Metachromatic leukodystrophy (MLD) is an autosomal recessive sulfatide storage disease, classically due to deficiency of the lysosomal enzyme arylsulfatase A (ASA). Normally, ASA initiates the degradation of sulfatides (3-O-sulfogalactosylceramides), which are an essential component of myelin. A genotype-phenotype correlation has been established based on the two functionally different types of mutations: mutations encoding inactive ASA (0-alleles) and mutations encoding ASA with residual enzymatic activity (R-alleles). Genotypes comprising two 0-alleles will cause the severe late infantile type of MLD. Coincidence of a 0-allele and an R-allele induces predominantly the intermediate juvenile type, whereas two R-alleles usually cause the milder adult type of MLD, although juvenile and adult forms of MLD rather seem to form a continuum based on specific mutations as well as other, still unknown, genetic, epigenetic, and environmental factors.
In cooperation with Nicole Baumann (INSERM U711 Universite Pierre et Marie Curie, Paris, France), Volkmar Gieselmann (Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany), Hugo and Ann Moser (Johns Hopkins University, Baltimore, USA), Tylki-Szymanska (Childrens Memorial Health Institute, Warszawa, Poland) and many other MLD centers, we have collected DNA and clinical data of adult MLD patients and have selected and reviewed the clinical course of 22 patients homozygous for mutation P426L (R-allele) and 20 patients heterozygous for mutation I179S (R-allele), in all of which we could determined a second ASA mutation. P426L homozygotes principally presented with progressive gait disturbance caused by spastic paraparesis or cerebellar ataxia; mental disturbance was absent or insignificant at the onset of disease but became more apparent as the disease evolved. In contrast, compound heterozygotes for I179S presented with schizophrenia-like behavioral abnormalities, social dysfunction, and mental decline, but motor deficits were scarce. Reduced peripheral nerve conduction velocities and less residual ASA activity were present in P426L homozygotes vs I179S heterozygotes.
