AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Reye syndrome
Other disorders of very long-chain fatty acid oxidation (VLCAD)
Respiratory chain defects (complex I deficiency)

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Blood glucose and urine ketones
• • The hallmark biochemical feature of this condition is acute hypoketotic hypoglycemia.
  • Collect urine ketones in the acute episode.
• Creatine phosphokinase, ammonia, uric acid, liver enzymes, lactic acid
• • During acute episodes, elevated levels of creatine phosphokinase are observed.
  • Hyperammonemia may be observed in acute episodes.
  • Elevation of liver transaminases also is observed.
  • A high incidence of lactic acidemia accompanies the metabolic decompensation or acute episode.
• Urine organic acids
• • Test for 3-hydroxylated dicarboxylic acids and nonhydroxylated dicarboxylic acids.
  • Nonhydroxylated dicarboxylic acids are nonspecific changes found in other beta-oxidation defects and in association with liver failure.
• Plasma carnitine levels and acylcarnitine profile
• • Plasma carnitine levels are low.
  • Long-chain acylcarnitine levels are increased with 3-hydroxydicarboxylic derivatives of the C16:0, C18:1, and C18:2 species.
  • The profile may be completely normal during asymptomatic periods.
• Serum fatty acid analyses
• • Serum fatty acid analysis may be diagnostic.
  • Look for 3-hydroxylated compounds even between exacerbations.
• Fatty acid oxidation studies and enzyme assay
• • Diagnosis may be made by study of the oxidation of the 14C-labeled myristic (C14:0) and palmitic (C16:0) acids in fibroblasts.
  • The deficient activity of LCHAD may be diagnosed in fibroblasts, as well as the other enzyme activities of the trifunctional protein.
  • The enzyme usually is measured in fibroblasts in the reverse direction, with 3-oxopalmitoyl CoA as substrate and measurement of the decrease in absorbance at 340 nm of the nicotinamide adenine dinucleotide-reduced form (NADH) electron donor.
• Fasting: In patients in whom the diagnosis has been difficult, an induced fast under strict medical supervision in a facility with expertise in the diagnosis of the inborn errors of metabolism may be considered.
• Molecular studies: Molecular studies to identify the common mutation, G1528C, are available.
• Prenatal diagnosis: Prenatal diagnosis using biochemical studies has been attempted. In appropriate families in whom the molecular defect is known, prenatal diagnosis also is possible by mutation analysis.

Imaging Studies

• Chest roentgenogram may reveal enlargement of the cardiac silhouette if cardiomyopathy is present.
• Echocardiogram may reveal cardiac enlargement, poor contractility with decreased ejection fraction, and pericardial effusion in some cases.

Other Tests

• Abnormal nerve conduction velocities have been recorded in patients with LCHAD deficiency and peripheral neuropathy.
• ECG may reveal left ventricular hypertrophy and cardiac arrhythmias.
• Mitochondrial enzyme studies may reveal abnormal respiratory chain function in skeletal muscle specimens. A more generalized deficiency of mitochondrial enzymes or a more selective reduction of complex I may exist.

Procedures

• Skin biopsy to obtain cultures of skin fibroblasts for fatty acid oxidation studies or specific enzyme assay is necessary for confirmation of diagnosis.
• Muscle biopsy, though not necessary for diagnosis, may be performed because lactic acidosis present in this condition may suggest a respiratory chain defect.

Histologic Findings

Pathological evaluation has revealed microvesicular and macrovesicular accumulation of fat in skeletal muscle, heart, and liver. Necrotic myopathy without steatosis has been described, as well as degeneration of muscle fibers. Hepatic cirrhosis also has been observed.

