• Genetics
  • TRPV4 mutations ⁸⁰
    • Ankyrin domain: Intracellular; N-terminal
    • Arg269C; Arg269H, Arg315W, Arg316C
    • Missense
  • Allelic with
    • Distal SMA, Congenital
    • Scapuloperoneal SMA
• 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
    • 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
• 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: Mild axon loss; Myelin thickness normal

• Genetics
  • Allelic with: Hereditary distal motor neuropathy V (dSMA-V)
  • Mutations: Missense; G240R, L129P, G526R, E71G
  • Related tRNA synthetase disorders
    • YARS mutations in: CMT DIC
    • AARS mutations in: CMT 2N
• 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

• 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
  • Mutation locations
    • Most in exon 1
    • NEFL protein head domain: More NCV slowing
    • Coil 2B domain: Less NCV slowing
  • Allelic with: CMT 2E; AR-CMT
• Onset
  • Less than 13 years
    • 2nd decade: Pro8Arg; Glu528del
    • Early childhood: Other mutations
      • Differential diagnosis: Dejerine-Sottas
  • Gait disorder
• Clinical: Variable
  • Weakness
    • 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
  • F-waves: Normal or Slow
  • Terminal latencies: Prolonged in some patients
• Nerve pathology (1 patient)
  • Axonal loss: Large & Unmyelinated
  • Regenerating clusters
  • Onion bulbs (Small)
  • Thinly myelinated axons
  • Neurofilaments may occur in masses

• 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 NFL³³
    • Haploinsufficiency: Probably not pathogenic
  • Allelic with: CMT 1F; AR-CMT
• Neurofilament light chain protein
  • Required for organization of neurofilaments
  • Associated with radial axonal growth
• Onset
  • Age: 1st to 5th decade
  • Difficulty walking; Leg weakness
• Clinical features
  • 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
• 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

• 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: Missense; P39L; G84R; S135F, R136W; R140G
  • Mutations in HSPB1 also found in: Distal motor neuropathy (Distal HMN)
  • Mutations in Recessive CMT: Homozygous; In α-crystallin domain; L99M
• HSPB1 protein
  • Regulation & maintenance: Cytoskeleton; Transport (Microtubule regulator)
  • Interacts with intermediate filament proteins
  • Mutant HSPB1
    • Not transported in neurites of cortical neurons
    • Forms intracellular aggregates
    • Causes sequestration of NF-M & p150 dynactin
• Onset
  • Age: 6 to 54 years
  • Gait disorder
• Clinical
  • 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
  • Sensory loss: Some patients
    • 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
    • SNAP amplitudes: Small in some patients

• 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

• Epidemiology: 1 Chinese family
• Genetics
  • Mutation: Missense; Lys141Asn
  • Same gene mutated in: Distal hereditary motor neuropathy type II (dHMN II)
• HSPB8 protein
  • Chaperone
  • Transport regulation (Microtubule regulator)
• 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

• Epidemiology: French, Taiwan & Australian families
• Genetics
  • Mutation: Missense; Asn71Tyr, Arg329His
  • Other tRNA synthetase mutations
    • GARS: CMT 2D
    • YARS: CMT DIC
• AARS protein
  • Cytoplasmic
  • Aminoacyl-tRNA synthetase: Aminoacylation of tRNA^Ala
  • Ligase
  • Protein biosynthesis
• Onset
  • Age: Mean 28 yrs; Range 6 to 54 yrs
  • Leg weakness
  • Occasional asymptomatic patient
• Clinical
  • Weakness
    • Distal
    • Legs
    • Arms: Some patients
    • Symmetric; Occasional asymmetry
  • 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

• Epidemiology: Large British family
• Mutation: Missense; His306Arg
• DYNC1H1 protein
  • Dynein complex: Cytoplasmic; Retrograde axonal transport
  • DYNC1H1: Core of dynein complex; Responsible for protein complex binding to & moving along microtubules
  • Other axonal transport protein disorders
    • Dynactin p150 subunit: DMN 7B
    • KIF5A: SPG 10
    • ATSV (KIF1A): SPG30; HSMN with ulcero-mutilation
• 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
  • Pes cavus: Some patients
• Laboratory
• Mouse models
  • Legs at odd angles (Loa)
  • Cramping 1 (Cra1)
  • Sprawling (Swl)
  • DYNC1H1 deletion: Muscle spindle 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)¹⁷

• 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

• 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
• 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 syndrome⁷⁰
  • Genetics
    • General DNM2 mutation location: Pleckstrin homology domain
    • DNM2 mutation: K559del
    • Other CMT 2 mutations: Gly533Cys; Leu566His
    • Allelic with
      • Centronuclear myopathy, Dominant
      • CMTD1B
  • 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
  • 2 Families: Midwestern US (German); Bulgarian
• Genetics⁵⁹
  • Mutations: Missense (G41R & E196K); Deletion (In frame 153-156delVKQV)
  • Glycyl-tRNA synthetase (GARS) mutations in CMT 2D
  • AARS mutations in CMT 2N
• 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

• Epidemiology: 12 French, French-Canadian & Spanish patients
• Genetics: Mutations
  • Heterozygous
  • Location: Exons 2 (3' end) & 3 (Diaphenous-inhibitory domain; Nucleotides 300 to 500)
  • Mutation types: Missense; In-frame deletion
  • Penetrance: Incomplete
  • Allelic with: Dominant, Focal segmental glomerulosclerosis (Mutations downstream of nucleotide 500) (FSGS5)
  • Rare in CMT-I without renal disease
• INF2 protein
  • Formin family: Involved in remodeling actin & microtubule cytoskeletons
  • INF2: Promotes actin polymerization & filament severing + depolymerization
  • Interacts with other diaphanous-related formins: MAL
  • Peripheral nerve: Present in Schwann cells (Perinuclear; Endoplasmic reticulum) & some axons
  • Kidney: Podocytes
  • 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
  • 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
  • CNS MRI: White matter hyperintensity; Ventricles enlarged
  • Renal: Focal segmental glomerulosclerosis; Proteinuria

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

Recessive, Axonal CMT

• Epidemiology: North African families
• Genetics
  • Mutation: R298C; Homozygous
  • Allelic syndromes
• 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

• Epidemiology: Alajuela, Costa Rican family with Spanish and Amerindian ancestry
• MED25 mutation: Ala335Val; Homozygous ⁷⁶
• 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
• Onset
  • Age: 28 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
    • Progression: Slow
    • 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

