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HEREDITARY MOTOR SENSORY NEUROPATHIES (HMSN; CMT)

OVERVIEW

Prevalence Hereditary neuropathies: ~30 per 100,000 CMT Type 1: 15 per 100,000 CMT 1A: 10.5 per 100,000 CMT 2: ? 7 per 100,000 Tissue 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 GDA P1: CMT 4A (Demyelinating); Axonal CMT with hoarseness Other hereditary motor-sensory neuropathies Often associated with complex clinical syndromes, or Specific metabolic abnormalities Also see: hereditary distal motor neuropathies

Charcot (left) & Babinski at the Salpêtrière clinic.

HMSN types: Comparison of clinical features36 Disorder Gene Location Usual onset Early or distinct symptoms Tendon reflexes Average NCVs CMT1: Dominant; Demyelinating CMT 1A PMP-22 17p11 1st decade Distal weakness Absent 15 to 20 M/s CMT 1B P0 1q22 1st decade Distal weakness Absent <20 M/s CMT 1C LITAF 16p13 2nd decade Distal weakness Reduced 16 to 25 M/s CMT 1D EGR2 10q21 2nd decade Distal weakness Absent 26 to 42 M/s CMT X (S-D*) Connexin-32 Xq13 2nd decade Distal weakness Absent distal 25 to 40 M/s HNPP PMP-22 17p11 3rd decade Focal episodic weakness Normal Entrapments Dejerine-Sottas   (HMSN 3) PMP-22 8q23 EGR2 17p11 8q23 10q21 2 years Severe weakness Absent <10 m/s CMT   Intermediate   NCV DNM2 10q24 1p34 P0 CMT-X 19p12 10q24 1p34 1q22  Xq13 1st or 2nd decade Distal weakness   25 to 50 M/s CMT2: Dominant; Axonal CMT 2A KIF1Bβ 1p36 10 yrs Distal weakness Absent distal > 38 M/s Mitofusin 2 1 CMT 2B RAB7 3q13 2nd decade Distal weakness Sensory loss Acromutilation Absent distal Axon loss CMT 2C   12q23-q24 1st decade Vocal cord & Distal weakness Absent > 50 M/s CMT 2D GARS 7p15 16 to 30 yrs Distal weakness   Arms > Legs Reduced Axon loss CMT 2E NF-68 8p21 1 to 40 yrs Distal weakness Reduced Axon loss CMT 2F HSPB1 (HSP 27) 7q11 2nd decade Difficulty walking Reduced ankle Axon loss CMT 2G   12q12 15 to 25 years Distal weakness Reduced 42 to 58 M/s CMT 2L HSPB8 12q24 15 to 33 years Distal weakness Reduced Axon loss HMSN-P   3q13 17 to 50 yrs Proximal weakness Cramps Absent Axon loss HSMN + Ataxia   7q22 13 to 27 yrs Gait ataxia Absent Axon loss CMT 2 P0 P0 1q22 37 to 61 years Leg weakness Pupil or Hearing Δ Reduced < 38 M/s to Normal AR-CMT2: Recessive; Axonal AR-CMT2A Lamin A/C 1q21 2nd decade Distal weakness Reduced Axon loss AR-CMT2B   19q13 3rd & 4th decade Distal weakness Absent distal Axon loss AR-CMT2 Ouvrier   Autosomal 1st decade Distal weakness Reduced Axon loss Andermann KCC3 15q13 1st decade Hypotonia Absent Mildly reduced Cowchock   Xq24-q26 1st decade Distal weakness Absent Axon loss CMT4: Recessive; Demyelinating CMT 4A GDA P1 8q13 Childhood Distal weakness Reduced Slow CMT 4B MTMR2 11q22 2 to 4 yrs Distal & Proximal weakness Absent Slow CMT 4B2 SBF2 11p15 1st 2 decades Distal weakness Sensory loss Absent 15-30 m/s CMT 4C KIAA1985 5q23 5 to 15 yrs Delayed walking Reduced 14 to 32 M/s CMT 4D (Lom) NDRG1 8q24 1 to 10 yrs Gait disorder Absent 10 to 20 M/s CMT 4E EGR2 10q21 Birth Infant hypotonia Absent 9 to 20 M/s CMT 4F Periaxin 19q13 1 to 3 yrs Motor delay Absent Absent CMT 4H FGD4 12q12 10 to 24 mo Walking delay Absent < 15 M/s HMSN-Russe   10q22 8 to 16 yrs Distal leg weakness   Moderately reduced Dejerine-Sottas   (HMSN 3) P0 CMT 4F Autosomal 2 years Severe weakness Absent <10 m/s Congenital   Hypomyelinating   Neuropathy P0 EGR2 PMP-22 Autosomal Birth Severe weakness Absent <10 m/s CCFDN CTDP1 18q23 1st or 2nd decade Distal leg weakness Reduced 20 to 34 M/sec * Semi-Dominant

• GeneTests
• Inherited Peripheral Neuropathies Mutation Database

SPECIFIC HMSN SYNDROMES

CMT IA

CMT IA types   PMP-22 duplication   PMP-22 point mutation   Other mutations     Homozygote     Recessive PMP-22   Clinical-Genetic correlations   Gene mutations   Protein Also see: HNPP

Duchenne

CMT 1A PMP-22 duplication

• Genetic types of PMP-22 gene mutations
  • Duplication of one gene (3 total copies of PMP-22): Types
    • Segmental duplication in gene area
      • Due to unequal crossing over of chromosomes during meiosis
      • 
    • Trisomy of short arm on chromosome 17 (17p): Mosaic
  • Point mutation
    • Human
    • Mouse: Trembler
  • Homozygote for duplication (4 copies)
  • Deletion: Most commonly associted with HNPP
  • Recessive
• PMP-22 protein
  • 2 transcripts with 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
    • Small percentage of PMP-22 is transported to Golgi, glycosylated & incorporated into myelin
  • Abundance: 2% to 5% of PNS myelin protein
  • Location: Compact myelin
  • Functions
    • Structural: In myelination
    • 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
• 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 in 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
      • Breakpoints located outside, but near, 700 bp interval
        containing most rearrangements of paternal origin