Ultrastructurally, the mitochondria appear to be increased in size and number with swollen appearance. Condensation of the mitochondrial matrix and irregular cristae is noted.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Evaluation for LCHAD deficiency may be performed on an outpatient basis with acylcarnitine profile, serum free fatty acids, and urine organic acids; however, patients who are asymptomatic at the time of evaluation may not show abnormalities. If high index of suspicion exists on the basis of the history, a skin biopsy could be performed for fatty acid oxidation studies in fibroblasts.
• In cases of acute decompensation with unconfirmed diagnosis, collect samples during the acute episode while the hypoglycemia is being corrected.
• If the patient presents with acute hypoketotic hypoglycemic encephalopathy, the main goal is to secure sufficient energy intake by infusions of intravenous glucose.
• The management of affected patients is directed at the avoidance of fasting. Most patients also are provided with uncooked cornstarch and medium chain triglyceride (MCT) oil supplementation to further decrease exposure to fasting. Consider carnitine supplementation if hypocarnitinemia is present; however, carnitine should not be used during acute decompensation.

Consultations

• Genetic metabolic services
• Nutritionist
• Cardiologist
• Ophthalmologist
• Neurologist

Diet

• A low-fat, high-carbohydrate diet with limited long-chain fatty acid intake (10% of total energy) is beneficial.
• Addition of MCT-oil treatment (providing 10-20% of energy requirements) is reported to be beneficial with improvement in dicarboxylic aciduria and a normalization of the plasma level of long-chain acylcarnitines.
• Use of uncooked cornstarch (2 g/kg/dose) at bedtime prevents early morning hypoglycemia after the overnight fast.
• Supplementation with vegetable oils, as part of the 10% total long-chain fatty acid intake, provides essential fatty acids (ie, linoleic acid, linolenic acid) and prevents retinal disease, peripheral neuropathy, growth restriction, and dermatitis. Prevention of fasting with frequent feeds is crucial.
• A daily multivitamin and mineral supplement that includes all fat-soluble vitamins is required.
• Supplementation with heptanoate (C7) triglyceride has been evaluated for other long-chain fatty acid oxidation defects and has been suggested to be potentially useful for LCHAD deficiency; however, this advantage has not been clearly documented.

Activity

• Advise tempered activity when increased risk for rhabdomyolysis and myoglobinuria exists.
• Advise avoidance of strenuous exercise activity and maintenance of adequate fluid intake to prevent dehydration with physical activity.
• Advise restriction of activity when cardiomyopathy is present.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Try carnitine supplementation in patients with evident hypocarnitinemia and continue if symptoms improve; however, start carnitine supplementation with caution during acute fulminant symptoms because of the potential risk of cardiac arrhythmias.

Drug Category: Dietary supplements

L-carnitine at high doses corrects the metabolic abnormalities and hypocarnitinemia present in cases of LCHAD deficiency. It may be important for the conjugation and excretion of fatty acids, for the enhancement of the excretion of toxic metabolites, and to generate free CoA; however, use with extreme caution during acute metabolic crises.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Admit for medical management of acute hypoketotic hypoglycemic encephalopathy.
• • Dextrose (10%) at rates of 10 mg/kg/min or greater may be required to achieve normoglycemia. Do not estimate rate of IV glucose infusion on blood glucose levels alone.
  • In principle, use IV carnitine only in cases of documented severe secondary carnitine deficiency. Carnitine therapy in long-chain fatty acid oxidation disorders is in question because it promotes long-chain acylcarnitine formation, and these acylcarnitines may cause ventricular arrhythmogenesis.
  • Carefully monitor liver transaminases because acute hepatic dysfunction may accompany the metabolic crises.
• Admit patient for management of rapidly evolving cardiomyopathy that may or may not be associated with the hypoglycemic crises.
• Admit patient for management of severe rhabdomyolysis and myoglobinuria to prevent renal failure.

Further Outpatient Care

• Aggressively treat infections and fever to prevent a catabolic state.
• Carefully review diet compliance regarding avoidance of fasting, compliance with fat-restricted diet, supplementation of uncooked cornstarch, and intake of MCT oil.
• Monitor carnitine levels and determine if carnitine supplementation is required.
• Refer patient for ophthalmological evaluation for possible pigmentary retinopathy.
• Conduct a neurological evaluation with nerve conduction studies to assess for possible peripheral neuropathy.

In/Out Patient Meds

• Medications include L-carnitine, which should be tried in patients with evident hypocarnitinemia and should be continued if it ameliorates the symptoms. Use with caution during acute episodes because L-carnitine could potentially trigger cardiac arrhythmias.