• Nosology
  • Called CMT 2K by OMIM
  • AR-CMT + Hoarseness
  • CMT4C4
  • AR-CMT Ouvrier type
• Syndrome: CMT 2K, Recessive, Axonal (AR-CMT + Hoarseness)
  • Genetics
    • Mutations
      • Stop codons, or Nonsense mutations
      • S194X: Moroccan families
      • L239F: Polish, German, Italian, Czech & Bulgarian; Milder phenotype
    • Same gene as
      • Recessive, demyelinating CMT 4A
      • CMT 2K, Dominant
      • CMT RIA: Intermediate nerve conductions
    • Similar locus to AR-CMT with pyramidal involvement
    • Same mutations may produce demyelinating or axonal phenotype : S194X
  • GDAP1 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
  • 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 axons: Especially large, None > 7μM
      • Axonal regeneration & atrophy, occasional degeneration
      • No demyelination
      • Occasional onion bulbs
      • Unmyelinated axons: Increased; Probably regenerating
• Variant syndrome: CMT 2K, Dominant, Axonal
  • GDAP1 Mutations
    • Heterozygous
    • Missense
    • Ser34Cys, Arg120Trp, His123Arg, Ala156Gly, Thr157Pro,
      Gln218Glu, Arg226Ser, Cys240Tyr, Pro274Leu
    • May have reduced penetrance
  • Onset
    • Age: Late 2nd or 3rd decade
    • Gait difficulty
  • Clinical
    • General
      • Milder phenotype than recessive syndromes with 2 GDAP1 mutations
    • Weakness
      • Distal
      • Hands & Feet
    • Sensory loss
      • Distal
      • Arms & Legs
      • Pan-modal
    • Tendon reflexes: Reduced at knees & ankles
    • Progression: Very slow
  • Laboratory
    • NCV: Axon loss; Velocities preserved
• 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
• Variant syndrome: Recessive CMT with mild phenotype
  • Epidemiology: Polish, German, Italian, Czech & Bulgarian families
  • GDAP1 mutations: L239F
    • Homozygous
    • Heterozygous with another missense mutation
  • Onset age: 2 to 10 years
  • Clinical: Milder phenotype
    • 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
  • CMT 2A2
• Onset: Early childhood
• Weakness: Distal; Symmetric; Legs before arms
• Sensory loss: Mild
• Progression: Slow; Severe distal weakness by 20 years
• Pathology: Axonal loss

• 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

• Epidemiology: 3 families
• ATSV mutations
  • Truncating
  • Commonly located in alternatively spliced exon 25b
  • Allelic with
    • Hereditary spastic paraparesis (SPG30): Mutations in ATSV kinesin motor domain
    • Nonsyndromic intellectual disability
    • Similar to: Axonal CMT (CMT2) with Acrodystrophy, Recessive
• ATSV protein
  • Interacts with the domain Encoded by HSN2 Exon of WNK1
  • Synaptic vesicle transport
• Clinical: Ulcero-mutilating sensory neuropathy
  • Onset: 6 to 15 years
  • Sensory loss: Feet & Hands; Vibration & Joint position
  • Ulcero-mutilation: Amputations
  • Progression: Slow
  • Weakness: Distal; Hands & Feet
  • Tendon reflexes: Absent in legs
  • Developmental delay & Short stature: 1 patient
• Laboratory
• Nerve conduction
  • SNAPs: Absent
  • CMAPS: Small amplitude or Absent
  • Conduction velocities: Normal or Mildly reduced
• EMG: Distal denervation; Large motor units
• ATSV variant syndrome: Hereditary Spastic Paraparesis, Recessive (SPG 30) ⁹⁵
  • Epidemiology: 1 Palestinian Muslim family; 3 brothers
  • Genetics: ATSV mutation in kinsein motor domain; Ala225Val; Homozygous
  • Clinical: Pure spastic paraparesis
    • Onset age: Early Childhood; 2 years
    • Spasticity
      • Distribution: Legs; Gait
      • Plantar responses: Extensor
      • Tendon reflexes: Brisk in legs
    • Normal: Lower limb sensation, Sphincters, Upper limbs, Intellectual functions
  • Laboratory
    • EMG: Normal
    • NCV: Normal
    • Brain MRI: Normal

• Epidemiology: Turkish family, consanguinous
• Similar to: Hereditary Ulcero-mutilating Sensory > Motor Neuropathy, Recessive
• 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

• Epidemiology: Canada, Rural Eastern family
• Genetics
  • Mutation: Coding exon consensus splice acceptor AG to AA
• LRSAM1 protein
  • E3 ubiquitin ligase
  • Regulates cell adhesion molecules
  • Role in receptor endocytosis and viral budding
  • RING finger protein
  • Mutation: Causes loss of protein
  • Nosology: TAL (TSG101-associated ligase); RIFLE
• Clinical
  • Onset age: 2nd to 5th decade
  • Weakness: Distal; Legs > Arms
  • Cramps: Extremities & Trunk
  • Sensory loss: Pan-modal; Distal; Legs > Arms
  • Autonomic: Variable; Erectile dysfunction
  • Tendon reflexes: Absent
  • Skeletal: Pes cavus
  • Course: Slow progression; Wheelchair in some
• Laboratory
  • Serum CK: High; 1000-2000
  • NCV: Axon loss; NCS >l 38 m/s; CMAPS small amplitude; SNAPs absent
  • EMG: Denervation, Distal & Proximal
  • CSF protein: Mildly high
• Variant LRSAM1 Syndrome: CMT 2P ; Axonal neuropathy, Dominant
  • Epidemiology: Dutch family
  • Mutation: p.Leu708Argfx28
  • Clinical
    • Onset age: 27 to 40 years
    • Weakness & Wasting
      • Distal
      • Legs > Arms
    • Tendon reflexes: Reduced
    • Sensory loss: Pan-modal
    • Course: Slowly progressive
  • NCV: SNAP & CMAP amplitudes reduced

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 10q21.3; 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

Hereditary Liability to Pressure Palsies (HNPP)

• PMP-22 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

• 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

• 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 peroneal
  • Not predictive of sites of symptoms
  • QST: Abnormal vibration
• CNS⁶⁴
  • Electrophysiology
    • Abnormal: Blink reflex, Jaw-opening reflex, Acoustic evoked potentials
  • MRI: Subclinical abnormalities
    • Bilateral T2-weighted signal alterations lateral to putamen
• Pathology⁵⁰
  • Focal thickening (Tomaculae) & folding of myelin sheath:
    • Location: Perinodal or Internodal
    • Frequency: Most HNPP patients
    • Present at 5% to ≥ 25% of internodes
    • Differential diagnosis: Less frequent in other disorders
      • CMT 1B
      • MAG neuropathy
      • CIDP: Rare
    • Images
      • Teased fiber
      • Ultrastructure
      • External link
  • Other myelin changes
    • Demyelination: Segmental; Most patients
    • Onion bulbs: Usually small
    • Uncompacted myelin sheaths (20%)
  • Axons
    • Loss: Moderate to marked in 80%
    • Regenerating clusters: Common
    • Axonal degeneration (25%)
• Mouse models
  • Heterozygous PMP22-deficient mouse
  • PMP22-deficient mouse (Homozygous): Not reported to develop transient weakness or sensory loss

• Epidemiology: 2 patients
• Genetics
  • KARS gene: Encodes both cytoplasmic & mitochondrial KARS
  • KARS Mutations
    • Heterozygous: Ile302Met
    • Compound heterozygous: Leu133His; c.524_525insTT (Frameshift; Stop)
• Lysyl-tRNA Synthetase protein
  • Charges tRNA molecules with lysine
  • Holoenzyme structure: Dimeric & Tetrameric
• Clinical
  • ? Distal weakness & Sensory loss
  • Dominant Heterozygous mutation: Peripheral neuropathy
  • Recessive Compound Heterozygote mutations
    • Peripheral neuropathy
    • CNS
      • Developmental delay
      • Self abuse
    • Dysmorphic features
    • Vestibular Schwannoma
• Laboratory
  • NCV
    • Dominant Heterozygote: HNPP type
      • Conduction velocities: Normal
      • CMAP amplitudes: Normal
      • Distal latencies: Prolonged up to 2x
    • Recessive Compound Heterozygote: CMT Intermediate type (CMT RIB)
      • Conduction velocities: Mildly slowed (30 to 40 M/s in arms)

