Long-chain 3-hydroxyacyl -coenzyme A dehydrogenase deficiency
LCHAD defiency (Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency), is a rare autosomal recessive fatty acid oxidation disorder that prevents the body from converting certain fats into energy. This can become life-threatening, particularly during periods of fasting.
Typically, initial signs and symptoms of this disorder occur during infancy or early childhood and can include feeding difficulties, lethargy, hypoglycemia, hypotonia, liver problems, and abnormalities in the retina. Muscle pain, a breakdown of muscle tissue, and abnormalities in the nervous system that affect arms and legs (peripheral neuropathy) may occur later in childhood. There is also a risk for complications such as life-threatening heart and breathing problems, coma, and sudden unexpected death. Episodes of LCHAD deficiency can be triggered by periods of fasting or by illnesses such as viral infections.
Mutations in the HADHA gene cause LCHAD deficiency. The HADHA gene provides instructions for making part of an enzyme complex called mitochondrial trifunctional protein. This enzyme complex functions in mitochondria, the energy-producing centers within cells. As the name suggests, mitochondrial trifunctional protein contains three enzymes that each perform a different function. This enzyme complex is required to break down (metabolize) a group of fats called long-chain fatty acids. Long-chain fatty acids are found in foods such as milk and certain oils. These fatty acids are stored in the body's fat tissues. Fatty acids are a major source of energy for the heart and muscles. During periods of fasting, fatty acids are also an important energy source for the liver and other tissues.
Mutations in the HADHA gene that cause LCHAD deficiency disrupt one of the functions of this enzyme complex. These mutations prevent the normal processing of long-chain fatty acids from food and body fat. As a result, these fatty acids are not converted to energy, which can lead to some features of this disorder, such as lethargy and hypoglycemia. Long-chain fatty acids or partially metabolized fatty acids may also build up and damage the liver, heart, muscles, and retina. This abnormal buildup causes the other signs and symptoms of LCHAD deficiency.
Cytogenetig location: 2p23
Molecular Location on chromosome 2: base pairs 26,190,634 to 26,244,725
All patients were proven to be LCHAD-deficient, either by enzymatic analysis (38/50, 76%) and/or by mutation analysis (49 out of 50 patients). Mutation analysis demonstrated the presence of the common 1528G>C mutation in 84 out of the 98 alleles tested (allele frequency 86%). Thirty-six patients were homozygous and 12 were heterozygous for this mutation. One patient was found to be homozygous for the 583G>D mutation. All heterozygous 1528G>C and the homozygous 583G>D were enzymatically proven to be LCHAD-deficient.
All surviving patients (31) are treated with a low-fat, high-carbohydrate diet. Twenty-three patients receive a medium-chain triglycerides (MCT)-enriched diet, and 12 are being treated with L-carnitine (50–100 mg per kg bodyweight per day). No statistically significant difference in morbidity, as defined as the presence of recurrent metabolic attacks and/or muscle cramps, could be detected between the patients receiving and those not receiving L-carnitine supplements (Fisher exact test: P < .01).