eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Long-Chain Acyl CoA Dehydrogenase Deficiency

Author: Fernando Scaglia, MD, Assistant Professor of Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital
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Updated: Aug 2, 2006

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 LCHAD activities, and 4 beta subunits that contain the LCKT activity. This enzyme complex metabolizes long-chain fatty acids, and the LCHAD 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 LCHAD 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, though most have an isolated LCHAD 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. 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 a number of organ systems, including the CNS, secondary to the hypoketotic hypoglycemia. Hypotonia and cardiomyopathy also are usually present, reflecting the underlying energy deficiency. In addition, hepatomegaly usually is evident, and biopsy of the liver reveals fat accumulation and fibrosis.

Frequency

United States

Occurrence frequency of either isolated LCHAD 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 the majority of cases, the disease is severe and may lead to death during the first few months of life. The disease also may be a cause of sudden infant death, even neonatal. For those infants that are diagnosed and treated, a risk still exists for psychomotor retardation.

Race

Patients from all ethnic groups have been reported.

Sex

No sexual predilection exists because this is an autosomal recessive disorder.

Age

Patients with LCHAD 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.
• Some patients may present with myopathy characterized by profound weakness, which also may be accompanied by cardiomyopathy.
• 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.
• 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.

Causes

• A molecular defect that affects the MTP causes LCHAD deficiency.
• Molecular defects are responsible for the 2 types of defect of MTP (ie, LCHAD deficiencies, MTP deficiencies).
  • The molecular defect affects the function of the MTP, which contains the activity of LCHAD, 2-enoyl-CoA hydratase, and 3-oxoacyl CoA hydratase.
  • In most patients, the deficiency is isolated to LCHAD; yet, in some patients, defective activity of all 3 enzymes of the protein exists.
  • In isolated LCHAD 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 LCHAD 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 LCHAD.

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