CMT 4

• Inheritance: Recessive
• Demyelinating

• Genetics²²
  • Mutations: Nonsense & Missense
  • Same gene as: Recessive axonal CMT with hoarseness (CMT 2K); CMT RIA
  • Similar locus to AR-CMT with pyramidal involvement
  • Same mutation may produce evidence of axonal loss & demyelination: S194X; Q163X
  • Geographic segregation
    • Q163X: Common in Hispanic & North African families
    • S194X: Tunisian & Maghreb countries
    • L239F: Polish, German, Italian, Czech & Bulgarian CMT families (Axonal neuropathy)
• GDAP1 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
• Clinical
  • Onset: Childhood < 2 years
  • Weakness
    • Rapidly progressive
    • Distal limb: Hands & Feet
    • Legs > Arms
    • Vocal cord: Left
    • Respiratory
    • Severe
  • Sensory loss: Distal
  • DTRs: Absent diffusely or distally
• Nerve conduction
  • Velocity: Slow
  • Motor & Sensory: Mean 30 M/s; Range 25 to 35 M/s
  • CMAP & SNAP amplitude: Reduced or Absent
• Pathology: Demyelinating
  • Myelin
    • Hypomyelination
    • Segmental demyelination
    • Myelin folding: Mild or absent
  • Onion bulbs
  • Loss of myelinated axons: Especially large; At early age

• Mutations
  • Types: Nonsense; Frame shift; Exon skipping deletion
  • Effect: Reduced phosphatase activity
• Myotubularin-related protein-2
  • High levels in
    • Neurons
    • Schwann cells: Myelinating & Non-myelinating
  • Dual specificity phosphatase: Family of 20 proteins
    • Characterized by protein/tyrosine phosphatase & SID domain
    • SID domain interacts with proteins containing SET domain that associate with chromatin
  • Enzyme action: Dephosphorylates phosphatidylinositol 3-phosphate & phosphatidylinositol 3,5-bisphosphate
  • Myotubularin family disorders: Centronuclear myopathy; CMT 4B2
  • Interacts with: MTMR5 ; Dlg1
• Geographic location: Italian & Saudi Arabian families
• Clinical features
  • Onset: < 4 years; Mean 2 years
  • Weakness
    • Distal & Proximal lower extremity
    • Symmetric
    • Progressive: Adults often wheelchair bound
    • Facial: Some with synkinesis
    • Cause of death: Respiratory failure
  • Sensory loss: Panmodal; Distal
  • Tendon reflexes: Absent
  • Pes equinovarus
  • Prominent thick lips
• Electrophysiology
  • Demyelination: NCV 9 to 20 M/s
  • Myelinated axon loss
• Pathology
  • Irregular folding & redundant loops of myelin (Tomaculae)
    • Teased fiber
    • Ultrastructure
  • Myelinated axon loss
• Mouse models
  • Abnormal myelin folding: Paranodal; Distal nerves > Proximal
  • Nerve conducton velocities: Normal
  • Mutations
    • E276X mutation, homozygous
    • Conditional Knock-out
      • Schwann cell defects produce neuropathy
      • Neuronal defects do not

• Genetics
  • Mutations: Homozygous inframe deletions
  • Allelic with: HMSN with glaucoma
• Protein
  • Family: Myotubularins, pseudo-phosphatase branch
  • General actions: Phosphoinositide-mediated signalling events: ? Associated with control of myelination
  • Myotubularin family disorders: Centronuclear myopathy; CMT 4B
• Geographic location: Turkey; Tunisia; ? Japanese
• Onset: 1st 2 decades: No delayed motor development in childhood
• Clinical
  • Weakness
    • Onset: Distal legs; Intrinsic foot & anterior leg muscles
    • Pattern: Legs > Arms; Distal; Symmetric
    • Progression: Proximal weakness in some patients years after onset
    • Loss of ambulation in some patients
  • Sensory loss: Distal; Severe
  • Tendon reflexes: Absent in legs; Reduced in arms
  • Skeletal: Pes cavus; Hammer toes
• Electrophysiology
  • Slow nerve conduction velocities (15 to 30 M/sec)
  • Axonal loss: Motor & Sensory
• Pathology
  • Irregular folding & redundant loops of myelin (Tomaculae)
    • Teased fiber
    • Ultrastructure
  • Segmental demyelination
  • Onion bulbs
  • Myelinated axon loss: Large > Small

• Allelic with: CMT 4B2
• Geographic location: Japanese family
• Onset
  • 1st decade
  • Glaucoma
  • Weakness; Difficulty running
• Clinical
  • Weakness
    • Distribution: Distal; Legs & Arms; Symmetric
    • Progression: Slow
  • Sensory loss: Distal; Arms & Legs; Panmodal
  • Tendon reflexes: Absent
  • Skeletal: Pes cavus; Hammer toes
  • Intellect: Normal
  • Ocular
    • Visual acuity: Reduced
    • Intraocular pressure > 21 mm Hg
    • Glaucomatous changes in optic disk
• Laboratory
  • CSF: High protein
  • Electrophysiology
    • Slow nerve conduction velocities (15 to 20 M/sec)
    • Axonal loss: Motor & Sensory
  • Pathology
    • Irregular folding & redundant loops of myelin
    • Segmental demyelination
    • Thinly myelinated axons
    • Onion bulbs
    • Myelinated axon loss: Large > Small

• Focally folded myelin sheaths

• Epidemiology
  • Relatively frequent cause of AR-CMT
  • Several ethnic origins of families
  • Sporadic patients identified
• Genetics⁴¹
  • Mutations
    • Truncation (Nonsense) & Missense
    • Some missense mutations involve splicing changes: Alter sequence of full length protein
    • Hot spot: Exon 11
    • French Canadian & English: R954X
    • Spanish Gypsies: R1190X
  • All patients homozygous or compund heterozygous for mutation
• SH3TC2/KIAA1985 protein⁴¹
  • Expression: Neural tissues, including peripheral nerve Schwann cells
  • Structure: Contains SH3 (2 N-terminal) & TPR (5 C-terminal) motifs
  • Cellular location
    • Plasma membrane
    • Perinuclear endocytic recycling compartment
  • Function
    • Myelination
    • Axo-glial relations: Maintenance of node of Ranvier
    • Influences transferrin receptor dynamics: Targets to intracellular recycling endosome
    • Associates with small GTPase, Rab11
  • Mutation
    • Unable to associate with Rab11
    • Mistargeting away from recycling endosome
  • Knockout animals
    • Hypomyelination
    • Node of Ranvier: Abnormal organization
• Clinical
  • Variable severity: Mild to Severe, childhood-onset phenotypes
  • Onset
    • Age
      • Childhood (1 to 5 years) or Adolescence: Typical disorders
      • Adults: Foot deformitied & scoliosis
    • Early scoliosis: NCV may be relatively preserved
    • Other patients with infantile neuropathy: Early loss of ambulation & respiratory problems
  • Skeletal: Main presenting sign & disabling feature
    • Scoliosis: Progressive; Onset 3 to 9 years; Surgery in teens
    • Pes cavus: Common
  • Weakness
    • Delayed walking: Normal to 30 months
    • Distal: 100%
    • Proximal: Late; Some patients
    • Legs > Arms
    • Slowly progressive
  • Atrophy: In regions of weakness
  • Sensory loss
    • Distal
    • Cutaneous loss: Early in disease course
    • Vibration & joint position loss: Later
  • Areflexia in most
  • Cranial nerve: Some patients
    • Deafness
    • Nystagmus
    • Facial weakness
    • Pupils: Unresponsive
    • Tongue atrophy: Unilateral
  • No tremor or cerebellar ataxia
  • Prognosis
    • Very slow progression of neuropathy
    • Mild gait disorder after 15 years disease duration
    • Occasional patient in wheelchair in 20's to 40's
• Laboratory
  • CSF: Protein probably normal
  • Nerve conductions
    • Velocities: Slow; 10 to 34 M/s
    • Distal latency: Prolonged
    • Sensory potentials: Reduced or Absent
  • Pathology: Demyelinating neuropathy
    • Severe depletion of large myelinated axons
    • Myelin
      • Small & large focal thickenings
      • Nodes of Ranvier: Wide
    • Schwann cells: Membranous protrusions
      • Cytoplasmic extensions, especially from around unmyelinated axons
      • Surrounded by multiple basal membranes
    • Onion bulbs: Relatively small vs CMT1A
    • Occasional tomacula
• Heterozygotes
  • Increased frequency of: Carpal tunnel syndrome

