eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases
Long-Chain Acyl CoA Dehydrogenase Deficiency
Updated: Jul 22, 2009
Introduction
Background
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.
Pathophysiology
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.
Schematic demonstrating mitochondrial fatty acid beta-oxidation and effects of long-chain acyl CoA dehydrogenase deficiency (LCHAD) deficiency.
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.
Frequency
United States
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.
International
Analysis of the frequency of the most common mutation (G1528C) revealed a carrier frequency of 1:240 in Finland.
Mortality/Morbidity
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.
Race
Patients from all ethnic groups have been reported.
Sex
No gender predilection is observed because this is an autosomal recessive disorder.
Age
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.
Clinical
History
- Acute metabolic crises precipitated by intercurrent infections usually present with hypoketotic hypoglycemia that may be accompanied by cardiomyopathy, hypotonia, and hepatomegaly. These metabolic crises occur more frequently in infancy and early childhood.
- Careful analysis of patients who presented with hypoglycemia revealed that most of them had a constellation of easily missed, nonspecific symptoms before the hypoglycemic episode.
- Many patients may present with myopathy characterized by profound weakness, which may also be accompanied by cardiomyopathy. According to a more recent retrospective study, three fourths of patients studied with trifunctional protein deficiency, including long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity (LCHAD) deficiency had long term myopathic symptoms.1
- Some patients may present in infancy or childhood with myoglobinuria or as adults with exercise-induced muscle pains and rhabdomyolysis.
- Some patients present with peripheral sensorimotor polyneuropathy.
- Progressive visual loss has been documented in over 70% of cases with long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity deficiency.
- Rarely, affected infants can present with acute cholestatic jaundice or massive total hepatic necrosis in infancy.
Physical
- Neurological examination
- The acute episode of hypoketotic hypoglycemic encephalopathy may begin with a seizure.
- Most patients are hypotonic, at least in infancy.
- Examination may reveal profound weakness, decreased movements, and a frog-leg position.
- Deep tendon reflexes may be absent in infancy.
- The patient may toe-walk and display an equinus deformity.
- Extensor plantar responses have been reported.
- Cardiac: Examination of the heart may reveal cardiomegaly, poor heart sounds, and gallop rhythm.
- Abdomen
- Most patients have hepatomegaly.
- Jaundice may develop in infancy along with elevation of the transaminases.
- Ophthalmological examination
- In the youngest patients, the fundus may be pale. Thereafter, aggregation of pigment has been detected in the posterior pole and macular region.
- Progressive atrophy of the retinal pigment epithelium, choroid, neural retina, and retinal vessels follow initial pigment abnormalities. This may lead to a completely bare sclera in the central fundus.
- Posterior staphylomas and delicate lens opacities also may be observed. Cataracts have also been reported.
Causes
- A molecular defect that affects the mitochondrial trifunctional protein (MTP) causes long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity deficiency.
- Molecular defects are responsible for the 2 types of defect of MTP (ie, long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity deficiencies, MTP deficiencies).
- The molecular defect affects the function of the MTP, which contains the activity of long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity, 2-enoyl-CoA hydratase, and 3-oxoacyl CoA hydratase.
- In most patients, the deficiency is isolated to long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity; yet, in some patients, defective activity of all 3 enzymes of the protein is observed.
- In isolated long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity deficiency, most of the patients are homozygous for a guanine-to-cytosine transversion at position 1528, involving the alpha subunit of the MTP in the active site domain of the long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity encoding region. The nicotinamide adenine dinucleotide (NAD) cofactor-binding sequence resides in this region.
- Other mutations have been described, usually in compound with G1528C.
- MTP deficiency is caused by several mutations in either alpha or beta subunit DNA encoding regions with resulting decreased functioning of all 3 enzyme activities of long-chain 3-hydroxy acyl-coenzyme A dehydrogenase activity.
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| References |
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References
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Further Reading
Keywords
long-chain acyl CoA dehydrogenase deficiency, LCHAD deficiency, trifunctional protein deficiency, hypoketotic hypoglycemia, vomiting, hypotonia, cardiomyopathy, sudden infant death, hepatic necrosis, cholestatic jaundice, hepatomegaly, cardiomegaly, cataracts, treatment, diagnosis
