Generally, it is not difficult to differentiate these diseases from the acquired postinfectious variety that occurs predominantly in children (see Chap. 36).
Metachromatic Leukodystrophy (MLD, Arylsulfatase Deficiency, ARSA Mutation)
This is another of the lysosomal (sphingolipid) storage diseases (see Tables 36-3 and 36-6). The abnormality is the mutation of the gene for enzyme arylsulfatase A (ARSA), which prevents the conversion of sulfatide to cerebroside (a major component of myelin) and results in an accumulation of the former. The disease is transmitted as an autosomal recessive trait and usually becomes manifest between the first and fourth years of life (variants have their onset in the congenital period, in late childhood, and even in adult life). Variability of gene mutation accounts for the different forms. A less frequent form is due to a mutation in PSAP, which also results in the inability to break down sulfatides.
The disease in this age group is characterized clinically by progressive impairment of motor function (gait disorder, spasticity) in combination with reduced output of speech and mental regression. At first the tendon reflexes are usually brisk, but later, as the peripheral nerves become more involved, the tendon reflexes are decreased and eventually lost. Or, there may be variable hypotonia and areflexia from the beginning, or spasticity may be present throughout the illness, but with hyporeflexia and slowed conduction velocities. Signs of mental regression may be apparent from the onset or appear after the motor disorder has become established. Later there is impairment of vision, sometimes with squint and nystagmus; intention tremor in the arms and dysarthria; dysphagia and drooling; and optic atrophy (one-third of patients), sometimes with grayish degeneration around the maculae. Seizures are rare, and there are no somatic abnormalities. The head size is usually normal, but rarely there is macrocephaly. Progression to a bedridden quadriplegic state without speech or comprehension occurs over a 1to 3-year period, somewhat more slowly in late-onset types. The CSF protein is elevated.
There is widespread degeneration of myelinated fibers in the cerebrum (Fig. 36-5), cerebellum, spinal cord, and peripheral nerves. The presence of metachromatic granules in glia cells and engorged macrophages is characteristic and enables the diagnosis to be made from a biopsy of a peripheral nerve. The stored material, sulfatide, stains brown-orange rather than purple with aniline dyes. Sulfatides are also PAS-positive in frozen sections.
Genetic testing is now widely available but the diagnostic laboratory findings, in addition to the MRI and histologic changes, are the elevated CSF protein (75 to 250 mg/dL) and a marked increase in sulfatide in urine and an absence of arylsulfatase A in white blood cells, in serum, and in cultured fibroblasts. Assays of arylsulfatase A activity in cultured fibroblasts and amniocytes permit the identification of carriers and prenatal diagnosis of the disease but a pseudodeficiency of the enzyme is known (the Pd allelic variant). In this condition, measured enzyme activity is 10 percent of normal, but no clinical manifestations result.
Treatment with enzyme replacement or bone marrow transplantation is being tried. Marrow transplant appears to be of less benefit once the patient becomes symptomatic, but it may be useful early in the disease and in the treatment of an asymptomatic sibling of an index case.