Metachromatic leukodystrophy (MLD) is an autosomal recessively inherited disorder in which the desulfation of 3-0-sulfogalactosyl-containing glycolipids is defective. Desulfation of the 3-0-sulfogalactosyl residues depends on the combined action of arylsulfatase A (ASA) and saposin B, a nonenzymatic activator protein. MLD is caused by the deficiency either of ASA or, more rarely, of saposin B. Sulfated glycolipids occur in the myelin sheaths of 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 ofMLD are dominated by the demyelination observed in the central and peripheral nervous system.
The clinical onset and severity of MLD show great variation. Three major forms of MLD are usually distinguished based on the age of onset. First, a late infantile form with onset of clinical symptoms before 30 months of age and fatal in childhood; second, a juvenile form with onset between 2 1/2 and 16 years; and third, an adult form with onset after 16 years of age. In the late infantile form, which is the most frequent form children develop, symptoms usually appear in the second year of life after an initially normal development. Symptoms involve gait problems due to neuropathy, spasticity, and ataxia accompanied by mental regression. Disease course is highly invariable and stereotypic and leads to a complete loss of motor function usually before the age of 3 ½ years. Deterioration of gross motor function in juvenile MLD is more variable with respect to age range and dynamics. There may be impaired fine motor skills, concentration and behavioral problems as first symptoms. However, once loss of independent walking occurs in juvenile patients, their gross motor function declines as rapidly as in the late infantile form. In the adult forms, psychotic symptoms and behavioral abnormalities often precede or accompany a decline in intellectual capacities and motor function, leading to the misdiagnosis of a psychosis.
Demonstration of reduced nerve conduction velocity and of demyelination by magnetic resonance imaging (MRI) are the major laboratory findings. On MRI central white matter is early affected with typically butterfly-shaped confluent white matter hyperintensities on T2w with a characteristic tigroid pattern. Regardless of the type of disease, corpus callosum is involved early. White matter changes on MRI clearly precede the onset of clinical symptoms in juvenile and adult MLD. As the disease progresses, there is increasing white matter involvement including U-fibers and involvement of cerebellar white matter as well as cerebral atrophy.
More than 160 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 ...