• 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
• Epidemiology
  • Male: Female 1:1
  • + Family history: 60%
• Onset of neuropathy
  • Onset age: 1st decade in 75%; 2nd decade in 10%; Rare asymptomatic in 30's
  • Initial symptoms: Gait disorder; Foot deformity
  • Initial signs: 1st decade³⁴
    • 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
• Clinical features of neuropathy
  • Weakness
    • Related to degree of axonal loss⁵¹
    • 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%)
  • Sleep apnea¹⁵
    • 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
  • Clinical variants
    • More severe generalized weakness; Earlier onset
    • Roussy-Levy Syndrome : Neuropathy + Ataxia & Tremor
  • Drug interactions
    • Vincristine: Produces severe exacerbation of neuropathy
    • Thiopental anesthesia
      • Sensitive to low doses: Lower induction dose needed
      • Especially with severe motor & sensory involvement
• Electrophysiology
  • NCV: Demyelinating Neuropathy + Axonal loss
    • Conduction velocities
      • Uniformly slow in all nerves
      • Mean 17 to 20 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
    • No conduction block
    • 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
      • Often absent
      • Slow velocity & Small amplitude when present
  • EMG: Denervation, Distal > Proxiomal
  • Brainstem auditory evoked potentials: Delayed wave I
• CSF: High Protein, Less in duplication patients
• Pathology: Early excess myelin production
  • Onion bulbs
    • Small to moderate size & frequency
    • Many develop > 6 y.o.
    • More prominent in nerves with less severe axon loss
  • Early: Myelin sheaths thicker than normal
  • Late: Thinly myelinated axons
  • Large reduction in # of myelinated axons: Especially with disease progression
  • Transgenic animals with PMP-22 overexpression: Hypomyelination

• 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: Trembler; TremblerJ (Leu16Pro)
• Clinical features:
  • Often more severe than duplication
  • Some with mild subclinical forms
  • Variability in some families
  • Deafness³⁷
    • Clinical: Early onset; Severe
    • Mutations
      • Location: Base of first extracellular loop; Transmembrane domain near extracellular component
      • Specific mutations
        • Missense: Ala67Pro; Try28Arg; Ser72Leu; Ser76Ile
        • Inframe deletion: del 115-118
    • Vocal cord dysfunction in some patients
  • Also see: CMT1A Recessive
• Electrophysiology
  • 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
    • Teased fiber
    • Ultrastructure
    • External link

• Clinical features
  • Most severe weakness
  • Earlier onset < 1 year
• Electrophysiology: Very slow NCV

• Clinical features
  • Severe phenotype: HNPP or CMT1A

CMT IB + Other P₀ mutation syndromes ⁶¹

P0: Genetic features P0 protein P0 Clinical syndromes   CMT 1B: Dominant; Demyelinating   CMT 1E: Dominant; Demyelinating, Hearing loss   CMT 2I: Dominant; Axonal   CMT 2J: Dominant; Axonal; Pupil disorders; Hearing loss   CMT-DI3: Dominant; Intermediate nerve conductions   Congenital hypomyelinating neuropathy: Recessive; Demyelinating   Dejerine-Sottas: Dominant or Recessive; Demyelinating   Steroid responsive, Late-onset: Dominant; Demyelinating   Adult onset (Axonal)   P0 variant syndromes

P0

• Genetic features
  • Different mutations identified: > 95
  • 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
• P₀ Protein
  • Size: 28 kD; Myelin protein is 219 amino acids
  • Cells: Myelinating Schwann cells only
  • Most abundant protein in peripheral nerve myelin: 50% of total peripheral myelin protein
  • Myelin location
    • Compact myelin
    • Associated proteins: PMP-22 & Myelin basic protein
  • Absent from CNS myelin
  • Necessary for normal myelin structure & function
  • 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 MPZ 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 MPZ-mediated adhesion.
    • Mutations in this domain may cause severe demyeinating neuropathy
  • Regulation in Schwann cells
    • Increased with axonal contact
    • Reduced by loss of axonal contact: Turned off during Wallerian degeneration
• Clinical-genetic correlations
  • Most mutations cause specific phenotypes
  • CMT 1B demyelinating neuropathy mutations
    • Null: Ser34 deletion
    • Loss of function: Tyr53
    • Mutations in single amino acids in extracellular domain
      • Usually ® typical CMT clinical syndrome
      • Truncation mutations: Gly74frameshift; Tyr125stop; Tyr152stop
      • Occasionally ® Severe CMT: Ser34Cys; Arg69Cys; Trp72Cys
    • Other MPZ mutations: Asp35Tyr, Ile62Phe, Ser63del, Tyr68Cys, Gly93Glu, Arg98Cys, Val146Phe
    • MPZ mutation frequency: 5% of HMSN 1
  • 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)
  • Mutations may produce demyelinating or axonal neuropathies
    • Also see: Mutations producing axonal CMT2-P₀
• CMT-P₀ mutations: Onset age
  • Most common in 1st decade: 30% to 40%
  • Later onset
    • Similar frequency in decades 2 to 7
    • 30% > 30 years
• 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
      • Often in 1st decade: Delayed walking
      • Occasional 2nd decade; Rare > 30 years
    • Weakness: Distal > Proximal
    • Sensory loss: Distal; Mild; Vibration reduced
    • Tendon reflexes: Absent
    • Gait disorder: 2° distal weakness or foot deformities
    • ± Hypertrophic nerves: Nerves not usually clinically enlarged
    • Progression: Severe disability in some by 20 to 40 years
  • Laboratory
    • Electrophysiology
      • Usual: Marked slowing of NCV < 20 M/s
      • Rare: Near-normal NCV
    • CSF: High protein in 75%
  • Pathology: Demyelinating; 2 types depending 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)
      • ? Mutations interfere with homophilic adhesion function of P0
    • Focal folding & thickening of myelin: Also seen in CMT type 4B
      • 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
• P₀ mutations: Clinical variants
  • CMT 1E : Demyelinating CMT with deafness
  • Predominantly axonal neuropathy (Adult onset)⁹
    • Nosology
      • CMT DI3 : CMT with intermediate nerve conductions
      • CMT 2I : CMT, Axonal, Late onset
      • CMT 2J : CMT with hearing loss & pupillary abnormalities
    • Genetics
      • Inheritance: Dominant
      • P₀ mutations: Thr124Met (More common); His39Pro; Asp61Gly; Asp75Val; Ala76Val; His81Arg; Tyr119Cys; Lys130Arg; Gly167Arg
    • Onset
      • Age: Adult; Usually after 30 years
      • Legs
      • Paresthesias, Hypoesthesia (85%)
      • Other: Weakness, Cramps, Photophobia
    • Clinical
      • 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 features⁶²
        • 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 pathology⁶²
        • Axonal 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%
  • Steroid responsive polyneuropathy¹⁰
    • Mutation: Ile99Thr
    • Inheritance: Dominant
    • Onset
      • Late, often > 50 years
      • Paresthesias
      • Leg weakness
    • Clinical
      • Weakness: Legs > Arms; Distal > Proximal
      • Sensory loss: Legs > Arms; Distal > Proximal; Panmodal
      • Paresthesias
      • Tendon reflexes: Reduced
      • Progression: Over 6 months to 10 years
      • Steroid response: Best initially; May be reduced with time
    • Laboratory
      • NCV: Slowing, some variation among nerves
      • CSF: High protein
      • Nerve pathology: Axonal loss; Reduced myelin compaction

