Clinical Information

Metachromatic leukodystrophy (MLD) is a lysosomal 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. To date, late-infantile MLD is most commonly diagnosed (50%-60% of cases) and usually presents before 30 months of age with hypotonia, clumsiness, diminished reflexes, and dysarthric 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.

Metachromatic leukodystrophy is an autosomal recessive disorder caused by disease-causing 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, ARSA activity is not deficient. 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 ARSA, 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 has been found among patients with other 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. While sulfatides appear to be elevated in newborn dried blood spots and is used as a primary newborn screening test, the utility of sulfatide analysis in dried blood spots outside of newborn screening has not been determined.

Current treatment options for MLD depend on the clinical stage and presence of neurologic symptoms. Allogenic hematopoietic stem cell transplant can treat symptoms related to the central nervous system in pre- and very early-symptomatic juvenile- or adult-onset MLD. Recently, autologous hematopoietic stem cell-based gene therapy has been approved in the U.S. and elsewhere for individuals with presymptomatic late-infantile MLD, presymptomatic juvenile MLD, or early-symptomatic juvenile MLD with maintained ability to walk and before the onset of cognitive decline.

Early diagnosis is extremely important to achieve optimal outcomes, especially for patients with late-infantile and early juvenile MLD. Therefore, newborn screening for MLD has been proposed and has recently been implemented in Norway, Austria, and parts of Germany. The approach entails measurement of sulfatides in the newborns dried blood spot followed by measurement of ARSA activity as a second-tier test when sulfatides are elevated. In the United States, New York is the first state to provide routine newborn screening for MLD.