Research developments on lysosomal disorders: Metachromatic leukodystrophy and Gaucher disease

Patients with lysosomal disorders constitute a significant number of people who have symptoms due to the storage of undegraded substrates. Two of the most common, Gaucher disease and metachromatic leukodystrophy (MLD), can be diagnosed by measuring glucocerebrosidase and arylsulfatase A activity, respectively, in an easily obtained tissue sample. However, problems with the accurate identification of patients and carriers result from the occurrence of patients who have normal enzyme levels but are missing a required sphingolipid activator protein, and from the high incidence of an allele that causes low in vitro arylsulfatase A activity. These problems can be resolved in the laboratory if adequate information and a correct sample is available for analysis. Although DNA analysis for the pseudodeficiency allele can be useful in some families with MLD, in others ¹⁴C-sulfatide loading is required for accurate genotyping. Mutations in the prosaposin gene have been clearly implicated in some patients with MLD and Gaucher disease who have normal enzymatic activities. Patients with these disorders have been treated with bone marrow transplantation and enzyme replacement therapy with measurable success. However, treatment requires accurate diagnosis that may not be possible with simple enzyme-based assays. Methods are currently available to aid in diagnosing typical and atypical patients and in predicting clinical severity in a newly diagnosed patient.