Makindo Medical Notes

🧬 Metachromatic Leukodystrophy (MLD) is an autosomal recessive lysosomal storage disorder. It results from a deficiency of the enzyme arylsulfatase A, causing toxic accumulation of sulfatides. This leads to progressive demyelination of the central and peripheral nervous systems.

📖 About

• Also called Arylsulfatase A deficiency.
• Sulfatide accumulation damages oligodendrocytes (CNS) and Schwann cells (PNS), leading to widespread white matter loss.
• Named "metachromatic" because accumulated sulfatides stain a different (meta-) colour with certain dyes 🔬.

🧬 Aetiology

• Mutations in the ARSA gene (chromosome 22q13) → ↓ Arylsulfatase A activity.
• Rarely due to mutations in PSAP gene (encodes saposin B, a cofactor).
• Inheritance: Autosomal recessive.

🧒 Clinical Features

• Onset types:
  • 👶 Late-infantile (most common, severe):
    • Onset at 1–2 years with motor regression, gait disturbance, hypotonia → spasticity
    • Optic atrophy → blindness
    • Seizures, peripheral neuropathy, developmental arrest
    • Death usually within first decade
  • 🧒 Juvenile form:
    • Onset 4–12 years
    • School difficulties, behavioural changes
    • Progressive motor dysfunction, seizures
  • 🧑 Adult form:
    • Psychiatric features (depression, psychosis, personality change)
    • Dementia, peripheral neuropathy
    • Slower progression, survival into adulthood

🔬 Investigations

• 🧪 Arylsulfatase A enzyme assay: Low activity in leukocytes or fibroblasts (diagnostic).
• 🧬 Genetic testing: Confirms ARSA mutations; allows carrier & prenatal diagnosis.
• 💧 Urinary sulfatides: Elevated levels.
• 🧫 Histology: Metachromatic deposits in nerve biopsies with toluidine blue staining.
• 🧠 MRI brain: Symmetrical periventricular white matter changes (tigroid pattern of demyelination).

🩹 Management

• 💊 Supportive care: Anti-seizure drugs, physiotherapy, speech and occupational therapy.
• 🧵 Bone marrow / stem cell transplantation: May slow progression if done early in juvenile/adult forms.
• 🧬 Gene therapy: Experimental; early trials show promise for long-term correction.
• 💉 Enzyme replacement therapy (ERT): Recombinant arylsulfatase A in development.
• 🌱 Palliative care: For advanced disease, focus on comfort and quality of life.

📊 Prognosis

• Late-infantile: Rapid progression, death in childhood.
• Juvenile: Slower but still progressive, survival into adolescence/young adulthood.
• Adult: Variable, may live decades with psychiatric/neurodegenerative course.

📚 References

• NORD – Metachromatic Leukodystrophy
• Gieselmann V. Metachromatic Leukodystrophy. In: Adam MP et al., GeneReviews, 2019.