Interpretive Handbook

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. Galactosyl sulfatide and, to a smaller extent, lactosyl sulfatide, also accumulate within the kidney, gallbladder, and other visceral organs and are excreted in excessive amounts in the urine.

The 3 clinical forms of MLD are late-infantile, juvenile, and adult, depending on age of onset. All 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 age 1 to 2 years with hypotonia, clumsiness, diminished reflexes, and slurred speech. Progressive neurodegeneration occurs with a typical disease course of 3 to 10 years. 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).

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 a fairly common polymorphism 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.

Current treatment options for MLD are usually 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. 

Detection of metachromatic leukodystrophy.

Greatly reduced levels of arylsulfatase A in urine (<1 U/L), as well as in serum and various tissues, is seen in patients with metachromatic leukodystrophy.

Leukocytes are the preferred screening specimen for metachromatic leukodystrophy.

Due to the use of artificial substrate, this test does not reliably pick up carriers.

>1 U/L

Note: Results from this assay may not reflect carrier status because of individual variation of arylsulfatase A enzyme levels.

1. Jaeken J, Gieselmann V, von Figura K: Metachromatic leukodystrophy. In The Metabolic and Molecular Bases of Inherited Disease. Eighth edition. Edited by CR Scriver, AL Beaudet, WS Sly, et al. New York, McGraw-Hill Book Company, available at www.ommbid.com. Accessed 03/05/20132. Fluharty AL: Arylsulfatase A Deficiency. Available from URL: http://www.ncbi.nlm.nih.gov/books/NBK1130

3. Mahmood A, Berry J, Wenger D, et al: Metachromatic leukodystrophy: a case of triplets with the late infantile variant and a systematic review of the literature. J Child Neurol 2010 May;25(5):572-580.