RESUMO
Metachromatic leukodystrophy is a neurodegenerative disease that is characterized by a deficiency of arylsulfatase A, resulting in the accumulation of sulfatide and other lipids in the lysosomal network of affected cells. Accumulation of sulfatide in the nervous system leads to severe impairment of neurological function with a fatal outcome. Prognosis is often poor unless treatment is carried out before the onset of clinical symptoms. Pre-symptomatic detection of affected individuals may be possible with the introduction of newborn screening programs. The ability to accurately predict clinical phenotype and rate of disease progression in asymptomatic individuals will be essential to assist selection of the most appropriate treatment strategy. Biochemical profiling, incorporating the determination of residual enzyme protein/activity using immune-based assays, and metabolite profiling using electrospray ionization-tandem mass spectrometry, was performed on urine and cultured skin fibroblasts from a cohort of patients representing the clinical spectrum of metachromatic leukodystrophy and on unaffected controls. Residual enzyme protein/activity in fibroblasts was able to differentiate unaffected controls, arylsulfatase A pseudo-deficient individuals, pseudo-deficient compound heterozygotes and affected patients. Metachromatic leukodystrophy phenotypes were distinguished by quantification of sulfatide and other secondarily altered lipids in urine and skin fibroblasts; this enabled further differentiation of the late-infantile form of the disorder from the juvenile and adult forms. Prediction of the rate of disease progression for metachromatic leukodystrophy requires a combination of information on genotype, residual arylsulfatase A protein and activity and the measurement of sulfatide and other lipids in urine and cultured skin fibroblasts.