Long-Chain 3-Hydroxyacyl-Coa Dehydrogenase Deficiency

A number sign (#) is used with this entry because LCHAD deficiency is caused by homozygous or compound heterozygous mutations in the gene encoding long-chain hydroxyacyl-CoA dehydrogenase (HADHA; 600890).

Complete mitochondrial trifunctional protein deficiency (609015) is a less common disorder that is also caused by mutation in the HADHA gene.

Description

Isolated deficiency of long-chain 3-hydroxyl-CoA dehydrogenase (LCHAD) is an autosomal recessive disorder characterized by early-onset cardiomyopathy, hypoglycemia, neuropathy, and pigmentary retinopathy, and sudden death (IJlst et al., 1996).

Clinical Features

Wanders et al. (1989) described sudden infant death syndrome (SIDS) in a 3-day-old infant caused by deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase. Duran et al. (1991) reported that the younger sister of this patient began at the age of 5 months to have feeding problems, lowered consciousness, and liver dysfunction. Plasma long-chain acylcarnitine was increased. A clue to the diagnosis was given by the results of a phenylpropionic acid loading test. On a diet enriched with medium-chain triglycerides, the patient started to thrive, signs of cardiomyopathy disappeared, and her liver function returned to normal.

Rocchiccioli et al. (1990) described an infant with LCHAD deficiency who developed recurrent hypoglycemia in early infancy and died at 9 months of age from a rapidly progressive myopathy and cardiomyopathy. The activities of long-, medium-, and short-chain acyl-CoA dehydrogenases (609576, 607008 and 606885, respectively) and 3-ketoacyl-CoA thiolase (607809) were normal. The clinical features of this disorder bore similarities to those of systemic carnitine deficiency (212140) as well as with carnitine-palmitoyl-CoA transferase (255110 and 255120) and long-chain acyl-CoA dehydrogenase deficiencies. The differential diagnosis relies on the demonstration of long-chain urinary dicarboxylic acids with a hydroxyl group in the 3-position and on the study of the enzyme activity in cultured fibroblasts. Rocchiccioli et al. (1990) diagrammed the pathway of fatty acyl-CoA beta-oxidation in mitochondria.

Jackson et al. (1991) described the cases of 2 unrelated children. Recessive inheritance was supported by the finding of intermediate levels of enzyme activity in the fibroblasts from the parents of one of the children.

Bertini et al. (1992) reported the case of an 11-month-old girl with LCHAD deficiency and a new phenotype of sensorimotor polyneuropathy, pigmentary retinopathy, and fatal progressive cardiomyopathy.

Hagenfeldt et al. (1990) described 5 patients with a suspected defect in the beta-oxidation of fatty acids characterized by massive excretion of 3-hydroxydicarboxylic acids in the urine and accumulation of 3-hydroxy fatty acids in serum during acute illness. Long-chain and medium-chain acyl-coenzyme A dehydrogenases in fibroblasts were normal in all patients. Death due to cardiomyopathy and liver failure occurred in 4 of the 5 at 3 to 14 months of age. Elder sibs of 2 of the patients had died unexpectedly in early infancy. The parents of 1 of the patients were second cousins. Long-chain 3-hydroxyacyl-CoA dehydrogenase may have been the enzyme deficient in these cases.

Tyni et al. (1997) discussed the clinical presentation of 13 patients with LCHAD deficiency. 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 identified a homozygous 1528G-C mutation (E510Q; 600890.0001) in the HADHA gene. The mother had preeclampsia during the third trimester of her pregnancy.

In 2 girls, aged 8 and 15 years, with LCHAD deficiency, Schrijver-Wieling et al. (1997) observed extensive macular pigmentary depositions and a 'salt and pepper' scattering of pigment in their retinas. They had decreasing visual acuity. The investigators suggested that testing for LCHAD deficiency should be included in the diagnostic process in children with retinal dystrophy, in particular when other clinical symptoms suggesting this disorder occur. Uusimaa et al. (1997) reported 2 unrelated boys with pigmentary retinopathy in association with a mild clinical presentation of LCHAD deficiency.

