Carnitine metabolism disorders are autosomal recessive inherited disorders of mitochondrial oxidation of long chain fatty acids (LCFA). They are part of newborn screening.
Carnitine palmitoyltransferase 1A (CPT1A) deficiency
Carnitine palmitoyltransferase 1A (CPT1A) deficiency is very rare and caused by pathogenic variants in the CPT1A gene. It leads to impaired mitochondrial oxidation of long-chain fatty acids (LCFA) in the liver and kidney. Symptoms manifest in the first 18 months of life in the form of recurrent variably expressed hypoglycemia. Triggers include fasting or intercurrent illness. Neurologic disturbances may occur and there is a risk of progressive hepatocellular dysfunction. Diagnostically suggestive are elevated carnitine levels in the blood.
Diagnosis of CPT1A deficiency is part of newborn screening. If the findings are abnormal, the diagnosis can be confirmed by molecular genetics. Prognosis is good with appropriate therapy.
Carnitine palmitoyltransferase 2 (CPT2) deficiency
Carnitine palmitoyltransferase 2 (CPT2) deficiency is caused by pathogenic variants in the CPT2 gene. The most common of the three forms described, with approximately 300 cases to date, is the myopathic form, which is the least severe and manifests itself in recurrent attacks of muscle pain, weakness, sometimes with rhabdomyolysis and myoglobinuria during periods of fasting, viral diseases or after endurance activities. Differential diagnosis should include McArdle's disease, cytochrome c oxidase deficiency, and Duchenne type muscular dystrophy.
In the infantile form, even short fasting leads to metabolic derailment with hypoketotic hypoglycemia and hepatic encephalopathy. Newborns with the lethal neonatal form also show signs of dysmorphia and/or malformations of the CNS and/or kidneys. In both forms, CACT deficiency (see below) or very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) may also be considered here as differential diagnoses.
Diagnosis of CPT2 deficiency is part of newborn screening. If the findings are abnormal, the diagnosis can be confirmed by molecular genetics. The prognosis is favorable only for the myopathic form of the disease. Therapy is primarily with high-carbohydrate low-fat diet. The severe forms have been described in fewer than a total of 100 patients.
Carnitine acylcarnitine translocase (CACT) deficiency
Carnitine acylcarnitine translocase (CACT) deficiency is caused by pathogenic variants in the SLC25A20 gene, which encodes the transport protein CACT. As a result, the transport of long-chain fatty acids into the mitochondria and thus fatty acid oxidation is impaired. Most patients exhibit a severe phenotype in which hypoketotic hypoglycemia, hyperammonemia, cardiomyopathy, hepatic dysfunction, and various neurological disorders, among others, may occur within the first 48 hours after birth. The rare mild phenotype occurs in infancy or early childhood in the context of fasting and/or intercurrent illness and shows residual CACT activity. The prevalence for CACT deficiency is not known. Clinically, CACT deficiency can hardly be distinguished from CPT2 deficiency (see above). Congenital anomalies are sometimes seen in CPT2 deficiency, but never in CACT deficiency.
Diagnosis of CACT deficiency is part of newborn screening. If the findings are abnormal, the diagnosis can be confirmed by molecular genetics. The prognosis is favorable for the mild form of the disease if therapeutic measures, such as a low-fat diet, are followed.
Bennett MJ, Santani AB. Carnitine Palmitoyltransferase 1A Deficiency. 2005 Jul 27 [Updated 2016 Mar 17]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. / Wieser T. Carnitine Palmitoyltransferase II Deficiency. 2004 Aug 27 [Updated 2019 Jan 3]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.