Leukodystrophy

Group of disorders characterized by degeneration of white matter in the brain.

Leukodystrophy
Synonyms	White matter degeneration disorders
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Field	Neurology, Medical genetics
Symptoms	Muscle rigidity, ataxia, vision loss, hearing loss, seizures, cognitive decline
Complications	Progressive neurodegeneration, paralysis, dysphagia, respiratory failure, vegetative state
Onset	Typically in infancy or childhood, but can also occur in adolescence or adulthood
Duration	Chronic and progressive
Types	Metachromatic leukodystrophy, Krabbe disease, Adrenoleukodystrophy, Canavan disease, Alexander disease, Pelizaeus–Merzbacher disease, Vanishing white matter disease, Hypomyelination with atrophy of basal ganglia and cerebellum
Causes	Genetic mutation affecting myelin production or maintenance
Risks	Family history, X-linked recessive or autosomal recessive inheritance
Diagnosis	Magnetic resonance imaging, genetic testing, nerve conduction study, biochemical assays
Differential diagnosis	Multiple sclerosis, Tay–Sachs disease, Pelizaeus–Merzbacher disease, vanishing white matter disease
Prevention	No known prevention; early genetic screening may help at-risk families
Treatment	Hematopoietic stem cell transplantation, gene therapy, enzyme replacement therapy, symptomatic management
Medication	Steroids, muscle relaxants, antiepileptic drugs
Prognosis	Variable; life expectancy ranges from a few years in severe cases to decades in milder cases
Frequency	Estimated 1 in 7,600 births
Deaths	Progressive neurodegeneration leads to fatality, often due to respiratory failure

Leukodystrophies are a group of genetic neurological disorders characterized by degeneration of the white matter in the brain due to abnormalities in the development, maintenance, or destruction of myelin. The term comes from the Greek roots: leuko ("white"), dys ("abnormal"), and troph ("growth"). These disorders result from genetic mutations that impair the function of oligodendrocytes, the cells responsible for producing and maintaining myelin, the fatty substance that insulates neuronal axons and enables efficient nerve signal transmission.

Leukodystrophies can be classified as:

• Hypomyelinating leukodystrophies – Myelin formation is defective from birth.
• Demyelinating leukodystrophies – Myelin forms normally but degenerates over time.

These disorders differ from other demyelinating diseases such as multiple sclerosis, which are usually autoimmune or toxic in nature rather than congenital.

Signs and Symptoms

Symptoms of leukodystrophies vary by type and age of onset, but generally include:

• Neuromuscular symptoms:
• Muscle rigidity (spasticity)
• Loss of motor control and coordination (ataxia)
• Progressive muscle weakness
• Swallowing difficulty (dysphagia)

• Cognitive and behavioral changes:
• Cognitive decline
• Loss of developmental milestones in children
• Hyperirritability and hypersensitivity to stimuli

• Sensory deficits:
• Vision loss (optic atrophy)
• Hearing impairment
• Epileptic seizures

• Advanced stage complications:
• Respiratory failure
• Loss of voluntary movements
• Vegetative state in severe cases

Causes

Leukodystrophies are caused by genetic mutations affecting enzymes or proteins critical for myelin metabolism. The inheritance patterns include:

• Autosomal recessive (e.g., Krabbe disease, metachromatic leukodystrophy)
• X-linked recessive (e.g., X-linked adrenoleukodystrophy)
• Autosomal dominant (e.g., Adult-onset leukodystrophy)
• De novo mutations (e.g., Alexander disease)

These mutations lead to:

• Toxic accumulation of metabolites (e.g., very-long-chain fatty acids in adrenoleukodystrophy)
• Defective lysosomal enzyme function (e.g., arylsulfatase A deficiency in metachromatic leukodystrophy)
• Abnormal myelin formation (e.g., Pelizaeus–Merzbacher disease)

Types of Leukodystrophies

There are over 30 different types of leukodystrophies. The most well-studied forms include:

• Metachromatic leukodystrophy (MLD) – Caused by deficiency of arylsulfatase A, leading to sulfatide accumulation and progressive demyelination.
• Krabbe disease – Due to GALC gene mutation, causing toxic buildup of psychosine and loss of oligodendrocytes.
• Adrenoleukodystrophy (ALD) – Affects peroxisomal metabolism of very long chain fatty acids, leading to brain inflammation and demyelination.
• Canavan disease – Caused by mutation in the ASPA gene, leading to N-acetylaspartic acid accumulation and myelin disruption.
• Alexander disease – Associated with mutations in the GFAP gene, leading to astrocyte dysfunction and myelin loss.
• Vanishing white matter disease (VWM) – Affects eukaryotic initiation factor 2B (eIF2B), causing chronic white matter degradation.
• Pelizaeus–Merzbacher disease – X-linked disorder affecting proteolipid protein 1 (PLP1), leading to defective myelin formation.

Diagnosis

Diagnosis is made using:

• Magnetic resonance imaging (MRI) – Detects white matter abnormalities.
• Genetic testing – Identifies specific mutations.
• Nerve conduction studies – Differentiate leukodystrophy from other demyelinating conditions.
• Biochemical assays – Measure levels of enzymes or toxic metabolites.

Treatment

Currently, there is no cure for leukodystrophies, but treatment focuses on slowing progression and managing symptoms.

Potential Therapies: 1. Hematopoietic stem cell transplantation (HSCT):

• Used for X-ALD and MLD.
• Slows disease progression, especially if performed before symptom onset.

2. Gene therapy:

• Lentiviral gene therapy is being tested for X-ALD and MLD.
• Experimental stage for other leukodystrophies.

3. Enzyme replacement therapy (ERT):

• Potential treatment for Krabbe disease and MLD.
• Difficulty: Blood-brain barrier limits enzyme delivery.

4. Symptomatic management:

• Physical therapy for spasticity.
• Anti-seizure medications for epilepsy.
• Nutritional support for swallowing difficulties.

Prognosis

• Infantile-onset forms (e.g., Krabbe disease, MLD) → Severe progression and short life expectancy (2–10 years).
• Juvenile and adult-onset forms → Slower progression; patients may survive decades with supportive care.
• Stem cell and gene therapy have shown promising results in early-diagnosed cases.

See Also

• Leukoencephalopathy
• Neurodegeneration
• Myelin sheath
• Neurological disorders

External Links

• MLD Foundation – Metachromatic Leukodystrophy Resources
• Global Leukodystrophy Initiative
• World Leukodystrophy Alliance

NIH genetic and rare disease info

• NIH info on Leukodystrophy

Leukodystrophy is a rare disease.