in trans with tetramers of P₀ extracellular domains
      • Necessary structures: Glycosylation; Cys21-Cys98 disulfide bond in Ig domain
    • Similar in structure to single immunoglobulin variable region domain
    • Other post-translational modifications: Acylation; Sulfation; Phosphorylation
    • Aggregates as tetramers: Forms interperiod line
  • Trans-membrane domain: 1; Amino acids 125-150
  • Cytoplasmic domain
    • Basic; Positive charge
    • Necessary for mediationg adhesion by extracellular domains
    • Interacts with - charged head groups of membrane phospholipids
    • Holds together major dense line of myelin
    • PKC-mediated phosphorylation: Important component of regulation of P₀-mediated adhesion.
    • Mutations in this domain may cause severe demyeinating neuropathy
  • Schwann cells: Regulation
    • Increased with: Axon contact
    • Reduced by: Loss of axon contact; Turned off during Wallerian degeneration
    • Present in some Schwann cells without axons: Büngner bands & Onion bulbs
  • Node of Ranvier
    • Interacts with: Neurofascins 155 & 186
  • Mutation effects
    • Common
      • Gain of function
      • Endoplasic reticulum stress
    • Other
      • Myelin structure disorders: Abnormal folding
      • P0 hyperglycosylation + Myelin uncompaction: D61N mutation
      • Endoplasmic retention + Activation of unfolded protein response
      • Intercellular adhesion properties: Disruption
      • Myelination: Altered radial axonal sorting
• CMT1B: Demyelinating neuropathy
  • Inheritance
    • Dominant: Common
    • Sporadic presentation: May occur in 50% of cases
  • Clinical features
    • General
      • Reach early milestones (walking) at the normal time
      • Develop distal involvement (weakness) in 1st 2 decades
    • Onset age
      • Mean: 12 years
      • Often in 1st decade: 30% to 40%; Delayed walking
      • Some: 2nd decade
      • Rare: > 30 years
      • Earlier with NCV < 5 m/s
      • Later onset
        • Similar frequency in decades 2 to 7
        • 30% > 30 years
    • Weakness: Distal > Proximal
    • Sensory loss: Distal; Mild; Vibration reduced
    • Tendon reflexes: Absent
    • Gait disorder: 2° distal weakness or foot deformities
    • Nerve size
      • ± Hypertrophic nerves
      • Nerves not usually clinically enlarged
      • Cauda equina syndrome due to nerve hypertrophy reported (Gly173Arg) ¹⁶⁷
    • Progression: Severe disability in some by 20 to 40 years
    • Tremor (Roussy-Levy): Some patients
    • Cranial nerves
      • Gly163Arg mutation: Onset years after neuropathy onset ¹⁴⁵
        • Hemifacial spasm
        • Trigeminal neuralgia
      • Axonal neuropathy
        • Pupil involvement
        • Hearing loss
      • Vestibular disorder (D121G) ¹⁷⁴
  • Laboratory
    • Electrophysiology
      • Usual: Marked slowing of NCV < 20 M/s
      • Earlier onset & more loss of ambulation with NCV < 5 m/s
      • Adult onset: NCV, faster, often > 35 m/s
      • Rare: Near-normal NCV
    • CSF: High protein in 75%
  • Nerve Pathology
    • Common
      • Demyelinating
      • 2 Myelin Patterns: Depend on site of mutation
    • Uncompacted myelin
      • 23% to 68% of myelinated fibers
      • Onion bulbs
      • Fewer demyelinated axons
      • Mutations
        • Amino acids 5, 34(del), 35(del), 69, 90(del), 98, 138, 186(stop)
      • Myelin splits: Between dense lines
        • ? Mutations interfere with homophilic adhesion function of P0
    • Focal folding & Thickening of myelin
      • Mutation types: Point mutations
        • Amino acids 25, 34, 49, 61, 67, 101, 106 & 109
        • Usually extracellular domain
      • Folding locations: Outside or inside myelin sheath
      • Onion bulbs
      • Myelin: Thin sheaths; Tomaculae
      • Axonal loss: Myelinated & Unmyelinated
      • Myelin uncompaction: Rare
      • Also seen in: CMT type 4B
• P₀ mutations: Clinical variants
  • CMT 1E : Demyelinating CMT + Deafness
    • Genetics
      • Inheritance: Dominant
      • Mutation: Tyr145Ser
    • Clinical
      • Onset ages: Adult
      • Sensory loss: Distal, Panmodal
      • Weakness: Distal; Hands & Feet
      • Hearing loss
      • Adie's pupil
      • Course: Slow progression
    • Laboratory
      • NCV: 23 to 43 M/s
      • Nerve pathology: Axon loss
      • Vestibular function: Reduced
      • Auditory neuropathy
  • CMT-DID (CMT DI3) : CMT with Intermediate nerve conductions
    • Epidemiology: 1 family
    • Genetics
      • P0 Mutation: Asp6Tyr
      • Inheritance: Dominant
    • Clinical
      • Severity: Varied
      • Weakness: Distal; Symmetric
      • Sensory loss: Distal; Legs > Arms
    • Laboratory
      • NCV: Intermediate; 21 to 48 M/s
      • Nerve pathology: Axon loss; Segmental demyelination; No onion bulbs
  • CMT: Demyelinating; Semi-Dominant
    • Epidemiology: 1 Italian family
    • Genetics
      • P0 Mutation: D195Y; Homozygous; Intracellular region
      • Inheritance: Semi-Dominant
    • Clinical
      • Weakness: Distal; Hands & Feet
      • Sensory loss: Vibration; Distal; Legs
      • Skeletal: Pes cavus
      • Tendon reflexes: Reduced or Absent
    • Laboratory
      • NCV: < 30 M/s
      • Nerve pathology: Demyelination; Myelin outfoldings
    • Mutation carriers
      • Epidemiology: 2 patients
      • Mutation: D195Y; Heterozygous
      • Clinical
        • Sensory loss: Distal; Legs; Vibration
        • Strength: Normal
      • Laboratory
        • NCV: 41 to 44 M/s
  • Axonal predominant neuropathy (Adult onset) ⁹
    • Nosology
      • CMT 2I : CMT, Axonal, Late onset
      • CMT 2J : CMT + Hearing loss & Pupillary abnormalities
    • Genetics
      • Inheritance: Dominant
      • P0 mutations: Thr124Met (More common); His39Pro; Asp61Gly; Asp75Val; Ala76Val; His81Arg; Tyr119Cys; Lys130Arg; Gly167Arg
    • Clinical
      • Onset
        • Age: Adult; Usually after 30 years
        • Legs
        • Paresthesias, Hypoesthesia (85%)
        • Other: Weakness, Cramps, Photophobia
      • Sensory loss (90% to 100%)
        • Severe
        • Panmodal
        • Distal > Proximal
      • Weakness (80% to 100%)
        • Legs (80%) > Arms (35%)
        • Distal
        • Mild to Severe
      • Deafness (29% to 45%)
      • Pupil disorders: Adie's (35% to 70%)
      • Deep tendon reflexes: Reduced or Absent
      • Cough
      • Disability
        • Moderate, or more
        • More common than with demyelinating form of neuropathy
      • Other associated features ⁶²
        • Restless legs: His39Pro
        • Acute onset, painful neuropathy
          • Mutations: Arg36Trp; His39Pro
          • Pain: Distal legs; Burning & Shocklike
          • Hyperalgesia: Hands & Feet; Pin & Temperature sensations
          • Sensory loss: Vibration & Proprioception
        • Intrafamilial variability
    • Laboratory
      • NCV: Intermediate range of velocities
        • Velocity: Usually > 20 m/s to Normal
        • Often not clearly demyelinating
        • CMAPs & SNAPs: Reduced amplitude or Absent
      • Nerve pathology ⁶²
        • Axon loss
          • Myelinated: Especially large axons
          • Unmyelinated
          • Length dependent
        • Regeneration
        • Subperineurial edema
        • Segmental demyelination: Mild; Occasional patients
        • Focal nerve enlargements
          • Separation of axons from Schwann cells by inclusions in adaxonal portion of myelin
          • Contents: MPZ; Ubiquitin; αB-crystallin; PGP9.5
          • Location: Inner myelin intralaminar and/or periaxonal space
        • Paranode
          • Structure: Disordered
          • Caspr: Asymmetric distribution
        • Voltage-gated potassium channels (Kv1.2)
          • Normal: Limited to juxtaparanodes
          • MPZ mutations: Also present in internodal region, nondetectable
      • Serum CK: Mild elevation (47% to 75%); More frequent than in demyelinating form
      • CSF protein: High in 75%
  • Polyneuropathy, Steroid responsive ¹⁰
    • General
      • Syndrome may be immune neuropathy in setting of CMT IB
      • Similar Immune neuropathy-like disorders: CMT IA
    • Genetics
      • P0 Mutations: Ser63del; Arg98His; Ile99Thr
      • Inheritance: Dominant
    • Clinical
      • Onset
        • Adult: 28 to > 50 years
        • Paresthesias
        • Leg weakness
      • Weakness: Legs > Arms; Distal > Proximal
      • Sensory loss: Legs > Arms; Distal > Proximal; Panmodal
      • Paresthesias
      • Tendon reflexes: Reduced
      • Ophthalmoparesis: 1 patient
      • Pes cavus
      • Course & Progression
        • Over 6 months to 10 years
        • May be episodic or stepwise
      • Treatment
        • Steroid response: Best initially; May be reduced with time
        • Immunomodulating drugs: Other
    • Laboratory
      • NCV
        • Slowed velocities: Variation among nerves
        • Conduction block
      • CSF: High protein
      • Nerve pathology: Axon loss; Reduced myelin compaction
  • Hypertrophic radiculopathy ⁷⁹
    • Epidemiology: 1 Italian family
    • Mutation: Stop; c.306delA
    • Clinical
      • Onset age: 4th decade or Asymptomatic
      • Pain & Paresthesias: Arms ± Legs; Neck & Back
      • Sensory: Normal
      • Motor: Normal
      • Tendon reflexes: Normal or Reduced
      • Pes cavus
    • Laboratory
      • MRI: Hypertrophic radiculopathy, C3-T1 & T11-S3
      • NCV: 25 to 36 M/s; CMAP amplitudes relatively preserved
  • Roussy-Levy (Original family)
    • Genetics
      • MPZ mutation: Asn131Lys
      • Some families have PMP-22 mutations
      • Allelic disorders
      • Inheritance: Dominant
    • Clinical
      • Neuropathy
      • Ataxia: Gait
      • Tremor: Arms
  • Entrapment neuropathies, multiple & Focally folded myelin ⁹⁷
    • Epidemiology: Japanese patient
    • Genetics
      • MPZ (p0) mutation: Asn131Ser
      • Other mutation producing HNPP-like phenotype: Tyr145Stop
      • Other mutation with focal folding: Val102Stop
    • Clinical
      • Onset: Slow running as child
      • Distal Arms: Weakness; Wasting (Thenar); Dysesthesias
      • Distal Legs: Sensory loss
      • Tendon reflexes: Absent
    • Laboratory
      • Electrodiagnostic
        • NCV: Very slow
        • Axon loss: Sensory & Motor
      • Nerve biopsy
        • Axon loss
        • Myelination: Reduced thickness; Focal folding
  • CMT, Demyelinating +Increased P0 gene dosage ¹⁰³
    • Epidemiology: Taiwanese family
    • Genetics
      • Mutation
        • Duplication: Includes entire MPZ gene
        • Increased gene dosage: 5 MPZ copies
        • Flanking genes: SDHC & c1orf192
      • Inheritance: Dominant
    • Clinical: Intrafamilial variability
      • Onset age: 1 to 47 years
      • Pes cavus
      • Pupils: Tonic; Large
      • Weakness: Distal; Hands & Feet; Steppage gait
      • Muscle wasting: Distal
      • Tendon reflexes: Absent
      • Sensory loss: Distal
    • Electrodiagnostic
      • Median NCV: 9 to 47 M/s
      • Temporal dispersion
    • Nerve pathology
      • Axon loss
      • Myelin sheath: Thin
      • Onion bulbs

