Neuromuscular: Large+Small Sensory

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Sensory Disorders - Large + Small Fiber

Toxic
- Metals: Thallium; Mercury (Methyl)
- Drugs: Thalidomide; Taxol; Ethylene oxide; Misonidazole;
  Metronidazole; Trichloroethylene Phenytoin
Immune
- Paraneoplastic - Small Cell Neoplasms (Anti-Hu)
- Anti-Sulfatide
- Anti-MAG
- Sjögren's
- Cryoglobulin (with M-protein; Hepatitis C)
Hereditary
- Mitochondrial Syndromes
- Multiple Symmetric Lipomatosis
  l Autosomal Dominant
- Hereditary Sensory Neuropathy II (HSAN II)
  l Autosomal Recessive
- Hereditary Neuropathy with Ulcero-mutilation
  l Autosomal Dominant
- Hereditary sensory neuropathy with spastic paraparesis
  l 5p15; Recessive
- Navajo neuropathy with corneal ulceration
- Mitochondrial
  l POLG; Recessive
- Also see
  - Hereditary sensory neuropathies
  - Ulcero-mutilating neuropathies
Neuronopathy: Asymmetric & Proximal sensory loss
- Paraneoplastic (Anti-Hu; ANNA I): Often with limbic encephalitis, or ataxia
- Sjögren's
- Idiopathic (often subacute onset)

Chronic sensory neuropathy
High arches & Hammer toes
Preserved gastrocnemius size

Hereditary Sensory Neuropathy II (HSAN II)

l WNK1

; Chromosome 12p13.33; Recessive

Epidemiology: Genetically confirmed families in Eastern Canada
WNK1 genetics³: Mutations
- Location: Nervous system specific exon (HSN2 )
- Mutations: Truncating
  - Newfoundland families: 594delA causing frameshift in codon 198; Homozygous; Truncation to 206-aa peptide
  - Nova Scotia: 918–919insA mutation; Frameshift in codon 307; Truncation to 318-aa peptide
  - Nova Scotia: 943C-T nonsense mutation; Changes codon 315 (CAG, glutamine) to a TAG stop codon; Truncates protein to 314 aa
  - Lebanese: 947delC homozygous
- Other mutations in WNK1 cause pseudohypoaldosteronism type II
WNK1 protein with HSN2 exon (WNK1/HSN2 isoform)
- Location: Sensory components of PNS & CNS associated with relaying sensory & nociceptive signals
- More abundant in sensory than motor neurons
WNK1 protein
- Participates in regulation of K⁺ channels (ROMK1)
- Also regulates Na⁺, K⁺, 2Cl^– & Na⁺Cl^– cotransporters (NKCCs & NCCs; TRPV4))
Clinical features
- Onset
  - Usual: Early childhood or congenital
  - Range: 1st 2 decades
- Sensory loss
  - Distal > Proximal
  - Legs > Arms
    - Hands: Up to elbows
    - Feet: Up to knees
  - Trunk: Some patients
  - Modalities: Large & Small fiber; Touch most severely affected
  - Numbness aggravated by cold
- Muscle atrophy: Some patients
- Autonomic: Mild or asymptomatic
  - Sweating
    - Reduced, Distal
    - Hyperhidrosis, episodic
  - Pupils: Tonic
  - Other: Constipation; Apneic episodes.
  - Normal: Blood pressure; Sexual function
  - Absent axon flare after intradermal histamine: Indicates defective nociceptive fibers
- Tendon reflex loss: Proximal & Distal
- Mutilation: Hand & Foot; Skin ulcers, Fractures
- Progression
  - Slow change over time
  - Variants: Stable congenital form
- Mental development: Normal
Electrophysiology: Absent sensory nerve action potentials (SNAPs)
Pathology
- Myelinated axons: Severe loss
- Unmyelinated axons: Milder loss
- Occasional degenerating axon
- Cutaneous sensory receptors & nerve fibers: Absent
HSAN comparisons

Hereditary sensory neuropathy with spastic paraparesis: Autosomal recessive

Cavanagh's variant
l Autosomal recessive
- Sensory neuropathy
  - Loss of pain & temperature
  - Relatively preserved vibration & joint position sense
  - Pathology: Axon loss, Small > Large
- Acromutilation
- Spasticity
Moroccan⁴
l Chromosome 5p15.31–14.1; Recessive
- Epidemiology & Nosology
  - Moroccan family, consanguinous
  - May be same syndrome as Cavanagh variant
- Clinical
  - Onset: 1 to 5 years
  - Spastic paraplegia
    - Gait disorder
    - Tendon reflexes: Increased with ankle clonus
    - Plantar reflexes: Extensor
    - Progression: Slow
  - Sensory loss
    - Distal > Proximal
    - Pan-modal
    - Legs > Arms
  - Mutilating acropathy
  - Normal: Cranial nerves, Coordination, Cognitive function
  - Course: Most patients remain ambulant
- Laboratory
  - Electrophysiology: Axonal sensory neuropathy, severe
    - SNAP amplitudes: Reduced or Absent (Older patient)
    - Motor: Normal or mildly reduced velocities
    - Autonomic
      - Vagal hyperactivity
      - α-sympathetic responses: Decreased
      - β-sympathetic: Increased
  - Serum: Reduced Apo B, total cholesterol and triglycerides
  - MRI: Spinal cord atrophy

