Differential Diagnosis in Neurology

10.7. Neuropathies of Disorders of Defective DNA Repair

Xeroderma Pigmentosa (XP)

• General features:
  • Genetics:
    • 8 genes:
      • AR
      • Y groups with defective excision repair (XPA-XPG)
      • One variant with defect in semiconservative replication of damaged DNA
• Clinical presentation (neurologic forms: XPA; XPB; XPD; XPG):
  • Onset between 1–2 years
  • Increased sensitivity to sunlight (associated skin cancer)
  • Microcephaly
  • Mental retardation
  • Spasticity
  • Seizures
  • Deafness
  • Cerebellar ataxia
  • Dystonia
  • Choreoathetosis
  • Loss of large myelinated fibers
  • Decrease of life span due to associated malignancies
• EMG:
  • Decreased SNAP
• Pathology:
  • Loss of myelinated and unmyelinated axons; sensory fibers greater than motor

Non-Neurological Variants of XP (XPC; XPE; XPF)

• Clinical presentation:
  • Degenerative changes of the eyes and skin
  • Cutaneous pigmentation and scarring
  • 2000 fold increase in skin cancers in patients less than 20
• Laboratory:
  • Ultraviolet sensitivity of fiber blasts and of excision repair of DNA

Ataxia Telangiectasia

• General features:
  • Genetics:
    • AR; gene localized on chromosome 11q22–23 (ATM); radiosensitivity; chromosomal instability; impaired induction of ionizing radiation-induced cell cycle controls
    • Gene spans 150 kilobases
• Clinical presentation:
  • Onset in childhood
  • Telangiectasia may be noted on the sclera by age 1:
    • Flexor creases; usually evident by age 7
  • Cerebellar ataxia
  • Oculomotor dyspraxia
  • Cognitive deficits
  • Basal ganglia dysfunction:
    • Dystonia
    • Choreoathetosis
  • Sensory loss primarily of vibration and proprioception; distal motor weakness
  • Absent deep tendon reflexes
  • Associated medical features:
    • Growth retardation
    • Delayed sexual maturity
    • Glucose intolerance
    • Chronic upper respiratory infections
    • Low IgA and IgE levels
    • Increased incidence of leukemia and lymphoma
    • Impaired humeral and cellular immunity
• EMG:
  • Reduced SNAPs; slight decrease of motor NCV

Cockayne Syndrome

• General features:
  • Genetics: three forms of the disease (A, B, C):
    • CS-A; chromosome 5 and XP
    • CS-B chromosome 10q11–21
    • CS-C; combinations of CS
  • Deficient in repair of transcribed genes
• Clinical presentation:
  • Photosensitivity (no associated skin cancer)
  • Short stature (growth retardation)
  • Progeria
  • Hydrocephalus
  • Deafness
  • Pigmentary retinopathy
  • Ataxia
  • Demyelinating polyneuropathy
  • Hyporeflexia
• EMG:
  • Reduced motor nerve conduction velocities
• Pathology:
  • Demyelination in peripheral and CNS
• Laboratory:
  • Hypersensitivity of cultured CS cells to killing by UV light
  • Delayed recovery of DNA and RNA synthesis after UV radiation