Based on numbering from the start codon, which was used by IJlst et al. (1994), this mutation is designated glu510-to-gln (E510Q). Sims et al. (1995) had designated the mutation GLU474GLN (E474Q) based on numbering of the mature protein.
LCHAD Deficiency with Maternal Acute Fatty Liver of Pregnancy
IJlst et al. (1994) identified a 1528G-C transversion in exon 15 of the HADHA gene, resulting in an E510Q substitution, in approximately 87% of the chromosomes in patients with LCHAD deficiency (609016).
Sims et al. (1995) used single-strand conformation variance (SSCV) analysis of the alpha subunit of long-chain 3-hydroxyacyl-CoA dehydrogenase to determine the molecular basis of LCHAD deficiency in 3 families in which children presented with sudden unexplained death or hypoglycemia and abnormal liver enzymes (Reye-like syndrome). In all families, the mother had acute fatty liver and associated severe complications during pregnancy. The analysis in 2 affected children demonstrated homozygosity for the E474Q mutation. The third child was compound heterozygous for E474Q and Q342X (600890.0002).
IJlst et al. (1996) developed a PCR-RFLP method to identify the E474Q mutation in genomic DNA. Functional expression studies in S. cerevisiae showed that the mutation is directly responsible for the loss of LCHAD activity.
Tyni et al. (1997) discussed the clinical presentation of 13 patients with LCHAD deficiency due to a homozygous E474Q mutation. The patients had hypoglycemia, cardiomyopathy, muscle hypotonia, and hepatomegaly during the first 2 years of life. Recurrent metabolic crises had occurred in 7 patients; the other 6 had a steadily progressive course. Cholestatic liver disease, which is uncommon in beta-oxidation defects, was found in 2 patients. One patient had peripheral neuropathy, and 6 had retinopathy with focal pigmentary aggregations or retinal hypopigmentation. Radiologically, there was bilateral periventricular or focal cortical lesions in 3 patients and brain atrophy in 1. Only 1 patient, who had dietary treatment for 9 years, was alive at the age of 14 years; all others died before they were 2 years of age. The experience indicated the importance of recognizing the clinical features of LCHAD deficiency for the early institution of dietary management, which can alter the otherwise invariably poor prognosis.
Ibdah et al. (1999) reported a patient who presented at 2 months of age with generalized tonic-clonic seizure due to an acute infantile hypocalcemia and vitamin D deficiency. He also had occult, unexplained cholestatic liver disease and impairment of 25-hydroxylation of vitamin D secondary to hepatic steatosis. Sudden unexpected death occurred at 8 months. Molecular analysis revealed homozygosity for the E474Q mutation. The mother had preeclampsia during the third trimester of her pregnancy.
Mitochondrial Trifunctional Protein Deficiency 1
In a man with mitochondrial trifunctional protein deficiency (MTPD1; 609015), Liewluck et al. (2013) identified compound heterozygous mutations in the HADHA gene: E510Q and a splice site mutation (600890.0004). The patient presented in his late forties with exercise-induced rhabdomyolysis and was found to have features of a mild sensorimotor axonal peripheral neuropathy affecting the lower limbs. Laboratory studies showed an abnormal acylcarnitine profile, suggesting a defect in HADHA activity, although patient cells were not available for study.
