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

Carnitine Deficiency

Author: Fernando Scaglia, MD, FACMG, Associate Professor of Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital
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Updated: Jul 22, 2009

Introduction

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) is also 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).

OCTN2 mutations can affect carnitine transport by impairing maturation of transporters to the plasma membrane.

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 CNS, 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 are also 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

United States

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.

International

In a Japanese study, primary systemic carnitine deficiency was estimated to occur in 1 per 40,000 births.¹ In Australia, the incidence has been estimated to be between 1:37,000-1:100,000 newborns. The frequency of this condition in adults is not known. However, in the United Kingdom, a previous report identified 4 affected mothers in 62,004 infants screened, with a frequency of 1:15,500.

Mortality/Morbidity

In order to abate the mortality and morbidity of undiagnosed primary carnitine deficiency, this condition has been included in the expanded newborn screening program in several states within the United States.² Primary carnitine deficiency can be identified in infants by expanded newborn screening using tandem mass spectrometry.³ Low levels of free carnitine (C0) are detected. However, low carnitine levels in newborns may also reflect maternal primary carnitine deficiency.

• 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 correctly diagnosed 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 CNS dysfunction associated with these episodes. If no carnitine replacement is given, recurrent episodes of encephalopathy may ensue.

A significant cohort of patients with primary carnitine deficiency do not present in infancy or early childhood as previously thought but remain asymptomatic into adulthood. These observations are derived from the experience of expanded newborn screening programs that identified maternal primary carnitine deficiency in mothers who were for the most part minimally symptomatic or asymptomatic. One mother with primary carnitine deficiency was reported to have a history of syncope that worsened during pregnancy, when plasma carnitine levels are physiologically lower.⁴

Race

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

Sex

No sex predilection is observed in primary carnitine deficiency.

Age

The mean age at onset for primary carnitine deficiency not detected or ascertained by a newborn screening program 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

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.
  • Pericardial effusion has also been observed in association with primary carnitine deficiency.⁵
  • Muscle weakness, the third manifestation of the disease, may accompany the heart failure or present by itself.
  • Carnitine deficiency may be a cause of GI 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
  • 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.
  • 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.
  • Respiratory symptoms are associated with heart failure
• 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 may also 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) may also present with secondary carnitine deficiency. Secondary carnitine deficiency may also 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). Whether carnitine deficiency is related to the primary metabolic defect, to the concomitant liver disease observed in the initial presentation, or to benzoate therapy is unclear.
  • 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 may also 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: Numerous 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. 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: 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.

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