CMT 1C ²⁰

• Epidemiology
  • > 40 patients
  • Locations: Irish, English, German
  • Frequency: 0% to 1% of Dominant CMT
• Gene
  • Mutations: All missense
    • Missense: Ala111Thr, Gly112Ser, T115N, Trp116Arg, Leu122Val, Pro135Leu, Val144Met, Arg160Cys
    • Gly112Ser mutation
      • Adds potential new glycosylation site
      • Phenotype: Mild; NCV mildly slow (25 to 30 M/sec)
    • Location
      • Near transmembrane domain
      • Domain of the LITAF protein with role in peripheral nerve function
    • LITAF polymorphisms
      • Ile92Val: May be associated with early onset HNPP
      • Thr49Met & Tyr80Cys: Probably not disease related
  • Allelic disorders
    • Sensory neuropathy
    • HMSN digenic with EGR2
• LITAF protein
  • Expression
    • Normal: Many tissues; Abundant in Schwann cells
    • Reduced expression: Cancer (Breast, Lymphoma, Leukemia, Thyroid)
    • Increased expression: Obesity; Inflammatory bowel diseases
    • Upregulated by: Estrogen; p53; Lipopolysaccharide (LPS)
  • Functions
    • Regulation of endosome-to-lysosome trafficking & cell signaling
    • Stimulator of monocytes and macrophages
    • Causes secretion of tumor necrosis factor-α & other inflammatory mediators
    • May play a role in protein degradation pathways: No E3-ligase activity
    • Sort ubiquitinated substrates into multivesicular bodies
  • Interacts with: WWOX; NEDD4; TSG101
  • CMT IC mutations
    • Abnormal function: Impaired endosomal trafficking & sorting
    • Normal levels of LITAF protein in nerve & other tissues
• Clinical
  • Onset age: Mean 20 years; Range 5 to 33 years; Younger in males
  • Weakness
    • Distal
    • Arms, Legs or Both
  • Wasting
  • Sensory loss: Pan-modal
  • Tendon reflexes: Reduced or absent in 90%
  • Tremor (33%): Arms
  • Feet: High arches
  • Course: Progression slow; All remain ambulant
• Electrophysiology
  • Nerve conduction velocities
    • Demyelination (Intermediate velocities)
      • Mild or Moderate
      • NCV: Range 16 to 45 M/s; Mean 26 to 33 M/s
    • Axon loss: Reduced SNAP & CMAP amplitudes
  • EMG: Denervation
    • Distal: Hands & Feet
    • No spontaneous activity
• Nerve pathology
  • Onion bulbs
  • Mouse: Myelin infolding protruding into axons
• LITAF variant syndrome: Hereditary sensory neuropathy
  • Epidemiology: May be in same family as HMSN phenotype
  • Genetics
    • Mutations: c.478C>T (p.Arg160Cys), c.334G>A (p.Gly112Ser)
  • Clinical
    • Pain: Transient; toes or Fingers
    • Paresthesias
    • Cramps
    • Sensory loss: Distal legs
    • Tendon reflexes: Reduced at ankles
    • Feet: High arched

EGR2 mutations: CMT 1D & Other phenotypes

• Genetics
  • Inheritance: May be Dominant or Recessive
  • Mutations
    • > 30 described
    • Types: Missense common
    • Location: Zinc finger binding domain
    • Predicted to alter DNA binding
    • De novo mutations: Common
  • Allelic disorders
    • Dominant
      • CMT 1D: Arg409Trp; Arg359Gln; Asp355Val; Arg381Cys; Arg381His
      • Dejerine-Sottas (de novo): Arg359Trp; E412K
      • Asymptomatic: Symptomatic after Vincristine treatment
    • Recessive
      • AR-CMT2, Late onset
    • Dominant or Recessive
      • Congenital Amyelinating Neuropathy
      • Congenital Hypomyelinating (CHN): I268N; S382R/D383Y; Ile218Asn
    • Digenic: HMSN
• Protein: Early growth response-2 (Krox-20)
  • Family: Cys₂His₂ zinc finger
  • DNA binding: 2 specific DNA sites in promoter region of Homeo box A4
  • Regulates cellular proliferation
  • Expression associated with myelination in peripheral nerve
    • Transcription factor: Master regulator of myelin genes
    • Role in PNS myelin development and maintenance
      • Activated in Schwann cells before onset of myelination
      • Disruption blocks Schwann cells at early stage of differentiation
    • Activates transcription of several myelin-associated genes
      • Directly: PMP22, Cx32 & PRX
      • Via Egr2/Sox10 synergy: MPZ; MAG
  • Maintenance of boundary between CNS & PNS
  • See: EGR protein family
  • Disease-Molecular correlation
    • Severity of syndrome correlates with ability of mutant EGR2 to bind a cis-acting regulatory site
• Clinical syndromes ⁵⁸
  • CMT 1D
    • Genetics
      • Inheritance: Dominant
      • Mutations: Arg409Trp
    • Clinical
      • Onset: 2nd to 3rd decade
      • Weakness: Distal, Legs & Arms
      • Tendon reflexes: Absent or Absent distally
      • Sensory loss: Distal; Arms & Legs; Mild
      • Scoliosis: Progressive
    • Nerve conduction velocities: Slow (9 to 42 M/s)
  • Dejerine-Sottas
    • Genetics
      • Inheritance: Dominant, de novo
      • Mutations: Arg359Trp; Glu412Lys
    • Clinical
      • Onset
        • Age: 0 to 6 months
        • Signs: Hypotonia; Hip dysplasia; Distal weakness
      • Weakness: Distal; Hands & Feet
      • Sensory loss: Legs
      • Tendon reflexes: Reduced
      • Skeletal: Scoliosis; Hand contractures
    • Nerve conduction studies
      • Velocities: Very slow (< 10 M/s)
      • CMAPs: Small or absent
    • Pathology: Onion bulbs; Thin myelin sheaths; Axonal loss
  • Congenital Hypomyelinating Neuropathy
    • Genetics
      • Inheritance: Dominant, de novo, or Recessive
      • Mutations, dominant: cis Ser382Arg & Asp383Tyr
    • Clinical
      • Onset age: Birth
      • Cranial nerve: Ptosis; Tongue fasciculation
      • Walking age: 18 to 24 months
      • Respiratory: Normal or restrictive disease
      • Progression: Slow
    • Motor nerve conduction velocity: 3 M/s
  • Congenital Amyelinating Neuropathy: Recessive
  • AR-CMT2, Late onset ¹⁴¹
    • Epidemiology: 1 Spanish family, 5 patients
    • Genetics
      • Inheritance: Recessive
      • Mutation: p.R409Q
    • Clinical
      • Onset age: 20 to 50 years
      • Weakness: Distal; Legs > Arms; Varied severity
      • Sensory: Loss
    • Laboratory
      • Electrodiagnostic
        • Motor NCV: Usually > 40 M/s
        • CMAP & SNAP amplitudes: Reduced
        • EMG: Chronic denervation in distal arms & legs
      • Leg MRI: Fatty replacement of foot muscles & posterior + anterolateral distal legs
  • Asymptomatic: Symptomatic after Vincristine treatment < 5 mg ¹⁰²
    • Epidemiology: 1 patient
    • Genetics
      • Mutation: Missense; R353G
      • Dominant
    • Clinical
      • Weakness: Distal
      • Sensory: Paresthesias
      • Tendon reflexes: Absent
      • Progressive: Over weeks
    • Electrodiagnostic
      • Motor conduction velocity (MCV): 23 to 32 M/s
      • MCV in mother: 38 to 50 M/s
      • CMAP amplitude: Normal
  • EGR2 variant: HMSN, Digenic ¹⁶¹
    • Epidemiology: 1 family, 2 patients
    • Genetics
      • Mutations: EGR2 (P397H); LITAF (T49M)
      • P397H alone
        • Asymptomatic
        • Electodiagnostic: Demyelination in 1 patient also with diabetes
    • Clinical: HMSN
      • Onset age: Childhood to 5th decade
      • Weakness: Distal; Hands & Feet; Gait disorder
      • Tendon reflexes: Absent or Reduced
      • Sensory loss: Pan-modal
      • Pes cavus
    • Laboratory
      • NCV
        • Velocities: Intermediate or Normal
        • Axon loss: Sensory & Motor
• Mouse disease: Krox20 knockout (Lethal) causes abnormal
  • Hindbrain segmentation
  • Bone formation
  • PNS myelination

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

• Epidemiology: 23 families
• Genetics
  • Mutations
    • CMT 1H syndrome: Missense; Gly90Ser, Val126Met, Asp329Val, Arg331His, Arg373Cys (C-terminus)
    • D-HMN: T48I; G90S; V126M; G267S
  • Penetrance: Incomplete
  • Allelic with
    • Cutis laxa, Dominant 2 , Recessive IA
    • Macular degeneration, Age-related 3
• FBLN5 protein
  • Location: Extracellular matrix
  • Functions
    • Role in elastic fiber assembly
    • Endothelial cell adhesion
• Syndromes
  • CMT 1 (Demyelinating; Dominant)
    • Clinical
      • Onset
        • Age: 3rd to 6th decade; Earlier than D-HMN syndromes
        • Neuropathy
      • Weakness (80%): Distal; Legs & Arms
      • Carpal tunnel syndrome symptoms
      • Sensory loss: Distal
      • Tendon reflexes: Reduced or Absent
      • Foot deformities
      • Macular degeneration (10%)
      • Not present
        • Hyperelastic skin
      • Course: Slow progression
    • Nerve conduction testing: Arms
      • Motor conduction velocities: 22 to 38 M/s
      • Distal latencies: 7 to 8.4 Msec
      • Sensory conduction velocities: 28 to 30 M/s or absent
  • D-HMN (Motor; Dominant)
    • Clinical
      • Onset
        • Age: 1st to 9th decade
        • Macular degeneration or Neuropathy
      • Weakness: (70%): Distal; Legs & Arms
      • Tendon reflexes: Normal or Reduced
      • Sensory loss: Occasional
      • Macular degeneration (50%): Exudative or Dry
      • Hyperelastic skin (30%)
      • Joint hypermobility (20%)
    • Nerve conduction testing: Arms
      • Motor conduction velocities: Normal
      • Distal latencies: 3 to 5 Msec
      • SNAPs: Normal
• Pathology
  • Skin
    • Dermis: Increased FBLN5 reactivity in some patients
    • Elastin fibrils: Fragments; Short; Reduced in number
  • Nerve & Muscle: Normal FBLN5 staining

CMT 1G ¹²⁹

• Epidemiology: 8 families, 22 patients
• Genetics
  • Mutations: Ile43Asn, Ile50del, Thr51Pro, Ile52Thr, M114T, V115A (Mild NCV Δ)
• PMP2 protein
  • Basic P2 protein
  • Major proteins of peripheral myelin
  • Related to
    • Transport of fatty acids
    • Metabolism of myelin lipids
  • Lipid-binding activity
  • Organization of compact myelin
• Clinical
  • Onset age: 1 to 18 years
  • Pes cavus
  • Weakness
    • Distal
    • Legs: Severe at ankles
    • Hands: With disease progression; May be median > ulnar
    • Proximal: In few patients
    • Early onset: Delayed walking
  • Sensory loss: Pan-modal
  • Tendon reflexes: Absent
  • Hand tremor: Some patients
• Laboratory
  • NCV: Demyelinating neuropathy
    • Tibial NCV: 15 to 22 M/sec
    • Median CMAP: Reduced amplitude
    • SNAPs: Absent
  • EMG: Distal denervation
  • Nerve pathology
    • Demyelination
    • Onion bulbs
    • Myelin sheaths: Thin
    • Axon loss (Large)
    • Regenerating clusters

CMT 1 ¹⁵⁰

• Epidemiology: 2 patients, 1 family
• Genetics
  • Mutation: K28I (c.83A>T)
  • Allelic disorder: CMT-DI
• c1orf194 protein
  • Calcium regulator in neurons
• Clinical
  • Onset age: 6 & 40 years
  • Weakness
    • Arms & Legs
    • Distal
    • Gait: Steppage
    • Course: Progressive
  • Sensory loss
    • Distal
    • Arms
    • Modalities: Large & Small fiber
  • Tendon reflexes: Absent in Legs
  • Pes cavus
• Laboratory
  • Nerve conduction
    • Velocities: Demyelinating; Velocity 11 M/s
    • SNAPs: Absent
• c1orf194 variant: CMT-DI
  • Epidemiology: 6 patients. 1 family
  • Genetics
    • Mutation: I122N (c.365T>A)
    • Inheritance: Dominant
  • Clinical
    • Onset age: 20 to 33 years
    • Weakness
      • Distal
      • Legs
      • Gait: Steppage
    • Sensory loss
      • Distal
      • Legs
    • Tendon reflexes: Reduced or Absent in Legs
  • Laboratory
    • NCV
      • Motor NCV: 30 to 52 M/s
      • Sensory NCV: 43 to 57 M/s
    • Nerve pathology
      • Axon loss
      • Thinly myelinated axons: Regeneration
      • Myelin folding irregularities
    • Muscle fibers
      • Grouped atrophy
      • Hypertrophy