CMT 1C ²⁰

• Gene mutations
  • Missense: Gly112Ser, T115N, W116G
  • Gly112Ser mutation adds potential new glycosylation site
  • Location: Domain of the LITAF protein with role in peripheral nerve function
• LITAF protein
  • Stimulator of monocytes and macrophages
  • Causes secretion of tumor necrosis factor-α & other inflammatory mediators
  • May play a role in protein degradation pathways
  • CMT IC: Normal levels of LITAF protein in nerve & other tissues
• Epidemiology
  • 2 families: Unrelated by haplotype
  • Location: Irish & English
• Clinical
  • Onset: 2nd decade
  • Weakness: Distal
  • Wasting
  • Sensory loss
  • Tendon reflexes: Reduced
  • Feet: High arches
• Electrophysiology
  • Nerve conduction velocities
    • Demyelinating neuropathy
    • Range: 16 to 25 M/s
• Nerve pathology: Onion bulbs

EGR2 mutations: CMT 1D & Other phenotypes

• Gene: Mutations
  • Inheritance: May be Dominant or Recessive
  • Missense
    • Congenital hypomyelinating (CHN): S382R/D383Y, Ile218Asn
    • CMT 1D: Arg409Trp; Arg359Gln; Asp355Val; Arg381Cys; Arg381His
    • Dejerine-Sottas: Arg359Trp; E412K
    • Recessive CHN: I268N
  • Location: Zinc finger binding domain
  • Predicted to alter DNA binding
  • De novo mutations common
• 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
    • Plays 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
  • See: EGR protein family
• Disease-Molecular correlation
  • Severity of syndrome correlates with ability of mutant EGR2 to bind a cis-acting regulatory site
• Clinical syndromes⁵⁸
  • CMT 1D
    • Inheritance: Dominant
    • Clinical
      • Onset: 2nd decade
      • Weakness: Distal, Legs & Arms
      • Tendon reflexes: Absent
      • Scoliosis: Progressive
    • Nerve conduction velocities: Slow (9 to 42 M/s)
  • Dejerine-Sottas
    • Inheritance: Dominant, de novo
    • Onset
      • Age: 0 to 6 months
      • Signs: Hypotonia; Hip dysplasia; Distal weakness
    • Clinical
      • 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
    • Inheritance: Dominant or Recessive
    • Onset: Birth
    • Clinical
      • Cranial nerve: Ptosis; Tongue fasciculation
      • Walking age: 18 to 24 months
      • Respiratory: Normal or restrictive disease
    • Motor nerve conduction velocity: 3 M/s
  • Progression: Slow
• Mouse disease: Krox20 knockout (Lethal) causes abnormal
  • Hindbrain segmentation
  • Bone formation
  • PNS myelination

CMT: X-linked

• CMT X-linked, Type 1
    l Connexin-32 (GJB1) ; Chromosome Xq13.1; Semidominant
  • Mutations
    • Locations
      • Numerous: > 260 identified
      • Most parts of Connexin-32 (GJB1) protein
    • 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
    • External link: Mutation Database
  • Connexin-32 Protein
    • Protein family: 4-TM; Homology to PMP-22
    • Function: Gap junction formation
    • Location: Uncompacted myelin
    • Expression in CMT 1X: Reduced Connexin-32 & other myelin proteins
  • Genetic-Clinical correlations⁶⁷

    CMT 1X R142W mutation

    • Severity: General
      • Many mutations produce same disease severity as GJB1 deletions
      • ? Related to degree of protein function lost
      • No clear relation with 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: Pesent on plasma membrane ± in cytoplasm
        • Other mutations: Expressed in cytoplasm but not on 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))
    • Females: Mild signs & less demyelination, or asymptomatic
      
      • Heterozygotes
      • Manifest when mutant proteins inhibit cell communications
        
  • Clinical features
    • Onset
      • Males: < 20 years
      • Gait disorder
    • Motor
      • Weakness: Distal; Hand & Foot
      • Wasting: Legs > Hands
    • Sensory loss (> 75%): Early proprioceptive loss
    • Reflexes
      • Ankle: Absent (100%)
      • Knee: Males absent 90%; Females absent 50%
      • Preserved elsewhere
    • Hearing loss
      • 2° changes in central auditory pathways
      • Arg142Glu mutation
    • CNS
      • Transient encephalopathy with exercise at altitude
      • Other
        • Few clinical features
        • Slow central conduction in brainstem auditory evoked responses
      • Progression
        • Age-related: Relatively severe disability by 6th decade
  • Nerve conductions
    • Slow conduction velocities
      • Moderate slowing, most severe @ 22 to 25 M/s
      • Non-uniform: Asymmetric
    • Prolonged distal latencies
    • Prominent temporal dispersion: Female & Male
    • Axonal loss
      • Length dependent
      • Disability: Correlates with loss of motor units
      • Absent SNAP in legs: 70%
    • Intrafamilial variation
    • Females
      • Axonal loss
      • Temporal dispersion
      • Less slowing of NCV (30 to 54 M/s)
  • Pathology: Axonal loss & some Demyelination
    • Myelin
      • Thin sheaths: Uniform on teased fibers
      • Segmental demyelination: Some
    • Few onion bulbs
    • Regenerating clusters (Axonal sprouts): More than CMT1A
    • Less loss of large myelinated axons than CMT1A
  • CMT 1X: Variant syndromes
    • Females
      • Clinical
        • Mild signs or Asymptomatic (50%)
        • More severe neuropathy: Phe235Cys mutation⁵³
          • Pathophysiology
            • Leaky Connexin-32 hemichannels
            • Skewed X-inactivation of chromosome with normal gene
          • 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: Rare features
      • Episodic weakness: C164T mutation²¹
        • Duration: 5 hours to 3 days
        • Distribution of weakness
          • Common: Extremities
          • Other: Trunk & Head; Dysphagia; Dysarthria
      • Transient encephalopathy³⁰