Tyni et al. (2002) noted that pigmentary retinopathy is an important feature of LCHAD deficiency. In studies in cultured porcine retinal pigment epithelium (RPE) cells, they presented strong in vitro evidence for the presence of mitochondrial fatty acid beta-oxidation in RPE cells and the expression of the MTP in the RPE and other layers of the retina.

Sewell et al. (1994) stated that most reported cases were diagnosed at the age of several months and presented with fasting-induced hypoketotic hypoglycemia and muscular hypotonia. Thiel et al. (1999) reported a patient presenting 20 hours after birth with signs of tachypnea, hypotonia, and mild retractions, and Carpenter and Wilcken (1999) described a patient who developed hypoglycemia at birth; on dietary treatment, both patients remained well.

Although the mortality rate among children with deficiency of LCHAD or complete deficiency of the trifunctional protein had been reported to be 75 to 90%, Ibdah et al. (1999) found that 67% of the affected children in their study were alive and receiving dietary treatment at the most recent follow-up, and most were able to attend school. Dietary treatment of children with fatty-acid oxidation disorders dramatically reduces morbidity and mortality.

Van Hove et al. (2000) reviewed the acylcarnitines in plasma and blood spots of patients with LCHAD deficiency. Long-chain 3-hydroxyacylcarnitines of C14:1, C14, C16, and C18:1 chain length, and long-chain acylcarnitines of C12, C14:1, C14, C16, C18:2, and C18:1 chain length were elevated. Acetylcarnitine was decreased. In plasma, elevation of hydroxy-C18:1 acylcarnitine over the 95th centile of controls, in combination with an elevation of 2 of the 3 acylcarnitines C14, C14:1, and hydroxy-C16, identified over 85% of patients with high specificity (less the 0.1% false-positive rate). High endogenous levels of long-chain acylcarnitines in normal erythrocytes reduced the diagnostic specificity in blood spots compared with plasma samples. The results were diagnostic in the asymptomatic patients. Treatment with a diet low in fat and high in medium-chain triglyceride decreased all disease-specific acylcarnitines, often to normal, suggesting that this assay is useful in treatment monitoring.

Fryburg et al. (1994) suggested that LCHAD deficiency is responsible for the lipid myopathy in Bannayan-Riley-Ruvalcaba syndrome (see 158350), an autosomal dominant condition of macrocephaly in combination with lipomas/hemangiomas and developmental delay.

Acute Fatty Liver Pregnancy (AFLP) and Hypertension, Elevated Liver Enzymes, and Low Platelet (HELLP) Syndromes

Wilcken et al. (1993) and Treem et al. (1994) noted that isolated LCHAD deficiency in children may be associated with severe maternal illness occurring during pregnancies with affected fetuses. These maternal illnesses include the acute fatty liver pregnancy (AFLP) syndrome; hypertension or hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome; and hyperemesis gravidum. The AFLP syndrome is characterized by anorexia, nausea, vomiting, abdominal pain, and jaundice in the third trimester. Fulminant liver failure and death may occur. HELLP syndrome is more common and may represent the severe end of the spectrum of preeclampsia. In both syndromes, microvesicular fatty infiltration of maternal liver occurs, a pathologic picture similar to that in children with fatty acid oxidation defects. Thus, AFLP and HELLP are genetic disorders due to a primary defect in the fetus.

Ibdah et al. (1999) stated that little is known about the mechanism of the association between isolated deficiency of LCHAD in a fetus with the common 1528G-C mutation (600890.0001) on at least one allele and liver disease in the mother during the pregnancy. They hypothesized that in the presence of the 1528G-C mutation, long-chain 3-hydroxyacyl metabolites produced by the fetus or placenta accumulate in the mother and are highly toxic to the liver; this reaction is perhaps exaggerated by the decreased metabolic utilization of fatty acids during pregnancy.

