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 metachromatic leukodystrophy ( MLD ) , fatal at age 5 years , with deficient arylsulfatase A ( ARSA ) activity and increased galactosylsulfatide ( GS ) excretion . The two other siblings , apparently healthy at 12 ( 1 / 2 ) and 15 years , respectively , and their father , apparently healthy as well , presented ARSA and GS values within the range of MLD patients . Mutation screening and sequence analysis disclosed the involvement of three different ARSA mutations being the molecular basis of intrafamilial phenotypic heterogeneity . The late infantile 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 novel cytosine to thymidine transition at nucleotide 2435 in exon 8 , resulting in substitution of alanine 464 by valine ( A464V ) . The fathers genotype thus was 7delG / A464V . Mutation A464V was not found in 18 unrelated MLD patients and 50 controls . A464V , although clearly modifying ARSA and GS levels , apparently bears little significance for clinical manifestation of MLD , mimicking the frequent ARSA pseudodeficiency allele . Our results demonstrate that in certain genetic conditions MLD-like ARSA and GS values need not be paralleled by clinical disease , a finding with serious diagnostic and prognostic implications . Moreover , further ARSA alleles functionally similar to A464V might exist which , together with 0-type mutations , may cause pathological ARSA and GS levels , but not clinical outbreak of the disease . .
