LCHAD (Long-Chain 3-Hydroxyacyl CoA Dehydrogenase) deficiency

LCHAD (long-chain 3-hydroxyacyl CoA dehydrogenase) deficiency is a recessively inherited genetic disorder of fatty acid oxidation. As a result, the body is unable to break down fatty acids for energy use.

Genetics: LCHAD is 1 of 3 enzymatic activities that make up the mitochondrial trifunctional protein (MTP) 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). LCAD's activity is specific for fatty acids of C12-C16 length. The alpha and beta subunits reside in chromosome 2. The most common mutation, G1528C, has been identified in 87% of mutant alleles. There is no race or sex predilection.

Signs and symptoms: LCHAD deficiency can present in many ways, such as hypoglycemia, lethargy, SIDS, or Reye-like syndrome. LCHAD deficiency can also cause a child to have hypotonia and cardiomyopathy. Hepatomegaly usually is evident on examination, and biopsy of the liver reveals fat accumulation and fibrosis. The majority of the neurological complications come from the effects of hypoketotic hypoglycemic encephalopathy (e.g. seizures). In childhood, the presentation is myopathic. A late-onset neuromuscular disease has been reported in MTP deficiency. Peripheral neuropathy can also be seen.

Neurological examination can show hypotonia (especially in infancy), profound weakness (with frog-leg positioning), decreased deep tendon reflexes, extensor plantar reflexes, and toe walking. On ophthalmological exam, the fundus may be pale, with later progressive atrophy of the retinal pigment epithelium, choroid, neural retina, and retinal vessels (pigmentary retinopathy).

Carriers of the aberrant gene are asymptomatic. However, mothers pregnant with babies homozygous for the deficiency often have problems including anorexia, vomiting, abdominal pain, and jaundice during the third trimester of pregnancy (HELLP syndrome). If untreated, it can cause liver failure in the mother. This may result in the need for liver transplant or death. This is known as acute fatty liver of pregnancy or AFLP syndrome

Investigations: In an acute episode, blood and urine samples may show hypoketotic hypoglycemia. As well, there may be elevated CPK, ammonia, liver enzymes, and lactic acid.

Chronically 3-hydroxylated dicarboxylic acids and nonhydroxylated dicarboxylic acids will be positive. Plasma carnitine may be low, and long-chain acylcarnitine levels are increased. Serum fatty acid analysis and fatty acid oxidation assays may be diagnostic. Molecular analysis and prenatal diagnosis is also possible.

Pathological findings: Liver shows hepatomegaly, steatosis, and cirrhosis. Heart shows cardiomegaly and fatty deposition in the myocardium. Fatty depositions also occur in the renal tubules and muscle. Pathological findings in the CNS are usually mild and nonspecific, often a result of hypoketotic hypoglycemic encephalopathy. Muscle histopathology in particular shows fatty infiltration and degeneration of muscle fibers, as well as ragged red fibers. Electron microscopy shows swollen and increased numbers of mitochondria. Muscle pathology can easily be confused with respiratory chain disorders. Enzyme assays also may show dysfunction of some of the respiratory chain complexes, possibly due to accumulation of toxic intermediates from mitochondrial beta-oxidation.

Treatment: It is important to avoid fasting to prevent hypoketotic hypoglycemia. A low fat, high carbohydrate diet, MCA oils, essential oil supplementation (linoleic and linolenic acid) and carnitine have been used for treatment. During acute illnesses, it may be necessary to admit such a patient for close monitoring and IV glucose to prevent hypoglycemia.

Morbidity and Mortality: The disease is usually severe and may lead to death in the first few years of life, including from SIDS. Even treated, there can be psychomotor retardation.

Relevant reading:
Info from
Den Boer MEJ, Wanders RJA, Morris AAM, et al. (2002). Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: clinical presentation and follow-up of 50 patients. Pediatrics. 109:99-104.
Tyni T, Mahander A, Kalimo H, et al. (1996). Pathology of skeletal muscle and impaired respiratory chain function in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency with the G1528 mutation. Neuromuscular Disorders. 6(5):327-37.
Tyni T, Rapola J, Paetau A, et al. (1997). Pathology of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency caused by the G1528C mutation. Pediatric Pathology & Laboratory Medicine. 17:427-47.

Entry date: January 7, 2005.