Metachromatic leukodystrophy among the Navajo Indians: A study of the arylsulfatase A gene mutations present in this population
Metachromatic leukodystrophy (MLD) is an autosomal recessive disorder of myelin metabolism, resulting from the inability to properly degrade 3-sulfo-galactosylceramide (sulfatide). This metabolic block is often due to defective functioning of the lysosomal enzyme arylsulfatase A (ARSA). Unmetabolized sulfatide accumulates in the white matter of the central nervous system (CNS) and in the peripheral nerves, leading to progressive demyelination and death. Late infantile, juvenile and adult clinical variants of MLD have been described. A Navajo Indian child was diagnosed with late infantile MLD (LIMLD), and his ARSA gene was amplified by the polymerase chain reaction (PCR) and sequenced. A single mutation was found: a G $\to$ A transition at the first nucleotide of intron 4 (IVS4nt1) which abolishes the 5$\sp\prime$ splice site consensus sequence. This mutation had never previously been reported. Negligible amounts of ARSA mRNA were observed in Northern blots. However, PCR amplification and sequencing of the complementary DNA (cDNA) showed that all ARSA transcripts from the patient have exon 4 deleted, resulting in a premature stop codon within exon 5. In addition, splicing intermediates and other aberrantly spliced mRNA species were detected. Both parents carry this mutation and the father also carries the common pseudodeficiency (PD) allele. Three additional unrelated Navajo LIMLD patients were found to be homozygous for the IVS4nt1 mutation by allele specific oligonucleotide (ASO) hybridization and/or cycle sequencing. Family members of affected Navajo children were found to be carriers of this mutation, and the pseudodeficient mother of an affected child was also a carrier of the common PD allele. The source of genomic DNA for PCR amplification only needed to be a drop of blood dried onto filter paper. The IVS4nt1 allele appeared to be unique to the Navajo until an Eskimo child with MLD was found to be homozygous for this mutation. Her parents and three unaffected siblings carried this mutation while a fourth asymptomatic sibling was also homozygous. The healthy mother had low ARSA activity but was not a carrier of the common PD allele. Rapid DNA-based diagnostic methods could be used for carrier and patient identification in these populations.
Pastor-Soler, Nuria Maria, "Metachromatic leukodystrophy among the Navajo Indians: A study of the arylsulfatase A gene mutations present in this population" (1996). ETD Collection for Thomas Jefferson University. AAI9625293.