What are the signs and symptoms of leucodystrophy?

Signs and Symptoms of Leukodystrophy

Leukodystrophies present with a spectrum of neurological manifestations that vary based on age of onset, specific type, and disease progression, with progressive damage to white matter in both central and peripheral nervous systems leading to significant morbidity and mortality. 1

General Clinical Presentation

Early Infantile Presentation

• Progressive irritability and spasms upon noise stimulation
• Recurrent episodes of unexplained fever
• Progressive visual and hearing impairment (blindness and deafness)
• Rapidly progressive course with:
  • Frequent seizures
  • Hyperpyrexia (abnormally high fever)
  • Hypersalivation
  • Complete loss of social contact
  • Loss of bulbar functions 1

Late-Onset Presentation

• Visual impairment
• Ataxia (poor coordination)
• Irritability
• Variable age of onset and disease progression 1

Type-Specific Manifestations

Krabbe Disease (Globoid Cell Leukodystrophy)

• Early infantile form (EIKD):

  • Onset within first months of life
  • Peripheral neuropathy (always present)
  • Death typically within first 2 years due to respiratory complications 1

• Late-onset form (LOKD):

  • Visual impairment, ataxia, and irritability as first symptoms
  • Less frequent abnormal neurophysiologic studies compared to early-onset form 1

Metachromatic Leukodystrophy (MLD)

Based on age of onset, MLD presents with different clinical patterns:

• Late infantile type (40-60% of cases):

  • Onset between 6 months to 4 years
  • Initial symptoms: peripheral neuropathy, muscle weakness, appendicular hypotonia, hypo/areflexia
  • Subsequent symptoms: mental regression, visual/auditory impairment, loss of ambulation, evolution to hypertonia, dysarthria/ataxia, bulbar dysfunction, seizures (25%)
  • Uniform disease course with death within 5 years 1

• Juvenile type (20-35% of cases):

  • Onset between 4 to 16 years
  • Initial symptoms: decline in school performance, emotional/behavioral disturbances, dysarthria/ataxia, hyperreflexia
  • Subsequent symptoms: mental regression, optic atrophy, loss of ambulation, spastic quadriplegia, incontinence, bulbar dysfunction, seizures (50%)
  • More variable progression with death within 10-20 years 1

• Adult type (15-25% of cases):

  • Onset following puberty
  • Initial symptoms: decline in school/job performance, emotional lability, disorganized thinking, hallucinations/delusions
  • Subsequent symptoms: clumsiness, incontinence, spastic quadriplegia, choreiform movements, dystonia, bulbar dysfunction (seizures rare)
  • Variable progression with death within 5-20 years 1

Diagnostic Findings

Neurophysiological Abnormalities

• In early infantile Krabbe disease:
  • 100% show abnormal nerve conduction studies
  • ~90% have abnormal brainstem auditory evoked responses
  • 65% have abnormal electroencephalogram
  • 53% have abnormal flash visual evoked potentials 1

Neuroimaging Findings

• MRI typically shows demyelination of white matter
• Diffusion tensor imaging can help identify early involvement of motor tracts in asymptomatic patients 1

Clinical Pitfalls and Important Considerations

1. Misdiagnosis risk: Adult-onset leukodystrophies may initially present with psychiatric symptoms or be misdiagnosed as multiple sclerosis or other neurological disorders 2, 3

2. Symptom-based prognosis: The type of initial symptoms can predict disease progression, particularly in late-juvenile and adult forms:

   • Patients with motor symptoms at onset have more rapid progression
   • Patients with only cognitive symptoms at onset show significantly milder disease progression 4

3. Variable MRI findings: Some cases may show minimal white matter abnormalities on MRI despite significant clinical symptoms, particularly in adult-onset forms 5

4. Rapid cycling mood disorders: Some adult-onset leukodystrophies may initially present as psychiatric disorders including rapid cycling mood disorders before neurological symptoms become apparent 6

5. Early diagnosis importance: Early recognition is critical before irreversible organ damage occurs, especially in patients without cognitive impairment who may have subtle presentations 7

Diagnostic Algorithm

1. Consider leukodystrophy when:

   • Progressive neurological deterioration occurs
   • Combination of central and peripheral nervous system involvement
   • Family history of similar symptoms (though may be absent in recessive forms)

2. Initial evaluation:

   • Neurological examination focusing on motor function, reflexes, and cognitive status
   • MRI with special attention to white matter abnormalities
   • Nerve conduction studies to assess peripheral involvement

3. Confirmatory testing:

   • Enzyme activity measurement in leukocytes or dried blood spots
   • Molecular genetic analysis
   • Urinary sulfatide excretion tests (for MLD)

By recognizing these signs and symptoms early, clinicians can initiate appropriate diagnostic workup and supportive care to improve quality of life, even though most leukodystrophies currently lack curative treatments.