Carnitine Uptake Defect · CUD

Description

Primary carnitine uptake defect, often abbreviated CUD or systemic primary carnitine deficiency, is an autosomal recessive disorder of fatty acid oxidation. Pathogenic variants in SLC22A5 reduce or abolish the activity of OCTN2, the high-affinity sodium-dependent carnitine transporter on the plasma membrane. Without functional OCTN2, carnitine is lost in the urine and tissue carnitine stores fall. Long-chain fatty acids cannot enter the mitochondrial matrix for beta-oxidation, and energy supply to heart and skeletal muscle fails during fasting or illness. The causative gene is SLC22A5 on chromosome 5q31.

Clinical presentation falls along a wide spectrum. Infants and young children can present with hypoketotic hypoglycemia, hepatomegaly, and encephalopathy during a fasting illness. Older children and adults more often present with progressive dilated or hypertrophic cardiomyopathy, cardiac arrhythmia, or skeletal myopathy. Some adults remain effectively asymptomatic and come to attention only because a child screens positive on newborn screening, prompting maternal evaluation that reveals undiagnosed disease in the mother.

Detection is by newborn screening on the dried blood spot using tandem mass spectrometry. The marker is a low free carnitine, C0. Confirmation uses plasma free and total carnitine, fibroblast carnitine uptake assay, and SLC22A5 sequencing. Maternal plasma carnitine is checked in any newborn flagged for low C0, since a positive result can reflect maternal disease lowering fetal levels rather than disease in the infant.

Reported live-birth incidence in general newborn screening populations is roughly 1 in 40,000 to 1 in 100,000. The Faroe Islands carry a founder variant in SLC22A5 and have a much higher carrier rate; Rasmussen et al. (Journal of Inherited Metabolic Disease, 2014) report a Faroese disease frequency of approximately 1 in 297 live births from a nationwide screening program, the highest reported anywhere. Several Faroese sudden cardiac deaths in adolescents and adults were retrospectively attributed to undiagnosed primary carnitine deficiency, which prompted a national screening and treatment program.

Treatments to date

Treatment is lifelong oral L-carnitine supplementation, dosed to maintain plasma free carnitine in the normal range. Levocarnitine, marketed as Carnitor by Sigma-Tau, was approved by the FDA in 1985 for primary carnitine deficiency. An intravenous formulation supports acute illness when oral dosing fails or absorption is uncertain. Plasma free and total carnitine are monitored periodically and the dose is adjusted by weight and laboratory response.

Standard sick-day rules apply. Avoid prolonged fasting. During illness with poor oral intake, families seek prompt medical evaluation and intravenous dextrose. Cardiac surveillance with echocardiogram and electrocardiogram is part of routine follow-up because cardiomyopathy can develop or progress when supplementation is interrupted. Adherence is the central clinical issue across the lifespan, since carnitine clears rapidly from blood and tissue stores fall within days when doses are missed.

Treated children and adults generally have a normal life expectancy when diagnosis happens before cardiac damage and supplementation continues without long gaps. No gene therapy or small-molecule corrector for OCTN2 is approved. The Faroese national program pairs newborn screening, family cascade testing, and free supplementation, and is one of the clearest population-level examples of newborn screening preventing sudden cardiac death.