Small Fiber Sensory

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SENSORY DISORDERS: Small Fiber

Metabolic
- Diabetes mellitus
- Hypertriglyceridemia
Hereditary
Toxic: Kepone; Ciguatera
Infection: Leprosy
M-protein
Idiopathic: Often painful

Unmyelinated axons

Hereditary Sensory Neuropathy I (HSAN I; HSN I)

l HSAN IA

; Serine palmitoyltransferase, long-chain base subunit 1 (SPTLC1)

; Chromosome 9q22.31; Dominant
l HSAN IC

; Serine palmitoyltransferase, long-chain base subunit 2 (SPTLC2)

; Chromosome 14q24.3; Dominant

SPTLC Genetics
- SPTLC1
  - Misense mutations identified: C133Y, C133W, V144D, Ala352Val +
  - S331F: Severe, early onset disease
  - Founder effect in Australian & English families
  - Frequency in HSAN families: 19%
- SPTLC2 ⁵
  - Mutations: G382V; V359M; I504F
  - Frequency in HSAN families: 7%
- SPTLC3 : No mutations found
Serine palmitoyltransferase (SPT) enzyme: Sphingolipid biosynthesis
- SPTLC2: Colocalizes with ER marker calreticulin
- Function
  - Catalyzes pyridoxal-5'-phosphate-dependent condensation of L-serine & palmitoyl-CoA to 3-oxosphinganine
  - Rate limiting step in de novo biosynthesis of sphingolipids
- Mutation effects
  - Increased Glucosyl ceramide synthesis: ? Leads to apoptosis
  - Reduced serine palmitoyltransferase (SPT) activity
  - Normal levels of protein
  - Accumulation of abnormal toxic metabolites⁴
    - Deoxy-sphingoid bases (DSB): 1-deoxy-sphinganine (1-deoxy-SA) & 1-deoxymethyl-sphinganine
    - DSBs have neurotoxic effects on neurite formation in vitro
Clinical features
- Clinical features similar in: SPTLC1 & SPTLC2 mutations
- Onset age
  - Usual: 2nd decade or later; Average 25 years
  - Occasional mutations: < 10 years
- Distribution: Distal > proximal; Symmetric; Legs > Arms sensory, autonomic & reflex loss
- Sensory
  - Loss
    - Pain & Temperature (Small fiber)
    - Large fiber loss also occurs
    - Progressive
  - Spontaneous sensations
    - Paresthesias: Rare to Occasional
    - Lancinating pains: Some kindreds
    - Burning pain: 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
- Variants: SPTLC1 S331F mutation; SPTLC2 I504F mutation
  - Onset earlier: Childhood
  - Autonomic: Sweating disturbances
Laboratory
- Electrophysiology
  - Loss of C > Aδ & Aα axons
  - Nerve conduction velocities: Normal or Intermediate
- 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

Hereditary sensory neuropathy with loss of pain perception (HSAN5)

²
l Nerve growth factor-b (NGFB)

; Chromosome 1p13.2; Recessive

Genetic: Mutations (Homozygous)
- Missense: Arg211Trp
- Null: c.[680C>A]+[681_682delGG]
NGF-b protein
- Neurotrophin family
- Functions: Role in development & maintenance of sympathetic & sensory nervous systems
- Cellular location: Secreted
Epidemiology: Northern Swedish & Arab families
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 or Reduced
  - Fainting: 1 patient
  - GU & GI disorders: 1 patient
- CNS: Mental retardation (1 family)
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

Congential insensitivity to pain without anhidrosis (HSAN)

l Recessive

See: Hereditary sensory neuropathy with loss of pain perception (HSAN5)
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

Hereditary Ataxia with Thermoanalgesia & Loss of fungiform papillae¹

l ? Autosomal Dominant with incomplete penetrance or Recessive

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

Hereditary Ataxia with Thermoanalgesia³

l ? Autosomal Dominant with incomplete penetrance

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

Sensory & Autonomic Neuropathy with Chronic Diarrhea⁶
l Prion protein (PRNP)

; Chromosome 20p13; Dominant

Epidemiology: 1 family, 9 patients
Genetics: Y163X mutation
Clinical
- Onset: Early adulthood
- Polyneuropathy: Sensory; Axon loss
- Autonomic failure
  - Diarrhea: Chronic
- Later features (5th to 6th decade)
  - Cognitive decline
  - Seizures
Laboratory
- CNS: Prion protein deposition; Congophilic angiopathy
- Duodenum: Prion protein deposition

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References

1. Brain 1996;119:1011-1021
2. Hum Mol Genet 2004; April 2004, J Med Genet 2010 Oct 26
3. J Neurol Neurosurg Psychiatry 2009;80:518-523
4. J Biol Chem 2010; Online Jan
5. American Journal of Human Genetics 2010;87:513�522
6. J Neurol Neurosurg Psychiatry November 2010;81:e24

10/4/2011