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

Updated: Jan 11, 2019
Author: Anna V Blenda, PhD; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG 

Overview

Background

Long-chain 3-hydroxyacyl-CoA 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 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. The HADHA gene has been cloned, and a common mutation, c.1528G>C, has been identified in the mutant alleles of LCHAD deficiency.[1]

LCHAD deficiency is a severe fatty acid oxidation disorder that is fatal if untreated.[2] Infants with LCHAD deficiency, which is inherited as an autosomal recessive trait, present in infancy with acute hypoketotic hypoglycemia.[3, 4] 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 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. See the image below.

Schematic demonstrating mitochondrial fatty acid b Schematic demonstrating mitochondrial fatty acid beta-oxidation and effects of long-chain acyl CoA dehydrogenase deficiency (LCHAD) deficiency.

It has been suggested that mitochondrial energy and Ca2+ homeostasis disruptions caused by the predominant accumulation of the long-chain hydroxyl fatty acid (LCHFA) may contribute to the severe cardiac and hepatic clinical features,[5] muscular symptoms, and recurrent rhabdomyolysis[6] in patients with LCHAD deficiency. Another study confirmed that disturbance of mitochondrial functions caused by oxidative stress from the accumulating fatty acids is involved in the pathophysiology of LCHAD deficiency. This pathomechanism may play a role in chronic and neurologic symptoms of LCHAD deficiency.[7]

Increased rates of lipolysis after fasting have been observed.[8] 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 LCHAD 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 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. Chronic hemolytic anemia and delayed CNS myelination have also been reported.[9]

Epidemiology

Frequency

United States

The incidence of isolated LCHAD activity deficiency and trifunctional protein deficiency is unknown in the United States.

International

Analysis of the frequency of the most common mutation (c.1528G>C) in the HADHA gene that encodes for mitochondrial LCHAD estimated a carrier frequency of 1:240 in Finland.[10] This mutation was also present in 100% of alleles in patients in Ukraine, and, in 2018, the frequency of LCHAD deficiency in Ukraine was found to be 1:329,968, which is 2.1 times lower than the average in Europe.[11] A significantly higher frequency of the same mutation was found in the adult Kashubian population from North Poland.[12] The same study also found a higher frequency of another polymorphism, c.652G>C, in the HADHA gene within the population of Silesian in southern Poland. Fourteen living patients with LHAD deficiency were reported in Austria in 2015 and were all homozygous for the common mutation c.1528G>C.[13]

Mortality/Morbidity

In most cases, LCHAD deficiency 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. Infants who are diagnosed and treated still have a risk for psychomotor retardation. In addition, this homozygous mutation in fetuses was found to be highly associated with maternal acute fatty liver of pregnancy.[14]

Race

LCHAD deficiency has been reported in all ethnic groups.

Sex

LCHAD deficiency has no sexual predilection because it is an autosomal recessive disorder.

Age

Patients with LCHAD 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.

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; however, early diagnosis and adequate therapy may delay the progression of retinal complications.

Patient Education

Advise family members to learn cardiopulmonary resuscitation (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, acute fatty liver of pregnancy).

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.

 

Presentation

History

LCHAD deficiency can initially present with sudden unexpected postnatal collapse (SUPS) in the immediate newborn period.[15]

A study of four patients with LCHAD deficiency reported clinical onset in the form of acute encephalopathy between ages 9 months and 3 years.[16]

Acute metabolic crises usually manifest as 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, often accompanied by cardiomyopathy.[17] Three-fourths of patients studied with trifunctional protein deficiency, including LCHAD deficiency, had long-term myopathic symptoms.[18]

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. In one case, the patient showed peculiar clinical manifestations of severe sensory-motor neuropathy, pigmentary retinopathy, and cardiomyopathy.[19, 20] A case of acute dilated cardiomyopathy was reported in a 3-year-old patient with LCHAD deficiency.[21]

Progressive visual loss has been documented in over 70% of patients with LCHAD activity deficiency.

Rarely, affected infants can present with acute cholestatic jaundice or massive total hepatic necrosis in infancy.