        From: A Kornberg CMT 1X encephalopathy White matter pathology

        • Genetics
          • Connexin-32 mutations: Arg142Trp; Cys168Tyr
          • Mutated protein: Unable to form gap junctions
        • Triggers
          • Exercise
          • Altitude (> 8,000 feet)
          • Illness
          • Dehydration
          • Hyperventilation
        • Onset: 2 to 3 day delay
        • Clinical features
          • Ataxia
          • Dysarthria
          • Weakness: Bulbar; Proximal arms
        • Course: Resolution over weeks
        • MRI: White matter abnormalities
          • Nonenhancing, confluent, symmetrical
          • More pronounced posteriorly
  • Also see: Clinical pictures
  
  
• CMT X-linked, Type 2
    l Chromosome Xp22.2; Recessive
  • Onset 1st decade
  • Distal weakness
  • Associated with mental retardation
  
  
• CMT X-linked, Type 3 ⁶³
    l Chromosome Xq26.3-q27.1; Recessive
  • Epidemiology: 3 families
  • Onset
    • Age: 3 to 13 years
    • Pain & Paresthesias: Legs
  • Clinical
    • Weakness: Distal
    • Sensory loss: Distal; Arms & Legs; Pansensory or Small fiber
    • Tendon reflexes: Reduced or absent distally
    • Pes cavus
    • Progression: Arms involved 10 years after legs
    • CNS Normal mentation & BAERs Spasticity: 1 family
  • Electrophysiology
    • NCV: Axonal loss
    • EMG: Distal denervation
  • Female carriers
    • Asymptomatic
    • High arched feet
    • Weakness: Foot dorsiflexion
  
  
• Cowchock Syndrome (Type 4)
    l Chromosome Xq24-q26.1; Recessive
  • Genetics
    • ? Allelic to Charcot-Marie-Tooth X (CMTX1)
    • ? Contiguous gene syndrome
  • Onset: Birth to 5 years
  • Clinical
    • Axonal neuropathy
      • Weakness: Distal; Especially peroneal group
      • Sensory loss
      • Areflexia
    • Skeletal: Pes cavus & Hammer toes
    • Mental retardation (60%)
    • Deafness: Most by 5 years
  • Obligate heterozygous females: Asymptomatic
  • Electrodiagnostic testing
    • Median motor conductions: 33 to 56 m/s
    • Sensory conductions: Markedly abnormal
  • Nerve morphology: Axonal loss & regeneration
  
  
• CMT X-linked, Type 5⁵⁴
    l Phosphoribosylpyrophosphate synthetase I (PRPS1) ; Chromosome Xq22.3; Recessive
  • Epidemiology: Korean & European families
  • Genetics
    • Mutations: Missense; Glu43Asp, Met115Thr
    • Allelic with
      • Arts syndrome
      • Hyperuricemia, Mental retardation & Sensorineural deafness with PRPS1 superactivity
  • 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
  • Onset
    • Early
    • Hearing loss
  • Clinical
    • Weakness: Legs
      • Onset: 8 to 13 years
      • Gait difficulties
    • Hearing loss: Sensorineural
    • Optic neuropathy: Onset 7 to 10 years
    • 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 2

CMT 2A2

• 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 (1p36 & 1): Distal leg weakness early in course; ? Anticipation
  • CMT 2B (3q13-q22): Severe sensory loss; Acrodystrophy
  • CMT 2C: Vocal cord & Phrenic involvement; Onset 1st decade
  • CMT 2D (7p15): Hand involvement early in course
  • CMT 2E (Neurofilament light chain; 8p21): Legs > Arms
  • HMSN-P (3q13): Proximal weakness; Absent DTRs; Tremor; Diabetes mellitus
  • CMT 2-P₀ (P₀; 1q22): Severe sensory loss; Deafness; Adie's pupil

• Epidemiology with KIF1B mutation: Families in Japan¹³
• Mutation
  • Missense: Q98L
  • Loss of function mutation in motor domain: ATP binding P loop
• 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
  • Other kinesin mutations
    • SPG 10: KIF1Bβ
    • CFEOM1: KIF21A
  • External link: Kinesin home page

From: B Baloh MD

• Epidemiology: Most CMT 2A families
• MFN2 genetics: Mutations
  • Missense
    • 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: Occasional patient
  • Penetrance: Variable
  • Homozygous or Compound heterozygous mutations: More severe disease
    • Patients: Severe; Early onset (2 to 3 years); Axon loss; Mild hearing loss
    • Parents: Normal or Mild neuropathy
• MFN2 protein⁵⁵
  • Mitochondrial fusion protein
  • Ubiquitously expressed: Present in spinal cord & peripheral nerve; Muscle; Heart
  • Localization
    • Outer mitochondrial membrane
    • Co-localizes with Bax (proapoptotic protein)
  • 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
  • Functions
    • Required for 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
  • Regulates OXPHOS expression
    • Loss-of-function
      • Inhibits pyruvate, glucose and fatty acid oxidation
      • Reduces mitochondrial membrane potential
      • Reduced expression of subunits in complexes I, II, III and V
    • Gain-of-function
      • Increased glucose oxidation
      • Increased mitochondrial membrane potential
    • Independent of effect on mitochondrial fusion
  • MFN2 deficient mice: Lower mitochondrial mobility
  • MFN2 mutant protein: May have dominant negative effect
• Clinical⁵⁷
  • Similar to CMT 2A1, CMT 2E & CMT 2F
    • Severe phenotype more common: Early onset; More weakness
  • Optic atrophy
    • Associated with more severe neuropathy phenotype
    • Mutations: R94W; T206; Q276R; H361Y; R418X
  • Some patients with mutations remain asymptomatic & without NCV changes
  • Frequency: 19% to 23% of CMT2 probands
  • CMT with pyramidal features (HMSN V): MFN2 missense mutation H165D
  • Variant syndrome: HMSN VI
  • Nerve conduction testing
    • Velocity: Slightly reduced
    • CMAP amplitude: Reduced, severe
    • SNAP amplitude: Reduced, severe
  • Nerve pathology
    • Myelinated axons: Loss
    • Mitochondria: Degeneration