CMT 1J ¹⁷⁰

• Epidemiology: 4 families
• Genetics
  • Mutations: Heterozygous; Val615Met (Adult onset), Met1064Val, Thr1424Met, Arg2524Cys (Child onset)
  • Mutation mechanism: Dominant negative
  • Allelic disorder
    • Diabetes (T1D) susceptibility
• ITPR3 protein (IP₃R3)
  • Location in Schwann cells (Rat): Paranode
  • Transduces hormonal signals that regulate Ca⁺⁺-dependent processes
  • Apoptosis control
  • IP₃ signaling pathway
    • Other components: FIG4; SBF2
  • ITPR3 knockdown: Altered Ca⁺⁺ flux dynamics in response to GPCR agonist ATP
• Clinical
  • Onset ages: 4 to 27 years
  • Weakness: Distal; Symmetric
  • Sensory loss: Distal; Panmodal except Joint position
  • Tendon reflexes: Absent
  • Pes cavus or planus
  • Course: Slow progression
• Laboratory
  • NCV: Demyelination + Axon loss
    • Velocities (Arms): 30 to 52 M/s
    • CMAP & SNAP amplitudes: Reduced or Absent in legs
  • Muscle: Chronic partial denervation; Grouped atrophy, Type grouping
  • Nerve: Onion bulbs; Axon loss

CMT: X-linked

CMT X-linked, Type 1 (CMTX1)   ● Connexin-32 (GJB1) ; Chromosome Xq13.1; Semi-Dominant Genetics: Mutations Locations Numerous: > 400 identified; World-wide Most parts of Connexin-32 (GJB1) gene Mutations in noncoding DNA in 11% (3' & 5' UTR) Effects on Cx-32 protein: Normally located on cell surface membrane Markedly reduced abundance: 175 frameshift Cytoplasmic accumulation & none on surface G12S, R142W, E186K, E208K Cytoplasmic accumulation & some on surface R15Q, V63I, V139M, R220Stop "Dominant negative" effects on other connexins R142W reduces Cx-26 expression Genetic-Clinical correlations 67 Severity: General Many mutations produce same disease severity as GJB1 deletions ? Related to degree of protein function lost No clear relation: Ability of Cx32 mutants to form functional channels Mild phenotype: Rare Point mutations: Missense (e.g. Val84Ile) Mild electrophysiological changes: NCV > 40 M/s Moderate-Severe (Typical) phenotype Point mutations: Missense Mutation locations: Many Found in most regions of protein Not in 4th transmembrane domain Also in Promoter, or 5' untranslated region Many other missense & stop mutations GJB1 Protein Some mutations: Present on plasma membrane ± cytoplasm Other mutations: Expressed in cytoplasm but not cell surface Clinical: Typical age-related progression Electrodiagnostic Mixed Axonal-Demyelinating Neuropathy NCV: Intermediate (30-40 M/s) Severe phenotype Mutations Out of frame deletion or insertion: 175 frame shift Stop codon: Arg22Stop Missense: Phe235Cys Causes abnormal leakiness of connexin hemichannels May be associated with severe or typical phenotype Protein: None or absent from surface membrane Earlier onset: < 10 years More disability Demyelinating Neuropathy (NCV: Slow (10-37 M/s)) CNS involvement Females: Heterozygous carriers Connexin-32 Protein Protein family: 4-TM; Homology to PMP-22 Expression: Schwann cells Function Gap junction formation Radial diffusion pathway: Between adaxonal & perinuclear Schwann cell cytoplasm Location: Myelinating Schwann cells Uncompacted myelin: May co-localize with MAG Para-nodal regions Schmidt-Lanterman incisures CMT 1X: Reduced expression of Connexin-32 & other myelin proteins Clinical features General: Intrafamilial variability common Onset Males: < 20 years Gait disorder Motor Weakness Distal Hands & Feet Split hand: Thenar > Hypothenar involvement Wasting: Legs > Hands Sensory loss (> 75%): Early proprioceptive loss Reflexes Ankle: Absent (100%) Knee: Males absent 90%; Females absent 50% Preserved elsewhere Extensor plantar: Some patients; Unilateral or Bilateral Hearing loss 2° changes in central auditory pathways Arg142Glu mutation May be asymmetric Tremor: Postural CNS Exercise related: White matter & corpus callosum lesions Transient encephalopathy at altitude Stroke-like episodes Dysarthria Weakness Other Few clinical features Slow conduction: Brainstem auditory evoked responses Progression Slow Age-related: Relatively severe disability by 6th decade Nerve conductions Slow conduction velocities Moderate slowing Range in males: 25 to 35 M/s Most severe @ 22 to 25 M/s Range in females: > 35 M/s Non-uniform Asymmetric Among & Within nerves Distal latencies: Prolonged Temporal dispersion: Prominent; Female & Male Axonal loss Length dependent Disability: Correlates with loss of motor units Absent SNAP in legs: 70% Intrafamilial variation Females Axon loss Temporal dispersion Less slowing of NCV (30 to 54 M/s) Pathology Similar in most patients Not related to specific gene mutations Axons Loss Large > Small myelinated axons Less than CMT1A Regeneration Axon clusters: More than CMT1A Myelin Thin sheaths Internodes: Short; Uniform on teased fibers Segmental demyelination: Some Onion bulbs: Few CMT 1X: Variant syndromes Females Genetics: Heterozygotes Clinical Common: Mild signs or Asymptomatic (50%) Manifesting carriers More frequent than other X-linked CMT types More severe neuropathy: Phe235Cys mutation 53 Pathophysiology Leaky Connexin-32 hemichannels Skewed X-inactivation: Chromosome with normal gene Manifest: Mutant proteins inhibit cell communications Onset: Early childhood Weakness: Face, Proximal & Distal; Progressive to severe Sensory loss: Distal Nerve pathology: Axonal loss; Onion bulbs; Thin myelin Family history Mother with same mutation, but much milder phenotype Nerve conductions: Axonal or Less demyelination than males Episodic: Unusual GJB1 features Episodic weakness: C164T mutation 21 Duration: 5 hours to 3 days Distribution of weakness Common: Extremities Other: Trunk & Head; Dysphagia; Dysarthria Transient encephalopathy 30 Genetics Connexin-32 mutations CNS manifestations F51L, R75W, E102del, V139M, Arg142Trp, R142Q, R164Q, Cys168Tyr Mutated protein Unable to form gap junctions or junctional coupling PNS only manfestations Y151C, V181M, R183C, L239I Mutated protein Forms gap junction plaques Normal junctional coupling Clinical features Triggers Exercise Altitude (> 8,000 feet) Illness Dehydration Hyperventilation Onset: 2 to 3 day delay Altered consciousness Ataxia Dysarthria Weakness: Bulbar; Proximal arms Course: Resolution over weeks MRI: White matter & corpus callosum lesions Nonenhancing, confluent, symmetrical More pronounced posteriorly Also see: Clinical pictures

CMT 1X R142W mutation From: A Kornberg CMT 1X encephalopathy White matter pathology



• CMT X-linked, Type 2 (CMTX2)
    ● Chromosome Xp22.2; Recessive
  • Epidemiology: 1 family, 5 patients
  • Clinical
    • Onset Infancy & 1st decade
    • Weakness
      • Distal
      • Legs > Arms
    • Sensory loss (40%)
    • Tendon reflexes: Absent
    • Mental retardation (40%)
    • Pes cavus
    • Hearing: Normal
  • Laboratory
    • NCV: Slow; Axon loss
    • EMG: Denervation
  
  
• CMT X-linked, Type 3 (CMTX3) ⁶³
    ● Chromosome Xq27.1; Recessive
  • Epidemiology
    • Several families in Australia, New Zealand & US
    • Probable Scottish founder mutation
  • Genetics
    • Mutation
      • Large DNA interchromosomal insertion in CMTX3 locus.
      • 78 kb insertion originates from chromosome 8q24.3: Produced trisomy of 8q24.3
    • Possible effect of insertion: FGF13 dysregulation
    • Other Xq27.1 interchromosomal insertion syndromes: Hypoparathyroidism, Hypertrichosis, Ptosis, XX male sex reversal
    • 1 original family reevaluated & not at this locus: HMN 5C (BSCL2 mutation)
  • Clinical
    • Onset
      • Age: Birth to 13 years
      • Fott deformities
      • Pain & Paresthesias: Legs
    • Weakness: Distal; Hands & Feet; Gait disorder
    • Sensory loss: Distal; Arms & Legs; Pansensory or Small fiber
    • Tendon reflexes: Reduced or absent distally
    • Skeletal: Pes cavus (60%); Hip dysplasia (20%); Scoliopsis (20%)
    • Progression
      • Arms involved with or after legs
      • More rapiod than other CMT
      • Some in wheelchair in 2nd or 3rd decade
    • CNS
      • Normal mentation & BAERs
      • Spasticity: 1 family
    • Carrier females: Asymptomatic
  • Electrophysiology
    • NCV
      • Axon loss
      • Demyelinating features (90%)
        • ≤ 23 M/s in 1 or more nerves (100%)
        • Varied among nerves
        • Conduction block (40%)
    • EMG: Distal denervation
  • Female carriers
    • Asymptomatic
    • High arched feet
    • Weakness: Foot dorsiflexion
  
  
• Cowchock Syndrome (Type 4; COWCK; CMTX4)
    ● Apoptosis-Inducing Factor mitochondrion-associated 1 (AIFM1) ; Chromosome Xq26.1; Recessive
  • Genetics
    • Allelic disorders
    • Obligate heterozygous females: Asymptomatic
  • Clinical
    • Onset age: Birth to 5 years
    • Neuropathy, Axonal
      • Weakness
        • Distribution: Distal; Especially peroneal group
        • Severe
      • Sensory loss
      • Areflexia
    • Skeletal: Pes cavus & Hammer toes
    • Mental retardation (60%)
    • Deafness: Most by 5 years
  • Laboratory
    • Electrodiagnostic testing
      • Median motor conductions: 33 to 56 m/s
      • Sensory conductions: Markedly abnormal
    • Nerve morphology: Axon loss & regeneration
  
  
• CMT X-linked, Type 5 ⁵⁴
    ● Phosphoribosylpyrophosphate synthetase I (PRPS1) ; Chromosome Xq22.3; Recessive
  • Epidemiology: Korean & European families
  • Genetics
    • Mutations: Missense; Glu43Asp, Met115Thr; Ala121Gly
    • Allelic with
      • Arts syndrome
      • Hyperuricemia, Mental retardation & Sensorineural deafness with PRPS1 superactivity
      • Deafness, X-linked 1
  • PRPS1 protein
    • Ubiquitously expressed in human tissues, including cochlea
    • Catalyzes phosphoribosylation of ribose 5-phosphate to 5-phosphoribosyl-1-pyrophosphate
    • Mediates biochemical step in purine metabolism & nucleotide biosynthesis
    • Mutation: Reduced enzyme activity
  • Clinical
    • Onset
      • Age: Early
      • Hearing loss
    • Weakness
      • Distal
      • Legs
      • Onset age: 8 to 13 years
      • Gait difficulties
    • Hearing loss: Sensorineural
    • Optic neuropathy: Onset age 7 to 10 years; Most patients
    • Sensation: Normal
    • Tendon reflexes: Reduced
  • Laboratory
    • Electrophysiology: Axonal neuropathy ± Mild demyelination
      • NCV: Normal or Mildly slowed
      • SNAP amplitudes: Mildly reduced
    • Pure tone audiogram: Bilateral sensorineural hearing loss, severe
    • Nerve pathology: Loss of myelinated axons
  • Nosology
    • Similar syndrome to Rosenberg–Chutorian
      • Optic atrophy
      • Polyneuropathy
      • Deafness
  
