AUTHOR INFORMATION

Section 1 of 11

Authored by Fernando Scaglia, MD, Assistant Professor of Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital

Fernando Scaglia, MD, is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society of Human Genetics, Juvenile Diabetes Foundation, and Society for Inherited Metabolic Disorders

Edited by Christian J Renner, MD, Consulting Staff, Department of Pediatrics, University Hospital for Children and Adolescents, Erlangen, Germany; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Leonard G Feld, MD, PhD, MMM, Chairman of Pediatrics, Carolinas Medical Center; Chief Medical Officer, Levine Children's Hospital, Carolinas Healthcare System; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Fernando Scaglia, MD
Editor's Email:	Christian J Renner, MD

eMedicine Journal, July 26 2006, VOLUME 7, Number 7

INTRODUCTION

Section 2 of 11

Background: Carnitine is a naturally occurring hydrophilic amino acid derivative, produced endogenously in the kidneys and liver and derived from meat and dairy products in the diet. It plays an essential role in the transfer of long-chain fatty acids into the mitochondria for beta-oxidation. Carnitine binds acyl residues and helps in their elimination, decreasing the number of acyl residues conjugated with coenzyme A (CoA) and increasing the ratio between free and acylated CoA.

Carnitine deficiency is a metabolic state in which carnitine concentrations in plasma and tissues are less than the levels required for normal function of the organism. Biologic effects of low carnitine levels may not be clinically significant until they reach less than 10-20% of normal. Carnitine deficiency may be primary or secondary.

Pathophysiology: Primary carnitine deficiency is caused by a deficiency in the plasma membrane carnitine transporter, with urinary carnitine wasting causing systemic carnitine depletion. Intracellular carnitine deficiency impairs the entry of long-chain fatty acids into the mitochondrial matrix. Consequently, long-chain fatty acids are not available for beta-oxidation and energy production, and the production of ketone bodies (which are used by the brain) also is impaired.

Regulation of the intramitochondrial free CoA also is affected, with accumulation of acyl-CoA esters in the mitochondria. This, in turn, affects the pathways of intermediary metabolism that require CoA (eg, Krebs cycle, pyruvate oxidation, amino acid metabolism, mitochondrial and peroxisomal beta oxidation).

The 3 areas of involvement include (1) the cardiac muscle, which is affected by progressive cardiomyopathy (by far, the most common form of presentation), (2) the central nervous system, which is affected by encephalopathy caused by hypoketotic hypoglycemia, and (3) the skeletal muscle, which is affected by myopathy.

Muscle carnitine deficiency (restricted to muscle) is characterized by depletion of carnitine levels in muscle with normal serum concentrations. Evidence indicates that the causal factor is a defect in the muscle carnitine transporter.

In secondary carnitine deficiency, which is caused by other metabolic disorders (eg, fatty acid oxidation disorders, organic acidemias), carnitine depletion may be secondary to the formation of acylcarnitine adducts and the inhibition of carnitine transport in renal cells by acylcarnitines.

In disorders of fatty acid oxidation, excessive lipid accumulation occurs in muscle, heart, and liver, with cardiac and skeletal myopathy and hepatomegaly. Long-chain acylcarnitines also are toxic and may have an arrhythmogenic effect, causing sudden cardiac death.

Encephalopathy may be caused by the decreased availability of ketone bodies associated with hypoglycemia. Preterm newborns also may be at risk for developing carnitine deficiency because immature renal tubular function combined with impaired carnitine biosynthesis renders them strictly dependent on exogenous supplies to maintain normal plasma carnitine levels.

Valproic acid may cause an acquired type of secondary carnitine deficiency by directly impairing renal tubular reabsorption of carnitine. The effect on carnitine uptake and the existence of an underlying inborn error involving energy metabolism may be fatal; in other cases, it may primarily affect the muscle, causing weakness.

Frequency:

• In the US: No studies have estimated the incidence of primary carnitine deficiency in the United States, however, it may be similar to the incidence in Japan from the cases already reported.

• Internationally: In a Japanese study, primary systemic carnitine deficiency was estimated to occur in 1 per 40,000 births. In Australia, the incidence has been estimated to be between 1:37,000-1:100,000 newborns. No estimates are available for Europe.

Mortality/Morbidity:

• Sudden death: Unfortunately, the first clinical manifestation in asymptomatic individuals with primary carnitine deficiency may be sudden death. This also may occur in patients with secondary carnitine deficiency as a consequence of ventricular tachycardia or fibrillation.

• Heart failure: Patients with primary carnitine deficiency develop a progressive cardiomyopathy that usually presents at a later age. The cardiac function does not respond to inotropes or diuretics. If the condition is not diagnosed correctly and no carnitine is supplemented, progressive heart failure eventually leads to death. Heart failure caused by dilated cardiomyopathy may be the presenting syndrome in patients with secondary carnitine deficiency caused by defects in beta-oxidation, such as long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency.

• Hypoglycemic hypoketotic encephalopathy: Acute encephalopathy accompanied by hypoketotic hypoglycemic episodes usually presents in younger infants with primary carnitine deficiency. Periods of fasting in association with viral illness trigger these acute episodes. Some patients have developmental delay and central nervous system dysfunction associated with these episodes. If no carnitine replacement is given, recurrent episodes of encephalopathy may ensue.

Race: Overall, this disorder is panethnic, and, in some families, consanguinity is present in cases of primary carnitine deficiency.

Sex: No sexual predilection exists for primary carnitine deficiency.

Age:

• The mean age at onset for primary carnitine deficiency is 2 years, with onset ranging from 1 month to 7 years. Infants typically present with hypoketotic hypoglycemia, whereas older children present with skeletal or heart myopathy.

• Symptoms of muscle carnitine deficiency may appear early yet generally occur later (ie, second or third decade of life).

