Leukodystrophies

Overview – Leukodystrophies

Leukodystrophies are a group of rare, inherited disorders characterised by defective formation or maintenance of myelin in the central nervous system. Unlike multiple sclerosis (where myelin is destroyed), leukodystrophies result from insufficient myelin production due to genetic defects. These progressive disorders typically present in infancy or early childhood with developmental regression, motor dysfunction, and sensory impairment. This page outlines the key clinical features and pathogenesis of leukodystrophies for final-year medical students.

Definition

Leukodystrophies are genetic disorders affecting the white matter of the brain, leading to abnormal or deficient myelin formation. Myelin is essential for proper conduction of nerve impulses.

Aetiology

• Genetic mutations affecting enzymes involved in:
  • Myelin synthesis
  • Myelin maintenance
  • Lipid metabolism
• Inherited in autosomal recessive, autosomal dominant, or X-linked patterns
• Many types, including:
  • Metachromatic leukodystrophy
  • Adrenoleukodystrophy
  • Krabbe disease
  • Canavan disease

Pathophysiology

• Defective enzymes → accumulation of toxic metabolites
• Leads to impaired oligodendrocyte function → poor myelin synthesis
• Consequence: Slowed or blocked nerve impulse transmission
• Differs from demyelinating diseases (e.g. MS) where myelin is initially normal and later lost

Clinical Features

• Typically presents in infancy or early childhood
• Gradual neurological deterioration after a period of normal development
• Signs include:
  • ↓ Body tone (hypotonia)
  • ↓ Voluntary movements
  • Gait abnormalities
  • Dysphasia (language regression)
  • Dysphagia
  • Visual and auditory impairment
  • Behavioural changes
  • Slowed mental and physical development
• May lead to severe disability and early death

Investigations

• MRI brain: Symmetrical white matter changes
• Genetic testing: Confirms subtype
• Enzyme assays: In leukocytes or fibroblasts
• Nerve conduction studies: Slowed conduction velocities

Management

• Currently incurable
• Supportive and multidisciplinary care:
  • Physiotherapy, occupational therapy, speech therapy
  • Nutritional support
  • Assistive mobility devices
• Bone marrow or stem cell transplantation is being studied for some subtypes (e.g. adrenoleukodystrophy)

Complications

• Severe neurological disability
• Respiratory failure
• Seizures
• Visual and hearing loss
• Early mortality in many subtypes

Differential Diagnosis

• Cerebral palsy
• Mitochondrial disorders
• Autism spectrum disorder (in early stages)
• Demyelinating diseases (e.g. MS, ADEM)
• Hypoxic-ischaemic encephalopathy

Summary – Leukodystrophies

Leukodystrophies are genetically inherited disorders of myelin synthesis in the CNS, leading to progressive neurological deterioration in children. These rare conditions present with hypotonia, developmental regression, and sensory deficits. Diagnosis is supported by neuroimaging and genetic testing, and while no curative treatment exists, supportive care is essential. For a broader context, see our Nervous System Overview page.