  
• CMT X-linked, Type 6 (CMTX6) ¹⁰⁷
    ● Pyruvate dehydrogenase kinase, isoenzyme 3 (PDK3; PDHK3) ; Chromosome Xp22.11; Semi-Dominant
  • Epidemiology: 1 family
  • Mutation: Missense; R158H
  • PDK3 protein
    • Mitochondrial matrix
    • Tissues: Highest in heart & skeletal muscle
    • Regulates pyruvate dehydrogenase complex (PDC), by reversible phosphorylation
    • Mutation effects
      • Enzyme hyperactivity
      • Binds with stronger affinity to inner-lipoyl (L2) domain of E2p chain of PDC
  • Clinical
    • Onset age: Mean 7 years; &le 13 years
    • Foot deformity: Pes cavus, Bilateral; Clawed toes
    • Gait disorder
    • Motor: Wasting & Weakness
      • Legs: Distal
      • Hands: Reduced grip strength
    • Ankle reflexes: Absent
    • Sensory loss
      • Distal
      • Pan-modal
    • Tremor: Hands
    • Course
      • Slow progression
      • All remain ambulant
  • NCV
    • Axon loss: Motor & Sensory
    • SNAPs: Often absent in arms & legs
    • CMAPs: Reduced amplitude or absent in legs
  • Carrier females: Mild features or asymptomatic
    • Hands: Intrinsic muscle wasting
    • Foot deformity: Onset in teens
    • Ankle reflexes: Reduced
    • Hand tremor: 5th decade

CMT 2

• Axonal Neuropathy (NCV: Axonal Loss)
• Inheritance: Dominant
• Prevalence: 4 to 12 per 100,000
• Onset: Peak in 2nd decade; Some as late as 7th decade
• Clinical
  • Weakness: Symmetric; Distal in most
  • Sensory loss: Distal; Panmodal
  • Tendon reflexes: Reduced most at ankles; Often preserved proximally
• NCV: > 38 m/s in Median nerve
• Associated with: Increased frequency of restless legs syndrome
• Characteristic clinical features
  • CMT 2A (MFN2; 1p36): Distal leg weakness early in course; ? Anticipation
  • CMT 2B (RAB7; 3q13): Severe sensory loss; Acrodystrophy
  • CMT 2C (TRPV4; 12q24): Vocal cord & Phrenic involvement; Onset 1st decade
  • CMT 2D (GARS; 7p15): Hand involvement early in course
  • CMT 2E (NFL; 8p21): Legs > Arms; Ataxia worse with heat or fever
  • CMT 2F (HSPB1; 7q11): Preominantly motor
  • HMSN-P (3q13): Proximal weakness; Absent DTRs; Tremor; Diabetes mellitus
  • CMT 2-P₀ (P₀; 1q22): Severe sensory loss; Deafness; Adie's pupil
  • CFEOM3 (TUBB3; 16q24): Eye movement limitation
  • HMN 5B (BSCL2; 11q13): Motor predominant; Early arm weakness

• Clinical features
  • Onset
    • Age: 1 to 52 years; Variable in family; ? Anticipation
    • Symptoms: Foot drop; Dysfunction in gait, running or climbing stairs
    • MFN2: Moderate symptoms in early childhood
  • Weakness
    • Distal
    • Legs: Anterior & Posterior
  • Sensory loss
    • Mild: Variably present
    • Distal
    • Legs > Arms
  • Tendon reflexes: Reduced or absent in lower extremities; Absent at ankles
  • Tremor: Intention; Up to 88%
  • Pes cavus (100%)
  • Leg pain: Some patients
  • Hearing loss: 59% with MFN2 mutations
  • Progression: Gait aids or wheelchair may be needed in 4th or 5th decade
• Laboratory
  • Electrodiagnostic: Axonopathy
    • Median NCV
      • Velocity: Slightly decreased; 38 M/s to 62 M/s
      • CMAP amplitude: Reduced (< 4 mV)
      • SNAP amplitude: Reduced (< 10 μV)
    • EMG: Denervation in distal muscles
  • Sural nerve pathology
    • Reduced numbers of myelinated axons, especially large
    • Rare myelin changes: None on teased fibers

• Epidemiology with KIF1B mutation
  • Families in Japan ¹³
  • Patients also have MFN2 mutation
• Mutation
  • Missense: Q98L
  • Loss of function mutation in motor domain: ATP binding P loop
  • May not be pathogenic in disease
• Kinesin family member 1Bβ protein (KIF1Bβ)
  • Protein superfamily: Kinesin
  • N-terminal-type microtubule motor protein
  • Function: Anterograde transport of synaptic vesicle precursors
  • Subcellular location: Normal KIF1B
    • Cytoplasmic: Cell periphery
    • Synaptic vesicle membranes
    • Cofractionates with membranous organelles containing synaptotagmin, synaptophysin & SV2
  • Mutant KIF1B (Q98L)
    • Subcellular location: Aggregated in the perinuclear region
    • Microtubule-activated ATP turnover rates reduced
    • ? Functional loss of motor activity
  • Kinesin mutations & disorders
  • External link: Kinesin home page

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: Dominant CMT 2 type More common in: Severe CMT2 population MFN2 genetics Inheritance: Dominant 90%; Recessive 10% Mutations > 50 described Types Missense examples Val69Phe; Leu76Pro; Arg94Gln; Met105Thr; H165D; Thr213Ile; F223L; T236M; V244M; Pro251Ala; V273G; Arg280His; F284Y; K357N; E424G; Trp740Ser Stop: R418X Locations in gene Cytoplasmic Within or immediately upstream of the GTPase domain Within two coiled-coil domains Associated with functioning or mitochondrial targeting of MFN2 De novo 14% to 63% of patients Locations Common: Arg94Trp/Gln; Arg364Trp Guanine & cytosine nucleotides in CpG dinucleotide sequences Other: Lys307Glu, Gln367Pro, Ser249Phe, Pro251Ser, Val244Leu, Tyr752X Onset age: May be earlier Semi-Dominant: Thr362Arg; Thr362Met Penetrance: Variable Common location: Arg94 Milder disease: Trp740 Recessive mutations (Homozygous or Compound heterozygous): More severe disease Patients: Severe; Early onset (2 to 3 years); Axon loss; Mild hearing loss Parents: Normal or Mild neuropathy z` Allelic disorders HMSN V (CMT + Pyramidal features): H165D mutation HMSN VI (HMSN & Optic atrophy): Multiple mutations Axonal neuropathy, Recessive (AR-CMT2) CMT 2A2B: Axonal, Recessive CMT 2A2A: Dominant Severe, early onset axonal neuropathy (SEOAN) Early onset stroke without neuropathy HMSN + Cognitive impairment & Brain mitochondrial dysfunction Sensory neuropathy with Anhidrosis, Late onset: c.776 G>A mutation Lipodystrophic syndrome (Recessive) Mutation: 1 is Arg707Trp Canine fetal-onset neuroaxonal dystrophy: Homozygous deletion MFN2 protein 55 Mitochondrial: Transport & Fusion protein Dynamin-related Ubiquitously expressed: Present in spinal cord & peripheral nerve; Muscle; Heart Cellular localization Outer mitochondrial membrane Co-localizes with Bax (proapoptotic protein) Most of protein is cytosolic 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 models 180 Mitochondria Mobility & Axon transport reduced Fragmentation & Dysfunction Neurofilament heavy chain: Increased in cell bodies Axons Transport: Anterograde & Retrograde reduced Swellings 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 Pyramidal signs: Some patients 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) Epidemiology: > 20 families 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 Epidemiology: > 50 patients Genetics MFN2 Mutations Missense (Phe216Ser; Thr362Met; Arg519Pro); Nonsense (Glu308X); Splice (c.600-31T>G); Intragenic deletion Common: Compound heterozygous Homozygous Adult onset: R632W Severe childhood onset: Gly176Ser; c.600-31T>G 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 MFN2 Variant Syndrome: HMSN + Pyramidal signs (HMSN5) MFN2 Variant Syndrome: Canine fetal-onset neuroaxonal dystrophy Mutation: Homozygous deletion

From: R Baloh MD CMT 2A2 CMT 2A2

• Epidemiology
  • Families & Sporadic patients
• Genetics: RAB7 mutations
  • Missense
  • Specific mutations: Leu129Phe; Asp161Thr; Val162Met
• RAB7 protein ²⁰¹
  • Expression: Ubiquitous, including sensory & motor neurons
  • RAB family of RAS-related GTP-binding proteins
  • Regulators of vesicular transport & membrane trafficking
  • May have a role in linking vesicles and target membranes to the cytoskeleton
  • Localization: Late endosomes
  • RAB7 functions
    • Small GTPase
    • Degradation pathways
      • Transport between: Late endosomes & Lysosomes
      • Interaction between: Mitochondria & Lysosomes
        • Driven by: RAB7 GTP hydrolysis at contact sites
        • Mediates: Lysosome regulation of mitochondria dynamics
        • Locations: Axons & Soma
        • Role in cellular vacuolation induced by cytotoxin VacA of Helicobacter pylori
      • Autophagy pathway
    • RAB7-effector protein RILP
      • Induces recruitment of dynein-dynactin motors
      • Regulates transport toward minus-end of microtubules
    • Golgi targeting of glycosphingolipids
  • Mutation effects
    • GTP hydrolysis: Defective
    • GTP binding: Increased
    • Mitochondria-Lysosome contacts: Prolonged contact site tethering in axons
    • Lysosome: Defective morphology; Increased size
• Clinical features ¹¹
  • Onset
    • 2nd & 3rd decade
    • Foot ulcers & Infections
  • Weakness: Most patients
    • Distal
    • Legs (Most common) > Arms (50%)
    • Symmetric
  • Sensory loss: Severe
    • Distal
    • Symmetric
    • Lower limbs > Upper
  • Tendon reflexes: Normal, except reduced at ankles
  • Foot deformities (100%)
    • Pes cavus or planus; Hammer toes; Onset in childhood
    • Acromutilation & Foot ulcers: Male > Female
  • Pain: Unusual; Lancinating
  • Autonomic dysfunction
    • Light-headedness
    • Hypohidrosis: Distal
    • Abnormal skin innervation
  • Phenotype variable within families: Severe in some, Mild in others
  • CNS: Cerebellar atrophy & nystagmus reported in 1 patient
  • Progression: Few need wheelchair
• Electrodiagnostic
  • Axonal loss: Absent sural potentials; Small CMAPs in legs
  • Tibial H-reflexes: Preserved
  • Mild slowing of NCV
  • May detect disease carriers
• Nerve biopsy
  • Axonal loss: Small & large myelinated axons; Unmyelinated axons
  • Axon degeneration: Unmyelinated axons
  • Axonal regeneration: May be abundant
  • Occasional onion bulb
  • Reduced staining for RILP (Rab interacting lysosomal protein)
  • Skin axon loss: Length-dependent; Male > Female
• Variants
  • Mutilating neuropathy not linked to chromosome 3p
  • Ulcero-mutilating neuropathies
  • Acromutilating sensory neuropathy without weakness: RAB7 mutation Asp161Thr

• Epidemiology
  • > 50 patients
  • 0% to 7% of Axonal CMT in US, Europe & Australia
• Genetics
  • TRPV4 mutations ⁸⁰
    • Ankyrin domain: Intracellular; N-terminal
    • Arg232Ser; Arg232Cys; Arg269C; Arg269H, Arg315W, Arg316C,
    • Missense
  • Allelic disorders
• TRPV4 protein
  • Functions
    • HMSN2C mutations
      • Abnormal TRPV4-regulated Ca⁺⁺ influx
      • Higher basal intracellular Ca⁺⁺ levels
    • Brachyolmia mutation (V620I): Increased constitutively activated current & response to agonists
  • TRPV4 Protein distribution
    • Normal: Cytoplasm
    • Mutant: Increased perinuclear
• Clinical features
  • Onset
    • Age: < 2 to 57 years
    • Stridor
    • Leg weakness
  • Severity
    • Variable within families
    • Some patients with mutations may be normal
  • Weakness
    • Distal: Hands & Feet; Mild to Severe
    • Proximal: None to Mild
    • Diaphragm & Intercostal paralysis: Shortness of breath
    • Vocal cord
      • Altered voice; Hoarseness
      • Stridor
      • May be only sign in mildly affected patients
    • Scapula
    • May progress to proximal & face muscles
    • May be worse in cold
  • Sensory loss: Asymptomatic; Reduced Vibration sense
  • Tendon reflexes: Depressed or Absent
  • Hearing loss: Sensorineural
  • Urinary bladder: Urgency; Incontinence
  • Skeletal
    • Pes cavus (70%)
    • Arthrogryposis: Some patients
    • Scoliosis
    • Dysplasia (20%)
• Electrodiagnostic
  • Median NCV > 50 M/s
  • CMAP amplitudes often reduced
  • Phrenic CMAP: Reduced amplitude
  • SNAPs: Normal or Reduced amplitude
  • EMG: Chronic denervation
• Pathology
  • Muscle: Chronic denervation
  • Sural nerve
    • Axon loss: Mild
    • Myelin thickness: Normal
• Laboratory
  • Serum CK: 2x to 3x high