LCHAD deficiency should also be considered in patients who present clinically with hemophagocytic lymphohistiocytosis (HLH), especially those with a family history of consanguineous marriage and laboratory results of hypoglycemia, metabolic acidosis, and high creatinine kinase levels.[22]

Physical

LCHAD deficiency often manifests as a combination of chronic nonspecific symptoms. Early diagnosis is difficult in the absence of the classical metabolic changes.[23]

Neuropsychological examination   

Patients with LCHAD deficiency have a specific cognitive pattern, including intellectual disability and specific autistic deficiencies.[24] They may have a normal intelligence quotient (IQ) with weaknesses in auditive verbal memory and adaptive and executive functions.

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.

Skeletal muscle

In 8 cases, light microscopy of muscle specimens showed fatty infiltration and fiber degeneration.[25]

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 LCHAD activity deficiency.

Molecular defects are responsible for the two types of defect of MTP (ie, LCHAD activity deficiencies, MTP deficiencies).

The molecular defect affects the function of the MTP, which contains the activity of LCHAD activity, 2-enoyl-CoA hydratase, and 3-oxoacyl CoA hydratase.

In most patients, the deficiency is isolated to LCHAD activity; yet, in some patients, defective activity of all 3 enzymes of the protein is observed.

In isolated LCHAD 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 LCHAD 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 numerous mutations in either alpha or beta subunit DNA encoding regions with resulting decreased functioning of all 3 enzyme activities of LCHAD.[26]

 

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[27]

Peripheral neuropathy

Pigmentary retinopathy

Pregnancy: Pregnancy complications reported in LCHAD deficiency carriers (with a LCHAD-deficient fetus), include HELLP syndrome and acute fatty liver of pregnancy.

 

DDx

 

Workup

Laboratory Studies

The studies listed below may be indicated in LCHAD deficiency

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 is also 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 (sequencing) to identify the common mutation, G1528C, are available. In addition, if only one mutation is identified in one allele, the presence of deletions can be checked on the other allele by oligonucleotide-based array comparative genomic hybridization (CGH).

Prenatal diagnosis: Prenatal diagnosis using biochemical studies has been attempted. In appropriate families in whom the molecular defect is known, prenatal diagnosis is also possible by mutation analysis. Guidelines for prenatal screening have been established.

Newborn screening of blood spots with tandem mass spectrometry

Newborn screening of blood spots with tandem mass spectrometry is used to detect abnormal acylcarnitine profiles for both LCHAD and mitochondrial trifunctional protein (MTP) deficiencies.[28] Using umbilical cord blood for acylcarnitine analysis was shown to be effective and reliable in at-risk newborns.[29] However, further molecular or functional analysis is crucial for accurate diagnosis.[30]

Imaging Studies

Chest roentgenography may reveal enlargement of the cardiac silhouette if cardiomyopathy is present.

Echocardiography may reveal cardiac enlargement, poor contractility with decreased ejection fraction, and pericardial effusion in some cases.

Since LCHAD deficiency is often characterized by retinopathy, modern multimodal imaging techniques have been used to better assess photoreceptor dystrophy.[31, 32]

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.

Electroretinography may reveal progression of chorioretinopathy.[33]

Electroneurography (ENG) has been used in long-term studies to evaluate the development of polyneuropathy.[34]

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 be noted.

If elevated C16-OH ± C18:1-OH and other long chain acylcarnitines are present on newborn screening, the pediatrician should do the following:

  • Contact the family to inform them of newborn screening results and determine clinical status and whether poor feeding, vomiting, and lethargy are present
  • Contact pediatric metabolic specialist
  • Evaluate infant for hepatomegaly, signs of hypoglycemia and metabolic acidosis and cardiomyopathy
  • Evaluate family history to determine whether a history of sudden death in a sibling and whether maternal liver disease was noted during pregnancy
  • Educate family about signs and symptoms of hypoglycemia and metabolic acidosis

A metabolic specialist needs to confirm or exclude diagnosis of LCHAD deficiency by requesting an acylcarnitine profile and urine organic acid analysis. If carnitine levels are low, consider carnitine supplementation. In addition, an evaluation should be done to exclude hypoglycemia, elevated liver transaminases, bilirubin, lactate, ammonia, and creatine phosphokinase, which could be suggestive of LCHAD and trifunctional protein deficiencies.

In addition, sequencing of the gene that encodes LCHAD is clinically available for molecular confirmation.[28] If only one mutation is found in one allele, a possible deletion should be screened in the other allele by using oligonucleotide-based array CGH.