CMT 2A2

• 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

• Genetics: RAB7 mutations
  • Missense
  • Specific mutations: Leu129Phe; Asp161Thr; Val162Met
• RAB7 protein
  • 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
    • Role of RAB7 in the cellular vacuolation induced by the cytotoxin VacA of Helicobacter pylori
    • Transport between late endosomes and lysosomes
    • Autophagic pathway
    • RAB7-effector protein RILP
      • Induces recruitment of dynein-dynactin motors
      • Regulates transport toward minus-end of microtubules
    • Golgi targeting of glycosphingolipids
  • Expression: Ubiquitous, including sensory and motor neurons
• Epidemiology
  • 4 families; American, Austrian, English & Scottish
  • 1 Sporadic Belgian patient
• Clinical features¹¹
  • 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
  • Pain: Unusual; Lancinating
  • Autonomic dysfunction: Not reported
  • 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)
• Variants
  • Mutilating neuropathy not linked to chromosome 3p
  • Ulcero-mutilating neuropathies
  • Acromutilating sensory neuropathy without weakness: RAB7 mutation Asp161Thr

CMT 2C (HMSN 2C) ²⁷
  l Chromosome 12q23-q24: Dominant

• Clinical features
  • Onset: Early 1st decade
  • Weakness
    • Distal: Hands & Feet
    • Diaphragm & Intercostal paralysis: Shortness of breath
    • Vocal cord: Altered voice; May be only sign in mildly affected patients
    • May progress to proximal & face muscles
  • Sensory loss: Asymptomatic; Reduced Vibration sense
  • Tendon reflexes: Depressed or absent
  • Skeletal: Pes cavus (70%); Arthrogryposis in some patients
• Electrodiagnostic
  • Median NCV > 50 M/s
  • CMAP amplitudes often reduced
  • Phrenic CMAP: Reduced amplitude
  • SNAPs: Normal or Reduced amplitude
  • EMG: Chronic denervation

---

CMT 2D
  l Glycyl tRNA Synthetase ; Chromosome 7p15; Dominant

• Genetics
  • Allelic with: Hereditary distal motor neuropathy V (dSMA-V)
  • Mutations: Missense; G240R, L129P, G526R, E71G
• Epidemiology: 4 or 5 families described; North American, Bulgarian, Mongolian
• GARS protein
  • Family: Aminoacyl tRNA synthetases
  • Function: Charge tRNAs with cognate amino acid (glycine)
  • Expression: Ubiquitous
  • Other disease association: Antibody target (EJ) in immune myopathy
• Clinical features
  • Onset: 16 to 30 years; Hand weakness
  • Weakness
    • Distal
    • Arms > Legs: Especially thenar & 1st dorsal interosseus
    • Bilateral
  • 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

---

CMT 1F³⁹
  l Neurofilament light chain (NEFL) ; Chromosome 8p21; Dominant or Sporadic

• Genetics
  • Mutations: Missense & Deletions
    • Head domain: Glu7Lys; Pro8Arg; Pro8Gln; Pro8Leu; Pro8Arg; P22T; Pro22Ser; Glu89Lys
    • Coil 1A: Asn97Ser
    • Coil 1B: A148V
    • Coil 2B: Gln333Pro
    • Tail: E397K; Glu528del
  • Allelic with: CMT 2E
• Onset
  • Less than 13 years
    • 2nd decade: Pro8Arg; Glu528del
    • Early childhood: Other mutations
      • Differential diagnosis: Dejerine-Sottas
  • Gait disorder
• Clinical
  • Weakiness
    • Legs & Arms
    • Distal > Proximal
    • May be severe
  • Early: Delayed motor milestones or gait disorder
  • Muscle atrophy
  • Tendon reflexes: Often reduced or absent
  • Sensory loss
  • Tremor: Some patients
  • Cerebellar: Ataxia, some patients
• Electrophysiology
  • Motor NCV: 15 to 38 M/s
  • SNAPs: Often absent
  • Mutation locations
    • NEFL protein head domain: More NCV slowing
    • Coil 2B domain: Less NCV slowing
• Nerve pathology (1 patient)
  • Axonal loss: Large & unmyelinated axons
  • Regenerating clusters
  • Onion bulbs (Small)
  • Thinly myelinated axons

CMT 2E⁴
  l Neurofilament light chain (NEFL) ; Chromosome 8p21; Dominant

• 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 NFL³³
    • Haploinsufficiency: Probably not pathogenic
  • Allelic with: CMT 1F
• Neurofilament light chain protein
  • Required for organization of neurofilaments
  • Associated with radial axonal growth
• Epidemiology: Multiple families
• Onset
  • Age: 1st to 5th decade
  • Difficulty walking; Leg weakness
• Clinical features
  • Neuropathy
    • Weakness
      • Distal
      • Legs > Arms
    • Sensory loss
      • Distal
      • Legs > Arms
      • Pansensory, especially vibration
      • Sensory ataxia (20%)
    • Tendon reflexes: Reduced or Absent
    • Episodic ataxia: In childhood; Triggered by fever
    • Progression: Slow over years; Some severe, others mild, disability
  • Hearing loss (30%)
  • Postural tremor (30%)
  • Systemic features
    • Pes cavus: 100% over 20 years of age
    • Occasional patients with hyperkeratosis
• 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 pathology⁴⁸
  • Giant axons
    • Filled with densely packed neurofilaments
    • Surrounded by thin myelin sheath
    • Not present with Glu396Lys mutation
  • Axonal atrophy: Some regions with no neurofilaments
  • Regenerating clusters
  • Demyelination: Secondary; Occasional small onion bulbs
  • Similarities to: Giant axonal neuropathy

---

CMT 2F¹⁹
  l HSPB1 (HSP 27) ; Chromosome 7q11-q21; Dominant

• Epidemiology: Russian (Voronezh) & Belgian families
• Genetics
  • Mutations: Missense; S135F, R136W
  • Mutations in HSPB1 also found in: Distal motor neuropathy
• Onset: 15 to 25 years
• Clinical
  • Weakness
    • Distal; Legs > Arms; Symmetric
    • May be severe with foot drop
  • Tendon reflexes: Reduced
  • Sensory loss: Mild
    • Distal
    • Feet & Hands
    • Especially pain & temperature
  • Fasciculations: 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: Distal denervation

---

CMT 2G⁴⁶
  l Chromosome 12q12–q13.3; Dominant

• Epidemiology: Spanish family
• Genetics: Locus similar to CMT 4H
• Onset
  • Age: 2nd decade; Range 9 to 76 years
  • Foot deformity
  • Difficulty walking
• Clinical
  • Weakness: Legs > Arms
  • Sensory loss: Legs; Distal
  • Tendon reflexes: Reduced at ankles
  • Foot deformity
  • Course: Slowly progressive
• Laboratory
  • Electrodiagnostic
    • Motor
      • NCV: Normal or slightly slowed
      • CMAPs: Small in legs
    • SNAPs: Small amplitude in legs
    • EMG: Distal denervation in legs
  • Pathology
    • Axonal loss: Distal > Proximal; Regeneration
    • Anterior horn cells: Reduced number
    • Dorsal root ganglion cells: Reduced number

