PubMed · 1500115
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C R Banapurmath, S Kallinath, S Banapurmath, N Kesaree. 1992. Adrenoleukodystrophy.. https://pubmed.ncbi.nlm.nih.gov/1500115/
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Adrenoleukodystrophy (ALD) is an X-linked disorder that exhibits a wide range of phenotypic variability within individuals in a single family carrying the mutant allele. A 2-locus epistatic model has been proposed to explain the inheritance of the severe childhood form of ALD and the milder adult-onset adrenomyloneuropathy (AMN). Under a dominant epistatic model, a single M allele at an autosomal modifier locus ameliorates the most severe effects of the disease allele leading to the milder AMN phenotype; only males with genotype mm would have ALD. Under a recessive epistatic model, 2 copies of the M allele would be necessary to have the milder AMN phenotype. Here, we show that recurrence risks for a second affected male depend on the frequency of the protective allele at this modifier locus. Whereas it is most likely that 2 affected brothers will be concordant for their disease phenotypes, discordant pairs of affected brothers are possible at all frequencies of M. Within a narrow range of modifier allele frequencies, the predicted distribution of affected sib pairs (over all families) is consistent with empiric data from a large clinic population. Here we suggest sampling discordant affected sib pairs as a strategy for detecting linkage between a polymorphic DNA marker and a possible modifier gene. Since both epistatic models predict that discordant affected pairs should not share 2 alleles at the modifier locus, we expect that departures from the null distribution could be detected with relatively small numbers of sib pairs.
Erucic acid (C22:l fatty acid) has been found to be useful in the treatment of adrenoleukodystrophy (ALD). It appears to work by reducing the blood levels of very-long-chain fatty acids (VLCFAs) which destroy the myelin sheaths of the nerves. Erucic acid was purified by reversed-phase high-performance liquid chromatography (HPLC) on columns packed with YMC C18 (10-20 microns, 120 A). Using ethanol-water as the mobile phase, the recovery of erucic acid was 69% and the purity was more than 97% as measured by gas chromatography. The amount of saturated VLCFAs was found to be within the limits specified for ALD treatment. The production rate (yield per 8 h shift) was low, however. Using methanol-water instead of ethanol-water as the mobile phase, a ninefold increase in the production rate was achieved. The recovery of erucic acid was 65% and the purity of erucic acid was 98%. All other purity specifications were met. By performing a low-temperature crystallization after the preparative HPLC step, the production rate was increased a further 142%. This represents a 22-fold increase in production rate over the ethanol-water method. The crystalline erucic acid was found to be 99% pure. All other purity requirements were met. The yield for the combined process (HPLC plus crystallization) decreased to 55%, however.
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