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, although 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 has also 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

Medical Care

Patients with LCHAD deficiency may have normal growth and development with early appropriate treatment.[35]

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. However, the availability of DNA studies (eg, sequencing and oligonucleotide-based array comparative genomic hybridization [CGH]) may supersede the need to start with fatty acid oxidation studies in cultured fibroblasts.

In cases of acute decompensation with unconfirmed diagnosis, collect samples during the acute episode while the hypoglycemia is 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.

Oral supplementation with docosahexanoic acid ethyl ester (DHA) may be considered to improve visual function. Consider carnitine supplementation if hypocarnitinemia is present; however, carnitine should not be used during acute decompensation.

Consultations

See the list below:

  • 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 usually recommended. However, short-term higher-protein diets were shown to be safe and well-tolerated by overweight and obese children with LCAD deficiency. These patients benefited from the lowered energy intake and increased energy expenditure compared to a standard high-carbohydrate diet.[36]

Addition of medium-chain triglycerides (MCT) 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.

Coordinating MCT supplementation (0.5 g per kg of lean body mass) with periods of increased activity may improve the metabolic control of children with LCHAD and trifunctional protein deficiency following exercise.

The 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.[37] Use of flax/walnut oils (containing the least amount of nonessential fatty acids) when compared to canola oil may reduce the accumulation of disease specific acyl-CoA intermediates, preventing peripheral neuropathy.[38]

Prevention of fasting with frequent feeds is crucial.

DHA supplementation (100 mg/d) as some reports have demonstrated improvements of visual function with supplementation.

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.

Because the incidence of obesity and overweight is increasing among children with LCHAD or trifunctional protein deficiency, a diet higher in protein and lower in carbohydrates may help to lower total energy intake and maintaining good metabolic control. However, long-term studies are needed in order to determine whether higher protein diets reduce risks of overweight and obesity.

Activity

Advise tempered activity in patients at an increased risk for rhabdomyolysis and myoglobinuria.

Advise that coordinating MCT supplementation with periods of increased activity may improve metabolic control following exercise.[39]

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.

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.

Screening for LCHAD deficiency should be performed in newborns from mothers with hepatic complications during pregnancy such as acute fatty liver of pregnancy or severe hemolytic anemia, elevated liver enzymes, low platelet count (HELLP) syndrome.

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 medium-chain triglyceride (MCT) oil.

Monitor carnitine levels and determine if carnitine supplementation is required.

Refer patient for ophthalmological evaluation for possible pigmentary retinopathy. All of these subjects should have a baseline ophthalmological evaluation within the first month of diagnosis and annual follow-ups. Fundus photography and repeated electroretinography examinations should be performed.

Conduct a neurological evaluation with nerve conduction studies to assess for possible peripheral neuropathy.

Further Inpatient Care

Admit patients with LCHAD deficiency 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 intravenous (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.

Inpatient & Outpatient Medications

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.

 

Medication

Medication Summary

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.

Several novel therapies[40] are currently under development, as follows:

  • Ketone body replacement therapy has shown a positive effect on numerous LCHADD symptoms, including motor development, liver size, and leukodystrophy.
  • Triheptanoin improves biochemical abnormalities, cardiomyopathy, and hypoglycemia in patients with LCHAD deficiency.
  • Other potential therapies include gene therapy and bezafibrates, the latter of which promotes transcription of fatty acid oxidation genes.

Dietary supplements

Class Summary

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.

Levocarnitine (Carnitor)

An amino acid derivative synthesized from methionine and lysine, required in energy metabolism. Can promote excretion of excess fatty acids in patients with defects in fatty acid metabolism or specific organic acidopathies, which bioaccumulate acyl CoA esters. Normal levels occur in liver, and mild level increases occur in skeletal muscle.

High doses are able to restore the level of free carnitine in plasma to normal, and many patients improve with this therapy; however, the concentration of long-chain acyl-carnitines increases, which can be detrimental and cause serious cardiac arrhythmias in fulminant crises.

Use in long-chain fatty acid oxidation disorders (eg, LCHAD deficiency, MTP deficiency) is a matter of continued debate, mainly during acute fulminant crises when it enhances the formation of long-chain acylcarnitines, which may cause ventricular arrhythmogenesis.