Multiple Symmetric Lipomatosis (Madelung syndrome)

From Johns Hopkins Medicine

l Autosomal Dominant, Mitochondrial, or Sporadic

Epidemiology
- Middle-aged males
- Mediterranean region
- History of alcohol abuse
- Protease inhibitor treatment
Clinical features
- Fat accumulations: Multiple lipomas
  - Distribution: Symmetric; Distal arms & legs are spared
  - Types
    - I: Lipomas in nape of the neck, supraclavicular & deltoid regions: Bull-neck
    - II: Lipomas extend over the body: Appearance of simple obesity
- Polyneuropathy
  - Distribution: Distal; Symmetric
  - Modalities: Sensory-Motor; ± Autonomic involvement
  - Pathology
    - Distal predominance
    - Axon loss: Large > Small
Metabolic
- Hyperuricemia
- Triglycerides (VLDL, chylomicrons): High
- High-density lipoproteins (HDL): High
Mitochondrial MSL disorder
- A8344G mutation in mitochondrial tRNA^Lys
- Some families also with MERRF syndrome
- Muscle: May have ragged red fibers
Treatment
- Surgical removal of lipomas for compression or cosmetic reasons
- Lipomas usually recur

Ulcero-mutilating Neuropathies: Dominant

Hereditary Sensory > Motor Neuropathy with Ulcero-mutilation¹
l Autosomal Dominant

Genetics
- No linkage to other mutilating hereditary neuropathies HSAN I or HMSN IIB
Epidemiology
- South Austrian family
- Males more severely affected than Females
- Variable severity in family
Onset
- Foot deformities in childhood or teens
- Clinical features: 15 to 30 years
Clinical
- Ulcero-mutilation
  - Callus; Poorly healing ulcers; Amputations
  - Distribution: Feet; Asymmetric
  - Improvement during pregnancy
- Sensory
  - Large & small fiber modalities lost: Symmetric; Legs > Arms; Distal
  - Joint position sense preserved
  - No pain or paresthesias
  - No correlation between foot ulcers & severity of sensory loss
- Weakness (30%)
  - Mild
  - Symmetric
  - Distribution: Intrinsic foot muscles; Toe & Ankle dorsiflexors
- Reflexes
  - Tendon: Always preserved
  - No Babinski
- Sweating: Some patients with hyperhidrosis on Feet & Distal legs
Electrodiagnostic: Axonal loss
- NCV: Normal to mildly slowed motor & sensory velocities
- SNAP: Reduced; Absent in more severely affected individuals
- CMAP: Reduced amplitude; Chronodispersion

Hereditary Sensory-Motor Neuropathy with Ulcero-mutilation²
l Autosomal Dominant

Genetics
- No linkage to other mutilating hereditary neuropathies HSAN I or HMSN IIB
Epidemiology
- Italian family
- Full penetrance
Onset
- Age: Mean 14 years; Range 2 to 30 years
- Osteomyelitis
- Sensory loss
Clinical
- Ulcero-mutilation
  - Callus; Poorly healing ulcers; Amputations
  - Distribution: Feet & Hands; Asymmetric
- Sensory
  - Large & small fiber modalities lost: Symmetric; Legs > Arms; Distal
  - No pain or paresthesias
- Weakness (100%)
  - Distal
  - Symmetric
  - Feet & Hands
- Tendon Reflexes: Often absent
- Autonomic: Normal
Electrodiagnostic: Axonal loss
- NCV: Normal to mildly slowed motor & sensory velocities
- SNAP: Reduced; Absent in legs
- CMAP: Reduced amplitude; Absent in legs
Nerve Pathology
- Axonal loss: Especially small myelinated & Unmyelinated axons
- Endoneurial fibrosis

Go to Large fiber neuropathies
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References
1. Neurology 2000;54:45-52
2. Neuromuscular Disorders 2002;12:286-291
3. Am J Hum Genet 2004;74: May, J Clin Invest 2008 Jun 2
4. European Journal of Human Genetics 2005; Online December

6/9/2008