Complications in the genotypic molecular diagnosis of pseudo arylsulfatase A deficiency

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Abstract
Metachromatic leukodystrophy (MLD) is a severe neurodegenerative disease associated with deficient arylsulfatase A activity. Biochemical confirmation of this disorder has been complicated by a clinically normal but enzymatically deficient variant, pseudo arylsulfatase‐A deficiency (PD). The PD mutation is associated with two A→G transitions in the arylsulfatase A gene. They can be detected simultaneously with a recently developed 3′‐mismatch polymerase chain reaction, hence providing a rapid method for genotypic identification and resolving ambiguities of carrier identification based solely on enzyme analyses. However, we now report further genotypic complexities in the molecular diagnosis of PD due to the occurrence of another variant in which only one of the two A→G mutations of the PD allele was present. This variant confers reduced but readily detectable enzyme activity and behaves as a silent allele in the 3′‐mismatch polymerase chain reaction, thus leading to conflicting and erroneous genotype assignments in a family in which both variants and MLD co‐exist. The inconsistency was resolved after pedigree validation and further molecular analyses in which the two A→G mutations were assayed separately with allele‐specific oligonucleotides. Because arylsulfatase A analysis is one of the most commonly requested lysosomal enzyme assays and the PD mutant allele frequency is high in the general population, complexities as described in this family may be a recurrent problem that can be solved only with combined enzymatic and detailed molecular analyses.