---

CMT 2L⁴⁷
  l HSPB8 ; Chromosome 12q24-qter; Dominant

• Genetics
  • Mutation: Missense; Lys141Asn
  • Same gene mutated in: Distal hereditary motor neuropathy type II (dHMN II)
• Epidemiology: 1 Chinese family
• Onset
  • Age: 15 to 33 years
  • Leg weakness
• Clinical
  • 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

---

HMSN-P

CMT 2-P₀

---

Hereditary Sensory-Motor Neuropathy with Ataxia²⁶
  l Chromosome 7q22-q32; Dominant

• Epidemiology: Single American family of Irish ancestry
• Onset
  • Age: 13 to 27 years; No anticipation
  • Gait disorder, especially in dark
• Clinical: Variable expression
  • 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)¹⁷

DI-CMT, Type A
  l Chromosome 10q24.1-q25.1; Dominant

• Epidemiology
  • Italian family
• Onset: 1st or 2nd decade
• Clinical
  • 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

DI-CMT, Type B
  l Dynamin 2 (DNM2) ; Chromosome 19p12-p13.2; Dominant

• 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 2 syndromes
• 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: CMT2 Axonal neuropathy ± Eye syndrome⁷⁰
  • Genetics
    • General location: Pleckstrin homology domain
    • DNM2 mutation: K559del
    • Other CMT 2 mutations: Gly533Cys; Leu566His
    • Allelic with: Centronuclear myopathy, Dominant
  • 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
    • Congenital cataracts
    • Eye: 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

DI-CMT, Type C⁴³
  l Tyrosyl-tRNA synthetase (YARS) ; Chromosome 1p34-p35; Dominant

• Epidemiology
  • 2 Families: Midwestern US (German); Bulgarian
• Genetics⁵⁹
  • Mutations: Missense (G41R & E196K); Deletion (In frame 153-156delVKQV)
  • Glycyl-tRNA synthetase mutations in CMT 2D
• Protein
  • Normal
    • Function: Catalyzes aminoacylation of tRNA^tyr with tyrosine
    • 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
  • Other disease association: Target of antibodies in myositis-antisynthetase syndrome
• Onset: Range 7 to 59 years; Most in 1st or 2nd decade
• Clinical
  • 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

Other CMT disorders with intermediate NCV

• CMT-DI3: P₀ mutations
• CMT-X
• CMT 2E

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Recessive, Axonal CMT

AR-CMT2A: 1q21 AR-CMT2B: 19q13.3 AR-CMT2-Acrodystrophy AR-CMT2-Ouvrier: Early childhood onset Andermann (Corpus callosum Δ): 15q13 CMT X-linked HMSN + CNS: Heterogeneous Giant axonal neuropathy: Gigaxonin; 16q24 HMSN + Deafness HMSN + Optic neuropathy ± Deafness Lethal Neonatal Neuroaxonal dystrophy

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Axonal CMT (AR-CMT2A; CMT2B1)¹
  l Lamin A/C ; Chromosome 1q21.2; Recessive

• Epidemiology: North African families
• Genetics
  • Mutation: R298C; Homozygous
  • Allelic with
    • Emery-Driefuss muscular dystrophy 2
    • Autosomal dominant dilated cardiomyopathy with A-V block (CMD1A)
      • Mutations in rod domain
    • Familial partial lipodystrophy (Köbberling-Dunnigan Syndrome)
      • Mutations in globular C-terminal domain
    • LGMD 1B
    • Mandibuloacral dysplasia :
      • Mutation: R527H (C-terminal domain), Recessive
      • May be associated with partial lipodystrophy
    • Atrial fibrillation: Early onset; Missense (E161K) mutation¹⁰
    • Quadriceps myopathy with dilated cardiomyopathy: Missense (R377H) mutation
    • Premature aging
      • Hutchinson–Gilford progeria : Recessive; Abnormal nuclear architecture
      • Werner’s syndrome, atypical : Dominant; More severe
• Onset
  • Age: 2nd decade; Mean 15 years; Range 4 to 24
  • Signs: Distal weakness, especially legs
• Clinical
  • 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

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Axonal CMT (AR-CMT2B; CMT2B2)¹²
  l Chromosome 19q13.3; Recessive

• Epidemiology: Costa Rican family, Spanish ancestry
• Onset
  • Age: 26 to 42 years; Mean 32 years
  • Weakness: Symmetric; Ankles ± Hands (66%)
• Clinical
  • 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
    • Slowly progressive
    • Most remain ambulatory with or without cane
  • Skeletal: Normal or Mild foot deformities
• Laboratory
  • Nerve conduction: Axonal 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

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Axonal CMT (AR-CMT) with hoarseness (CMT 2K)²³
  l Ganglioside-induced differentiation-associated protein 1 (GDA P1) ; Chromosome 8q21.1; Recessive

• Nosology
  • Called CMT 2K by OMIM
  • CMT RIA: Intermediate nerve conductions
• Genetics
  • Mutations
    • Stop codons, or Nonsense mutations
    • Moroccan families: S194X
  • Same gene as recessive, demyelinating CMT 4A
  • Similar locus to AR-CMT with pyramidal involvement
  • Same mutations may produce demyelinating or axonal phenotype : S194X
• GDA P1 protein⁵²
  • Expressed in: Neurons (DRG) > Schwann cells; CNS (Brain & spinal cord)
  • Subcellular location: Mitochondria, localized by C-terminal transmembrane domains
  • Structural family: Sequence similarities to Glutathione S-transferases but no GST activity
• Epidemiology: Spanish families
• Onset
  • Age: Birth to 2 years
  • Hypotonia
  • Feet: Deformity; Weakness
• Clinical
  • Vocal cord paralysis
    • Onset: 2nd decade
    • Hoarseness (80%)
    • Not present in some families: S194X mutation; Czech families⁶⁸
  • Other cranial nerves: Normal
  • Weakness (100%)
    • Distal
      • Severe
      • Feet > Hands: Hand onset later in 1st decade
    • Proximal: Moderate; Legs > Arms
    • Gait disorder: Onset in early childhood
  • Sensory loss (100%): Distal; Hands & Feet
  • Tendon reflexes: Absent
  • Skeletal
    • Club foot: Early onset
    • Scoliosis: Mild
  • Progression
    • Disability by end of 1st decade
    • Wheelchair: 4 to 16 years
• Laboratory
  • Nerve conduction testing
    • CMAPs: Reduced or absent
    • NCV: Normal or mildly reduced in proximal nerves; 40 to 50 M/s
    • SNAPs: Reduced or absent
  • CSF protein: Normal
  • Nerve biopsy
    • Loss of myelinated axon: Especially large, None > 7μM
    • Axonal regeneration & atrophy, occasional degeneration
    • No demyelination
    • Occasional onion bulbs
    • Unmyelinated axons: Increased; Probably regenerating
  • Also see: AR-CMT Ouvrier type