• Epidemiology: 13 families
• Genetics
  • Mutations: Missense; E71G, Glu125Lys, L129P, G240R, His472Arg, G526R
  • Allelic disorders
    • Hereditary Distal Motor Neuropathy V (dSMA-V)
    • CMT2D
    • SMAJ1
    • ? Bulbar ALS: 1 patient ¹⁴³
  • Related tRNA synthetase disorders
    • YARS: CMT DIC
    • AARS: CMT 2N
    • KARS: CMT RIB
  • Also see: Other ARS syndromes
• GARS protein
  • Family: Aminoacyl tRNA synthetases
  • Function: Charge tRNAs with cognate amino acid (glycine)
  • Expression: Ubiquitous
  • Location: Mitochondrial & Cytoplasmic
  • Other disease association: Antibody target (EJ) in immune myopathy
• Clinical features
  • Onset
    • Age: 3 months to 59 years
    • Hand weakness
  • Weakness
    • Distal
    • Arms > Legs: Especially thenar & 1st dorsal interosseus
    • Bilateral
    • Respiratory & Feeding: Early onset
  • Sensory loss
    • Variable: Sensation normal in some family members
    • Pattern: Distal; Arms & Legs; Pansensory
  • Tendon reflexes: Absent or reduced arms; Decreased legs
  • Progression: Slow over years
• Electrodiagnostic
  • Axonal loss: Hands
  • Normal NCV
• GARS1 variant: Spinal muscular atrophy, infantile, James type (SMAJI)
  • Epidemiology: 7 patients
  • Genetics
    • Inheritance: de novo, Dominant
    • Mutations: Missense; Glu125Lys, Gly652Arg, Gly598Ala
  • Clinical
    • Onset: < 1 year
    • Motor milestones: Delayed
    • Weakness
      • Distal > Proximal
      • Arms > Legs
      • Feeding difficulty
      • Vocal cord
      • Respiratory
    • Skeletal
      • Foot deformities
      • Spine: Hyperlordosis, Scoliosis
      • Contractures: Hip
    • Course: Slow progression
  • Laboratory
    • EMG: Denervation
    • NCV: CMAPs small
    • Muscle biopsy: Grouped atrophy

• Epidemiology: <1% of CMT; ~70 families
• Genetics
  • Mutations: Missense & Deletions
    • Head domain: Glu7Lys; Pro8Arg; Pro8Gln; Pro8Leu; Pro8Arg; P22T; Pro22Ser; Glu89Lys; E90K; N98S
    • Coil 1A: Asn97Ser
    • Coil 1B: A148V
    • Coil 2B: Gln333Pro
    • Tail: E397K; P440L; Glu528del
    • Possible modifier mutation: E488K with more axon loss
  • Mutation locations
    • Most in exon 1
    • NEFL protein head domain: More NCV slowing
    • Coil 2B domain: Less NCV slowing
  • De novo mutations: N98S
  • Allelic disorders
    • CMTDIG
    • CMT 2E
    • AR-CMT
• Neurofilament proteins
  • Intermediate filaments
• Clinical: Variable
  • Onset
    • Less than 13 years
      • < 3 years: 30%; P8L; E90K; N98S
      • 2nd decade: Pro8Arg; Glu528del
      • Early childhood: Other mutations
        • Early: Delayed motor milestones or Gait disorder
        • 6th decade onset: L311P
        • Differential diagnosis: Dejerine-Sottas
    • Gait disorder
  • Weakness
    • Legs & Arms
    • Distal > Proximal
      • Proximal weakness with disease progression
    • Face: Early onset disease
    • May be severe
  • Muscle atrophy
  • Tendon reflexes: Often reduced or absent
  • Sensory loss
    • Large & Small fiber modalities
    • Sensory ataxia
  • CNS
    • Tremor: Some patients
    • Cerebellar: Ataxia, some patients
    • Pyramidal tract signs: 20%
      • Mutations: Y265C, Y389C, E396K, F439I, P440L
    • Hearing loss
• Laboratory
  • Electrophysiology
    • Motor NCV: 15 to 38 M/s
    • SNAPs: Often absent
    • F-waves: Normal or Slow
    • Terminal latencies: Prolonged in some patients
  • Nerve pathology (1 patient)
    • Axon loss: Large & Unmyelinated
    • Regenerating clusters
    • Onion bulbs (Small)
    • Thinly myelinated axons
    • Neurofilaments may occur in masses
  • Muscle: Neurogenic changes
  • Brain MRI: Normal or Cerebellar atrophy
• NEFL variant disorder: Charcot-Marie-Tooth, Dominant, Intermediate (CMTD1G)
  • Epidemiology: 5 families
  • Genetics
    • Inheritance: Dominant
    • Mutation: Missense; E396K
  • Clinical
    • Similar to CMT 1F

• Epidemiology: Multiple families
  • Taiwan: 17% of Han Chinese families with CMT 2
• Genetics
  • Mutations
    • Types
      • Missense
      • Deletion: In frame & frame shift
    • Locations
      • Usually in head & rod domains
      • Thr21fs; Pro22Ser; Leu93Pro; Leu268Pro; del322Cys_326Asn; Gln333Pro; Leu334Pro; Glu396Lys
    • Mutation effect: ? Alters self assembly of NFL ³³
    • Haploinsufficiency: Probably not pathogenic
  • Allelic disorders
    • CMT 1F
    • AR-CMT (CMT 2B5)
    • CMT + Intermediate NCV (CMT DIG)
    • ?? Neuropathy vs Rod myopathy
• Neurofilament light chain protein
  • Required for organization of neurofilaments
  • Associated with radial axon growth
• Clinical features
  • Onset
    • Age: 1st to 5th decade
    • Difficulty walking; Leg weakness
  • Neuropathy
    • Weakness
      • Distal
      • Legs > Arms
    • Sensory loss: Minor to Severe
      • Distal
      • Legs > Arms
      • Pansensory, especially vibration
      • Sensory ataxia (20%)
    • Tendon reflexes: Reduced or Absent
    • Progression: Slow over years; Some severe, others mild, disability
  • Hearing loss (30%)
  • Episodic ataxia: In childhood; Triggered by fever or heat
  • Postural tremor (30%)
  • Systemic features
    • Pes cavus: 100% over 20 years of age
    • Occasional patients with hyperkeratosis
• Laboratory
  • Electrodiagnostic: Nerve conduction studies
    • Axonal loss: Small CMAP
    • NCV: Normal or slightly reduced; Median - Range of 29 to 55 M/s
    • Distal latencies: May be prolonged
    • Brainstem auditory evoked potentials: Abnormal
  • MRI of brain & spinal cord: Normal
  • Nerve pathology ⁴⁸
    • Giant axons
      • Focal swellings
      • Filled with: Densely packed neurofilaments
      • Surrounded by: Thin myelin sheath
      • Not present with: Glu396Lys mutation
    • Axon atrophy: Some regions with no neurofilaments
    • Regenerating clusters
    • Demyelination: Secondary; Few small onion bulbs
    • Similarities to: Giant axonal neuropathy
  • Serum CK: May be high
• ?? NEFL Variant syndrome: Neuropathy vs Nemaline rod myopathy
  • Epidemiology: 1 family
  • Genetics
    • Inheritance: Dominant
    • Mutation: R421X
  • Clinical
    • Onset
      • Age: Congenital
      • Hypotonia
    • Weakness
      • Face
      • Legs, distal
      • Arms, distal: 1 patient
      • Respiratory
      • Progressive
    • Skeletal
      • Contractures: Knees, Ankles, Hips, Fingers
      • Scoliosis
  • Laboratory
    • Muscle
      • Grouped atrophy
      • Rods: Possibly in some patients
      • Endomysial connective tissue: Increased
    • EMG: Denervation
    • NCV: SNAPs & CMAPs small

• Epidemiology: Palestinian & Japanese families
• Genetics
  • Mutations: Null; E210X; Glu140X
  • Allelic with: CMT 1F; CMT 2E
• Clinical: Severe phenotype
  • Onset
    • Age: Early childhood; Often < 2 years
    • Hypotonia
  • Weakness
    • Degree: Severe in legs; Moderate in arms
    • Distal > Proximal
    • Slowly progressive
  • Sensory loss: Pan-modal
  • Tendon reflexes: Absent
• Electrodiagnostic
  • NCV: 12 to 25 m/s
  • SNAP amplitudes: Progressively reduced
  • VER: Slowed
• Nerve pathology
  • Myelinated axons: Marked loss
  • Remaining axons
    • Small size (< 3μM)
    • No neurofilaments or intermediate filaments

• Epidemiology: English, Indian, Pakistan, Russian (Voronezh) & Belgian families
• Genetics
  • Mutations
    • > 30 described
    • Dominant CMT: Missense (Pro39Leu; G84R; V97L; S135F, R136W; R140G; Pro170Thr; C-terminal IXI/V (180-187); Stop (Glu186*)
    • Recessive CMT: Homozygous; In α-crystallin domain; L99M; S135F, R136L
  • Allelic disorders
    • Distal motor neuropathy 2B (Distal HMN)
    • ALS-like disorder
• HSPB1 (HSP27) protein
  • sHSP family
  • Expression: Ubiquitous; Most in Nervous system, Heart, Muscle
  • Chaperone
    • Widely expressed sHSP
  • Interacts with
    • Intermediate filament proteins
    • SQSTM1/p62: Autophagy mechanisms
    • Misfolded proteins: Prevents aggregation
  • Functions
    • Protection against: Oxidative stress
    • Promotes axon regeneration
    • Regulation & maintenance: Cytoskeleton; Transport (Microtubule regulator)
  • Mutant HSPB1
    • Not transported in neurites of cortical neurons
    • Forms intracellular aggregates
    • Causes sequestration of NF-M & p150 dynactin
• Clinical
  • Onset
    • Age: 6 to 54 years
    • Gait disorder
  • Weakness
    • Distal
    • Proximal legs: Some patients
    • Legs > Arms
      • Legs: Early in disease course
      • Arms: After 5 to 10 years of disease
    • Symmetric
    • May be severe with foot drop
    • Early onset: More severe phenotype
  • Tendon reflexes: Reduced or Increased
  • Sensory loss: Some patients
    • Mild
    • Distal
    • Feet & Hands
    • Especially pain & temperature
  • Fasciculations & Cramps: In elderly patients
  • Cranial nerves: Normal
  • CNS: Normal
  • Progression
    • Slow
    • Disability in most after 15 to 20 years
    • Some patients remain ambulant after 30 years
• Laboratory
  • Electrodiagnostic: Axonal loss
    • CMAPs: Small or Absent; 30% to 50% in hands; 10% of normal or unobtainable in feet
    • NCV: 42 to 58 M/s
    • EMG: DEnervation, Distal or Diffuse
    • SNAP amplitudes: Small in some patients
  • Nerve pathology
    • Axon loss
    • Regenerative clusters
    • Thin myelin sheaths
• HSPB1 variant: ALS-like disorder ¹⁵⁷
  • Genetics
    • Inheritance: de novo; No family history
    • Mutations: Arg27Leu; c.570G>C (p.Gln190His), c.610dupG (p.Ala204Glyfs* 6)
  • Clinical: ALS
    • Bulbar onset: Dysarthria; Dysphagia
    • Weakness: Arms, asymmetric; Respiratory
    • Mild cognitive impairment
  • Laboratory
    • EMG: Diffuse denervation
    • Serum CK: High