• In secondary carnitine deficiency caused by fatty acid oxidation disorders, the age of onset varies. Metabolic decompensation triggered by viral illness, associated with encephalopathy, and accompanied by liver involvement, hypotonia, or cardiomyopathy tends to occur in infancy. Cardiomyopathy or skeletal myopathy tends to present later. Carnitine deficiency also may occur in preterm newborns receiving total parenteral nutrition (TPN) with no carnitine supplementation.

CLINICAL

Section 3 of 11

History:

• Primary carnitine deficiency


• • One classic initial presentation of primary carnitine deficiency is hypoketotic hypoglycemic encephalopathy, accompanied by hepatomegaly, elevated liver transaminases, and hyperammonemia.
  
  
  
  • Cardiomyopathy is the other classic presentation (affecting older children); onset may occur with rapidly progressive heart failure. Cardiomyopathy can also be observed in older patients with a metabolic presentation, even if they are asymptomatic from a cardiac standpoint.
  
  
  
  • Muscle weakness, the third manifestation of the disease, may accompany the heart failure or present by itself.
  
  
  
  • Carnitine deficiency may be a cause of gastrointestinal dysmotility, with recurrent episodes of abdominal pain and diarrhea.
  
  
  
  • Hypochromic anemia and recurrent infections are other manifestations of the disease.

  • Few patients who were asymptomatic most of their lives have presented following the birth of a child.

  • Mild developmental delay can be the only manifestation in rare cases.
  
  
  
• Muscle carnitine deficiency


• • Severe reduction in muscle carnitine levels and normal serum carnitine concentrations characterize muscle carnitine deficiency. This disorder is restricted to muscle, with no renal leak of carnitine or signs of liver involvement.

  • Symptoms of muscle carnitine deficiency can appear in the first years of life, but they may occur later during the second or third decade. Patients may experience proximal muscular weakness of varying degree, exercise intolerance, or myalgia.
  
  
  
• Secondary carnitine deficiency


• • Fatty acid oxidation defects: Breastfed infants may experience a catabolic state shortly after birth, when the production of milk is not adequate to meet nutritional requirements. Acute metabolic decompensation with hypoketotic or nonketotic hypoglycemia usually occurs in infancy, whereas cardiac and skeletal muscle disease manifest later. The episodes of metabolic decompensation, triggered by fasting or common viral illness, consist of altered consciousness that can be complicated by seizures, apnea, or cardiorespiratory arrest. Patients may have a history of failure to thrive, developmental delay, or nonspecific abdominal problems.
  
  
  
  • Patients with organic acidemias causing secondary carnitine deficiency may present with crises consisting of hypoglycemia, ketoacidosis, and hyperammonemia.
  
  
  
  • Patients with respiratory chain defects or mitochondrial disorders and secondary carnitine deficiency may present with abnormal fatigability and lactic acidosis associated with exertion. These children also may present with encephalopathy and/or lipid storage myopathy and carnitine depletion. Carnitine deficiency has been observed in children with urea cycle defects, and it may exacerbate episodes of hyperammonemia.
  
  
  
  • Carnitine deficiency in the preterm newborn: Signs and symptoms related to carnitine deficiency are not completely defined in the newborn. Apnea, cardiac death, and sudden death have been found in infants with carnitine depletion.
  
  
  
  • Carnitine deficiency can develop in children with renal Fanconi tubulopathy; it may be idiopathic and present with renal tubular acidosis or secondary to acquired or inherited conditions.
  
  
  
  • Carnitine deficiency may present in children being treated with valproic acid and may be associated with fulminant liver failure and presentation similar to that in Reye syndrome. It also may present with a myopathy and increased lipid storage in patients with AIDS who are being treated with zidovudine.
  
  
  

Physical:

• In primary carnitine deficiency, physical findings may vary depending on the form of presentation.


• • CNS: If the presentation is encephalopathy caused by hypoketotic hypoglycemia, the patient may present limp, unresponsive, and comatose after a prolonged fast. Pyramidal movements or minimal athetoid movements can persist after this type of presentation. Modest hepatomegaly also can be appreciated.
  
  
  
  • Skeletal muscle: In the myopathic presentation, patients may have mild motor delays, hypotonia, or progressive proximal weakness.
  
  
  
  • Cardiac muscle: Patients with primary carnitine deficiency may present with cardiomyopathy. Onset may occur with rapidly progressive heart failure or murmur. Cardiomegaly may be found on the physical examination, associated with the presence of a heart murmur. A gallop rhythm can be found, associated with a dilated cardiomyopathy.
  
  
  
• Muscle carnitine deficiency findings are limited to muscle and can be associated with proximal weakness and signs of exercise intolerance and cardiomyopathy.



• Secondary carnitine deficiency presents with clinical manifestations of fatty acid oxidation disorders.


• • Episodes of metabolic decompensation triggered by infection or fasting may present with lethargy that may be accompanied by seizures or apnea.
  
  
  
  • This encephalopathy also may present with hypotonia and hepatomegaly.
  
  
  
  • Signs of cardiac hypertrophy may be evident, with gallop or heart murmur on the cardiac examination.
  
  
  
  • Less frequently, these patients may have other findings, such as pigmentary retinopathy, peripheral neuropathy, cardiac arrhythmias, or myoglobinuria.
  
  
  
  • Disorders such as glutaric aciduria type II or carnitine palmitoyltransferase II (CPT-II) deficiency can present with dysmorphic features, such as mid-facial hypoplasia and frontal bossing (Zellwegerlike phenotype) and congenital abnormalities of the abdominal wall.
  
  
  

Causes:

• Primary carnitine deficiency is caused by a defect in the plasma membrane carnitine transporter in kidney and muscle. The lack of the plasma membrane carnitine transporter results in urinary carnitine wasting and in decreased intracellular carnitine accumulation. Causative mutations in a gene called OCTN2 are responsible for this condition.



• Carnitine deficiency limited to the muscle is observed in myopathic carnitine deficiency with severe reduction in muscle carnitine levels. The basic biochemical defect has not been identified.