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Axonal CMT (AR-CMT): Ouvrier type
  l Autosomal Recessive

• Onset: Early childhood
• Weakness: Distal; Symmetric; Legs before arms
• Sensory loss: Mild
• Progression: Slow; Severe distal weakness by 20 years
• Pathology: Axonal loss
• Also see: AR-CMT with hoarseness

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

• Genetics: Similar locus to AR-CMT with hoarseness
• Epidemiology: Tunisian family
• Onset: 4 to 8 years; Difficulty walking
• Clinical features: Homogeneous in family
  • 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

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Axonal CMT with acrodystrophy
  l Recessive⁸

• Epidemiology: Turkish family, consanguinous
• Clinical
  • Onset: 7 to 10 years; Painless ulcers on feet
  • Weakness: Distal > Proximal; Symmetric; Hands & Feet
  • Wasting: Distal
  • Sensory loss: Distal; Symmetric; Hands & Feet; Panmodal
  • Tendon reflexes: Absent
  • Acrodystrophy: Mutilation & Ulcers on feet & hands
  • Course: Slowly progressive
• Laboratory
  • NCV
    • Normal velocity when obtainable
    • Motor & Sensory amplitudes: Reduced
  • EMG: Distal denervation
  • Nerve pathology
    • Myelinated axons: Reduced or absent
    • Unmyelinated axons: Reduced (30% of normal)
    • Endoneurial collagen: Increased

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HMSN III (Dejerine-Sottas)³²

• General
  • Severe
  • Infant onset
  • Slowly progressive
• Genetic types: Dominant are often sporadic
  • DSS-A: PMP-22 point mutations
      l Chromosome 17; Dominant
    
    • Genetics
      • Mutation locations
        • Transmembrane domains
          • Domains 1, 2, 3 & 4
          • Transmembrane domain mutations also seen in CMT1A)
        • Hot spot for mutations: Ser72
          • 26% of PMP-22 point mutations
          • Mutations: Ser72Pro; Ser72Trp; Ser72Leu (Most frequent)
          • Phenotype: Usually severe; Onset 1st year; Most never walk
      • Mutation type: CG to TG transitions common (~ 40% of mutations)
  • DSS-B: P0 point mutation
      l Chromosome 1q22; Recessive or Dominant
    • Genetic disease mechanisms
      • Dominant negative
        • Missense mutations in membrane, intracellular, or extracellular domain
          • 19 mutations identified
          • Transmembrane mutations of P0 over-represented in DSS group
        • Examples: Gly167Arg; Tyr82Cys
        • Heterozygous
        • May appear sporadically & then transmit as Dominant
      • Other mutaton patterns producing severe disease
        • Mutations which disrupt the MPZ tertiary structure
        • Most mutations that truncate the cytoplasmic MPZ domain: Eliminate amino acids 198–201 (RSTK)
        • Point mutation altering Ser204 (? Phosphorylated via PKC binding to the RSTK domain)
      • Homozygous absence of P0 protein
    • Clinical
      • Onset
        • Age: 1st 2 years
        • Tone: Hypotonic prior to 9 months
        • Walking: Usually after 18 months
      • Tendon reflexes: Absent
      • Course
        • Walking
          • Most patients able to walk at some time
          • Most patients eventually need ambulation aids
          • Wheelchair: Some patients
        • Progression in weakness: Some patients
        • Life expectancy
          • Most normal
          • Some early deaths due to respiratory failue
      • Nerve hypertrophy: Some patients
    • Laboratory
      • CSF protein: 50 to 167 mg/dL
      • Electrophysiology
        • Motor nerve conduction velocities: < 15 m/s in arms
        • No conduction block or temporal dispersion
        • CMAP & SNAP amplitudes: Small
    • Pathology: Irregular folding & redundant loops of myelin (Tomaculae)
      • Teased fiber
      • External link: EM
  • DSS-C
      l Chromosome 8q23-q24; Dominant
    • Epidemiology: Iowa family
    • Onset: 2 years; Steppage gait
    • Clinical
      • Weakness: Progressive; Distal > Proximal; Hands & Feet
      • Sensory loss: Distal > Proximal
      • Tendon reflexes: Absent
      • Enlarged nerves
      • Charcot joints
  • CMT 4F
      l Periaxin; Chromosome 19q13; Recessive
  • Dominant
    • Hearing loss
    • Unusual faces
  • DSS-EGR2
      l Early Growth Response 2 (EGR2) ; Chromosome 10q21.1-q22.1; Dominant, de novo
    • Mutation: Arg359Trp
    • Clinical features: See EGR2
    • Other EGR2 mutations
      • Congenital hypomyelinating neuropathy
      • CMT1
  • CMT 1F
  
  
• Dejerine-Sottas: Clinical features
  • Onset: < 3 years
  • Weakness
    • Diffuse; Distal > Proximal
    • Delayed motor milestones: Walking 15 to 48 months
    • Peak performance: 5 to 20 years
    • Tone: Reduced
  • Sensory loss: All modalities; Severe; Distal > Proximal
  • Tendon reflexes: Areflexic
  • Nerve enlargement
    • Some patients: Gly138Arg mutation³¹
    • May be asymmetric & multifocal or symmetric
  • Cranial nerve disorders: Occasional
    • May be associated with cranial nerve enlargement
    • Ocular
      • Miosis
      • Pupil: Reduced response to light
      • Ptosis
      • Nystagmus
      • EOM limitation
    • Hearing loss: Mild
  • Morphology: Short stature, Coarse facial features & Full lips occur
  • Skeletal: Kyphoscoliosis; Foot deformities (Club feet)
  • Progression: Mild until teens; Severe disability may occur
• Laboratory
  • Electrophysiology: Demyelinating + Axonal loss
    • NCV: Very Slow (< 12 M/s)
    • Distal latency: Prolonged
    • CMAPs: Reduced amplitude
    • SNAPs: Absent
  • CSF protein: Moderately high; 70 to 200 mg/dl
  • Pathology
    • Onion bulbs
    • Enlarged nerves: Increased fascicular area
    • Myelin sheaths
      • Hypomyelination
      • Long lengths of demyelinated axons
      • Few macrophages with myelin debris
    • Axons
      • Large myelinated axons: Reduced number, especially distally
      • Unmyelinated axons: Normal number; Mild reduction in size
  
