Primary Carnitine Deficiency

Primary carnitine deficiency (carnitine uptake defect, systemic primary carnitine deficiency) is an autosomal recessive disorder due to biallelic variants in SLC22A5, with severely reduced plasma carnitine and impaired fatty acid oxidation. It causes hypoketotic hypoglycaemia in infancy, cardiomyopathy in childhood and fatigue or sudden death in adults, and is readily treatable with oral carnitine.

Pathophysiology. SLC22A5 encodes the organic cation transporter OCTN2, which carries carnitine into cells and reabsorbs it in the renal tubule. Loss causes excess urinary carnitine loss and low tissue levels. Without carnitine, long chain fatty acids cannot enter mitochondria for oxidation.

Heart, skeletal muscle and liver are most affected.

Mothers of affected infants may be diagnosed through low carnitine on newborn screening.

• Infantile metabolic decompensation (age 1 month to 2 years): hypoketotic hypoglycaemia, hepatic encephalopathy, hyperammonaemia, and Reye like illness during fasting or infection.
• Childhood cardiomyopathy (age 1 to 7 years): dilated or hypertrophic cardiomyopathy, with heart failure.
• Skeletal myopathy with weakness and raised creatine kinase.
• Failure to thrive and irritability.
• Adults: asymptomatic, or fatigue, palpitations and arrhythmia, and sudden cardiac death.
• Women identified through the infant's newborn screen are often asymptomatic.

• Plasma free carnitine: very low (under 5 micromol/L), with low total carnitine and acylcarnitines.
• Urine carnitine: inappropriately high excretion relative to plasma levels.
• Newborn screen: low free carnitine (C0) on dried blood spot, requiring confirmation. Maternal screening is needed for low values.
• SLC22A5 sequencing with deletion and duplication analysis.
• Fibroblast carnitine uptake assay: reduced.
• Glucose, ketones, ammonia, liver tests and creatine kinase during illness.
• Echocardiography and ECG.

Differential diagnosis.

• Secondary carnitine deficiency (valproate, pivalate containing antibiotics, organic acidurias, renal Fanconi syndrome, dialysis, malnutrition)
• Other fatty acid oxidation disorders (medium chain acyl-CoA dehydrogenase deficiency)
• Cardiomyopathy from other causes (mitochondrial disease)
• Reye syndrome

• Levocarnitine: 100 to 200 mg/kg daily orally in 3 divided doses, increasing to a maximum of 400 mg/kg daily if plasma free carnitine stays low (adults 2 to 6 g daily in 2 to 3 divided doses). Lifelong therapy is required. Adjust to maintain plasma free carnitine in the normal range.
• Side effects: diarrhoea and a fishy body odour, controlled by dose reduction or division.
• Avoid fasting: frequent meals and a high carbohydrate diet in illness. During vomiting or reduced intake give intravenous 10% glucose.
• Acute decompensation: 10% dextrose 2 mL/kg bolus then infusion at 8 to 10 mg/kg/min, with intravenous levocarnitine 100 mg/kg loading dose followed by 100 mg/kg daily in divided doses.
• Cardiomyopathy: carnitine often reverses cardiac dysfunction. Add conventional heart failure treatment: enalapril 0.1 mg/kg daily increasing to 0.5 mg/kg daily (adults 2.5 mg twice daily increasing to 10 mg twice daily) and furosemide 1 mg/kg once or twice daily for fluid overload.
• Avoid precipitants: valproate and pivalate containing antibiotics (pivampicillin).
• Family screening: measure plasma carnitine in parents and siblings, since affected siblings and mothers may be asymptomatic.
• Pregnancy: continue carnitine treatment, with adjustment of dose.
• Genetic counselling: a 25% recurrence risk in each pregnancy, with prenatal diagnosis available.

Special groups.

• Infants identified by newborn screening: confirm that the mother is not the source of low carnitine before treating the child.

Monitoring. Plasma free carnitine every 3 months in childhood and every 6 to 12 months in adults. Echocardiography and ECG yearly, and creatine kinase and growth at each visit.

Referral and escalation. Refer to clinical genetics, metabolic medicine and cardiology. Emergency for hypoglycaemia, encephalopathy, heart failure or arrhythmia.