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Sensory Disorders: Large Fiber & Ataxic

Toxic   Vitamin B6   cis-platinum   Semi-synthetic penicillins   Taxol Deficiency/ Malabsorption   Vitamin B12   Vitamin E Immune   Antibody     GALOP     GD1b antibody     MAG   Miller Fisher Syndrome   Sensory ganglionopathy     Hu (Paraneoplastic)     Sjögren's     Idiopathic Infection  Syphilis - Tabes dorsalis Hereditary   Recessive 2     a-β-lipoproteinemia (Bassen-Kornzweig): MTP     AOA2: SETX     Ataxia Telangectasia: ATM     AVED: TTPA     CANVAS: RFC1     DAIPT (Scoliosis): PIEZO2     Friedreich Ataxia: FXN     Mitochondrial       POLG       IOSCA: TWNK       MC4DN11: COX20     PCARP: FLVCR1   Dominant     Sensory ataxic neuropathy: PLD3     Sensory ataxic neuropathy 2: ZFHX3       SCA 4     Sensory ataxia (SNAX1): RNF170; 8p11     Posterior column ataxia (Biemond)     Sensory neuropathy + Scoliosis (Robinson) Also see   Hereditary     Ataxic neuropathy + Thermoanalgesia     Sensory & Autonomic Neuropathies     Mitochondrial: Sporadic   More pathology   Large and Small Axon loss     Neuropathies     Ganglionopathies

Peripheral Nerve Loss of large myelinated axons

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Posterior column ataxia (Biemond)

  ● Autosomal Dominant or Single generation

• Epidemiology: 2 families
• Clinical features
  • Onset age: 19 to 30 years
  • Sensory loss
    • Large fiber modalities: Position & Vibration
    • Sensory ataxia: Limbs & Gait; Worse in dark
    • Pain & Temperature sensations: Preserved
    • Course: Progressive
  • Tendon reflexes: Absent
  • Plantar responses: Flexor
  • Scoliosis
• Pathology: Loss of large axons in dorsal root & posterior columns
• Also see
  • PCARP: FLVCR1

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Sensory neuropathy with Scoliosis (Robinson)

  ● Autosomal Dominant

• Epidemiology: 2 families
• Clinical features
  • Onset age: 1st to 6th decades
  • Sensory neuropathy
    • Sensory ataxia: Gait; Romberg positive
    • No ulcerating acropathy or pain
    • Tendon reflexes: Absent
  • Autonomic: Normal
  • Cranial nerves
    • Oculomotor dysfunction: 1 patient
    • Hearing loss: Occasional
  • Extensor plantar response: 1 patient
  • Scoliosis
• Electrophysiology
  • SNAPS: Absent
  • Motor potentials: Normal
• Pathology: Loss of myelinated axons
• Also see: Sensory neuropathy + Scoliosis, Recessive: PIEZO2
  

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SCA46: Ataxia, Sensory Neuropathy + Cerebellar 1   ● Phospholipase D family, member 3 (PLD3) ; Chromosome 19q13.2; Dominant Epidemiology: 1 Dutch family; 5 patients Genetics Mutation: Missense; Leu308Pro PLD3 protein Catalyze hydrolysis of membrane phospholipids Expression: High in cerebellum Cell localization: Endoplasmic reticulum Clinical Onset age: 35 to 70 years Sensory Large fiber loss Vibration: Reduced or Absent Proprioception: Reduced Distal > Proximal Legs > Arms Ataxia: Gait Small fiber loss: Pain sensation mildly reduced Strength: Normal Reflexes: Reduced or absent in legs Cerebellar Eyes: Square wave jerks; Nystagmus; Saccades slow Dysarthria Course: Slow progression Laboratory Nerve conduction SNAP amplitudes: Reduced or Absent Conduction Velocity: Normal Pathology Myelinated axons: Reduced to 10% of normal No regenerating clusters or onion bulbs Sensory evoked potentials: Often unobtainable or reduced amplitude Brain MRI: Normal or Cereberllar atrophy, mild

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Sensory Ataxic Neuropathy 2/SCA4 ³

  ● ZFHX3 ; Chromosome 16q22.2-q22.3; Dominant

• Epidemiology: Swedish-Scandanavian, German & Chilean families
• Genetics
  • Mutations
    • GGC repeat: Expanded; Loss of interruptions
    • Exonic: Poly-Glycine
    • GGC Repeat numbers
      • Disease: 42 to 74
      • Control: 14 to 26; Median 21
  • Anticipation: Common in families; Correlates with repeat length
  • Onset age: Younger with longer repeat length
  • Allelic disorders
    • Atrial fibrillation 8, susceptibility to, Dominant (ATFB8)
    • Epilepsy, idiopathic generalized 20, Recessive (EIG20)
    • Prostate cancer, somatic
    • Spinocerebellar ataxia 4
• ZFHX3 protein
  • CNS & PNS
  • Neuronal developmant & differentiation
• Clinical
  • Onset age
    • 12 to 65 years; Mean = 39
    • Anticipation: 5 to 7 years earlier per generation
  • Polyneuropathy
    • Sensory loss
      • All modalities
      • Distal
      • Facial
      • Ataxia: Gait disorder
    • Weakness: Distal 20%
    • Dysarthria
    • Reflexes
      • Tendon reflexes absent: Ankles 100%; Knees 85%
      • Plantar responses: Extensor in 10% to 20%
      • Course: Progressive over decades; Wheelchair common
    • Autonomic
      • Orthostatic dysfunction
      • GI: Constipation or Diarrhea
      • Urinary retention
      • In most severely affected patients
  • Cerebellar
    • Saccades: Slow
    • Gait ataxia
  • Systemic
    • Weight loss
    • Cough
• Laboratory
  • Electrodiagnostic: Axon loss (Sensory > Motor)
    • Sural SNAP: Absent in > 90%
    • CMAP: Reduced in 38%
  • Brain MRI: Cerebellar atrophy
  • Pathology
    • Spinal cord: Loss of axons in posterior columns
    • Sensory
      • Dorsal root ganglion cells: Reduced
      • Axons in peripheral nerve: Reduced
    • CNS: Brainstem & Cerebellar pathology
    • Inclusions
      • p62 & α-Synuclein
      • In neuronal & enteric nuclei & cytoplasm

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Toluidine blue stain Loss of large myelinated axons with relative preservation of small myelinated axons

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References
1. Brain 1995;118:1557-1563
2. Nat Rev Neurol 2022 Mar 24
3. Am J Hum Genet 2023 Nov 28, J Neurol 2024 Aug 2

12/20/2024