  
  
• Also see: Congenital hypomyelinating neuropathy
• Rule out: Childhood CIDP

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Hereditary Liability to Pressure Palsies (HNPP)

  l PMP-22 deletion; Chromosome 17p11.2-p12; Dominant

HNPP: Genetics

• Mutations
  • Common mutation: Deletion in 85%
    • Chromosomal deletion of region containing PMP-22
    • Deleted region is identical to region duplicated in CMT IA
    • 
    • Deleted region contains other genes including COX10
  • Point mutations¹⁸
    • Types
      • Nonsense: Stop codon G183A (Trp61stop), G372A (Trp124stop); Leu7stop
      • Frameshift: Premature termination (19-20delAG, 434delT); Longer transcript 281-282insG
      • Splice site: 78+1G>T; 179+1G>C (Mild phenotype)
      • Missense: Val30Met; Ala67Thr; Thr118Met⁶⁵
    • Usually cause loss of function of PMP-22
    • Database of PMP-22 point mutations: IPNMDB
  • Homozygous missense mutation
    • Thr118Met: Associated with severe axonal loss with no demyelination⁶⁵
• Clinical - Genetic Correlations
  • Penetrance: Variable
  • Family history
    • 37% of patients with gene deletion have no family history
    • "Sporadic" cases often have deletions of paternal origin.
      • Due to unequal crossing over of homologous Chromosome 17s
      • Rare maternal origin: Due to intrachromosomal rearrangement
    • 20% of patients affected with HNPP & PMP-22 deletion have de novo mutation
  • 16% to 30% of families with HNPP phenotype have no PMP-22 deletion
    • Some have PMP-22 point mutation
    • G-insertion in a stretch of six Gs at nt 276-281
  • Some PMP-22 deletions can present as chronic demyelinating neuropathy mimicking CMT 1A
• PMP-22 Protein: Expression reduced in nerves in HNPP

HNPP: Clinical features⁴⁴

• Onset
  • Age
    • Mean: 19 to 26 years
    • Range: 2 to 64 years
    • Some patients asymptomatic
  • Asymmetric weakness
• Episodes of nerve paresis
  • Acute onset
  • Sensation
    • Paresthesias
    • Numbness
    • Usually painless
    • Loss may occur without weakness
  • Weakness: In distribution of nerve lesion
  • Prodromes
    • Mild trauma or compression: 40%
    • Repeated local exercise
    • Stretching
    • On awakening: 10%
    • Surgery: Occasional reports⁴⁵
  • Number: 1 to 10
  • Recovery
    • Over days to months
    • Complete 50%
    • Severe long term motor defecit 9%
• Neuropathy features
  • Motor: Weakness
    • Related to nerve palsies: Commonly mild & transient
    • Persistent: Ulnar hands (Mild); Foot drop (Asymmetric)
  • Sensory loss
    • Vibration & Pain commonly reduced: Distal; Symmetric; Legs
    • Other regions related to nerve palsies
  • Asymmetric
    • Often
    • Focal lesions (62%): Related to stretching, minor repetitive focal trauma or pressure
  • Nerve size
    • Enlarged: Diffusely; Visible by ultrasound
  • Focal signs
    • General
      • Locations: At usual sites of nerve compression
      • Variable among patients
    • Radial: Spiral groove of humerus
    • Ulnar: Elbow
    • Median: Wrist; Isolated carpal tunnel syndrome rare
    • Peroneal: Head of fibula
    • Brachial plexopathy
      • Not painful vs Hereditary neuralgic amyotrophy (HNA)
      • May be recurrent
  • Tendon reflexes
    • Normal in 62%
    • Absent in some patients
    • Ankle most often lost
  • Cramps: 40%
  • Skeletal
    • Pes cavus: Some patientsl Less severe or common than with CMT1A
    • Scoliosis: Occasional patient
  • Course
    • Episodic changes
    • Some permanent weakness may develop
    • Severe disability: Rare
    • Progressive axon loss: Not prominent, except associated with nerve compression
  • Occasional features
    • Focal signs & sensory loss at
      • Unusual sites of compression
      • Cranial nerves
        • Trigeminal
        • Facial
        • Hearing loss⁶⁶
          • Onset: Post-natal
          • Sensorineural: Mild
          • Progressive
        • Recurrent laryngeal (Vocal cords)
        • Hypoglossal⁴²
    • Progressive generalized sensory-motor neuropathy
      • May occur without pressure palsies
      • CMT 1 + HNPP syndrome with frame shift G insertion in nt 276-281
      • May have onset late in course: 5th & 6th decade
      • Occasional cases rapidly progressive
    • Tremor
    • Variant: Davidenkow phenotype
• Differential diagnosis: Patients with multifocal neuropathies without a 17p11 deletion
  • Recurrent neuralgic amyotrophy
  • Multiple lesions at common entrapment sites
  • Patchy axonal neuropathy
  • PMP-22 point mutation

HNPP: Laboratory features

• NCV: Diffuse sensory-motor polyneuropathy + Focal changes²⁸
  • NCV
    • Sensory
      • Diffusely reduced, especially in upper extremities
      • More slowing in median & ulnar than sural
    • Motor
      • Minor slowing at regions other than compression sites
      • More slowing in distal nerves
        • Distal motor latencies: Prolonged
        • Compression sites: Conduction commonly slow
      • Slowing variable among nerves: Most median; Least tibial & proximal muscles
      • Conduction block: Occasional (6% to 22%); ? Associated with transient episodes
    • F-waves: Prolonged or absent in 80%
  • Age changes⁵⁶
    • Reduction in CMAP amplitudes in nerves vulnerable to compression
    • Initially reduced, but little age-related change
  • Asymptomatic carriers: Abnormal even in childhood
    • Prolonged distal motor latency: Median or Peroneal
    • Slow NCV: Sensory or perone