Ibdah et al. (2001) performed molecular prenatal diagnosis in 9 pregnancies, 8 in 6 families with isolated LCHAD deficiency and 1 in a family with complete trifunctional protein deficiency. Analyses were performed on chorionic villus samples in 7 pregnancies and on amniocytes in 2. Molecular prenatal diagnosis successfully identified the fetal genotype in all 9 pregnancies. Two fetuses were affected, and the pregnancies were terminated. Two other fetuses had normal genotype and 5 others were heterozygotes. All 7 pregnancies were uncomplicated and all the offspring were liveborn and healthy. Ibdah et al. (2001) concluded that women heterozygous for trifunctional protein alpha-subunit mutations who carry fetuses with wildtype or heterozygous genotypes have uncomplicated pregnancies.

Clinical Management

Jones et al. (2003) analyzed the effects of dietary treatment of LCHAD deficiency in an in vitro model of cultured skin fibroblasts from 2 patients with LCHAD deficiency, 1 with MPT deficiency, and controls. The results suggested that a medium-chain triglyceride preparation reduces the accumulation of potentially toxic long-chain 3-hydroxy-fatty acids in LCHAD deficiency and that a preparation with a higher ratio of decanoate to octanoate may be most effective.

Molecular Genetics

To identify the molecular basis of the deficiency in 26 Dutch patients with a deficiency in long-chain 3-hydroxyacyl-CoA dehydrogenase, IJlst et al. (1994) sequenced the cDNAs encoding the alpha and beta subunits of the trifunctional enzyme and identified a 1528G-C transversion in the dehydrogenase-encoding region of the alpha subunit. The single base change resulted in an glu510-to-gln (E510Q; 600890.0001) amino acid substitution, based on numbering from the start codon. The base substitution created a PstI restriction site. Using RFLP methods, they found that in 24 of 26 unrelated patients, only the 1528C was expressed. The other 2 patients were compound heterozygotes with 1 allele carrying this mutation. IJlst et al. (1996) used S. cerevisiae for expression of wildtype and mutant protein to show that the 1528G-C mutation is directly responsible for the loss of LCHAD activity. Furthermore, they described a newly developed method allowing identification of the 1528G-C mutation in genomic DNA. The finding of an 87% allele frequency of this mutation in 34 LCHAD-deficient patients made this a valuable test for prenatal diagnosis. IJlst et al. (1996) showed that the E510Q mutation is directly responsible for the loss of dehydrogenase activity without changing the structure of the enzyme complex.

Sims et al. (1995) used single-strand conformation variance (SSCV) analysis of the exons encoding the alpha subunit of trifunctional protein to elucidate the molecular defects (see, e.g., 600890.0001-600890.0002) in 3 families with children with isolated LCHAD deficiency and mothers with either AFLP syndrome or HELLP syndrome. Based on numbering of the mature peptide, Sims et al. (1995) designated the 1528G-C mutation as glu474-to-gln (E474Q).

Inheritance

LCHAD deficiency usually shows autosomal recessive inheritance. Baskin et al. (2010) reported an unusual case of LCHAD deficiency due to paternal isodisomy of chromosome 2. The patient was a 22-month-old child identified by newborn screening. Molecular analysis showed homozygosity for the common 1528G-C mutation (E510Q; 600890.0001), but only the father was found to be heterozygous for the mutation; it was not present in the mother. Genotype analysis of chromosome 2 using STR markers demonstrated uniparental isodisomy. The patient did not have other phenotypic abnormalities, suggesting that chromosome 2 is not imprinted. The finding was important, as it reduced the recurrence risk of this disease for this couple.

Population Genetics

Ibdah et al. (1999) found 17 different mutations among the 24 children in their study. In the 19 children with isolated deficiency of LCHAD, 71% of alleles had the E510Q mutation, and none of the 10 alleles (all of which were abnormal) in the 5 children with trifunctional protein deficiency had this mutation. Among 351 normal subjects, they found that 2 were heterozygous for the E510Q mutation. If this group of subjects was representative of the general population, then isolated deficiency of LCHAD would occur once in every 62,000 pregnancies, and either trifunctional protein or long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency would occur once in 38,000 pregnancies.