Metachromatic Leukodystrophy

Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disorder that affects myelin in the brain and spinal cord. Genetic mutations result in the creation of a dysfunctional arylsulfatase A (ARSA) enzyme, which is unable to break down cerebroside sulfate. The accumulation of this metabolite results in permanent damage to oligodendroglial and Schwann cells (myelin) in both the central and peripheral nervous systems. Patients can present with seizures, weakness, and behavioral and personality changes. Blood enzyme and urine testing for ARSA-A and sulfatides, respectively, are the best diagnostic tests. Treatment is challenging and usually focuses on relieving symptoms, although new gene therapies are available for specific subgroups of MLD patients. Serious complications include dementia and seizures.

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Metachromatic leukodystrophy (MLD) is an autosomal recessive white matter disease caused by a deficiency in arylsulfatase A resulting in accumulation of cerebroside sulfate. This accumulation leads to the destruction of myelin and causes neurologic deficits.


Based on age at symptom onset:

  • Late infantile form
  • Juvenile form
  • Adult form


  • Rare, autosomal recessive inherited condition
  • Incidence: 1 in 40,000 live births in the United States
  • No racial or sexual predilection
  • Most common form of inherited leukodystrophy


  • Caused by deficiency in gene for arylsulfatase A (ARSA): 
    • Gene located on chromosome 22 (22q13.31qter).
    • Function of ARSA: hydrolyzes sulfated glycosphingolipids
  • Pseudodeficiency: partial loss of enzyme activity; no clinical consequences
  • MLD can also be caused by deficiency in sphingolipid activator protein B (SAP-B) deficiency. SAP-B acts with ARSA to hydrolyze sulfated glycosphingolipids.


  • Deficiency in ARSA activity → excessive white matter storage of sulfated glycosphingolipids
  • Accumulate in oligodendrocytes, macrophages, and other subtypes of neurons
  • Results in demyelination and neurodegeneration

Clinical Presentation

Late infantile form

  • Most common (50% of cases)
  • Age at presentation: < 30 months
  • Symptoms:
    • Initial developmental milestones are met and then progressively lost.
    • Regression of motor skills
    • Seizures
    • Hypotonia
    • Extensor plantar posturing
    • Optic atrophy
  • Patients die at < 5 years of life if untreated.

Juvenile form

  • Age at presentation: 3 to < 16 years
  • Symptoms:
    • Initial developmental milestones are met and then progressively lost.
    • Intellectual regression
    • Behavioral and personality changes
    • Peripheral neuropathy
    • Patients presenting at later ages often have seizures
  • Death usually occurs < 2 decades after symptom onset.

Adult form

  • Similar to juvenile form but more protracted course 
  • Age at presentation: > 20 years
  • Slow progression
  • Symptoms:
    • Dementia
    • Seizures
    • Diminished reflexes
    • Optic atrophy


Consider diagnostic testing in patients expressing typical clinical features.

  • Diagnosis is confirmed with biochemical, urine, and genetic analysis:
    • Decreased or absent ARSA activity in leukocytes or cultured skin fibroblasts
    • Increased urinary sulfatide secretion (Patients with pseudodeficiency have normal secretion.)
    • Genetic analysis for common mutations
  • Brain MRI is diagnostic adjunct and may show: 
    • Hyperintensity in periventricular white matter
    • Hyperintensity in subcortical supratentorial white matter
  • Electroneurographic recordings show decreased nerve conduction velocities.
  • Other results consistent with MLD but not required for diagnosis:
    • Increased CSF protein
    • Metachromatic deposits in sural nerve
    • Metachromatic granules in urinary sediment
Tigroid pattern in MLD

Brain MRI of a patient with metachromatic leukodystrophy:
Brain MRI showing hyperintensity in periventricular white matter (A) and in subcortical supratentorial white matter (B) can help confirm laboratory diagnosis of metachromatic leukodystrophy.

Image: “Tigroid pattern” by Department of Diagnostic Imaging, Hospital for Sick Children, University of Toronto, 555, University Avenue, Toronto, Ontario M5G 1X8, Canada. License: CC BY 2.0


No curative therapy for MLD is widely available. Umbilical cord blood transplantation for children with presymptomatic late-infantile MLD or minimally symptomatic juvenile MLD can slow disease progression.

Supportive therapy is preferred for patients with symptoms and for all patients with juvenile and late-onset forms MLD:

  • Seizure prophylaxis with antiepileptics (e.g., levetiracetam) 
  • Treatment for spasticity (e.g., with baclofen)
  • Mood/behavioral issues should be addressed with behavioral therapy and medication (e.g., antidepressants).

Clinical trials of recombinant human arylsulfatase A (rhARSA) enzyme demonstrated its safety in children with late-infantile MLD.

Differential Diagnosis

  • Krabbe disease: autosomal recessive lysosomal storage disease caused by deficiency in beta-galactosidase (GALC). Krabbe disease can present during all stages of life. All patients present with peripheral motor-sensory neuropathy. Common symptoms also include irritability, hypertonia, hyperesthesia, hypotonia, and abnormal deep tendon reflexes. Diagnosis is confirmed through GALC enzyme activity.
  • X-linked adrenoleukodystrophy: X-linked disorder of peroxisomes caused by mutations in ATP-binding cassette, subfamily D, member 1 gene (ABCD1) that results in accumulation of very-long-chain fatty acids in most tissues of the body. Patients present with adrenal insufficiency, decreased cognition, behavioral issues, vision and hearing impairment, and dysarthria. Brain MRI and genetic testing is diagnostic.
  • Canavan disease: progressive neurodegenerative autosomal recessive leukodystrophy seen primarily in Ashkenazi Jewish populations. Canavan disease is caused by aspartoacylase deficiency. Symptoms include spasticity, ataxia, seizures, hypotonia, and optic atrophy. Diagnosis is confirmed by discovering elevated levels of N-acetyl aspartate (NAA) in urine and abnormal diffuse white matter disease on MRI.


  1. Biffi, A., Lucchini, G., Rovelli, A., et al. (2008). Metachromatic leukodystrophy: an overview of current and prospective treatments. Bone Marrow Transplant 42:2–6.
  2. Hohenschutz, C., Eich, P., Friedl, W., Waheed, A., Conzelmann, E., Propping, P. (1989). Pseudodeficiency of arylsulfatase A. Hum Genet 82:45–48.
  3. U.S. National Library of Medicine. Metachromatic leukodystrophy. MedlinePlus. Retrieved April 27, 2021, from
  4. Friede, R. L. (1975). Metachromatic leukodystrophy (sulfatase A deficiency) and multiple sulfatase deficiency. In: Developmental Neuropathology. Vienna: Springer.

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