• Secondary carnitine deficiency, which manifests with a decrease of carnitine levels in plasma or tissues, may be associated with genetically determined metabolic conditions, acquired medical conditions, or iatrogenic states.


• • Disorders of the carnitine cycle or disorders of fatty acid beta-oxidation can cause secondary carnitine deficiency via several mechanisms. Block in fatty acid oxidation contributes to the accumulation of acyl-CoA intermediates. Transesterification with carnitine leads to the formation of acylcarnitine and the release of free CoA. These acylcarnitines are excreted readily in the urine. They inhibit carnitine uptake at the level of the carnitine transporter in renal cells, causing increased carnitine losses in the urine and systemic secondary depletion of carnitine.
  
  
  
  • Other genetic conditions that are associated with Fanconi syndrome (eg, Lowe syndrome, cystinosis) may present with secondary carnitine deficiency because of increased renal losses of carnitine. Lysinuric protein intolerance is associated with an increased excretion of lysine in the urine, and the biosynthesis of carnitine needs lysine. Other metabolic disorders (eg, propionic acidemia, methylmalonic acidemia) also may present with secondary carnitine deficiency. Secondary carnitine deficiency also may be observed in respiratory chain defects.
  
  
  
  • Aminoacidopathies (eg, isovaleric acidemia, propionic acidemia, methylmalonic acidemia, glutaric acidemia type I, 3-hydroxymethylglutaryl-CoA lyase deficiency) also contribute to the accumulation of acyl-CoA intermediates at the site of the metabolic block. This occurs with the formation of acylcarnitine esters, which are transported out of the cell and excreted in the urine. The decreased threshold for carnitine excretion causes low total carnitine levels in plasma and tissue.
  
  
  
  • Carnitine deficiency has been observed in children with urea cycle defects (eg, ornithine transcarbamylase deficiency, carbamoyl phosphate synthetase deficiency). It is unclear whether carnitine deficiency is related to the primary metabolic defect, to the concomitant liver disease observed in the initial presentation, or to benzoate therapy.
  
  
  
  • Carnitine deficiency is observed in disorders of the mitochondrial respiratory chain, such as cytochrome c oxidase deficiency, in which the ATP depletion may compromise the energy-dependent carnitine uptake. An interference with carnitine transport occurs in tissues, including renal reabsorption, which explains the low plasma and tissue levels in these patients.
  
  
  
  • Other inborn errors of metabolism or genetic disorders may cause secondary carnitine deficiency because of impairment of carnitine biosynthesis secondary to increased urinary losses of lysine, which occurs in lysinuric protein intolerance. Increased urinary loss of carnitine associated with Fanconi syndrome may be observed in syndromes such as cystinosis or Lowe syndrome (ie, X-linked oculocerebrorenal syndrome).
  
  
  
  • Acquired medical conditions may affect carnitine homeostasis. Cirrhosis or chronic renal failure may impair the biosynthesis of carnitine. Diets with low carnitine content (eg, lacto-ovo–vegetarian diet) or malabsorption syndromes may cause secondary carnitine deficiency. It also may be observed in conditions of increased catabolism present in patients with critical illness. Increased losses of carnitine in the urine, which occur in renal tubular acidosis or Fanconi syndrome, may cause secondary carnitine deficiency. Preterm neonates are at risk for developing carnitine deficiency because they have impaired reabsorption of carnitine at the level of the proximal renal tubule and immature carnitine biosynthesis.

  • In cases of maternal primary carnitine deficiency, few infants were found to have dramatically reduced levels of carnitine in newborn screening. However, these levels rapidly normalized with supplementation. The diagnostic work-up revealed that their mothers had primary carnitine deficiency and were asymptomatic all of their lives, with the mother’s disorder being unmasked by low carnitine levels in their infants.
  
  
  
  • Iatrogenic causes of secondary carnitine deficiency include several drugs associated with secondary carnitine deficiency (eg, valproate, pivampicillin, emetine, zidovudine).
    • Valproate: A number of mechanisms have been cited, such as sequestration of CoA by valproic acid and metabolites (causing a secondary disturbance of intermediary metabolism) and direct inhibition of fatty acid oxidation enzymes by valproic acid metabolites. It has been shown that, in cultured fibroblasts, valproic acid impairs the plasma membrane carnitine uptake in vitro. This impairment of carnitine uptake may explain serum depletion caused by decreased renal tubular reabsorption of carnitine and muscle depletion caused by decreased muscle uptake.

    • Zidovudine: It is thought that the muscle mitochondrial impairment caused by zidovudine in patients with AIDS results in decreased content of muscle carnitine levels caused by decreased carnitine uptake in muscle.
  
  
  

DIFFERENTIALS

Section 4 of 11

Cardiomyopathy, Dilated
Heart Failure, Congestive
Hyperammonemia
Hypoglycemia
Long-Chain Acyl CoA Dehydrogenase Deficiency
Myoglobinuria
Sudden Infant Death Syndrome

Other Problems to be Considered:

Reye syndrome

WORKUP

Section 5 of 11

Lab Studies:

• Immediately check blood glucose and urine ketones if a child presents to the emergency room with lethargy, seizures, apnea, or any episode of decreased consciousness. The absence or low amounts of ketones in the urine, combined with the episode of hypoglycemia in primary carnitine deficiency (as well as in other defects in the carnitine cycle or fatty acid oxidation), causes secondary carnitine deficiency.



• Obtain ammonia level, liver enzymes (ie, aspartate aminotransferase [AST], alanine aminotransferase [ALT], glutamyltransferase [GGT]), chemistry panel, uric acid, creatine kinase (CK), lactic acid, and coagulation tests.


• • Ammonia levels can be moderately elevated, especially in primary carnitine deficiency and particularly if the child has a presentation similar to that of Reye syndrome.
  
  
  
  • Transaminases usually are moderately elevated in primary carnitine deficiency.
  
