Heterozygosity for the common LCHAD mutation (1528g>C) is not a major cause of HELLP syndrome and the prevalence of the mutation in the Dutch population is low

Abstract

Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency is an autosomal recessive disorder of mitochondrial fatty acid oxidation. Apart from life-threatening metabolic derangement with hypoketotic hypoglycemia, patients often show liver disease, cardiomyopathy, and neuropathy. A common mutation (1528G>C) in the gene coding for the alpha-subunit of the mitochondrial trifunctional protein harboring LCHAD activity is found in 87% of the alleles of patients. LCHAD is considered a rare disorder with only 63 patients reported in the literature. Whether this is due to a truly low prevalence of the disorder or because many patients remain unrecognized as a result of aspecific symptomatology is not clear. A remarkable association between LCHAD deficiency and the hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome, which is a severe complication of pregnancy, has been reported. Because of this, we studied the frequency of the common LCHAD mutation in the Dutch population by analyzing 2,047 Guthrie cards and 113 women who had suffered from HELLP syndrome. To be able to perform this large-scale study in dried bloodspots, we developed a new sensitive PCR-restriction fragment length polymorphism method. The carrier frequency for the common LCHAD mutation in the Dutch population was found to be low (1:680), consistent with the observed low incidence of the disorder. In the group of women with a history of HELLP syndrome, the prevalence of the common LCHAD mutation was also low (1:113). We conclude that LCHAD deficiency is, indeed, a rare disorder and that heterozygosity for the common mutation is not a major cause of the HELLP syndrome.