Long-chain 3-hydroxy acyl-coenzyme A dehydrogenase (LCHAD) is 1 of 3 enzymatic activities that make up the trifunctional protein of the inner mitochondrial membrane. The other 2 activities of the protein are 2-enoyl coenzyme A (CoA) hydratase (LCEH) and long-chain 3-ketoacyl CoA thiolase (LCKT). The protein is an octamer composed of 4 alpha subunits that contain the LCEH and long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activities, and 4 beta subunits that contain the LCKT activity. This enzyme complex metabolizes long-chain fatty acids, and the long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity is specific for compounds of C12-C16 chain length. The genes for the alpha and beta subunits have been localized to chromosome 2.
Affected infants with long-chain 3-hydroxy acyl-coenzyme A dehydrogenase deficiency, which is inherited as an autosomal recessive trait, present in infancy with acute hypoketotic hypoglycemia. These episodes typically appear for the first time after a fast, which usually occurs in the context of intercurrent illness with vomiting.
The molecular defect occurs in the mitochondrial trifunctional protein (MTP). Some patients who are deficient in all 3 enzymatic activities of the protein have been described, although most have an isolated long-chain 3-hydroxy acyl-coenzyme A dehydrogenase deficiency, which results in the inability to metabolize long-chain fatty acids. Thus, the clinical features may result from either toxicity due to long-chain acyl-CoA esters that cause cardiomyopathy and cardiac arrhythmias or from a block in long-chain fatty acid oxidation that leads to an inability to synthesize ketone bodies and/or adenosine triphosphate from long-chain fatty acids. See the image below.
Increased rates of lipolysis after fasting has been observed. The increased lipolysis may represent a compensatory mechanism to meet energy demands after few hours of fasting. However, this effect may be achieved at the cost of fatty acid infiltration and of toxic effects of β-oxidation intermediates on organ functions. Patients with long-chain 3-hydroxy acyl-coenzyme A dehydrogenase deficiency may develop a profound CNS deficiency of docosahexanoic acid ethyl ester (DHA), 22:6n-3. An association between retinopathy and DHA deficiency has been demonstrated. The etiology of the severe peripheral neuropathy of trifunctional protein deficiency may result from the unique metabolite, 3-keto-acyl-CoA, after conversion to a methylketone via spontaneous decarboxylation. The gene for the protein has been cloned and a common mutation, G1528C, has been identified in 87% of mutant alleles.
The fatty acid oxidation defect results in adverse effects on numerous organ systems, including the CNS, secondary to the hypoketotic hypoglycemia. Hypotonia and cardiomyopathy are also usually present, reflecting the underlying energy deficiency. In addition, hepatomegaly is usually evident, and biopsy of the liver reveals fat accumulation and fibrosis. Chorioretinopathy may also develop over time.
Occurrence frequency of either isolated long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity deficiency or trifunctional protein deficiency is unknown in the United States.
Analysis of the frequency of the most common mutation (G1528C) revealed a carrier frequency of 1:240 in Finland.
In most cases, the disease is severe and may lead to death during the first few months of life. The disease may also be a cause of sudden infant death, even neonatal. For those infants that are diagnosed and treated, a risk for psychomotor retardation is still noted.
Patients from all ethnic groups have been reported.
No gender predilection is observed because this is an autosomal recessive disorder.
Patients with long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity deficiency usually present with hypoketotic hypoglycemia, cardiomyopathy, hypotonia, and hepatomegaly at a median age of 6 months. In childhood, the presentation is myopathic. A minority of patients (up to 15%) may present during the neonatal period. A late-onset neuromuscular disease has been reported in MTP deficiency.
What would you like to print?