• Epidemiology: 1 Chinese family
• Genetics
  • Mutation: Missense; Lys141Asn
  • Allelic disorders
• HSPB8 protein
  • Chaperone
  • Transport regulation (Microtubule regulator)
• Clinical
  • Onset
    • Age: 15 to 33 years
    • Leg weakness
  • Weakness
    • Distal: 100%
    • Legs: 100%
    • Proximal: Occasional patient
    • Hands: 30%
    • Symmetric
  • Sensory loss
    • Distal
    • Legs
    • No painless injury or ulceration
  • Tendon reflexes: Reduced or Absent
  • Skeletal
    • Pes cavus 80%
    • Scoliosis 15%
  • Course
    • Progression: Slow
    • Never wheelchair dependent
• Laboratory
  • Electrophysiology
    • NCV: Normal
    • SNAPs: Absent or Small amplitudes
    • EMG: Chronic denervation
  • Nerve pathology
    • Axonal loss
    • Regeneration

• Epidemiology: > 30 families
• Genetics
  • Mutations: Missense; Asn71Tyr, Arg326Trp (North European), Arg329His, Glu337Lys
  • Mutation locations: Most in catalytic domain; Some in editing & C-terminal domains
  • Allelic with
    • d-HMN
    • EIEE29
  • Other tRNA synthetase mutations
    • ARS2 genes
    • CMT
      • GARS: CMT 2D
      • YARS: CMT DIC
• AARS protein
  • Cytoplasmic
  • Aminoacyl-tRNA synthetase: Aminoacylation of tRNA^Ala
  • Ligase
  • Protein biosynthesis
  • Autoantigen: PL-12 immune myopathy
• Clinical
  • Onset
    • Age: Mean 28 yrs; Range 6 to 54 yrs
    • Leg weakness
    • Occasional asymptomatic patient
  • Weakness
    • Distal
    • Legs
    • Arms: Some patients
    • Asymmetry common
    • Moderate to Severe
  • Sensory loss
    • Distal
    • Legs
  • Tendon reflexes
    • Knees: Reduced
    • Ankles: Absent
  • Skeletal: Pes cavus; Hammer toes
  • Deafness: Sensorineural; Variable
  • Course
    • Progression: Slow
    • Cane: Occasional in 5th or 6th decade
    • Never wheelchair dependent
• Laboratory
  • Electrophysiology: Axonal to Intermediate
    • NCV: 32 to 50 M/s; CMAP amplitudes reduced
    • SNAP amplitudes: Small
    • EMG: Denervation
• Variant syndrome: Distal Motor Neuropathy (dHMN) ¹⁰⁴
  • Genetics
    • AARS Mutation: Missense; D893N
    • Allelic with: CMT 2N
  • Clinical
    • Onset age: 2 years to 6th decade
    • Weakness
      • Distal
      • Legs: Anterior & Posterior
    • Tendon reflexes: Ankles absent; Knees reduced
    • Sensory: Normal
    • Foot: Deformities; Pes cavus
    • Course: Minimal progression
  • Laboratory
    • Electrodiagnostic
      • EMG: Neurogenic; Large
      • motor unit potentials
      • SNAPs: Normal
      • Motor NCVs: Normal velocity
    • Muscle MRI: Abnormal gastrocnemius & vastus lateralis
• Variant syndrome: Early-Onset Epileptic Encephalopathy with Persistent Myelination Defect, Recessive (EIEE29)
  • Epidemiology: 3 patients, 2 families
  • Genetics
    • Inheritance: Recessive
    • AARS mutations: K81T, R751G
  • Clinical
    • Onset age: Infancy
    • Microcephaly
    • Failure to thrive
    • Vertical tali
    • Spasticity
    • Myoclonic epilepsy, Refractory
    • Extrapyramidal: Blepharospasm, Orobuccal dyskinesia, Dystonia, Chorea,
    • Tendon reflexes: Reduced, ? Polyneuropathy
  • Laboratory
    • EEG: Slowing; Multifocal polyspike & slow-wave discharges; High-amplitude paroxysmal fast activity
    • Brain MRI: Progressive diffuse cerebral atrophy; Hypomyelination

• Epidemiology: British, Australian & Bulgarian families
• Genetics
  • Mutations
    • General location: Tail domain
    • Missense: Arg264Leu; His306Arg; Arg598Cys
  • Allelic disorders
    • SMA-LED
    • Intellectual disability with neuronal migration defects (MRD13)
      • Motor domain mutations: Glu1518Lys, His3822Pro
    • CMT 2O
• DYNC1H1 protein
  • Dynein complex
    • Location: Cytoplasmic
    • Functions
      • ATPase-dependent movement along microtubules
      • Recruitment of all other dynein components
      • Retrograde axon transport
      • N-terminal tail domain: Assembly of structural & regulatory subunits & Docking of cargos & adaptors
      • C-terminal motor domain: 6 ATPase domains & Microtubule-binding stalk
    • Associated with: Dynactin
    • Disorders
  • DYNC1H1
    • Core of dynein complex
    • Responsible for protein complex binding to & moving along microtubules
    • Mutations: Increase interaction with adaptor BICD2
  • Axon transport: Other
    • Proteins
    • Disorders
• Clinical
  • Onset: Early childhood
  • Motor milestones: Delayed
  • Weakness: Distal; Legs > Arms
  • Sensory loss: Distal; Pan-modal; Normal in some patients
  • Tendon reflexes: Normal or Reduced
  • CNS: Learning difficulties
  • Skeletal
    • Pes cavus: Some patients
    • Contractures: Multiple & Congenital
      • More severe phenotype
      • Legs > Arms
      • Mutation: Arg264Leu
• Laboratory
  • NCV: Axon loss, Sensory & Motor
  • EMG: Denervation
  • Muscle: Neurogenic atrophy
• Mouse models
  • Legs at odd angles (Loa)
  • Cramping 1 (Cra1)
  • Sprawling (Swl)
  • DYNC1H1 deletion: Muscle spindle loss

• Epidemiology: Chinese family, 8 patients
• Genetics
  • Mutations: Heterozygous; Y485X
  • Allelic disorders
    • 2-Aminoadipic & 2-Oxoadipic aciduria (AMOXAD) . Recessive
    • Spinal muscular atrophy (SMA) + Cognitive delay, Infant-onset, Recessive: 1 patient
    • Amyotrophic Lateral Sclerosis: Heterozygous mutations ¹⁸⁴
      • Epidemiology: More common in Germany
      • Limb onset (80%)
      • May have: Features of Neuropathy + ALS; More rapid progression
• DHKTD1 protein
  • Location: Mitochondrial
  • 2-Oxoglutarate dehydrogenase complex: Catalyzes conversion of
    • 2-Oxoglutarate to succinyl-CoA & CO₂
    • 2-Oxoadipate to Glutaryl-CoA
• Clinical
  • Onset age: 13 to 25 years
  • Weakness: Symmetric; Distal; Legs & Arms
  • Muscle wasting: Distal arms & legs
  • Sensory loss: Pan-modal
  • Tendon reflexes: Reduced
  • Pes cavus
• Laboratory
  • NCV
    • CMAP amplitude: Small in arms & legs
    • Conduction velocities: Normal
  • Muscle: Angulated muscle fibers; Mitochondrial vacuoles

• Epidemiology: 1 family; 7 patients
• Genetics: Mutation
  • 85 kb deletion in Chromosome 4p
  • Heterozygous
  • Genes involved
    • TACC3 : Intron 6 to Exon 16
    • FGFR3: Total deletion
    • LETM1: Intron 10 to Exon 14
• Clinical: CMT2
  • Onset age: Childhood to 3rd decade
  • Weakness: Distal; Hands & Feet
  • Sensory loss: Small fiber & Vibration
  • Tendon reflexes: Reduced or Absent
  • Course: Slow progression
• Laboratory
  • Nerve: Loss of most myelinated axons
  • Skin & Sweat gland biopsy: Complete axon loss
  • NCV: Axon loss; Motor & Sensory
  • Autonomic functions: Often normal

• Epidemiology: 3 families
• Genetics
  • Mutation: Tyr172Cys
• CADM3 protein
  • Adhesion molecule
  • Expressed on axons
  • Binds to CADM4 on Schwann cells
  • Mutation: Activates unfolded protein response
• Clinical
• Onset age: 1 to 29 years
• Weakness
  • Distal
  • Arms & Legs
• Sensory loss
  • Distal or Normal
  • Panmodal
• Tendon reflexes
  • Varied: Absent at ankles to Brisk
• Laboratory
  • NCV: Axon loss (CMAP amplitudes reduced); Velocities intermediate
  • Nerve: Loss of myelinated axons; Tomaculae
  • Brain & spine MRI: Normal

• Epidemiology: 4 families; 7 patients
• Genetics
  • Mutations
    • Single nucleotide change: Ala1137Val, Arg1461Gln, Cys982Tyr, Trp1175Ter
    • Location: Often at GDP/GTP-binding site of ARF1
  • Allelic disorder: CMT DIA
• GBF1 protein
  • Facilitates GDP-to-GTP exchange for ARF family of small GTPases
  • Golgi: Maintenance of structure & function
  • ARF1-GBF1 complex
  • Formation of coatomer protein complex I (COPI) vesicles
  • Lipid droplet metabolism
  • Mitochondrial function & dynamics
  • Location: Ubiquitous; Present in motor neurons: Soma & Growth cone
  • Golgi disorders
    • Muscle
    • Nerve
      • GBF1: CMT2/Distal HMN
      • BICD2: SMALED2A
      • FAM134B: HSAN II
      • VAPB: ALS8
    • Antibodies
      • Yo
      • Giantin
• Clinical
  • Onset ages: Childhood to 57 years
  • Weakness
    • Distal
    • Legs > Arms
    • Gait disorder
    • Early onset: Walking delay
  • Sensory: Reduced vibration in legs or Normal
  • Bulbar: Dysarthria in 1 patient
  • Tendon reflexes: Reduced at ankles; May be increased at knees
  • Skeletal: Pes cavus
• Laboratory
  • EMG: Chronic neurogenic; Fibrillations or Positive sharp waves in some
  • NCS: Axon loss, Motor ± Sensory
  • Muscle MRI: Asymmetric; Distal fatty replacement

• Epidemiology
  • Italian family
• GBF1 protein
• Clinical
  • Onset: 1st or 2nd decade
  • Weakness
    • Distal
    • Legs & Arms
    • Symmetric
    • More severe by 4th & 5th decade
  • Sensory loss: Distal; Mild
  • Tendon reflexes: Absent
  • Cranial nerves: Normal
  • Autonomic functions: Normal
  • Progression: Slow over decades; More in 5th decade; Many never use wheelchair
• Laboratory
  • Electrodiagnostic
    • CMAPs: Small or Absent
    • NCV: 25 to 45 M/s
    • SNAPs: Low amplitude
  • CSF protein: Normal, or Mildly increased
  • Pathology
    • Loss of large myelinated axons
    • Onion bulbs: Occasional on EM

• Epidemiology: 2 Japanese families
• Genetics
  • Mutation: 5 bp deletion (c.247.10_247.6delCACTC) in splicing element of intron 2
• COX6A1 protein
  • Mitochondrial
    • Respiratory complex IV
    • Inner membrane
  • Required for the stability of COX holoenzyme
  • Expression: Ubiquitous except muscle
• Clinical
  • Onset age: 1st decade
  • Weakness: Distal; Arms & Legs
  • Sensory loss: Pan-modal; Distal; Arms & Legs
  • Tendon reflexes: Reduced or Absent
• Laboratory
  • Electrodiagnostic
    • EMG: Distal denervation
    • Motor nerve conduction velocities: Mildly reduced
    • SNAPs: Reduced amplitude or Absent
  • Nerve pathology: Onion bulbs; Axon loss