  
  
  • In some defects of the carnitine cycle that cause secondary carnitine deficiency (eg, CPT-II deficiency), a hepatocardiomuscular form can present with liver involvement. Other fatty acid oxidation disorders, such as LCHAD deficiency, can present with liver involvement.
  
  
  
  • A chemistry panel may show evidence of metabolic acidosis.
  
  
  
  • Hyperuricemia may be present in carnitine deficiency because carnitine competes for renal tubular excretion.
  
  
  
  • Elevated serum CK levels may be observed in primary carnitine deficiency and in fatty acid oxidation disorders.
  
  
  
  • Elevated lactate can be observed in respiratory chain defects or in LCHAD deficiency.
  
  
  
  • Altered coagulation with prolonged prothrombin time may be found.
  
  
  
• Plasma carnitine: In primary carnitine deficiency, the carnitine level in plasma usually is less than 5% of normal, with acylcarnitines proportionately reduced. The ratio between acylcarnitine and free carnitine is normal. A feature of most fatty acid oxidation disorders is that they are associated with decreased plasma carnitine concentrations. This feature also is observed in other inborn errors of metabolism that cause secondary carnitine deficiency, such as organic acidemias caused by the formation of carnitine esters.



• Urine carnitine: This is only useful in primary carnitine deficiency in which the transporter in kidney cells has decreased capacity for reabsorption, causing increased carnitine excretion.

• Newborn screen: Recently, several patients with primary carnitine deficiency have been ascertained through newborn screening programs. In these cases, the acylcarnitine profile reveals a low level of free carnitine and all acylcarnitine species. However, plasma carnitine levels can be within the reference range if obtained too early, due to the transfer of carnitine through the placenta to the fetus.



• Urine organic acids: In primary carnitine deficiency, the urine organic acid analysis usually is normal. In cases of fatty acid oxidation disorders that cause secondary carnitine deficiency, inappropriate dicarboxylic aciduria occurs during periods of illness. Urinary organic acid profile usually is normal in these patients when they are well, except in cases of MCAD deficiency. In some disorders (eg, MCAD, LCHAD, short-chain acyl-CoA dehydrogenase [SCAD] deficiency) specific patterns can be seen. It is very important to collect this specimen during illness.



• Urine acylglycines: In MCAD deficiency, the urine contains increased amounts of glycine conjugates. The test also may be used in individuals with suspected glutaric aciduria type II or SCAD deficiency.



• Acylcarnitine profile and free fatty acids: Tandem mass spectrometry analyses of acylcarnitine profile and free fatty acids may be used to detect metabolic defects that cause secondary carnitine deficiency (eg, fatty acid oxidation disorders, organic acidemias) because acyl-CoA intermediates proximal to the block in fatty acid or amino acid oxidative pathway may be transesterified to carnitine. Modest amounts of long-chain 3-hydroxy fatty acids consistently are found in the plasma of patients with LCHAD deficiency, even if these patients are asymptomatic.



• In a fasting test, patients undergo a controlled and prolonged fast under strict medical supervision. Take blood samples at regular intervals to measure glucose, ketone bodies, and free fatty acids. Acylcarnitine profile may be obtained at the same time. Fasting may be continued in children for up to 24 hours, unless blood glucose drops to less than 3 mmol/L. An inadequate production of ketones with a high free fatty acid–to–ketone bodies ratio suggests a defect in long-chain fatty acid oxidation.



• Fatty acid oxidation studies in fibroblasts are used if a fatty acid oxidation defect is suspected clinically. The most appropriate first line of investigation in these patients is to study the entire fatty acid oxidation pathway. Methods involve (1) monitoring the rate of production of radioactive end products of fatty acid oxidation disorders for radiolabeled precursor fatty acids or (2) measuring by tandem mass spectrometry the disease-specific acylcarnitines produced when stable isotope fatty acid precursors are incubated with cells in the presence of excess L-carnitine.



• Enzyme assay, the criterion standard for demonstrating an enzyme defect, measures the activity in cultured fibroblasts or in some other tissue, such as muscle or liver. To account for the frequent finding of overlapping chain-length specificities, complex analysis using a mixture of different chain-length substrates and immunoprecipitation with antibodies to different enzymes is required.



• Carnitine transport assay in cultured fibroblasts specifically demonstrates the absence of active carnitine transport in cultured fibroblasts. This finding is specific for primary carnitine deficiency.



• Molecular diagnosis provides information on the gene for the carnitine transporter defective in primary carnitine deficiency, which has been cloned (OCTN2) and can be screened for mutations. Most patients have private mutations, and few mutations have been reported more than once. No genotype-phenotype correlation exists.

• The genes for most of the enzymes of fatty acid oxidation that are defective in fatty acid oxidation disorders and may cause secondary carnitine deficiency have been identified, and mutation analysis is available for a number of genes (eg, CPT1, CPT2, VLCAD, TFP, MCAD). Prevalent mutations have been identified in patients with MCAD deficiency (A985G) and LCHAD deficiency (G1528C). In the adult form of CPT-II deficiency, a C439T mutation accounts for 60% of mutations in patients with adult onset.

Imaging Studies:

• Roentgenograms reveal cardiac enlargement in primary carnitine deficiency and fatty acid oxidation disorders, such as LCHAD or VLCAD deficiency, which may cause secondary carnitine deficiency.



• In primary carnitine deficiency (as well as in fatty acid oxidation disorders, which also may present with cardiomyopathy), the echocardiogram may reveal cardiac enlargement and increased thickness of the left ventricular wall.



• Brain imaging studies (eg, cranial ultrasound, brain MRI) may show cystic lesions in glutaric aciduria type II or basal ganglia involvement in mitochondrial disorders that may be associated with secondary carnitine deficiency.

Other Tests:

• The ECG reveals left ventricular hypertrophy and peaked T waves in primary carnitine deficiency. Cardiac arrhythmias can be observed in translocase deficiency and in the lethal neonatal form of CPT-II deficiency.