Transfer

• If diagnosis of LCHAD deficiency is suspected but workup facilities are inadequate and no metabolic specialists are available, transfer of patient to a tertiary care hospital for further workup and management may be necessary.

Deterrence/Prevention

• Prevent fasting with frequent feeds and use of uncooked cornstarch to avoid episodes of hypoglycemia.
• Aggressively treat infections and fever to prevent a catabolic state.
• Advise a fat-restricted diet with high-carbohydrate content. Triacylglycerols should provide less than 10-15% of the patient's total energy supply. Supplementation of dietary fat with medium-chain fatty acids is necessary.
• Use docosahexanoic acid to prevent retinal degeneration.
• Ensure carnitine supplementation in patients with documented secondary carnitine deficiency, especially if it contributes to alleviation of symptoms.
• Advise avoidance of exercise and dehydration with hot temperatures because rhabdomyolysis and myoglobinuria may occur with LCHAD deficiency.

Complications

• Psychomotor retardation and seizures derived from episodes of hypoketotic hypoglycemic encephalopathy
• Hypotonia and delayed motor development that may be permanent or transient after symptomatic periods
• Hepatic dysfunction that may be as severe as massive total hepatic necrosis in infancy
• Dilated cardiomyopathy that may present as a rapidly fatal cardiomyopathy in infancy
• Peripheral neuropathy
• Pigmentary retinopathy
• Pregnancy complications reported in LCHAD deficiency carriers in pregnancies (with an LCHAD deficient fetus), which include hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome and acute fatty liver of pregnancy (AFLP)

Prognosis

• In LCHAD deficiency, the fulminant acute symptoms may be difficult to manage and resistant to therapeutic attempts (with high mortality) because the presentations may involve a lethal acute liver failure, a rapidly evolving cardiomyopathy, or hypoketotic hypoglycemic encephalopathy. However, treatment may improve the long-term prognosis.
• Conventional therapy may not be sufficient to prevent ophthalmological changes.

Patient Education

• Advise family members to learn CPR.
• Teach family members to recognize signs and symptoms of hypoglycemia and instruct them to provide oral sources of glucose, glucose gel, or glucagon injection while waiting for emergency aid.
• Educate family members about frequent feeds and avoidance of fasting in general. If decreased oral intake occurs, the child should be seen immediately at the pediatrician's office or rushed to the emergency department.
• Educate the family about the importance of a fat-restricted high-carbohydrate diet with MCT oil supplementation and use of uncooked cornstarch to prevent episodes of hypoglycemia (see Diet).
• Provide education about routine ophthalmological follow-up care to screen for the onset of pigmentary retinopathy.
• Educate the family about pregnancy complications mainly described in heterozygous mothers giving birth to affected fetuses (eg, HELLP syndrome, AFLP).
• Arrange for genetic counseling and discussion of recurrence risk for future pregnancies.
• Educate about the possibility of prenatal diagnosis, which may be performed by measuring acylcarnitine profiles, measuring the activity of specific enzymes, or by searching for identified mutations (G1528C) from amniocytes or chorionic villus cells.
• Provide education about carnitine supplementation if significant hypocarnitinemia during the asymptomatic state is documented.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to investigate LCHAD deficiency as a cause of dilated cardiomyopathy may cause delays in treatment and unnecessary evaluation for cardiac transplantation.
• Failure to recognize LCHAD deficiency and to obtain adequate samples during a critical episode of hypoketotic hypoglycemic encephalopathy may put the patient at further risk of CNS dysfunction or death.
• Failure to inform the family about special diet requirements (eg, low fat, high carbohydrates) might place the patient at risk for another episode of hypoketotic hypoglycemia.
• Failure to evaluate for other complications, such as pigmentary retinopathy and progressive sensorimotor neuropathy, is a potential medical/legal pitfall.
• Failure to recognize HELLP or AFLP as possible complications from LCHAD deficiency in carrier females is a potential pitfall.
• Failure to screen for LCHAD deficiency in the newborn is a potential medical/legal pitfall.

