Metachromatic leukodystrophy (MLD) is an autosomal recessively inherited disorder in which the desulfation of 3-0-sulfogalactosyl-containing glycolipids is defective. These sulfated glycolipids occur in the myelin sheaths in the central and peripheral nervous system and to a lesser extent in visceral organs like kidney, gallbladder, and liver. In MLD the sulfated glycolipids accumulate in lysosomes of these tissues and are responsible for their metachromatic staining. The clinical and histopathologic manifestations of MLD are dominated by the demyelination observed in the central and peripheral nervous system.

The clinical onset and severity of MLD show great variation. The late infantile form is usually recognized in the second year of life and fatal in early childhood. The juvenile form presents between age 4 and puberty; the adult form may become clinically overt at any age after puberty. In both of these variants, gait disturbance and mental regression are the earliest signs. In the childhood variants, other common signs are blindness, loss of speech, quadriparesis, peripheral neuropathy, and seizures. In the adult, behavioral disturbances and dementia are the major presenting signs, often inducing the misdiagnosis of a psychosis. The disease may progress slowly over several decades. Demonstration of demyelination by computed tomography or magnetic resonance imaging and reduced nerve conduction velocity are the major laboratory findings.

Desulfation of the 3-0-sulfogalactosyl residues in glycolipids depends on the combined action of arylsulfatase A (ASA) and saposin B, a nonenzymatic activator protein. Deficiency either of ASA or, more rarely, of saposin B causes MLD.

More than 60 different mutations have been characterized in the ASA gene. Only a few mutations occur with high frequency. Homozygosity for null alleles is the cause of the late infantile form of MLD. In the juvenile and adult forms of MLD, one or both ASA alleles are associated with at least some residual activity. There is strong evidence that the severity of the disease correlates inversely with the residual activity of ASA.

Diagnosis of MLD is based on the clinical symptoms and laboratory findings caused by the demyelination and on demonstration of the deficiency of ASA or saposin B. Prenatal diagnosis is possible by determination of ASA activity in cultured amniotic fluid cells or chorionic villi.

The diagnosis of MLD is complicated by the facts that absence of ASA activity does not prove MLD and that its presence does not exclude it. Apparent absence of ASA activity is observed in individuals homozygous for the benign ASA pseudodeficiency allele, which encodes only 5–15 percent of residual activity. Up to 2 percent of Europeans are homozygous for the pseudodeficiency allele. The apparent residual activity that is detected with the commonly used colorimetric assays for ASA in late infantile MLD, in which no functional ASA is synthesized, is in the range of that found in individuals homozygous for the pseudodeficiency allele. The latter can be identified with DNA-based assays. A further complication arises from the fact that MLD-causing mutations occur in the pseudodeficiency allele as frequently as in the wild-type ASA allele. Normal ASA activity is observed in MLD patients with a deficiency of saposin B, because the colorimetric assay for ASA does not depend on saposin B.

There is no specific treatment for MLD. Prevention of the disease is restricted to the possibility of prenatal diagnosis and carrier identification in families with known risk or in populations with a high incidence of MLD. A mouse model for MLD has been developed, which mimics most of the biochemical alterations seen in MLD but exhibits only moderate demyelination and a mild phenotype.