LONG-CHAIN 3-HYDROXYACYL-COA DEHYDROGENASE-DEFICIENCY - HIGH-FREQUENCY OF THE G1528C MUTATION WITH NO APPARENT CORRELATION WITH THE CLINICAL PHENOTYPE

In 1992 two groups of investigators reported the identification of a new mitochondrial beta-oxidation enzyme protein harbouring long-chain enoyl-CoA hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase and long-chain 3-ketothiolase activity (Carpenter et al 1992; Uchida et al 1992). The enzyme appears to be a hetero-octamer of 4 alpha and 4 beta subunits strongly bound to the inner mitochondrial membrane. In earlier years, patients were described with a deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD). It is now clear that LCHAD deficiency is not only clinically heterogeneous but also biochemically diverse. Indeed, at least two biochemically distinct phenotypes can be distinguished. In one group of patients of which two have been reported so far (Jackson et al 1992; Wanders et al 1992), the mitochondrial trifunctional protein is completely missing, as shown by immunoblot analysis, leading to a combined deficiency of long-chain enoyl-CoA hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase and long-chain 3-ketothiolase, although the extent of the deficiency is different for each of these enzyme activities (43%, 25% and 1.7%, respectively, of control values as measured in homogenates). In the second group, now comprising at least 40 different patients (Ijlst, Ruiter and Wanders, unpublished), the mitochondrial trifunctional protein is present, as shown by immunoblot analysis, albeit at a somewhat reduced level. Enzyme activity measurements have shown that in these patients long-chain 3-hydroxyacyl-CoA dehydrogenase is deficient to the same extent as in group I patients, whereas long-chain enoyl-CoA hydratase and long-chain 3-ketothiolase are partially deficient at 78% and 59%, respectively, of control levels. In order to distinguish between the two groups of patients, we suggest the use of the nomenclature 'multifunctional protein deficiency' and 'long-chain 3-hydroxyacyl-CoA deficiency (LCHAD-deficiency)' for the two groups of patients. We recently reported the identification of a point mutation at position 1528 of the cDNA for the alpha-subunit of mitochondrial trifunctional protein (see Kamijo et al 1993) in fibroblasts from a patient with LCHAD deficiency (Ijlst et al 1994). The mutation found changes a highly conserved glutamate to a glutamine. We now report that this mutation is very frequent among LCHAD-deficient patients. Furthermore, patients homozygous for this mutation show widely different phenotypes.