Procedures:

• Skin biopsy can be performed to confirm diagnosis of primary carnitine deficiency by demonstrating reduced carnitine transport in fibroblasts that express the transporter. Fibroblasts may be used for fatty acid oxidation studies or enzyme assay.



• Muscle biopsy may be necessary to confirm the diagnosis of some conditions that may cause secondary carnitine deficiency (eg, respiratory chain defect) or to measure the carnitine concentration in muscle in cases of myopathic carnitine deficiency.

TREATMENT

Section 6 of 11

Medical Care:

• Evaluation for carnitine deficiency may be performed on an outpatient basis. In cases of acute decompensation, inpatient studies may be necessary in the acute phase and following stabilization of the patient.



• In acute situations, if the patient presents with hypoketotic hypoglycemic encephalopathy, insure stabilization with 10% dextrose in water at rates of 10 mg/kg/min IV initially; adjust infusion rate according to blood glucose concentrations.



• Intravenous (IV) carnitine restores tissue carnitine concentrations for the transport of fatty acids in the mitochondria. This treatment removes toxic metabolites in the form of carnitine esters that are readily excreted in the urine. Use of IV carnitine should be considered only when the diagnosis of primary carnitine deficiency is entertained or confirmed. The use of IV carnitine in disorders of fatty acid oxidation in which long-chain acylcarnitines accumulate and have the potential of being arrhythmogenic is controversial. IV carnitine may be considered in cases of organic acidemias (eg, isovaleric acidemia, propionic acidemia, methylmalonic acidemia) when oral intake is not feasible.



• Consider pharmacological support for cardiomyopathy.



• Medical therapy with oral carnitine in primary carnitine deficiency improves fasting ketogenesis, cardiac function, growth, and cognitive performance.



• Direct the therapy in secondary carnitine deficiency to replenish carnitine and treat the primary metabolic defect with specific diet and other supplements, such as riboflavin, glycine, or biotin.

Consultations:

• Genetic metabolic services



• Nutritionist

Diet:

• Patients with primary carnitine deficiency requires no special diet as long as they are taking carnitine supplementation and are not faced with situations of stress and starvation.



• Patients with fatty acid oxidation disorders require a high-carbohydrate fat-restricted diet (30% calories from fat) and must eat frequently.



• Prescribe medium-chain triglyceride supplementation in patients with long-chain fatty acid disorders.



• Advise use of uncooked cornstarch at bedtime to prevent early morning hypoglycemia after the overnight fast.



• Supplementation of essential fatty acids (ie, linoleic acids, linolenic acids) prevents the growth restriction and dermatitis that are associated with fatty acid deficiency.



• Consider specific protein-restricted diets in patients with aminoacidopathies and organic acidemias associated with secondary carnitine deficiency.

Activity:

• Once carnitine supplementation has been instituted for primary carnitine deficiency, cardiac function, strength, and growth improve significantly. No specific recommendations to limit physical activity are indicated if the cardiomyopathy has reverted.



• Secondary carnitine deficiency caused by fatty acid oxidation disorders may require tempered or restricted activity in certain cases, including the following:


• • Conditions associated with increased risk for rhabdomyolysis and myoglobinuria (eg, CPT-II deficiency, VLCAD deficiency)
  
  
  
  • Conditions in which a cardiomyopathy is present (eg, LCHAD deficiency, VLCAD deficiency)
  
  
  
• Strenuous exercise or activity should be avoided, and frequent snacks and good hydration should be procured with physical activity.

MEDICATION

Section 7 of 11

Use of L-carnitine in primary carnitine deficiency restores plasma carnitine levels to nearly normal, but muscle carnitine levels rise slightly. Muscle function can be normalized in patients with carnitine deficiency when muscle carnitine levels remain less than 10% of controls. Cardiomyopathy often responds well to carnitine supplementation. Carnitine supplementation in fatty acid oxidation disorders and other organic acidurias is to correct carnitine deficiency and to allow removal of toxic intermediates. The other goal of therapy is to restore CoA levels. Carnitine therapy for long-chain fatty acid oxidation defects has become questionable because it promotes formation of long-chain acylcarnitines that may cause arrhythmogenesis and membrane dysfunction. Carnitine supplementation in TPN prevents secondary carnitine deficiency in preterm newborns.

Drug Category: Dietary supplements -- At high doses, L-carnitine corrects severe carnitine depletion and associated metabolic abnormalities observed in primary carnitine deficiency and enables the production of ketone bodies during fasting. In secondary carnitine deficiency, carnitine enhances excretion of toxic metabolites and generation of free CoA.

Drug Name	Levocarnitine (Carnitor, L-Carnitine) -- 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. May cause reversal of skeletal and heart muscle abnormalities.
Adult Dose	1 g PO/IV tid; not to exceed 3 g/d
Pediatric Dose	50 mg/kg/d PO initially; may gradually increase to 100-400 mg/kg/d PO divided bid/tid; not to exceed 3 g/d
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Monitor blood chemistries, vital signs, plasma carnitine concentrations and overall clinical condition; in secondary carnitine deficiency, a number of metabolic disorders must be correctly diagnosed before initiation of carnitine supplementation; use in long-chain fatty acid oxidation defects (eg, LCHAD deficiency, trifunctional protein deficiency, VLCAD deficiency) may enhance formation of long-chain acylcarnitines which may cause ventricular arrhythmogenesis; adverse effects with toxic doses are nausea, vomiting, diarrhea, and a fish odor derived from a metabolite of carnitine (trimethylamine)

