Clinical Information

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by a deficiency of the enzyme arylsulfatase A (ARSA), which 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, to a lesser extent, in visceral organs including the kidney and gallbladder. Cells that produce myelin are especially affected causing the characteristic leukodystrophy seen in MLD. Patients with MLD excrete excessive amounts of sulfatides in their urine.

The 3 clinical forms of MLD are late-infantile, juvenile, and adult, depending 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 usually presents before 30 months of age with hypotonia, clumsiness, diminished reflexes, and slurred speech. Progressive neurodegeneration occurs and, unless successfully treated, most patients do not survive past childhood. Juvenile MLD (20%-30% of cases) is characterized by onset between 30 months to 16 years old. 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 caused by variants in the ARSA gene. This disorder is distinct from conditions caused by deficiencies of arylsulfatase B (Maroteaux-Lamy disease) and arylsulfatase C (steroid sulfatase deficiency). Saposin B deficiency is a rare autosomal recessive disorder with symptoms that mimic MLD; however, the ARSA enzyme level is normal. Like MLD, patients with saposin B deficiency can excrete excessive amounts of sulfatides in their urine. Individuals with multiple sulfatase deficiency, which is clinically distinct from MLD, will also have deficiency of arylsulfatase A, however, other sulfatase enzymes will also be deficient.

Individuals with "pseudodeficiency" of ARSA have very low levels of ARSA activity but are otherwise healthy. Pseudodeficiency is being recognized with increasing frequency among patients with other apparently unrelated neurologic conditions as well as among the general population, therefore a diagnosis of MLD cannot be based upon reduced ARSA activity alone To confirm a diagnosis, additional studies, such as molecular genetic testing of ARSA (CGPH / Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies; specify Gene List ID: IEMCP-WHFH2K), urinary excretion of sulfatides (CTSU / Ceramide Trihexosides and Sulfatides, Random, Urine), and/or histological analysis for metachromatic lipid deposits in nervous system tissue are recommended.

Current treatment options for MLD are focused on managing disease manifestations such as seizures, decline in mobility and cognitive ability, and feeding difficulties. Hematopoietic stem cell transplantation is an option but outcomes are dependent on the clinical stage and the presence of neurologic symptoms.