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  • Primary carnitine deficiency, also known as carnitine uptake defect, is an autosomal recessive disorder caused by defective activity of the OCTN2 carnitine transporter. The lack of membrane transporters results in carnitine wasting in urine with systemic carnitine deficiency. Lack of carnitine impairs mitochondrial fatty acid oxidation and can result in fasting-induced hypoketotic hypoglycemia usually associated with hepatic dysfunction, or in progressive skeletal muscle and cardiac myopathy. Some patients remain asymptomatic into adult life.

  • Metabolic decompensation is usually precipitated by involuntary fasting associated with infection. Cardiomyopathy can develop even without any trigger and, if untreated, can result in death from cardiac failure or arrhythmia.

  • The OCTN2 carnitine transporter is encoded by the SLC22A5 gene on chromosome 5q31.1-32. The gene is regulated by peroxisome proliferator-activated receptor (PPAR) α through a peroxisome proliferator response element. The mature protein of 557 amino acids is ubiquitously expressed but has the highest levels in human heart placenta, skeletal muscle, kidney and pancreas. OCTN2 is localized to the apical membrane of renal tubular cells, consistent with its role in tubular reabsorption.

  • OCTN2 functions as a sodium-dependent carnitine transporter accumulating carnitine within cells against a concentration gradient, particularly in high energy-requiring tissues. Carnitine is essential in the transport of long-chain fatty acids into the mitochondrion for β-oxidation, a pathway which is compromised in carnitine deficiency states such as the carnitine transporter defect.

  • Patients with the carnitine uptake defect have very low levels of total carnitine in the circulation (usually less than 9 μmol/L, normal 25-50 μmol/L). Diagnosis is confirmed by functional assays in fibroblasts or DNA testing. Newborn screening can detect low levels of free carnitine (C0) in blood spots of affected children. Cases of maternal carnitine transporter deficiency have also been identified based on low neonatal carnitine levels.

  • Treatment of the carnitine uptake defect is effective and relies on high-dose carnitine supplementation (100-400 mg/kg/day). Outcomes are favorable, but treatment needs to be continued for life. At this time, it is not clear whether the apparently asymptomatic maternal cases of the defect require the same degree of therapy as this is a recent observation and insufficient follow up is available.


The discovery of the genetic defect in the plasma membrane carnitine transporter, OCTN2, first reported in 1988,1 represents the culmination of a century of research on the role of carnitine in normal physiology and in disease states. During the course of this history, carnitine attracted a great deal of speculation about its possible functions as a vitamin, an essential nutrient, and as a treatment for a variety of metabolic disorders affecting fatty acid oxidation in liver, muscle, and heart. Much of this speculation has not been substantiated, but continues to generate confusion about the role of carnitine deficiency in causing disease and its therapeutic use. This chapter will focus on the role of genetic defects in OCTN2 associated with primary carnitine deficiency. In addition, the chapter will discuss ...

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