Disease-causing mutations in cis with the common arylsulfatase A pseudodeficiency allele compound the difficulties in accurately identifying patients and carriers of metachromatic leukodystrophy.

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder most often caused by mutations in the sulfatide sulfatase or arylsulfatase A (ASA) gene. This results in the storage of sulfatides in the peripheral and central nervous systems as well as in the kidneys. Patients with MLD exhibit a wide range of clinical features presenting from the late infantile period to adulthood. Testing for this disease is performed on a majority of the patient samples received for diagnostic testing in the authors' laboratory. If low ASA activity is measured, additional testing is required to confirm the diagnosis due to several factors. ASA activity is also low in individuals with multiple sulfatase deficiency and in individuals with copies of the so-called pseudodeficiency (Pd) allele. Due to the high frequency of the common Pd allele, it is possible for individuals, both with and without neurologic disease, to have low ASA activity but not have MLD. Unfortunately, the finding of the Pd mutation by molecular analysis does not rule out a diagnosis of MLD. In a recent 25 month period, this laboratory diagnosed 52 patients with MLD, and of these, 13 patients from 10 families had one or two copies of the Pd mutation. Sequencing of the ASA gene in these 10 families revealed four new mutations in cis with the Pd allele (S43R, R84Q, R311X, and E329R) and two additional new mutations (R299W, C488R). Six patients had previously reported mutations on the Pd background. Thus, a total of 14 mutations have been found to occur in cis with the Pd allele. We estimate that 1-2% of Pd alleles will have a disease-causing mutation, and this complicates the identification of patients and the assignment of risk for a couple when a copy of the Pd allele is detected.