• Epidemiology: Single American family of Irish ancestry
• Mutation: Missense; Ile172Val ⁷⁷
• IFRD1 protein
  • Expression
    • Early gestation: Brain, Spinal cord & Spinal ganglia
    • Late gestation: Ubiquitous
  • Trophic factor stimulation
    • Upregulates Ifrd1 expression
    • Results in translocation from cytoplasm to nucleus
  • NucleIFRD1:
    • Acts as a transcriptional corepressor
    • Interacts SIN3 histone deacetylase complex
• Clinical: Variable expression
  • Onset
    • Age: 13 to 27 years; No anticipation
    • Gait disorder, especially in dark
  • Ataxia: Dysmetria; Ataxic gait; Nystagmus
  • Sensory loss: Vibration > Proprioception; Positive Romberg
  • Tendon reflexes: Reduced or Absent
  • Extensor plantar reflexes: 50%
  • Weakness: Distal or Proximal; Legs or Arms; 70%; More at older ages
  • Skeletal: Pes cavus; Hammer toes
  • No dementia
  • Progression: Slow; Normal life span
• Laboratory
  • NCV: Axonal neuropathy; Small or absent SNAPs; Occasional prolonged distal latencies
  • EMG: Chronic denervation
  • MRI: Cerebellar atrophy, mild, in older patients

CMT with Intermediate NCV (DI-CMT; CMT-DI) ¹⁷

• Epidemiology
  • Australian, Belgium & North America families
• DNM2 genetics
  • Mutations
    • Located in pleckstrin homology domain
    • Reduce binding of DNM2 to membranes
  • Allelic with
    • Centronuclear myopathy, Dominant
    • CMT 2M
    • Other allelic disorders
• DNM2 protein
  • Family of large GTPases
  • Part of cellular fusion-fission apparatus
• Onset age: 1st or 2nd decade
• Clinical
  • Weakness: Distal; Legs & Arms; Symmetric
  • Sensory loss: Distal
  • Tremor
  • Cranial nerves: Normal
  • Autonomic functions: Normal
  • Progression
    • Slow over decades
    • Many never use wheelchair
  • Systemic: Neutropenia (Lys558 mutations)
• Laboratory
  • Electrodiagnostic
    • CMAPs: Small or Absent
    • NCV: 24 to 54 M/s
    • SNAPs: Low amplitude
  • CSF protein: Normal, or Mildly increased
  • Pathology
    • Loss of large myelinated axons
    • Onion bulbs: Occasional
• Variant: CMT2M; Axonal neuropathy ± Eye syndrome ⁷⁰
  • Genetics
    • General DNM2 mutation location: Pleckstrin homology domain
    • DNM2 mutation: K559del
    • Other CMT 2 mutations: Gly533Cys; Leu566His
    • Allelic with
      • Centronuclear myopathy, Dominant
      • CMTD1B
      • Other allelic disorders
  • Clinical
    • Onset
      • Age: Congenital to 4th decade
      • Cataracts: Early
      • Neuropathy: Childhood
    • Neuropathy
      • Distribution
        • Length-dependent
        • Legs > Arms
      • Sensory: Pan modal loss; Sensory ataxia; Paresthesias
      • Weakness: Distal; Legs > Arms
      • Tendon reflexes: Reduced at ankles
      • Progression: Mild
    • Eye
      • Cataracts: Congenital
      • Ophthalmoparesis
      • Ptosis
    • Pes cavus
  • Laboratory
    • NCV: Axonal loss
    • Neutropenia
    • Pathology: Nerve
      • Axon loss
      • Axonal regeneration
      • Internodes: Homogeneously short
      • Onion bulbs: Rare
    • Pathology: Muscle
      • Muscle fibers: Scattered small angular
      • No myopathy

• Epidemiology
  • 3 Families: Midwestern US (German); Bulgaria; Korea
• Genetics ⁵⁹
  • Mutations: Missense (G41R & E196K); Deletion (In frame 153-156delVKQV)
  • Allelic disorders
    • Motor neuropathy
      • Proximal
      • Distal
    • Infantile-onset Multisystem Neurologic, Endocrine, & Pancreatic Disease 2 (IMNEPD2), Recessive
    • Multisystem disorder ¹⁷⁸: Arg367Trp, Homozygous
  • Cytoplasmic ARS syndromes
    • AARS: CMT 2N; PL-12 antigen, Early-Onset Epileptic Encephalopathy with Persistent Myelination Defect, Recessive
    • DARS: Leukoencephalopathy + Spasticity
    • EPRS : Hypomyelinating Leukodystrophy
    • FARSA: RILDBC2 ; Zo antigen
    • FARSB : RILDBCB1
    • GARS: CMT 2D; HMN 5A; EJ antigen
    • HARS: Sensory-Motor neuropathy; Jo-1 antigen
    • IARS
      • Growth retardation, Intellectual Disability, Hepatopathy, Hypotonia (GRIDHH)
      • Weak calf syndrome: Japanese black cattle
    • KARS: CMT-RIB; DFNB89 ; Encephalopathies
    • LARS : ? Liver failure, Infantile (ILFS1)
    • MARS1: CMT 2U; ILLD ; Pulmonary alveolar proteinosis
    • NARS1: Encephalopathy + Neuropathy
    • QARS: Progressive Microcephaly, Cerebral-Cerebellar Atrophy & Intractable Seizures
    • RARS1 (RARS) : Hypomyelinating leukodystrophy (HLD9) ¹²⁴
    • SARS
      • Neurodevelopmental disorder + Microcephaly, Ataxia & Seizures (NEDMAS), Recessive
      • Charcot-Marie-Tooth, Intermediate, Dominant
    • VARS : Neurodevelopmental disorder + Microcephaly, Seizures, & Cortical atrophy (NDMSCA)
    • WARS: HMN, Distal; Neurodevelopmental disorder + Microcephaly
    • YARS: CMTD1C
    • AIMP1: HLD3
    • AIMP2 : Hypomyelination
  • Also see: Other ARS-related disorders
    • Mitochondrial ARS
    • ARS autoantibodies
• Protein
  • Cytoplasmic ARS: General
    • aa tRNA synthetases: 37 different genes
    • Form large 11-subunit multisynthetase complex (MSC)
    • Function: Aminoacylation of ARS subunits; Channel loaded tRNAs to ribosome
  • Normal YARS ¹⁵⁴
    • Functions
      • Catalyzes aminoacylation of tRNA^Tyr with tyrosine
      • Transcriptional regulation network
    • Expression: Ubiquitous, including brain & spinal cord
    • Concentrated in granular structures in growth cone, branch points & distal neurites
  • Mutant
    • Partial loss of activity
    • May have dominant negative effect on function of normal protein
    • Transcription factor E2F1 hyperactivation
  • Other disease association: Target of antibodies in myositis-antisynthetase syndrome
• Clinical
  • Onset age: Range 7 to 59 years; Most in 1st or 2nd decade
  • Weakness: Distal; Legs > Arms; Symmetric
  • Sensory loss: Distal; Mild
  • Cranial nerves: Normal
  • Autonomic functions: Normal
  • Progression: Slow over decades; Many never use wheelchair
  • ? Less severe in females
• Laboratory
  • Electrodiagnostic
    • NCV: 30 to 50 M/s
  • Pathology
    • Loss of large myelinated axons: More with increasing age
    • Regenerating clusters
    • No onion bulbs
• YARS1 variant: Motor neuropathy, Proximal ¹⁹¹
  • Epidemiology: 1 patient
  • Genetics
    • Inheritance: Dominant
    • Mutation: Asp308Tyr; Loss of function
    • Allelic disorders
  • Clinical
    • Onset age: 18 years
    • Weakness
      • Hands: Distal
      • Legs: Proximal
    • Cramps
    • Fasciculations
    • Tendon reflexes: Absent or Reduced
    • Tremor
    • Nystagmus: Rotary
    • Kyphoscoliosis
    • Sensory: Normal
  • Laboratory
    • Serum CK: 300 to 1,692
    • EMG: Denervation, diffuse; MUPs large
    • NCV: Normal velocities
    • Muscle pathology: Gropuped atrophy
• YARS1 variant: Motor neuropathy, Distal ¹⁹³
  • Epidemiology: 4 patients; 1 family
  • Genetics
    • Inheritance: Dominant
    • Mutation: c.587A>G, p.Glu196Gly
    • Allelic disorders
  • Clinical
    • Onset age: 3rd decade
    • Weakness: Ankle & 1st toe dorsiflexion
    • Tendon reflexes: Absent at ankle
    • Sensory: Normal
  • Laboratory
    • NCV
      • Motor: CMAPs small amplitude in legs; Velocities 25 to 45 M/s
      • Sensory: Normal
    • EMG
      • Legs: Distal MUAPs polyphasic, large amplitude; Fibrillations, few
      • Arms: Distal reinnervation, Minor

• Epidemiology: > 20 families
• Genetics: Mutations
  • Heterozygous
  • Mutation Locations
    • Exons: 2 (3' end), 3 (Diaphenous-inhibitory domain; Nucleotides 300 to 500) & 4
    • Amino acids: Leu57 to Glu184
  • Mutation types: Missense; In-frame deletion
  • Mutation effects
    • Disrupt cytoskeleton: Actin & Microtubules
    • Abnormal mitochondrial & other organelle interactions
  • Penetrance: Incomplete
  • Allelic disorder
    • Focal segmental glomerulosclerosis, Dominant (FSGS5)
      • Mutations: Downstream of nucleotide 500; Amino acids Glu184 to Leu245
      • Decreased podocyte integrity
      • No neuropathy
  • Rare in CMT-I without renal disease
• INF2 protein
  • Formin family: Involved in remodeling actin & microtubule cytoskeletons
  • Endoplasmic reticulum: Cytoplasmic face
  • Tissue locations
    • Peripheral nerve: Present in Schwann cells (Perinuclear; Endoplasmic reticulum) & some axons
    • Kidney: Podocytes
  • Functions
    • INF2-induced actin filaments: May drive initial mitochondrial constriction
    • Promotes actin polymerization & filament severing + depolymerization
    • Microtubules: Colocalize; Bind; Mediate bundling & stabilization
    • Interacts with other diaphanous-related formins: MAL
    • Cdc42 effector: Actin filament nucleation, elongation & polymerization activities
  • INF2 mutations: More protein in cytoplasm
• Clinical
  • Family history: 50% sporadic
  • Onset
    • Ages: 5-28 years
    • Pes cavus
    • Cramps
    • Proteinuria
  • Weakness (100%)
    • Mild to Severe
    • Legs > Arms
    • Distal
    • Gait disorder
  • Pes cavus
  • Tendon reflexes: Reduced in legs or diffusely
  • Sensory
    • Loss (50%): Distal; Pain ± Large fiber; Legs ± Hands
  • CNS: Cognitive impairment in some patients
  • Hearing loss (30%): Sensorineural
  • Renal: Progressive to end-stage
• Laboratory
  • NCV: Intermediate (23 to 45 M/s in median); SNAPs reduced amplitude or absent in legs
  • Nerve pathology: Axon loss; Onion bulbs; Irregular myelin folding
  • CNS MRI: White matter hyperintensity; Ventricles enlarged
  • Renal: Focal segmental glomerulosclerosis; Proteinuria

• Epidemiology
  • Taiwanese family + 4 patients
  • CMT frequency: 0.8%
• Genetics
  • Mutations: Gly53Asp, Lys57Glu, Lys89Glu, Gln220Arg
• GNB4 protein
  • Functions: Cellular signal-transduction systems
  • Nerve locations
    • Axons & Schwannn cells
    • Colocalized with neurofilament heavy chain & S100
    • Not compact myelin
• Clinical
  • Onset age: 5 to 70 years
  • Weakness (80%)
    • Distal
    • Legs (80%) > Arms (20%)
    • Symmetric
    • Gait: Steppage
    • Progression: 1 patient in wheelchair
  • Sensory
    • Loss (80%): Panmodal; Distal
    • Dysesthesias: Limbs & Tongue
  • Tendon reflexes: Absent
  • Skeletal: Pes cavus; Scoliosis
• Laboratory
  • NCV
    • More severe motor changes in males
    • SNAPs: Usually absent
    • CMAPs: Legs reduced amplitude; Hands Normal or Mildly reduced amplitude
    • NCV: 16 to 52 m/s; Demyelinating or Axonal range
  • Nerve biopsy: Demyelinating
    • Onion bulbs
    • Myelinated axons: Loss; Regeneration