• Epidemiology: Gypsies in Lom, Bulgaria, Slovenia, Spain & Italy
• Mutation: Premature-termination codon at position 148
• NDRG1 Protein
  • Expression: Ubiquitous; High levels in Schwann cells
  • Possible functions
  • Growth arrest & Cell differentiation
  • Signaling protein shuttling between cytoplasm and the nucleus
• Disease course
  • Onset: 1 to 10 years of age; Disordered gait; Foot deformities
  • Progression: Severe disability by 5th decade
• Clinical
  • Motor: Distal > Proximal; Tongue atrophy; Hand weakness @ 5 to 20 years
  • Sensory loss: All modalities; Distal
  • Tendon reflexes: Absent
  • Skeletal: Pes cavus (50%); Scoliosis (20%)
  • Deafness: Onset 3rd decade; Speech perception reduced; Auditory nerve lesion
  • Vestibular dysfunction: Asymptomatic
  • Intelligence: Normal
• Carriers: Asymptomatic; Normal NCV
• Electrophysiology
  • NCV: Very slow (9 to 20 M/s); Prolonged terminal latency
  • Axonal loss: Absent or reduced sensory potentials
  • Hearing: Slow BAEP (Demyelination in VIII nerve); Sensorineural type hearing loss
  • EMG: Denervation in distal legs
• Pathology
  • Demyelination
    • Onion bulbs
      • Especially younger patients
      • Regression with increasing age
    • Older patients: Schwann cell processes in circular pattern; Fewer onion bulbs
    • Uncompacted myelin
  • Schwann cell inclusions: Adaxonal cytoplasm; Pleomorphic
  • Axon loss: Severe loss of Myelinated axons; Distal > Proximal
  • Axonal inclusions: Curvilinear bodies; Similar to pathology in vitamin E deficiency
  • Endoneurial collagenization: Vessels surrounded by multiple layers of basal lamina
• Animal disease
  • Greyhounds: 10 bp deletion⁸³

• Gene mutations: Nonsense & Frameshift
• Periaxin protein
  • Membrane protein
  • 3 locations during development
    • Nuclear: Early
    • Adaxonal: Plasma membrane
    • Abaxonal: With myelin maturation; Schmidt-Lanterman incisure; Paranodal membranes
  • Expressed by: Myelinating Schwann cells
    • During myelination: L-periaxin located near adaxonal membrane
    • Mature myelin sheaths: Localized close to abaxonal membrane (near basal lamina)
  • Function
    • Interacts with dystrophin-related protein 2 (DRP2): Via PDZ domains
    • Forms cluster at Schwann cell membrane with dystroglycan
    • ? Participates in membrane-protein interactions that stabilize myelin sheath
    • ? Interacts with basal lamina surrounding Schwann cell
  • Isoforms contain PDZ motif & Nuclear localization signal
• Epidemiology: Several ethnicities
  • Lebanese Shiite Muslim; North American Hispanic; Northern European; Vietnamese
• Clinical: Dejerine-Sottas
  • Onset: Early childhood; 4 weeks to < 7 years
  • Early development
    • Gestation & Delivery: Normal
    • Motor delay
      • Sitting age: 12 to 18 months
      • Walking & Talking: Delayed to 2 years
    • Gait: Wide based; Ataxic
  • Weakness
    • Severe
    • Distal legs at 9 to 10 years
    • Hands at 14 to 15 years
    • Progression: Slow
  • Sensory loss
    • More severe than other DSS or CMT
    • Ataxia (80%)
    • Pansensory
    • Arms & Legs
  • Cranial nerves: Normal
  • Tendon reflexes: Absent
  • Skeletal: Mild kyphoscoliosis; Pes cavus (75%)
• Clinical: CMT phenotype with early sensory loss
  • Genetics: C715X mutation, Homozygous
  • Onset: Childhood; Gait disorder
  • Clinical features
    • Scoliosis: Severe at 10 years
    • Weakness: Distal; Legs & Arms; Symmetric
    • Sensory loss: Severe; Distal; All modalities
    • Tendon reflexes: Absent
    • Progression: Very slow
• Laboratory
  • Nerve conduction studies
    • Motor: Absent motor potentials or Severely slowed velocity (3 to 15 M/s)
    • Sensory potentials (SNAPs)
      • Usual: Absent
      • May be preserved in childhood, especially milder syndromes
  • Nerve pathology
    • Axonal loss (Severe)
    • Onion bulbs
    • Hypomyelination
    • Abnormal myelin folding: Occasional

• Epidemiology
  • Northern Bulgarian family (Russe): Kalderas
  • Romanian & Spanish Gypsies: Similar haplotype to Bulgarian family
• Mutations
  • G>C in alternative untranslated exon (AltT2)
  • G>A in adjacent intron
• HK1 protein
  • Ubiquitous expresssion: 5' splicing produces tissue specificity
  • Catalyzes 1st step in glucose metabolism: Uses ATP for phosphorylation of glucose to glucose-6-phosphate
  • Subcellular
    • Cytoplasmic or
    • Outer mitochondrial membrane: Interacts with porin (VDAC1)
  • Patients: Normal activity & histochemistry
• Onset
  • Age: 5 to 16 years; Mean 11 years
  • Leg weakness
• Clinical
  • Weakness
    • Distal: Anterior & Posterior leg
    • Symmetric
    • Distal legs: Onset at 8 to 16 years
    • Hands: Onset 10 to 43 years; Mean 22 years
    • Progression
      • Continuous
      • Severe weakness
        • Distal to knees & elbows by 4th to 5th decades
        • Proximal legs
  • Sensory loss: Distal; Hands & Feet; Panmodal; Prominent
  • Tendon reflexes: Absent
  • Deformities
    • Foot: Pes cavus; Clawed toes; 100%
    • Hands: Clawing; 80%
    • Neuropathic joints: Occasional
  • Cranial nerve involvement: Occasional ptosis, facial weakness or dysphonia
• Laboratory
  • NCV: Axonal loss
    • SNAPs & Distal CMAPs: Absent
    • NCV: Moderately reduced; 30 to 35 M/s
    • Electical stimulation of nerves: Increased threshold
  • Nerve pathology
    • Axonal loss: Especially large myelinated axons
    • Regeneration: Abundant; Many small caliber axons
    • Hypomyelination: Uniformly reduced thickness of myelin sheath

