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SENSORY DISORDERS: Small Fiber

Metabolic Diabetes mellitus Hypertriglyceridemia Hereditary Amyloidosis Hereditary Sensory Neuropathy I (HSAN I) Congenital sensory neuropathy with anhidrosis (HSN IV) Congential insensitivity to pain sensation without anhidrosis Hereditary ataxia with thermoanalgesia & loss of fungiform papillae An-α-lipoproteinemia (Tangier's) α-galactosidase (Fabry's) Hereditary sensory neuropathy + Spastic paraparesis (Cavanagh's variant) Hereditary sensory neuropathy with loss of pain perception Congenital indifference to pain Navajo neuropathy with arthropathy Cold-Induced Sweating Syndrome Toxic: Kepone; Ciguatera Infection: Leprosy M-protein Idiopathic: Often painful

Unmyelinated axons

• Genetics
  • Misense mutations identified: C133Y, C133W, V144D, Ala352Val +
  • S331F: Severe, early onset disease
  • Founder effect in Australian & English families
• Serine palmitoyltransferase (SPT) enzyme: Sphingolipid biosynthesis
  • Catalyzes pyridoxal-5'-phosphate-dependent condensation of L-serine & palmitoyl-CoA to 3-oxosphinganine
  • Mutation effects
    • Increased Glucosyl ceramide synthesis: ? Leads to apoptosis
    • Reduced serine palmitoyltransferase activity
    • Normal levels of protein
• Clinical features
  • Onset: 2nd decade or later; Average 25 years
  • Distribution: Distal > proximal; Symmetric; Legs > Arms sensory, autonomic & reflex loss
  • Sensory
    • Loss: Pain & Temperature (Small fiber); Large fiber loss also occurs
    • Spontaneous sensations: Paresthesias are Rare; Lancinating pains in some kindreds; Burning pain in some
  • Charcot's joints (Neurogenic osteoarthropathy)
    • Progression: Succession of exacerbations
    • Location: Feet, Severe mutilation & shortening; Occasional hands, Thickened fingers
    • X-rays: Distal demineralization; Metatarsal tapering (Licked candy-stick)
  • Weakness
    • Common late in course
    • Distal
  • Autonomic involvement
    • Rare
    • Occasional: Horner syndrome
  • Sensorineural deafness: Variably present
  • Skin: Blistering; Edema & discoloration of foot; Chronic ulcers; Painless injuries
  • Time course: Slow progression
• Laboratory
  • Electrophysiology: Loss of C > Aδ & Aα axons
  • Immune: Increased Synthesis of IgA
• Pathology
  • Loss of dorsal root ganglion cells & later motor neurons
  • Predominant loss of small myelinated & unmyelinated axons
  • No CNS changes
• See: Other Hereditary sensory neuropathies

• Onset: Congenital
• Clinical
  • Sensory loss
    • Pain
    • Temperature
    • Location: Extremities
  • Acromutilation
  • Normal: Large fiber sensation; Strength; Tendon reflexes
• Nerve pathology
  • Small myelinated A-delta fibers: Absent
  • Unmyelinated axons: Normal

• Genetic: Mutation
  • Missense: Arg211Trp
• NGF-b protein
  • Neurotrophin family
  • Functions: Role in development & maintenance of sympathetic & sensory nervous systems
  • Cellular location: Secreted
• Epidemiology: Northern Swedish family
• Clinical: Variable degrees of severity
  • Onset: Early childhood to adult
  • Sensory loss
    • Pain perception: Reduced
    • Temperature: Reduced
  • Skeletal: Charcot joints & Fractures
    • Onset: Childhood or Adult (3rd & 4th decade)
    • Lower extremities: Feet; Ankles; Knees
  • Autonomic
    • Sweating: Normal
    • Fainting: 1 patient
    • GU & GI disorders: 1 patient
• Laboratory
  • Electrophysiology
    • Nerve conduction velocity: Normal
    • Sensory loss: Temperature ± Vibration
    • R-R interval: Normal
  • Nerve pathology
    • Axon loss: Thinly myelinated & Unmyelinated
    • Less axon loss in adult onset cases

• Epidemiology: Japanese & New Zealand families
• Onset age: 5th decade
• Clinical
  • Neuropathy
    • Sensory
      • Pain & Temperature sensation: Lost or reduced globally
      • Vibration: Reduced distally
      • Unsteady gait
    • Motor: Normal
  • Ataxia: Benign
    • Nystagmus
    • Dysarthria
    • Limb ataxia
  • Autonomic
    • Fungiform papillae of tongue: Absent
    • Lacrimation: Reduced
    • Taste: Reduced
    • Temperature control: Abnormal, Fevers
    • GI: Constipation/diarrhea
    • Vasomotor instability
    • Bladder dysfunction: Urinary frequency
    • Sweating: Normal
    • Sympathetic & Parasympathetic involvement
  • Other
    • Emotional instability
    • IQ: Reduced
    • Hearing loss
    • Eye
      • Saccadic pursuit
      • Corneal sensation: Reduced
• Laboratory
  • NCV
    • SNAPs: Absent
    • CMAPs: Normal or mildly reduced
  • EMG: Chronic denervation
  • Caloric responses: Absent
  • CNS imaging
    • CNS MRI: Atrophy of spinal cord, cerebellum, brainstem & corpus callosum
  • Sural nerve: Loss of myelinated & unmyelinated axons

• Epidemiology: Northeast Spanish family
• Genetics
  • Not linked to known SCA loci
  • Incomplete penetrance
• Clinical
  • Onset
    • Age: 4th to 7th decade
    • Gait instability
    • Fatigue
  • Cerebellar
    • Ataxia: Limbs, dysmetria; Gait imbalance
    • Dysarthria
    • Eye: Nystagmus (30%); Slow saccades
  • Sensory
    • Paresthesias: Face & Extremities
    • Pain sensation: Reduced early & diffusely
    • Vibration: Early preserved; Late reduced distally in legs
  • Strength: Normal
  • Tendon reflexes: Present
  • Other CNS: Dementia (50%); Cognitive affective syndrome
  • Course: Progressive ove decade
• Laboratory
  • Nerve conductions
    • Sensory: SNAPs absent
    • Motor: Normal
    • Autonomic: Absent sudomotor response
  • EMG: Denervation
  • MRI: Cerebellum, Medulla & Spinal cord atrophy
  • Pathology
    • Cerebellum & Medulla: Atrophy
    • Spinal cord: Abnormal posterior column, lateral & anterior spinothalamic & posterior spinocerebellar tracts