Drug Name	Dextrose 10% (D10W, D-glucose) -- Monosaccharide absorbed from intestines and distributed, stored, and used by tissues. Parenterally injected dextrose is used in patients unable to sustain adequate oral intake. Direct oral absorption results in a rapid increase in blood glucose concentrations. Dextrose is effective in small doses. Concentrated dextrose infusions provide higher amounts of glucose and increased caloric intake in a small volume of fluid.
Adult Dose	10 mg/kg/min IV initially; adjust infusion rate according to blood glucose concentrations
Pediatric Dose	Administer as in adults
Contraindications	Avoid in diabetic coma if blood sugar levels are extremely high and in severely dehydrated patients; avoid administration in intraspinal or intracranial hemorrhage; avoid in dehydrated patients with delirium tremens, hepatic coma, or glucose-galactose malabsorption syndrome
Interactions	Caution when administering parenteral fluids to patients receiving corticosteroids or corticotropin, especially if the solution contains sodium ions
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May cause nausea, which also may occur with hypoglycemia; IV dextrose solutions may result in dilution of serum electrolyte concentrations or overhydration if fluid overload is present Caution in congestion or pulmonary edema; hypertonic dextrose given peripherally may cause thrombosis (administer through central venous catheter); caution in subclinical diabetes mellitus or carbohydrate intolerance; risk of inducing significant hyperglycemia or hyperosmolar syndrome is increased if solution is administered rapidly, especially in patients with chronic uremia or carbohydrate intolerance Do not administer concentrated solutions SC/IM; rates of dextrose infusion >0.5 g/kg/h may produce glycosuria; monitor fluid balance, electrolyte concentrations, and acid-base balance closely; dextrose administration may produce vitamin B-complex deficiency

Drug Name	Riboflavin (Vitamin B-2) -- Essential in activation of pyridoxine and conversion of tryptophan to niacin; component of flavoprotein enzymes, which are necessary for tissue respiration. Riboflavin functions as a cofactor for electron transport in complex I, complex II, and in the electron transfer of flavoprotein. It has proven useful for the treatment of some patients with SCAD deficiency, riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency, and milder forms of glutaric aciduria type II.
Adult Dose	400 mg/d PO
Pediatric Dose	100 mg/d PO
Contraindications	None reported
Interactions	Probenecid decreases absorption
Pregnancy	A - Safe in pregnancy
Precautions	Pregnancy category C if dose exceed RDA; riboflavin deficiency often occurs in the presence of other B vitamin deficiencies; large dose may turn urine bright yellow

Drug Name	Betaine (Cystadane) -- Methyl group donor used in the treatment of homocystinuria. Decreases elevated homocysteine blood levels. Used for conditions that can cause hyperhomocysteinemia and secondary carnitine deficiency (ie, cobalamin C deficiency).
Adult Dose	3 g PO bid; not to exceed 20 g/d
Pediatric Dose	<3 years: 100 mg/kg/d PO initially; increase weekly by 100 mg/kg >3 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May cause GI distress (eg, nausea, diarrhea)

Drug Name	Hydroxocobalamin (Vitamin B-12, Hydro cobex) -- Deoxyadenosylcobalamin and hydroxocobalamin are active forms of vitamin B-12 in humans. Vitamin B-12 synthesized by microbes but not humans or plants. Vitamin B-12 deficiency may result from intrinsic factor deficiency (pernicious anemia), partial or total gastrectomy, or diseases of the distal ileum. Used to treat conditions caused by altered cobalamin metabolism that may cause secondary carnitine deficiency (ie, cobalamin C deficiency).
Adult Dose	Maintenance: 1 mg IM qd initially; may adjust dose and administration frequency as symptoms allow
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; hypersensitivity to cobalt; hereditary optic nerve atrophy
Interactions	Aminosalicylic acid may decrease biologic and therapeutic action; chloramphenicol may decrease hematologic effects; excessive alcohol and colchicine may cause malabsorption
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Administer IM only; anaphylactic shock and death have occurred after parenteral vitamin B-12 administration; give intradermal test dose in patients sensitive to cobalamins; antibody formation may occur to the hydroxocobalamin-transcobalamin complex; may rapidly (ie, within 48 h) cause severe hypokalemia

Drug Name	Ubidecarenone (CoQ-10, Coenzyme Q, Ubiquinone) -- Coenzyme involved in mitochondrial energy production. Controls flow of oxygen within individual cells. Has essential antioxidant and membrane-stabilizing properties.
Adult Dose	100 mg PO qd
Pediatric Dose	4.3 mg/kg/d PO divided bid/tid
Contraindications	Documented hypersensitivity
Interactions	Decreases effectiveness of warfarin
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Because of complexities related to absorption, levels can be helpful in optimizing the dose; this hydrophobic compound can be dissolved in vegetable oil to make a liquid for those unable to swallow

Drug Name	Glycine (Aminoacetic acid) -- The simplest amino acid that helps improve glycogen storage is used in the synthesis of hemoglobin, collagen, and glutathione, and it facilitates the amelioration of high blood fat and uric acid levels. Glycine primarily is used for the treatment of isovaleric acidemia, which is an organic acidemia that causes secondary carnitine depletion.
Adult Dose	250 mg/kg/d PO divided tid
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; anuria
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May cause hemolytic anemia, thrombocytopenia, hypotension, bradycardia, ECG changes, electrolyte and CNS (including visual) changes alterations

Drug Name	Biotin -- Water-soluble vitamin, generally classified as a B-complex vitamin. An essential coenzyme in fat metabolism and in other carboxylation reactions. Used for the treatment of biotin responsive propionic acidemia, which can lead to secondary carnitine deficiency.
Adult Dose	10 mg PO qd
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Primidone and carbamazepine inhibit absorption in small intestine; phenobarbital, phenytoin, and carbamazepine increase urinary excretion; long-term treatment with sulfa drugs or other antibiotics may decrease bacterial synthesis, potentially increasing the requirement for dietary biotin.
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	None reported

FOLLOW-UP

Section 8 of 11

Further Inpatient Care:

• Admit for medical management of acute metabolic decompensation.


• • Prescribe 10% dextrose in water at rates of 10 mg/kg/min or higher to achieve normal glucose concentrations. If the rate of glucose infusion is based on blood glucose level alone, it may underestimate carbohydrate demand because tissues are depleted of glycogen stores.
  