Special Concerns

• AFLP and HELLP syndrome are serious conditions that may occur during pregnancy in heterozygous women whose fetuses later are found to have an LCHAD deficiency. In either of these cases, rule out LCHAD deficiency in the fetus.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Amirkhan RH, Timmons CF, Brown KO, et al. Clinical, biochemical, and morphologic investigations of a case of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Arch Pathol Lab Med. Jul 1997;121(7):730-4. [Medline].
• Bertini E, Dionisi-Vici C, Garavaglia B, et al. Peripheral sensory-motor polyneuropathy, pigmentary retinopathy, and fatal cardiomyopathy in long-chain 3-hydroxy-acyl-CoA dehydrogenase deficiency. Eur J Pediatr. Feb 1992;151(2):121-6. [Medline].
• Gillingham MB, Connor WE, Matern D, et al. Optimal dietary therapy of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Mol Genet Metab. Jun 2003;79(2):114-23. [Medline].
• IJlst L, Wanders RJ, Ushikubo S, et al. Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of the major disease-causing mutation in the alpha-subunit of the mitochondrial trifunctional protein. Biochim Biophys Acta. Dec 8 1994;1215(3):347-50. [Medline].
• Jackson S, Bartlett K, Land J, et al. Long-chain 3-hydroxyacyl CoA dehydrogenase deficiency. Pediatric Research. 1991;29:406-11. [Medline].
• Lawlor D, Kalina R. Pigmentary retinopathy in long chain 3-hydroxyacyl CoA dehydrogenase deficiency. Am J Ophthalmology. 1997;123:846-8. [Medline].
• Olpin SE, Clark S, Andresen BS, et al. Biochemical, clinical and molecular findings in LCHAD and general mitochondrial trifunctional protein deficiency. J Inherit Metab Dis. 2005;28(4):533-44. [Medline].
• Pons R, Roig M, Riudor E, et al. The clinical spectrum of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Pediatr Neurol. Apr 1996;14(3):236-43. [Medline].
• Pons R, De Vivo DC. Primary and secondary carnitine deficiency syndromes. J Child Neurol. 1995;10(Suppl 2):8-24. [Medline].
• Rocchiccioli F, Wanders RJ, Aubourg P, et al. Deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase: a cause of lethal myopathy and cardiomyopathy in early childhood. Pediatr Res. Dec 1990;28(6):657-62. [Medline].
• Roe CR, Coates PM. Mitochondrial fatty acid oxidation disorders. In: The metabolic and molecular bases of inherited disease. 1995:1501-34.
• Sewell AC, Bender SW, Wirth S, et al. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: a severe fatty acid oxidation disorder. Eur J Pediatr. Oct 1994;153(10):745-50. [Medline].
• Spiekerkoetter U, Sun B, Zytkovicz T, et al. MS/MS-based newborn and family screening detects asymptomatic patientswith very-long-chain acyl-CoA dehydrogenase deficiency. J Pediatr. Sep 2003;143(3):335-42. [Medline].
• Treem WR, Rinaldo P, Hale DE, et al. Acute fatty liver of pregnancy and long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. Hepatology. Feb 1994;19(2):339-45. [Medline].
• Tyni T, Majander A, Kalimo H, et al. Pathology of skeletal muscle and impaired respiratory chain function in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency with the G1528C mutation. Neuromuscul Disord. Oct 1996;6(5):327-37. [Medline].
• Tyni T, Pihko H. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Acta Paediatr. Mar 1999;88(3):237-45. [Medline].
• Wanders RJ, IJlst L, van Gennip AH, et al. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of a new inborn error of mitochondrial fatty acid beta-oxidation. J Inherit Metab Dis. 1990;13(3):311-4. [Medline].
• Wilcken B, Leung KC, Hammond J, et al. Pregnancy and fetal long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency. Lancet. Feb 13 1993;341(8842):407-8. [Medline].
• den Boer ME, Wanders RJ, Morris AA, et al. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: clinical presentation and follow-up of 50 patients. Pediatrics. Jan 2002;109(1):99-104. [Medline]. [Full Text].

Article Last Updated: Aug 2, 2006