• Epidemiology
  • Lebanese & Algerian families
  • Consanguenous families & Sporadic
• Genetics
  • Mutations
    • Types: Stop; Missense (M298R)
    • Homozygous
  • Similar locus to CMT 2G
• FGD4 protein
  • Guanine nucleotide exchange factor: Activates Rho GTPase cell division cycle 42 (Cdc42)
  • Cytoplasmic
  • Binds along sides of actin fibers
  • Alters Schwann cell shape: Induces formation of filopodia & lamellipodia
  • Possible disease mechanism: Impaired Rho GTPase signalling
• Clinical: Severe
  • Onset: Early
    • Age: 10 to 24 months
    • Delayed walking: 15 to 36 months
  • Gait: Unsteady
  • Weakness
    • Distal
    • Feet > Hands
    • Muscle wasting
  • Deep tendon reflexes: Absent
  • Sensory loss
    • Mild
    • Symmetrical
    • Legs > Arms
  • Skeletal
    • Scoliosis
    • Pes equinus
  • Course
    • Progression: Slow
    • Survival: Into adulthood
• Laboratory
  • Electrophysiology
    • SNAPs: Absent
    • NCV
      • Slow: Often < 15 M/s
      • Distal latencies: Prolonged
    • CMAPs: Low amplitude
  • Pathology
    • Axonal loss
    • Hypomyelination
    • Onion bulbs: Small
    • Abnormal myelin sheath folding
• Variant syndrome: R275X mutation
  • Northern Ireland family
  • Translated into truncated protein
  • Onset: Childhood; Poor balance
  • Clinical: Slowly progressive neuropathy
    • Cramps
    • Paresthesias
    • Pupils: Asymmetry
    • Weakness: Distal; Hands & Feet
    • Sensory loss: Pan-modal; Arms & Legs
    • Tendon reflexes: Absent
    • Ambulant into middle age
    • Pes cavus
  • Laboratory
    • NCV: 6 to 13 M/s

• Epidemiology: 4 Caucasian patients
• Genetics: Compound heterozygous mutations
  • Missense I41T: Common to all patients
  • Truncation (F98fsX102 in exon 4) or nonsense as other mutation
  • Allelic with: ALS 11
• FIG4 protein
  • Localization: Vacuolar membrane
  • Phosphatase: Dephosphorylates PtdIns(3,5)P₂ at 5th position of inositol
  • Required for both generation & turnover of PI(3,5)P₂
  • Associated with Vac14
  • May activate Fab1 (PIP5K3)
  • Other members of complex in yeast: ATG18 ; Vac7
  • Mutation effects
    • Reduced intracellular concentration of PtdIns(3,5)P₂
    • Abnormal transport of intracellular organelles
• Clinical
  • Onset
    • Congenital, Childhood or Adult
    • Motor delay
  • Weakness
    • Asymmetric
    • Distal & Proximal
    • Severe disease
    • Course: Progression
      • Over 5 to 10 years
      • To Wheelchair confined & Quadriparesis
  • Sensory: Mild loss
  • Upper motor neuron signs: Not present
• Laboratory
  • Electrodiagnostic
    • NCV: 2–50 M/s
    • Motor
      • CMAP amplitudes: Reduced; Asymmetric
      • Distal latencies: May be mildly prolonged
    • SNAP amplitudes
      • Reduced
      • Absent with disease progression
    • EMG
      • Diffuse denervation:
      • Proximal & Distal
      • Fibrillations & Positive waves
      • Motor unit potentials: Long duration; Polyphasic; Large amplitude
      • Recruitment: Reduced
  • Nerve
    • Axon loss, especially large axons
    • Demyelination
      • Thinly myelinated axons: Scattered
      • Onion bulbs: Small
    • Collagen: Increased in extracellular matrix
  • Fibroblasts
    • LAMP-2 aggregates
    • Vacuoles: May be associated with LAMP-2
    • Impaired trafficking of intracellular organelles
• Mouse disorder: ‘pale tremor’ mouse
  • Multi-organ disorder
  • Clinical: Impaired motor coordination, Muscle weakness, ‘Swimming’ gait
  • CNS Neuronal degeneration: Cortex layers 4 & 5; Deep cerebellar nuclei
  • Peripheral neuronopathy
    • Neurons in sensory & autonomic ganglia: Loss; Contain cytoplasmic vesicles
    • Sciatic nerve: Reduced numbers of large diameter myelinated axons
    • Nerve conduction testing: Slow velocity; Small CMAP amplitude
  • Pigmentation: Diluted

HMSN with CNS or Cranial nerve involvement

HMSN with CNS or Cranial nerve: Dominant, Demyelinating

• Hearing loss, Bilateral high-frequency + Sensory polyneuropathy¹⁶
    l Connexin-31 (GJB3) ; Chromosome 1p34.3; Dominant
  • Genetics
    • Mutation: D66del
    • External: Data bases
      • Connexin deafness;
      • Hereditary hearing loss
    • Variable penetrance
    • Other mutations cause: Non-syndromic deafness; Erythrokeratodermia variabilis
  • Protein
    • Gap junction membrane protein
    • Expressed in cochlea & sciatic nerve
  • Clinical: Variable penetrance
    • Hearing loss: Middle & High frequencies; Late onset
    • Polyneuropathy
      • Symmetric
      • Often mild
      • Predominantly sensory
      • Weakness: Few patients; Distal
      • Electrodiagnostic studies
        • Mild slowing of motor & sensory NCV
        • Mild reduction in amplitudes of SNAP & CMAP
      • Nerve pathology: Demyelination in one patient
  
  
• Other CMT 1 with hearing loss in some patients
  • HMSN IA: PMP-22 point mutation
  • CMT 1X: Connexin-32

HMSN with CNS or Cranial nerve: Dominant, Axonal

• HMSN with pyramidal features (HMSN 5)⁷
    l Autosomal Dominant
  • Some patients with MFN2 mutations: H165D
  • Clinical
    • Onset: 2nd decade or later
    • Weakness: Distal; Legs > Arms
    • Upper motor neuron
      • Extensor plantar responses
      • Tendon reflexes: Brisk (60%)
      • Spasticity: Some patients, but usually mild
    • Sensory
      • Loss: Distal legs; Symmetric
      • Pain: Legs; Most patients
    • Progression
      • Slow
      • Little disability in most patients
      • Occasional patients in wheelchair by 10 years
  • Laboratory
    • Electrophysiology: Axonal loss
    • Nerve pathology: Axonal loss
  
  
• HMSN & Deafness
    l Autosomal Dominant
  
  • P₀ mutation variants: Demyelinating CMT with deafness
  • PMP-22 point mutations
  
