Clinical Information

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by a deficiency of the arylsulfatase A enzyme, which leads to the accumulation of galactosyl sulfatide (cerebroside sulfate) in the white matter of the central nervous system and in the peripheral nervous system. Deficiency of the arylsulfatase A enzyme leads to the accumulation of sulfatides (both galactosyl and lactosyl sulfatide) in the white matter of the central nervous system, the peripheral nervous system, and visceral organs including the kidney and gallbladder. Patients with MLD excrete excessive amounts of sulfatides in their urine.

The 3 clinical forms of MLD are late-infantile, juvenile, and adult, which are categorized based on age of onset. All forms result in progressive neurologic changes and leukodystrophy demonstrated on magnetic resonance imaging. Late-infantile MLD is the most common (50%-60% of cases) and typically presents between 6 months to 2 years of age with hypotonia, clumsiness, diminished reflexes, and slurred speech. Progressive neurodegeneration occurs with most patients dying within 5 years of the diagnosis. Juvenile MLD (20%-30% of cases) is characterized by onset between 4 to 14 years. Typical presenting features are behavior problems, declining school performance, clumsiness, and slurred speech. Neurodegeneration occurs at a somewhat slower and more variable rate than the late-infantile form. Adult MLD (15%-20% of cases) has an onset after puberty and can be as late as the fourth or fifth decade. Presenting features are often behavior and personality changes, including psychiatric symptoms. Clumsiness, neurologic symptoms, and seizures are also common. The disease course has variable progression and may occur over 2 to 3 decades. The disease prevalence is estimated to be approximately 1 in 100,000.

MLD is an autosomal recessive disorder and is caused by mutations in the ARSA gene coding for the arylsulfatase A enzyme. This disorder is distinct from conditions caused by deficiencies of arylsulfatase B (Maroteaux-Lamy disease) and arylsulfatase C (steroid sulfatase deficiency). Saposin B deficiency can have an identical clinical presentation to MLD but arylsulfatase A enzyme level is normal; however, patients with saposin B deficiency also excrete excessive amounts of sulfatides in their urine.

Extremely low arylsulfatase A levels have been found in some clinically normal parents and other relatives of MLD patients. These individuals do not have metachromatic deposits in peripheral nerve tissues, and their urine content of sulfatide is normal. Individuals with this "pseudodeficiency" have been recognized with increasing frequency among patients with other apparently unrelated neurologic conditions as well as among the general population. This has been associated with fairly common polymorphisms in the ARSA gene, which leads to low expression of the enzyme (5%-20% of normal). These patients can be difficult to differentiate from actual MLD patients. Additional studies, such as molecular genetic testing of ARSA (ARSAZ / ARSA Gene, Full Gene Analysis), urinary excretion of sulfatides (CTSA / Ceramide Trihexosides and Sulfatides, Urine), and/or histological analysis for metachromatic lipid deposits in nervous system tissue are recommended to confirm a diagnosis.

Current treatment options for MLD are focused on managing disease manifestations such as seizures. Bone marrow transplantation remains controversial, and the effectiveness of enzyme replacement therapy may be limited due to difficulties crossing the blood-brain barrier. Other treatments under ongoing investigation include hematopoietic stem cell transplantation and fetal umbilical cord blood transplantation.