• Epidemiology: 1 family, 3 patients
• Genetics
  • Mutation: Missense; c.973A>G, p.I325V
  • Allelic disorder: Nephrolithiasis/osteoporosis, hypophosphatemic, 2
• SLC9A3R1 protein
  • Co-localizes with: Actin; Ezrin
  • PNS location: Schwann cell cytoplasm (S100); Nodes of Ranvier SC microvilli (Ezrin; Nav1.8)
  • NRG1-induced AKT phosphorylation
  • Functions
    • Schwann cell migration & process extension
    • Paranodal neurofascin expression
  • May be overexpressed in tumors
• Clinical
  • Onset age: 29 to 31 years
  • Gait disorder: Steppage
  • Weakness
    • Distal
    • Legs then Arms
  • Sensation: Pan-modal loss, especially Vibration & Joint position
  • Tendon reflexes: Absent at Knees & Ankles
  • Skeletal: Pes cavus
  • Course: Progressive
• Laboratory
  • NCV
    • CMAPs: Small amplitude or absent
    • SNAPS: Small amplitude or absent
    • Conduction velocities: Mildly reduced; 34 to 45 M/s
  • EMG: Chronic denervation; Some fibrillations
  • Muscle MRI: Fat replacement of hip, thigh & calf muscles
  • Mouse model: Schmidt-Lanterman incisures increased; Paranode structure damaged

• CMT-DI3 (CMT-DID): P₀ mutations
• CMT-X
• CMT 2E

Recessive, Axonal CMT

• Epidemiology: North African families
• Genetics
  • Mutation: Arg298Cys; Homozygous
  • Allelic syndromes
• Clinical
  • Onset
    • Age: 2nd decade; Mean 15 years; Range 4 to 24
    • Signs: Distal weakness, especially legs
  • Weakness
    • Limbs
      • Distal early
      • Legs ≥ Arms
      • Progresses to proximal involvement in legs (60%)
    • Legs > Arms
    • Symmetric
    • Progression
      • Rapid over 4 years
      • Scapular weakness
      • Distal to Proximal involvement
      • Prominent disability
  • Muscle wasting: Distal
  • Tendon reflexes: Reduced in lower extremities
  • Sensory loss
    • Distal
    • Hands & Feet
    • Modalities: Variable, especially large fiber
    • Mild: Worse with disease progression
  • Skeletal
    • Pes cavus (80%)
    • Kyphoscoliosis (30%): With proximal weakness; Mild
  • CNS: Normal; No pyramidal or intellectual disorders
• Laboratory
  • Nerve conduction: Axonal loss
    • Normal velocity
    • SNAPs: Often absent
  • Nerve biopsy
    • Myelinated axons: Reduced, especially large axons
    • Unmyelinated axons: Reduced
    • Regeneration: Mild to Prominent

• Epidemiology: Brazilian & Costa Rican families
• Genetics
  • Gene mutated: PNKP
    • Mutations: Gln517Ter; Thr408del
  • Allelic disorders
  • Initial incorrect gene identified: MED25 (Ala335Val; Homozygous) ⁷⁶
• PNKP protein
• Clinical
  • Onset
    • Age: 1 to 42 years; Mean 32 years
    • Weakness: Symmetric; Ankles ± Hands (66%)
  • Weakness
    • Distal
    • Symmetric
    • Legs (100%): Intrinsic feet; Peroneal; Calves; Anterior tibial
    • Hands (80%): Intrinsic muscles; Finger extension; Wrist flexion
  • Sensory loss
    • Distal
    • Feet & Hands
    • Type
      • Panmodal
      • Large fiber modalities: Especially involved
    • Sensory ataxia
  • Tendon reflexes
    • Often absent at ankles
    • May be reduced or absent elsewhere
  • Discomfort
    • Cramps: Distal
    • Paresthesias: Distal
  • Autonomic: Normal
  • Cranial nerves: Normal
  • Course
    • Progression: Slow
    • Most remain ambulatory with or without cane
  • Skeletal: Normal or Mild foot deformities
• Laboratory
  • Nerve conduction: Axon loss
    • Motor
      • Conduction velocity: Mildly reduced (30 to 65 M/s in arms)
      • CMAP: Small or absent in legs & arms
    • Sensory
      • Absent sural SNAPs
      • Reduced amplitude SNAPs in arms
      • Conduction velocity: Reduced
  • EMG: Distal denervation
  • Brain MRI: Cerebellar atrophy, mild
• MED25 protein
  • Subunit of the human activator-recruited cofactor (ARC)
  • Expression levels correlate with PMP22
  • Coactivator involved in regulated transcription of RNA polymerase II-dependent genes
  • Mutated protein: Reduced binding specificity; Recognition of broader range of SH3 domain proteins

• Nosology
  • Called CMT 2K by OMIM
  • AR-CMT + Hoarseness
  • CMT2H
  • CMT4C4
  • AR-CMT Ouvrier type
• Epidemiology
  • 1% of inherited peripheral neuropathies
  • Brazil: 7% of recessive CMT
• Genetics: > 100 mutations described
• GDAP1 protein ⁵²
  • Expressed in: Neurons (DRG) > Schwann cells; CNS (Brain & spinal cord)
  • Subcellular location: Mitochondria
    • Outer mitochondrial membrane
    • Localized by C-terminal transmembrane domains
  • Protein type
    • Structural family: Sequence similarities to Glutathione S-transferases but no GST activity
  • Activities
    • Membrane-remodeling activity
    • Participates in mitochondrial fission processes
    • Mitochondrial membrane contact sites (MCSs) with
      • Plasma membrane
      • Endoplasmic reticulum
      • Lysosomes: Interacts with LAMP1
• Clinical syndrome: CMT 2K, Recessive, Axonal (AR-CMT + Hoarseness; CMT2H)
  • Genetics
    • Mutations
      • Stop codons, Nonsense; Some misasense
      • S194X: Moroccan families
      • L239F: Polish, German, Italian, Czech & Bulgarian; Milder phenotype
      • A247V: Recessive; Japanese
      • Glu222Lys: Recessive severe; Dominant mild
    • Allelic disorders
      • General: Recessive disorders are more severe & earlier onset
    • Similar locus to AR-CMT with pyramidal involvement
    • Same mutations may produce demyelinating or axonal phenotype : S194X
  • Clinical
    • Onset
      • Age: Birth to 7 years; Typical 1 to 3 years
      • Hypotonia
      • Feet: Deformity; Weakness
    • Vocal cord paralysis
      • Onset: 2nd decade
      • Hoarseness (80%)
      • Not present in some families: S194X mutation; Czech families ⁶⁸
    • Other cranial nerves: Normal
    • Weakness (100%)
      • Distal
        • Severe
        • Feet > Hands: Hand onset later in 1st decade
      • Proximal
        • Moderate or None
        • Legs > Arms
      • Gait disorder: Onset in early childhood
    • Sensory
      • Loss (100%)
        • Distal
        • Hands & Feet
        • Large & Small fiber modalities
      • Paresthesias
    • Tendon reflexes: Absent or Reduced
    • Skeletal
      • Club foot: Early onset
      • Scoliosis: Mild
      • Hip dysplasia
    • Progression
      • Disability by end of 1st decade
      • Wheelchair: 4 to 16 years
  • Laboratory
    • Nerve conduction testing
      • CMAPs: Reduced amplitude or Absent
      • NCV: Normal or mildly reduced in proximal nerves; 40 to 50 M/s
      • SNAPs: Reduced amplitude or Absent
    • CSF protein: Normal
    • Nerve biopsy
      • Loss of myelinated axons: Especially large, None > 7μM
      • Axonal regeneration & atrophy, occasional degeneration
      • No demyelination
      • Occasional onion bulbs
      • Unmyelinated axons: Increased; Probably regenerating
• GDAP1 Variant syndrome: CMT 2K, Dominant, Axonal ¹¹⁴
  • GDAP1 genetics
    • Mutations
      • Heterozygous
      • Missense
      • Finland: His123Arg (Founder mutation); 14% of all CMT2
      • Other mutations: Ser34Cys, Arg120Trp, Ala156Gly, Thr157Pro,
          Gln218Glu, Arg226Ser, Cys240Tyr, Pro274Leu
      • May have reduced penetrance
    • Modifier gene: JPH1
      • Gene variant: R213P
      • Correlation: More severe disease
  • Clinical
    • General
      • Milder phenotype than recessive syndromes with 2 GDAP1 mutations
      • His123Arg mutation in Finland: Mild phenotype; Slow progression
    • Onset
      • Age: Late 2nd to 5th decade
      • Gait difficulty
    • Weakness
      • Distal: Hands & Feet
      • Proximal: Mild; Asymmetry
    • Sensory loss
      • Distal
      • Arms & Legs
      • Pan-modal
    • Tendon reflexes: Reduced at knees & ankles
    • Pes cavus
    • Progression: Very slow
  • Laboratory
    • NCV
      • Axon loss: Mild to Severe; Sensory before Motor
      • Velocities preserved
    • EMG: Denervation, Distal > Proximal
• GDAP1 Variant syndrome: CMT Recessive, Intermediate A (CMT RIA)
  • GDAP1 Mutations
    • Homozygous
    • 1-BP INS, 349T, IVS4DS, G-A, +1, Leu239Phe
  • Clinical
    • Onset
      • Age: Early childhood
      • Gait disorder
    • Weakness
      • Distal
      • Arms & Legs
    • Sensory loss
      • Distal
      • Arms & Legs
      • Pan-modal
    • Ankle & foot deformities
  • Laboratory
    • Nerve conduction testing
      • Velocities: 25 to 35 m/s
      • CMAP & SNAP amplitudes: Reduced or Absent
    • Peripheral nerve pathology: Axonal + demyelinating changes
      • Axon loss: Especially large axons
      • Regenerating clusters
      • Demyelinated axons
      • Onion bulbs: Small
• GDAP1 Variant syndrome: Recessive CMT with mild phenotype
  • Epidemiology: Polish, German, Italian, Czech & Bulgarian families
  • GDAP1 mutations: L239F
    • Homozygous
    • Heterozygous with another missense mutation
  • Clinical: Milder phenotype
    • Onset age: 2 to 10 years
    • Weakness: Distal; Arms & Legs
    • Sensory loss: Arms & Legs
    • Gait disorder: Falling
    • Walking into 2nd decade
    • Wheelchair in 2nd to 4th decade
    • Club feet
  • Electrodiagnostic: Axonal loss

• Genetics: Several disorders
  • AR-CMT with hoarseness (GDAP1)
  • CMT 2A2 (MFN2)
• Clinical
  • Onset age: Early childhood
  • Weakness: Distal; Symmetric; Legs before arms
  • Sensory loss: Mild
  • Progression: Slow; Severe distal weakness by 20 years
• Pathology: Axon loss

• Epidemiology: Tunisian family
• Genetics: Similar locus to AR-CMT with hoarseness (GDAP1)
• Clinical features: Homogeneous in family
  • Onset
    • Age: 4 to 8 years
    • Difficulty walking
  • Weakness & Wasting: Distal; Legs then Arms
  • Sensory loss: Distal
  • Tendon reflexes: Brisk, except absent at ankles
  • Other reflexes: + Hoffman & Palmo-mental
  • Course: Progressive
• Laboratory
  • Electrodiagnostic: Axonal loss
  • Nerve biopsy: Severe axonal loss; Occasional regeneration

• Epidemiology: 2 male patients
• Genetics
  • Mutations: Stop; c.805C>T (Q269*), c.1039C>T (p.Q347X)
• DRP2 protein
  • Schwann cell plasma membrane
  • Periaxin-DRP2-Dystroglycan complex
  • Maintenance of Cajal bands of myelinating Schwann cells
  • Expression: High in brain & spinal cord; Also kidney, ovary, epididymus
  • Homology: C-terminal region of dystrophin
• Clinical
  • Onset age: 18 to 50 years
  • Weakness: Distal; Legs then Hands
  • Muscle size: Calf atrophy
  • Sensory loss: Distal; Arms & Legs; Panmodal or Small fiber
  • Tendon reflexes: Ankles absent; Others normal
  • Pes cavus: Mild
  • Course
    • Slow progression
    • Episode of unilateral brachial plexopathy
• Laboratory
  • NCV
    • Distal latencies: Long
    • Conduction velocities: Intermediate; 36-52m/s; Non-uniform
    • F-wave latencies: Prolonged in legs
    • No conduction block or temporal dispersion
  • Epidermal axons: DRP2 absent; Cajal bands absent
  • CSF: Protein slightly high
  • Nerve biopsy
    • Axon loss
    • Myelin sheath width: Varied; Thin, Thick & Tomaculae