  
• HMSN & Deafness¹⁶
    l GJB3 (Connexin 31) ; Chromosome 1p35.1; Dominant
  • See: Connexin-31 Demyelinating neuropathy
  • Genetics
    • Mutation: D66del
  • Clinical
    • Deafness
    • Peripheral neuropathy
  
  
• HMSN & Optic atrophy, retinopathy, deafness
    l Autosomal Dominant
  • Clinical features
    • Severe visual loss
      • Onset age 7 to 10
        
      • To light perception only by age 30
        
      • Red-Green dyschromatopsia
        
      • Other dominant optic atrophies: Blue-Yellow defects
    • Asymptomatic sensory neuropathy
      • Distal sensory loss
      • Reduced tendon reflexes
    • Hearing loss
  • Laboratory
    • Electrodiagnostic: Axonal Sensory-motor neuropathy
      
  
  

HMSN with CNS or Cranial nerve: Recessive, Axonal neuropathy

• HMSN & Agenesis of Corpus Callosum: Andermann Syndrome:
    l KCC3 (SLC12A6) ; Chromosome 15q14; Recessive
  • Genetics
    • Mutation type: Protein truncating
    • Common mutations
      • General: Arg1011X (Exon 22)
      • French-Canadian: 2436delG
    • Knockout mice develop similar syndrome
      • Peripheral nerves have hypomyelination
      • Normal corpus callosum: Other factors may be involved in agenesis
  • KCC3 protein
    • Potassium-Chloride cotransporter
    • Location
      • Brain & Spinal cord
      • Cells
        • CNPase positive oligodendroglia in white matter
        • Basolateral membrane of choroid plexus epithelial cells
    • Increased activity with cell swelling
    • Family
      • Diuretic sensitive cation-chloride cotransporters
      • Other members
        • Thiazide sensitive Na⁺-Cl^- cotransporter (NCC)
        • Na⁺-K⁺-2Cl^- cotransporters (NKCC 1 & 2)
    • Glycoprotein: High mannose; May be complex
    • Mutations impair function of cotransporter
  • Epidemiology
    • French-Canadian: Charlevoix-Saguenay geographical focus; 1 in 2,100 live births
    • KCC3 mutations also found in non-French-Canadian families
  • Clinical Features
    • Cranial nerves: Symmetric or Asymmetric involvement
      • Ptosis
      • Facial weakness
      • Ophthalmoplegia: Reduced upgaze; Other
    • Neur(on)opathy
      • Motor
        • Early: Hypotonia
        • Severe weakness: Distal & Proximal
        • Progressive
        • Rarely walk independently
      • Sensory loss
      • Areflexia
      • Tremor
    • CNS
      • Cognitive
        • Mental retardation
        • Atypical psychosis: Onset in teens; Episodic
      • Seizures
      • Optic atrophy
    • Dysmorphic features
      • Face: Long; Hypertelorism
      • Brachycephaly; High arched palate
      • Toes: Syndactyly of 2nd & 3rd; Overiding 1st
      • Scoliosis
      • Pulmonary restriction
  • Laboratory
    • Electrodiagnostic: Axonal loss
      • Absent sensory potentials
      • Mildly reduced motor NCV
    • CSF: Protein mildly increased
  • Pathology
    • Agenesis of corpus callosum
      • Partial or complete (58%)
      • Due to defect in axon migration across midline
    • Cranial nerves: Axonal swellings with few neurofilaments
    • Peripheral nerve
      • Large myelinated axons: Reduced
      • Axonal swellings with few neurofilaments
  
  
• HMSN, Optic neuropathy ± Hearing loss
    l Recessive & X-linked forms
  • Spastic paraplegia also reported in 1 family
  
  
  
• HMSN & Deafness
    l Autosomal recessive
  
  • Clinical
    • Polyneuropathy
      • Course: Early onset; Slowly progressive
      • Weakness: Distal; Arms & Legs; Symmetric
      • Sensory: Reduced proprioception in legs; + Romberg
    • Sensorineural deafness: Congenital
    • Mental retardation: Mild
    • ± Pyramidal signs; Cerebellar atrophy
    • Tendon reflexes: Absent
  • Nerve conduction
    • Slow motor velocity: Median < ulnar
    • Absent sensory potentials
  • Pathology
    • Absence of α & β large myelinated axons
    • Normal: δ & unmyelinated fibers
  • Also see: CMT 2E; Hearing loss
  
  
• Also see: Childhood onset neuropathies

HMSN with CNS or Cranial nerve: Recessive, Demyelinating

• Congenital disorder of glycocosylation, Type 1a (CDG1A)
  
  
• HMSN (Demyelinating) & Hearing loss (Lom type; CMT 4D)
  
  
• Metachromatic Leukodystrophy
    l Arylsulfatase A (ARSA) ; Chromosome 22q13.33; Recessive
  • Clinical features
    • CNS: Mental retardation; Optic Atrophy; Spasticity
    • Polyneuropathy
      • Juvenile onset forms: Neuropathy may be presenting feature
      • Weakness: Proximal & Distal
      • Hypotonia
      • Tendon reflexes: Decreased or absent
      • Sensory loss: Mild; Distal
      • Treatment: Corticosteroids may produce symptomatic benetfit for 2 to 3 years
    • Laboratory
      • NCV: Demyelination
        • Slowing: Variable early; More uniform with progressive disease
        • Prolonged F-waves
        • No conduction block
      • Nerve Pathology
        • Hypomyelination
        • Metachromatic inclusions in Schwann cells and macrophages
          
        • Lamellar or dark ultrastructure
      • CSF protein: High
  • Rule out:
    • Multiple Sulfatase Deficiency (Recessive)
    • Activator Protein (Prosaposin) Deficiency
        l Chromosome 10q21-q22; Recessive
  
  
• Galactosylceramide Lipoidosis (Krabbe)
    l Galactosylceramide β-galactosidase (GALC) ; Chromosome 14q31.3; Recessive
  • Childhood³⁸
    • CNS
      • Mental retardation
      • Irritability: Excessive crying
      • Optic Atrophy
      • Tone: Spasticity; Hypertonia (Occasional hypotonia)
    • Polyneuropathy
      • Onset: < 6 months
      • Clinical
        • May be presenting syndrome (Up to 25% of patients): Before CNS
        • Motor delay
        • Hypotonia
        • Reduced movements
        • Tendon reflexes: Reduced or Absent
        • Other CNS features develop over months
      • Electrophysiology: Demyelinating neuropathy
        • Nerve conduction velocities: Slow
        • Distal latency: Prolonged
        • Conduction block: Occasional
        • F-wave responses: Delayed or Absent
        • CMAP: Mildly reduced amplitude
      • Nerve biopsy
        • Ultrastructure: Curved tubular inclusions in Schwann cell cytoplasm
        • Light microscopy: May show few features of myelin pathology
  • Later-onset forms²⁹
    • Onset
      • Age: > 10 years; Range 13 to 47
      • Limb weakness
      • Gait disorder
    • Spinal cord
      • Spasticity: Legs & Bladder
      • Tendon reflexes: Brisk or Absent
    • Polyneuropathy: Predominantly motor
      • May be asymmetric
      • Weakness
        • Early: Distal; Hands & Feet
        • Later: Proximal; Respiratory failure; Tongue
      • Pes cavus
      • Fasciculations: Proximal muscles
      • Course: Progressive over years
    • Other CNS signs
      • Dysarthria
      • Optic atrophy
      • Ataxia
      • Dementia
    • Genetics
      • Most mutations in region coding for 50 kDa subunit
      • Occasional mutations in 30 kDa subunit
  • Laboratory
    • CSF: High Protein
    • Electrophysiology: Demyelinating Neuropathy; Slow NCV
    • MRI: Corticospinal tract & periventricular demyelination
  • Pathology
    • Myelin
      • Hypomyelination of axons: Uniformly thin myelin sheath in most axons
      • Some patients with demyelination & onion bulbs
    • Inclusions
      • Locations: Schwann cells; Histiocytes
      • Structure
        • Shape: Straight or Slightly curved, Crystalloid & Prismatic
        • Contents: Clear & empty on paraffin & ultrastructure
    • Axonal loss

