Coincidence of two novel arylsulfatase A alleles and mutation 459+1G > A within a family with metachromatic leukodystrophy: Molecular basis of phenotypic heterogeneity

In a family with three siblings, one developed classical late infantile met achromatic leukodystrophy (MLD), fatal at age 5 years, with deficient aryls ulfatase A (ARSA) activity and increased galactosylsulfatide (GS) excretion . The two other siblings, apparently healthy at 12 1/2 and 15 years, respec tively, and their father, apparently healthy as well, presented ARSA and GS values within the range of MLD patients. Mutation screening and sequence a nalysis disclosed the involvement of three different ARSA mutations being t he molecular basis of intrafamilial phenotypic heterogeneity. The late infa ntile patient inherited from his mother the frequent 0-type mutation 459 1G>A, and from his father a novel, single basepair microdeletion of guanine at nucleotide 7 in exon 1 (7delG), The two clinically unaffected siblings carried the maternal mutation 459+1G>A and, on their paternal allele, a nov el cytosine to thymidine transition at nucleotide 2435 in exon 8, resulting in substitution of alanine 464 by valine (A464V). The fathers genotype thu s was 7delG/ A464V, Mutation A464V was not found in 18 unrelated MLD patien ts and 50 controls. A464V although clearly modifying ARSA and GS levels, ap parently bears little significance for clinical manifestation of MLD, mimic king the frequent ARSA pseudodeficiency allele, Our results demonstrate that in certain genetic conditions MLD-like ARSA an d GS values need not be paralleled by clinical disease, a finding with seri ous diagnostic and prognostic implications. Moreover, further ARSA alleles functionally similar to A464V might exist which, together with 0-type mutat ions, may cause pathological ARSA and GS levels, but not clinical outbreak of the disease. Hum Mutat 13:61-68, 1999. (C) 1999 Wiley-Liss, Inc.