  
  
  • Provide IV carnitine if the patient is known to have carnitine deficiency and a defect affecting the oxidation of long chain fatty acids has been excluded.
  
  
  

Further Outpatient Care:

• Carefully monitor adequate carnitine dose in primary and secondary carnitine deficiencies by evaluating plasma carnitine levels during follow-up visits.



• Carefully review diet compliance in secondary carnitine deficiency, considering avoidance of fasting, intake of fat-restricted, high-carbohydrate diet, and other dietary supplements that may be needed, such as riboflavin or glycine.



• Treat infections aggressively.

In/Out Patient Meds:

• Medications include carnitine for primary and secondary carnitine deficiency, as well as other cofactors that may be needed for different conditions associated with secondary carnitine deficiency (eg, riboflavin, coenzyme Q, biotin, hydroxocobalamin, betaine, glycine).



• If a seizure disorder has developed secondary to a past episode of hypoglycemia, valproic acid should not be used as an anticonvulsant.

Transfer:

• Patients may require transfer to a tertiary care center in which a more specialized metabolic workup for further diagnostic evaluation can be performed.

Deterrence/Prevention:

• Prevent fasting with frequent feedings to avoid triggering episodes of hypoglycemia.



• Treat infections aggressively to prevent a catabolic state.



• Snacks and liquids should be consumed before exercise.



• Avoid exercise and dehydration with warm temperatures because attacks of rhabdomyolysis may occur with certain conditions that cause secondary carnitine deficiency.



• For fatty acid oxidation disorders, follow a fat-restricted diet with high carbohydrate content.



• Ensure uninterrupted carnitine supplementation.

Complications:

• Dilated cardiomyopathy with congestive heart failure



• Sudden infant death syndrome (SIDS)



• Rhabdomyolysis with myoglobinuria and secondary renal failure



• Hypotonia



• Hypochromic microcytic anemia



• Failure to thrive



• Gastrointestinal dysmotility



• Pigmentary retinopathy



• Peripheral neuropathy



• Central nervous system dysfunction with developmental delay, pyramidal signs, and athetoid movements

Prognosis:

• Primary carnitine deficiency


• • Patients with primary carnitine deficiency have excellent prognosis with oral carnitine supplementation.
  
  
  
  • If the disorder is unrecognized, mortality may occur from cardiac failure, arrhythmias, or sudden death.
  
  
  
  • Lifelong treatment with L-carnitine and avoidance of fasting are required. Hypoglycemia or sudden deaths from arrhythmias (even without cardiomyopathy) have been reported in patients who stop their carnitine supplementation against medical advice.
  
  
  
• Secondary carnitine deficiency


• • Prognosis of secondary carnitine deficiency depends on the nature of the disorder.
  
  
  
  • Translocase deficiency and the infantile form of CPT-II deficiency have very poor prognosis regardless of treatment.
  
  
  
  • In general, disorders of fatty acid oxidation require lifelong prevention of fasting and diet modification.
  
  
  
  • Other metabolic disorders that cause secondary carnitine deficiency, such as organic acidemias, require lifelong diet modification and nutritional supplements.
  
  
  

Patient Education:

• Family members should receive cardiopulmonary resuscitation (CPR) training (cases of apnea or near-miss SIDS).



• Family members should be taught to recognize early signs and symptoms of hypoglycemia and should be instructed to provide either glucose gel or glucagon injection while waiting for emergency aid.



• Educate family members about frequent feedings and avoidance of fasting in general. If oral intake is decreased or poor, the child should be seen immediately at pediatrician's office or rushed to the emergency room.



• Educate family members about the importance of continuing carnitine supplementation.



• Educate family members about adhering to fat-restricted diet in fatty acid oxidation disorders or special protein-restricted diet in organic acidemias causing secondary carnitine deficiency.



• Refer parents for genetic counseling and discussion of recurrence risk for future pregnancies.



• Educate family members about the possibility of prenatal diagnosis. If the molecular defect has been established in the proband (MCAD deficiency), molecular analysis can be performed.

MISCELLANEOUS

Section 9 of 11

Medical/Legal Pitfalls:

• Failure to investigate primary or secondary carnitine deficiency as a cause of dilated cardiomyopathy, possibly creating delays in treatment and unnecessary evaluation for cardiac transplantation



• Failure to recognize other associated presentations, such as hypoketotic hypoglycemia, possibly placing the patient at risk for further CNS dysfunction or death



• Failure to inform the family about carnitine supplementation and dietary restrictions



• Failure to recognize or evaluate for other complications from causes of secondary carnitine deficiency, such as pigmentary retinopathy and progressive sensorimotor neuropathy



• Failure to recognize that supplementation with low doses of carnitine may improve nitrogen balance and growth in preterm newborns who are at risk for developing secondary carnitine deficiency

Special Concerns:

• Acute fatty liver of pregnancy and the HELLP syndrome (ie, hemolysis, elevated liver enzyme levels, low platelet count) are serious hepatic conditions that may occur during pregnancy in heterozygous women whose fetuses are later found to have a LCHAD deficiency.



• Hepatic carnitine palmitoyltransferase I deficiency may present as maternal illness during pregnancy.



• Individuals who are heterozygous for mutations in the OCTN2 gene responsible for primary carnitine deficiency are predisposed to late-onset benign cardiac hypertrophy.



• Premature infants are at risk for developing secondary carnitine deficiency if they are given parenteral nutrition with no L-carnitine supplementation. Secondary carnitine deficiency develops because of increased renal losses and immature biosynthesis of carnitine.

TEST QUESTIONS

Section 10 of 11

CME Question 1: Which of the following is the most common presenting syndrome in individuals with primary carnitine deficiency?

