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Lysosomal enzyme deficiencies may be sought in serum or plasma, in leukocytes (white cell pellet) or in cultured fibroblasts.
Although it is evident that there is great variation in the severity of the neurological disorders which may result from a severe lysosomal enzyme deficiency, extreme caution is necessary when partial deficiency is found, particularly 'within the heterozygous range', since in some of these disorders the prevalence of heterozygosity is quite high in the normal population.
The term 'pseudodeficiency' is used in lysosomal storage diseases to denote the situation in which individuals show greatly reduced enzyme activity but remain clinically healthy. Pseudodeficiencies have been reported for several lysosomal hydrolases. Pseudodeficiency is particularly important in relation to arylsulphatase A (ARSA), which is the enzyme classically deficient in metachromatic leukodystrophy (MLD). In pseudo-MLD, patients will not have the appropriate clinical features, and although they have ARSA levels of 10-15% of the normal mean, they do not have excess urinary sulphatides or toluidine blue staining metachromatic granules in urine (second morning specimen).
Genetic testing for the genes involved is often possible.
Considerations of sensitivity and specificity should prevent, for example, the diagnosis of MLD in a child with primary generalized epilepsy or isolated dystonia with heterozygous levels of ARSA. These clinical presentations would be inappropriate indications for assay of this enzyme, but having obtained a low result the clinician may feel bound to pursue the diagnosis by culturing fibroblasts and searching for sulphatide in urinary sediment and in sural nerve biopsy. Such temptations should be strongly resisted.
A further consideration is activator protein deficiency, best known in the case of MLD. The catabolism of sulphatide requires both the enzyme ARSA and a specific sphingohpid activator protein, saposin-B, encoded by the prosaposin gene (PSAP). ARSA activity is deficient in the classical forms of MLD, but a substantial proportion of cases of MLD are due to saposin-B deficiency with mutations in the PSAP gene and thus have normal ARSA but markedly increased urinary excretion of sulphatides.