• Refsum disease: Childhood onset (< 20 yrs) : Classic form
    l Phytanoyl-CoA Hydroxylase (PAHX: PHYH) ; Chromosome 10p13; Recessive
  • Nosology: Heredopathia atactica polyneuritiformis (HAP)
  • Genetics
    • PHYH gene mutations
      • Missense most common
      • Most mutations inactivate enzyme function
      • Some mutations produce protein with
        • Normal activity, but
        • Defective targeting to peroxisomes
    • Other Refsum-like (Peroxisome biogenesis) syndromes
      • PEX1
      • PEX2
      • PEX7
      • PEX26
      • ABHD12
  • Phytanoyl-CoA Hydroxylase
    • Enzyme function: Converts phytanoyl-CoA to 2-hydroxyphytanoyl-CoA
      • Phytanoyl-CoA + 2-oxoglutarate + O₂ =
          2-hydroxyphytanoyl-CoA + succinate + CO₂
      • 1st step in the α-oxidation of phytanic acid
    • Subcellular localization: Peroxisomes
    • Cellular localization: Liver, kidney, & T-cells
    • Deficient in liver in Zellweger syndrome
    • Phytanic acid
      • Source: Dietary; Milk products & Meat of ruminant animals
      • Byproduct of degradation of chlorophyll
      • Secondary metabolic pathway: ω-oxidation; Limited capacity
  • Clinical
    • Onset
      • Night blindness
      • 5 to 50 years of age
    • Demyelinating Neuropathy
      • Distribution of signs: Symmetric; Distal progressing to Proximal
      • Weakness: Distal; Legs > Arms
      • Sensory loss: Vibration & Proprioception > Pain & Temperature
      • Tendon reflexes: Reduced or Absent
      • Nerve size: Enlarged in some patients
      • Course
        • May present subacutely over weeks
        • Progressive or Relapsing
      • Nerve conduction: Very slow motor & sensory velocity (Some < 10 M/s)
      • CSF Protein: Very High
      • Nerve pathology
        • Hypertrophy: Proximal > Distal
        • Onion bulbs: Large
        • Myelinated axons: Reduced numbers
        • Ultrastructure: Inclusions in Schwann cell cytoplasm
    • Cranial nerves
      • Anosmia
      • Deafness
        • < 40 years
        • Sensorineural
      • Eye ⁸⁶
        • Retinitis Pigmentosa (Tapetoretinal Dystrophy)
          • Granular
          • Concentric constriction of visual fields
          • Night blindness
          • Reduced ERG
        • Pupil: Miosis; Reduced light response
        • Iris atrophy
        • Cataract
    • CNS
      • Clinical: Ataxia
      • Pathology: Reduced numbers of Purkinje cells & Neurons in Inferior olive, Dentate, Vestibular, Cochlear & Red nuclei
    • Systemic
      • Skin: Ichthyosis
      • Cardiac Failure
        • Arrythmias
        • Cardiomyopathy
        • May cause sudden death
        • Onset after childhood
        • In more severe diseae
      • Diabetes
      • Skeletal
        • Short 4th metatarsal
        • Epiphyseal dysplasia
        • Syndactyly
      • Renal
      • Hepatic
  • Laboratory: Biochemistry
    • Elevated serum phytanic acid (Branched chain fatty acid)
    • Reduced oxidation of phytanic acid in fibroblasts
    • Pristanic acid: Very reduced
    • Diagnostic test: Phytanic:Pristanic acid ratio
    • Peroxisomal dysfunction
    • Other syndromes with high blood phytanic acid
      • Zellweger spectrum disorders
        • Zellweger syndrome
        • Neonatal adrenoleukodystrophy
        • Infantile Refsum disease
      • Autosomal recessive rhizomelic chondrodysplasia punctata type 1 (PEX7 deficiency)
  • Treatment
    • Low phytanic acid diet
      • Avoidance of dietary sources of branched chain fatty acids
      • Normal caloric intake
      • Phytanic acid levels: < 10 mg/dL [320 mmol/L]
      • External link: Refsum disease
    • Plasma exchange
    • Intestinal lipase inhibitor, Orlistat (Xenical): Anecdotal report ⁸⁵
  
  
• Refsum disease: Adolescent or young adult (Typical form)
    l PEX7 ; Chromosome 6q23.3; Recessive
  • PEX7 mutations³⁵
    • Refsum disease
      • Compound heterozygote: 1 Mutation with mild effect in each patient
      • Y40X; 12-18dupGTGCGGT Frameshift; T14P
    • Mutations also cause: Rhizomelic chondrodysplasia punctata type 1
  • Protein: Peroxin 7
    • Function: Import into peroxisome of proteins containing peroxisomal targeting signal type 2 (PTS2)
  • Onset: 2nd to 4th decade
  • Clinical
    • Ataxia
    • Polyneuropathy
      • Sensory loss
      • Weakness
      • Nerve enlargement
    • Anosmia
    • Retinitis pigmentosa
    • Skeletal: Short 5th metacarpal; Pes cavus
  • Laboratory
    • Plasmalogen synthesis: Deficient
  
  
• Refsum's: Infantile onset
    l Peroxin-1 (PEX1) ; Chromosome 7q21.2; Recessive
  • Genetics
    • Homozygous mutation (Gly843Asp) found in
      • Infantile Refsum's & 1 patient with neonatal adrenoleukodystrophy (NALD)
    • Heterozygosity for this mutation (? other mutation) found in
      • Zellweger's; Neonatal Adrenal Leukodystrophy; Infantile Refsum's
  • PEX1 Protein
    • Required for peroxisomal matrix protein import
    • Peroxisome biogenesis
  • Clinical
    • Mental retardation
    • Neuropathy: Demyelinating
    • Deafness
    • Retinitis pigmentosa
    • GI: Hepatomegaly; Steatorrhea
    • Skeletal: Facial dysmorphism; Growth failure; Osteopenia
  • Biochemistry
    • Hypocholesterolemia
    • Accumulation of phytanic acid, pipecolic acid, very long chain fatty acids
  • Pathology
    • CNS: Leukodystrophy
    • Peroxisomes: Reduced or Absent
  
  
• Refsum's: Infantile onset 2
    l Peroxisome biogenesis factor 2 (PEX-2; PXMP3) ; Chromosome 8q21.11; Recessive
  • Genetics
    • Mutation: Missense; Glu55Lys
    • Allelic with: Zellweger syndrome 3 (Stop mutation)
  • Clinical
  