A: Hypoketotic hypoglycemia
B: Skeletal myopathy
C: Progressive cardiomyopathy
D: Acute encephalopathy
E: Gastrointestinal dysmotility

The correct answer is C: Progressive cardiomyopathy is the most common presenting syndrome and usually affects older children. Skeletal myopathy may affect children of the same age, but it occurs less frequently than cardiomyopathy. Hypoketotic hypoglycemia is associated with acute encephalopathy and usually manifests in younger infants. Some patients with systemic carnitine deficiency may have gastrointestinal manifestations, such as recurrent episodes of abdominal pain and diarrhea.

CME Question 2: Which of the following is the treatment of choice for primary carnitine deficiency?

A: Biotin
B: High doses of L-carnitine
C: Protein restricted diet
D: Dichloroacetate
E: Creatine

The correct answer is B: Treatment of this disease with carnitine is highly successful. Cardiomyopathy and skeletal muscle weakness respond dramatically. Biotin is used in the treatment of propionic acidemia, which can cause secondary carnitine deficiency and other inborn errors of metabolism, such as biotinidase deficiency and holocarboxylase synthetase deficiency. A protein-restrictive diet is of no use in primary carnitine deficiency. Dichloroacetate is used for the treatment of lactic acidosis, which is present in disorders of pyruvate metabolism and respiratory chain defects. Creatine is thought to be beneficial for the treatment of mitochondrial encephalomyopathies.

Pearl Question 1 (T/F): Phenobarbital is the anticonvulsant that has been associated with secondary carnitine deficiency.

The correct answer is False: Long-term therapy with valproic acid has been associated with carnitine deficiency. The mechanism is thought to involve impairment of the plasma membrane carnitine uptake.

Pearl Question 2 (T/F): Gastrointestinal symptoms (eg, diarrhea) and a particular body odor are described as adverse effects of carnitine replacement.

The correct answer is True: Intermittent diarrhea and a fishy body odor (derived from trimethylamine) are described as adverse effects of toxic oral doses of carnitine.

Pearl Question 3 (T/F): The pathogenesis of primary carnitine deficiency involves a defect in carnitine biosynthesis.

The correct answer is False: No evidence of defective biosynthesis of carnitine is found in patients with primary carnitine deficiency. The pathogenesis involves a defect in carnitine uptake with increased renal excretion of carnitine and secondary systemic depletion of carnitine.

Pearl Question 4 (T/F): Premature infants experience impaired fatty acid oxidation.

The correct answer is True: In premature infants, immature renal tubular function exists, with increased excretion of carnitine in the urine, and the capacity for carnitine biosynthesis is limited by relatively low tissue levels of gamma-butyrobetaine hydroxylase (the limiting enzyme of carnitine biosynthesis); therefore, an adequate supply of exogenous carnitine is important, especially for premature infants receiving parenteral nutrition.

BIBLIOGRAPHY

Section 11 of 11

• Angelini C, Vergani L, Martinuzzi A: Clinical and biochemical aspects of carnitine deficiency and insufficiency: transport defects and inborn errors of beta-oxidation. Crit Rev Clin Lab Sci 1992; 29(3-4): 217-42[Medline].
• Bok LA, Vreken P, Wijburg FA, et al: Short-chain Acyl-CoA dehydrogenase deficiency: studies in a large family adding to the complexity of the disorder. Pediatrics 2003 Nov; 112(5): 1152-5[Medline].
• Bonner CM, DeBrie KL, Hug G, et al: Effects of parenteral L-carnitine supplementation on fat metabolism and nutrition in premature neonates. J Pediatr 1995 Feb; 126(2): 287-92[Medline].
• Borum PR: Carnitine in neonatal nutrition. J Child Neurol 1995 Nov; 10 Suppl 2: S25-31[Medline].
• De Vivo D, Tein I: Primary and secondary disorders of carnitine metabolism. International Pediatrics 1990; 5: 134-41.
• Koizumi A, Nozaki J, Ohura T, et al: Genetic epidemiology of the carnitine transporter OCTN2 gene in a Japanese population and phenotypic characterization in Japanese pedigrees with primary systemic carnitine deficiency. Hum Mol Genet 1999 Nov; 8(12): 2247-54[Medline].
• Lamhonwah AM, Olpin SE, Pollitt RJ, et al: Novel OCTN2 mutations: no genotype-phenotype correlations: early carnitine therapy prevents cardiomyopathy. Am J Med Genet 2002 Aug 15; 111(3): 271-84[Medline].
• Longo N, Amat di San Filippo C, Pasquali M: Disorders of carnitine transport and the carnitine cycle. Am J Med Genet C Semin Med Genet 2006 May 15; 142(2): 77-85[Medline].
• Pons R, De Vivo DC: Primary and secondary carnitine deficiency syndromes. J Child Neurol 1995 Nov; 10 Suppl 2: S8-24[Medline].
• Rinaldo P, Raymond K, al-Odaib A, et al: Clinical and biochemical features of fatty acid oxidation disorders. Curr Opin Pediatr 1998 Dec; 10(6): 615-21[Medline].
• Rinaldo P, Stanley CA, Hsu BY, et al: Sudden neonatal death in carnitine transporter deficiency. J Pediatr 1997 Aug; 131(2): 304-5[Medline].
• Roe C, Coates P: Mitochondrial fatty acid oxidation disorders. In: Scriver CR, et al, eds. The Metabolic and Molecular Basic of Inherited Disease. 7th ed. New York, NY: McGraw-Hill, Health Professions Division; 1995: 1501-1533.
• Saudubray JM, Martin D, de Lonlay P, et al: Recognition and management of fatty acid oxidation defects: a series of 107 patients. J Inherit Metab Dis 1999 Jun; 22(4): 488-502[Medline].
• Scaglia F, Wang Y, Longo N: Functional characterization of the carnitine transporter defective in primary carnitine deficiency. Arch Biochem Biophys 1999 Apr 1; 364(1): 99-106[Medline].
• Scaglia F, Longo N: Primary and secondary alterations of neonatal carnitine metabolism. Semin Perinatol 1999 Apr; 23(2): 152-61[Medline].

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