At the locus for arylsulfatase A (ASA) at least four to five alleles exist: besides the normal ASA+ and at least two to three deficiency alleles (ASA-), a pseudodeficiency allele, ASAp, is known. On SDS-PAGE the ASAp enzyme migrates slightly faster than ASA+. Treatment of extracts from cells with ASA+/ASA+, ASAp/ASAp, or ASA+/ASAp genotypes with endoglycosidase F leads to the same deglycosylated subunit pattern. Presumably the degree of glycosylation is lower in ASAp than in ASA+. In a large-scale screening project we determined a gene frequency of 7.3% for ASAp. Thus, the ASA locus is polymorphic. In seven families, ASAp showed a codominant mode of inheritance with ASA+. Homozygosity for ASAp has no obvious clinical consequences. In subjects with the compound genotype ASA-/ASAp, the residual enzyme activity may fall below a critical threshold, so that the substrate can no longer be hydrolyzed sufficiently. Since these compounds are not so rare (estimated frequency 0.073%), this mechanism could be of importance in neuropsychiatric disorders with late onset.

Metachromatic leukodystrophy (MLD) is an autosomal recessive progressive demyelination disorder caused by the deficiency of arylsulfatase A (ASA). However, there exist individuals with low ASA activity without clinical symptoms. This state is described as ASA pseudodeficiency (PD). A number of patients with low ASA activity and various neuropsychiatric symptoms have been observed. It is controversial to what extent low ASA activity predisposes for neurological and/or psychiatric symptomatology. Therefore, persons with low ASA activity who were collected from a large-scale screening among neuropsychiatric patients and healthy controls are presently being extensively evaluated using biochemical, genetic, and clinical methods. Here we present a female patient, who had been first hospitalized with the diagnosis encephalomyelitis disseminata. Her ASA activity determined in fibroblast extracts is intermediate between adult MLD and PD. Sulfatide degradation in cultured fibroblasts is diminished. The subunit pattern obtained after SDS-polyacrylamide gel electrophoresis and immunoblotting was determined in the index patient and 2 sibs. It is compatible with a compound genotype ASA-/ASAp in the index case. It appears probable that in this patient low ASA activity leads to the accumulation of sulfatide and either causes the appearance of neuropsychiatric symptoms or at least contributes to the demyelination process.

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