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.^[1]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).

SLC22A5 mutations can affect carnitine transport by impairing maturation of transporters to the plasma membrane.^[2]

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.^[3]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.^[4]Primary carnitine deficiency can be identified in infants by expanded newborn screening using tandem mass spectrometry.^[5]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.^[6]

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.^[7]

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 Presentation

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