The SLC22A5 gene is associated with autosomal recessive primary carnitine deficiency (MedGen UID: 90999).
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Pathogenic variants in the SLC22A5 gene are the only known cause of primary carnitine deficiency (PMID: 16602102).
Multiple entries in Geneticus
OMIM: 212140 / MedGen UID: 90999
Systemic primary carnitine deficiency (CDSP) is a fatty acid oxidation disorder causing inadequate energy and ketone production. Organs with high energy needs, such as skeletal and cardiac muscle, have a high dependency on fats for energy production (the heart derives 50-70% of its energy from fats). Inadequate carnitine impairs the use of fats as an energy source and make such tissues highly vulnerable to damage (PMID: 16602102, 26828774). Carnitine is a crucial nutrient derived from amino acids and is found in every cell of our bodies. Specifically, it is required to transport long-chain fats from the cytosol into the mitochondria for oxidation to energy. Without sufficient amounts of carnitine, fats remains sequestered in the cytoplasm and insufficient amounts of energy are generated.
Systemic primary carnitine deficiency (CDSP) has a broad clinical spectrum ranging from severe, infantile-onset to childhood onset to an attenuated form with asymptomatic adults. Approximately 50% of patients present with the infantile-onset form (PMID: 22989098).
Infantile-onset patients generally present by two years of age with features typical of a fatty acid oxidation disorder including poor feeding, irritability, lethargy, hypotonia, hepatomegaly, hypoketotic hypoglycemia, hyperammonemia, and elevated liver transaminases. If untreated with intravenous glucose, symptomatic infants can deteriorate to coma and death (PMID: 16602102). Prolonged fasting or intercurrent illness may precipitate recurrent bouts of metabolic decompensation.
Childhood-onset CDSP generally has a myopathic presentation that may include hypotonia, dilated cardiomyopathy, skeletal muscle myopathy, and elevated creatine kinase. Patients with the myopathic form are at risk of progressive cardiac heart failure and/or sudden cardiac death from arrhythmias (PMID: 23379544).
Adult females with undiagnosed CDSP have been detected through abnormal newborn screening findings in their unaffected babies. During pregnancy, carnitine is transferred from the placenta to the fetus so low levels identified on a baby’s newborn screen can be reflective of the mother’s status (PMID: 11295726). The identification of maternal primary carnitine deficiency has prompted deeper investigations which have subsequently revealed undiagnosed cardiac arrhythmias and dilated cardiomyopathy in some mothers; while others have been affected with easy fatigability and exercise intolerance, and others remain completely asymptomatic (PMID: 20074989, 20027113, 17126586, 16865412).
The SLC22A5 gene encodes the plasma membrane organic cation/carnitine transporter type 2 (OCTN2) protein. OCTN2 transfers carnitine across the plasma membrane and maintains a high intracellular carnitine concentration. Defects in this transporter result in a failure to bring carnitine into the cell, increased excretion of carnitine in the urine, and overall carnitine depletion. OCTN2 is highly expressed in the heart, muscle and kidney (PMID: 26828774).
Primary carnitine deficiency due to pathogenic variants in the SLC22A5 gene has autosomal recessive inheritance. An affected individual likely inherited a pathogenic variant from each parent. When two parents each carry a pathogenic variant, their chance of having an affected child is 25%. Any children of an affected individual would inherit a pathogenic variant and their chance of having a child affected with CDSP depends on the carrier state of that individual’s partner. The carrier rate for CDSP is approximately 1% (PMID: 24385988).
Treatment for CDSP is very simple and involves oral carnitine supplementation (generally 100-400 mg/kg/day). If initiated prior to irreversible organ damage, CDSP responds very well to exogenous carnitine and treatment has been demonstrated to prevent crisis and reverse cardiomyopathy (PMID: 16602102, 22989098, 20027113). Avoidance of prolonged fasting, especially during illness, is also advised. Hospitalization and management with IV dextrose infusions are the standard treatment for prevention of hypoglycemic episodes or prior to procedures which require fasting.
It has been well established that some undiagnosed fatty acid oxidation defects (such as medium chain acyl-CoA dehydrogenase [MCAD] deficiency) can remain entirely asymptomatic through adulthood until manifesting as sudden death, or other acute presentation, during times of severe physiologic stress (PMID: 11258631, 16677980, 16677980, 12897989). It is therefore strongly advised that all individuals identified with CDSP, regardless of the apparent lack of overt symptoms, be considered at-risk and treated with carnitine supplementation (PMID: 17126586, 20027113).
Regular surveillance with echocardiograms and electrocardiogram is recommended for all affected and at-risk individuals due to the potential for cardiomyopathy.
Review date: November 2016
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