Carnitine Cycle Defects

Presentation ranges from lethal neonatal multiorgan disease to episodic adult muscle disease, according to the affected shuttle component.

Carnitine Palmitoyltransferase 1 A (CPT1A) deficiency typically presents in infancy or early childhood with fasting- or illness-induced hypoketotic hypoglycaemia and hepatomegaly, and occasionally acute liver failure, while the heart and skeletal muscle are characteristically spared.

Carnitine Palmitoyltransferase II (CPT2) deficiency can be divided into three phenotypes: a lethal neonatal form; a severe infantile hepatocardiomuscular form with hypoketotic hypoglycaemia, cardiomyopathy and multiorgan failure; and a comparatively common myopathic form with exercise- or fasting-triggered rhabdomyolysis and myoglobinuria from adolescence into adulthood.

Carnitine-acylcarnitine translocase (CACT) deficiency most often presents in the neonatal period with severe hypoketotic hypoglycaemia, hyperammonaemia, cardiac arrhythmia and cardiomyopathy. A metabolic imbalance is usually triggered by fasting or an underlying medical condition.

The carnitine-cycle defects are rare. The combined birth incidence lies well below 1/100,000 in newborn-screening cohorts; CPT1A deficiency is estimated between 1/780 (in Alaska) to 1/750,000 or even rarer than 1/1,500,000, with founder variants in some countries (e.g. Alaska and Hawaii). For CPT2 deficiency the highest incidence was reported approx. 1/250,000 (Japan) or as seldom as up to 1/2,000,000, whereas for CACT deficiency the highest incidence is 1:60,000 (Hong Kong) or as rare as CPT2 deficiency.

The carnitine-cycle defects result from biallelic germline pathogenic variants in three genes encoding the mitochondrial carnitine shuttle. CPT1A (11q13.3) encodes the outer-membrane carnitine palmitoyltransferase 1, SLC25A20 (3p21.31) the inner-membrane carnitine-acylcarnitine translocase, and CPT2 (1p32.3) the inner-membrane carnitine palmitoyltransferase 2. Loss of function of any component blocks import of long-chain acylcarnitines into the mitochondrial matrix, impairing long-chain fatty-acid beta-oxidation and energy production during fasting or metabolic stress.

All carnitine-cycle defects are inherited in an autosomal recessive manner. The parents of an affected child are typically asymptomatic heterozygous carriers, and each subsequent pregnancy carries a 25% recurrence risk. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified.

Diagnosis is based on a characteristic plasma acylcarnitine profile by tandem mass spectrometry. CPT2 and CACT deficiency show elevated long-chain acylcarnitines (C16, C18:1), whereas CPT1A deficiency shows a low C16/C18 ratio with raised free carnitine and an elevated C0/(C16+C18) ratio. Confirmatory enzyme-activity assay in fibroblasts or leucocytes and molecular genetic testing confirms the diagnosis.

Main differential diagnoses include:

• Primary carnitine deficiency: Very low plasma free carnitine, responsive to oral L-carnitine; SLC22A5
• Overlapping hypoketotic hypoglycaemia, cardiomyopathy and rhabdomyolysis, distinguished by a C14:1-predominant profile; ACADVL
• / mitochondrial trifunctional protein deficiency: Long-chain fatty-acid oxidation disorder (FAOD) with peripheral neuropathy and pigmentary retinopathy; HADHA, HADHB
• Fasting-induced hypoketotic hypoglycaemia with a medium-chain (C8-predominant) profile; ACADM

• Establishing the diagnosis: identification of the causative germline pathogenic variant confirms the clinical diagnosis at the molecular level.
• Condition-specific surveillance: identification of the pathogenic germline variant supports condition-specific monitoring and management decisions made by the treating physicians in consultation with the affected individual.
• Testing of family members: once the familial variants are known, at-risk relatives can be offered predictive or carrier testing to clarify their genetic status.

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• LoPiccolo MK, Vockley J. Carnitine palmitoyltransferase II deficiency. 2004 Aug 27 [updated 2026 Apr 9]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: PMID:.
• Morales Corado JA, Lee CU, Enns GM. Carnitine-acylcarnitine translocase deficiency. 2022 Jul 21. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: PMID:.
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