  
• Refsum's: Infantile onset 3
    l Peroxisome biogenesis factor 26 (PEX-26) ; Chromosome 2q11.21; Recessive
  • Genetics
    • Mutations: Missense & other; Met1Thr, Leu45Pro
    • Allelic with
      • Zellweger syndrome
      • Adrenoleukodystrophy, Neonatal
  • Clinical
  
  
• Adult onset Refsum's with pipecolicacidemia
    l ? Peroxisomal disorder; Chromosome 10p; Recessive
  • Rule out: PHYH mutations
  
  
• Refsum-like disorder ⁷¹
    l ABHD12 ; Chromosome 20p11.21; Recessive
  • Nosology
    • PHARC: Polyneuropathy, Hearing loss, Ataxia, Retinitis pigmentosa, Cataract
  • Epidemiology: 19 patients; Norwegian, Algerian, UAE & US
  • Genetics
    • Mutations
      • c.337_338 delGAinsTTT; Promoter & Exon 1 deletion; c.846_852 dupTAAGAGC ((p.His285fsX1); Arg352X
      • Null mutations
  • ABHD12 protein
    • Highly expressed in brain
    • Enriched in microglia
    • Monoacylglycerol lipase
    • Substrate: Main endocannabinoid 2-arachidonoyl glycerol (2-AG)
    • 2-AG functions: Synaptic plasticity; Neuroinflammation
  • Clinical
    • Onset
      • Age: Childhood to late teens
      • Polyneuropathy
    • Peripheral neuropathy
      • Sensory loss
      • Ankle reflexes: Absent
    • Ataxia
      • Gait disorder
      • Tremor
      • Dysarthria
      • Onset: Childhood to 5th decade
    • Spasticity
      • Some patients: Brisk reflexes or Extensor plantar response
    • Eye
      • Pigmentary retinopathy
      • Cataract: Onset third decade
      • Optic atrophy: Some patients
    • Ear: Hearing loss in 1st to 4th decades
    • Skeletal
      • Pes cavus
      • Tendoachilles contracture
    • Skin: Normal
    • Cardiac: Normal
    • Progression: Slow over decades
    • Cortical function: Usually normal
    • No anosmia
    • Carriers: Normal
  • Laboratory
    • Normal
      • Phytanic & Pristanic acid levels in plasma
      • Peroxisomal function
    • NCV: Demyelinating neuropathy
      • Slow velocities
      • Axon loss: Distal
      • SNAPs: Absent
    • Muscle biopsy: Normal
    • MRI: Normal

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

• Epidemiology
  • Japanese family: 3 severe males, 2 mild females
• Genetics: No specific X-linkage defined
• Onset
  • Age: Adult, 3rd decade
  • Symptom: Gait disorder
• Clinical
  • Weakness: Distal; Hands & Feet
  • Wasting: Distal; Hands & Feet
  • Upper motor neuron signs
    • Spasticity: Legs > Arms
    • Plantar responces: Extensor
  • Tendon reflexes
    • Ankles: Absent
    • Other: Brisk
  • Sensory loss: Distal; Panmodal
  • Cranial nerves: Normal
• Laboratory
  • Electrophysiology
    • NCV: 13 to 36 M/s
    • CMAPs: Absent or reduced amplitude
    • SNAP amplitude: Reduced or absent
    • Evoked potentials: Abnormal central somatosensory & motor pathways
  • Nerve biopsy: Non-diagnostic
  • MRI: Hyperintense lesions inperiventricular white matter
• Female heterozygotes: Milder than males
  • Onset: Adult
  • Clinical
    • Wasting & Weakness
      • Legs
      • Distal
    • Upper motor neuron
      • Gait: Mildly spastic
      • Plantar reflexes: Extensor
    • Tendon reflexes
      • Ankles: Absent
      • Other: Brisk
  • Electrodiagnostic
    • NCV: 22 to 48 M/s

Hereditary Neuropathies - Other

• Epidemiology: Sporadic patients; ~10
• Genetics
  • Mutations: Missense; Ser52Pro
  • Allelic with: Bile acid synthesis defect, congenital 4
• AMACR Enzyme function
  • Location: Peroxisomal
  • Metabolic: β-oxidation pathway of branched-chain fatty acids
  • Point mutations produce inactive proteins
• Onset
  • Childhood to Early adult
  • Encephalopathy
• Clinical²⁴
  • Polyneuropathy
    • Adult onset: Neuropathy present in 2 adult patients but probably not a child
    • Weakness: Legs > Arms
    • Sensory loss
    • Electrophysiology
      • Axonal loss (3 patients)
      • Demyelination (1 patient)
      • Sensory & Motor involvement
  • CNS: Variably present
    • Cerebellar ataxia
      • Late onset (5th decade)
      • Gait, Appendicular & Speech
    • Spastic paraparesis
    • Developmental delay (Mild): Learning difficulties
    • Seizures (80%)
    • Encephalopathy
      • Episodic (Relapsing)
      • May be focal, localized or diffuse
      • Static or Progressive
  • Retinitis pigmentosa: Visual acuity reduced
  • Rhabdomyolysis: 1 patient⁸⁷
    • Triggering factors: Neuroleptics; Infections; Anaesthesia
  • Differential diagnosis: SCP2 deficiency
• Laboratory
  • Pristanic acid (a branched chain fatty acid) in plasma: Increased
  • Phytanic acid: High
  • Di- & Tri- Dydroxycopristanic acids (DHCA & THCA): High
  • C27-bile-acid intermediates in plasma: Reduced
  • Fibroblasts
    • AMACR activity absent
    • Peroxisomes (Catalase staining): Reduced number; Increased size
  • Muscle
    • Morphology: Normal
    • Mitochondrial oxidative enzymes: Normal
  • MRI: Suggestive of mitochondrial disorders
    • Cortical edema during episodes
    • High T2 signal: White matter; Thalami; Brain stem

• Epidemiology: Single Japanese patient

  From K Sugie

• Genetics: Normal SRY & DHH genes
• Onset: 39 years; Distal numbness & weakness
• Clinical
  • Neuropathy
    • Weakness: Distal; Moderate; Arms & Legs
    • Sensory: Distal; Panmodal; Severe
    • Tendon reflexes: Absent
  • Gynecological
    • Breasts: Poorly developed
    • Pubic hair: Sparse
    • Vagina: Blinded
    • Uterus: Immature
    • Gonads: Streak
  • CNS: Normal
• Laboratory
  • Hormones: LH & FSH high; Testosterone & Estradiol low
  • Electrophysiology
    • SNAPs: Absent
    • Motor: Small CMAPs; Moderately slowed NCV
    • EMG: Denervation
  • Nerve pathology
    • Minifascicles: 60 small fascicles in sural nerve
    • Axonal density: Reduced small & large myelinated fibers; Normal unmyelinated axons
    • Myelin sheath: Thin
    • Perineurial cells: Abnormal basal lamina
• Also see: Polyneuropathy with Minifascicles, 46,XY Gonadal dysgenesis & Mental retardation

• Epidemiology: Single Northern New York white family; Italian descent
• Genetics: Missense mutation; M319K
• Clinical
  • Congenital vertical talus (CVT; Rocker-bottom foot)
    • Rigid dorsal dislocation of navicular over neck of talus
    • Bilateral or Unilateral
  • Neuropathy
    • Early onset
    • Mild
    • Feet only
    • May be asymmetric
• Laboratory: Not available