Clinical characteristics: Primary carnitine deficiency (PCD) is a disorder of the carnitine cycle that results in defective fatty acid oxidation. If untreated, it encompasses a broad clinical spectrum including: (1) metabolic decompensation in infancy typically presenting between age three months and two years with episodes of hypoketotic hypoglycemia, poor feeding, irritability, lethargy, hepatomegaly, elevated liver transaminases, and hyperammonemia triggered by fasting or common illnesses such as upper respiratory tract infection or gastroenteritis; (2) childhood myopathy involving heart and skeletal muscle with onset between age two and four years; (3) pregnancy-related decreased stamina or exacerbation of cardiac arrhythmia; (4) fatigability in adulthood; and (5) absence of symptoms. The latter two categories often include mothers diagnosed with PCD after newborn screening has identified low carnitine levels in their infants.

Diagnosis/testing: The diagnosis of PCD is established in a proband with consistent biochemical analyte findings and/or suggestive clinical and laboratory features by identification of biallelic pathogenic variants in SLC22A5 on molecular genetic testing. In individuals with suspected PCD and negative molecular testing, a carnitine transport assay using cultured skin fibroblasts may be available.

Management: Targeted therapy: Metabolic decompensation and skeletal and cardiac muscle function improve with 100-200 mg/kg/day oral levocarnitine if it is started before irreversible organ damage occurs.

Supportive care: Routine treatment includes preventing hypoglycemia with frequent feeding and avoidance of prolonged fasting; notifying designated metabolic center in advance of scheduled surgical or medical procedures; hospitalization for intravenous glucose administration for individuals who are required to fast for a procedure or who cannot tolerate oral intake due to illness such as gastroenteritis; implementing transitional care plan prior to adulthood. Emergency outpatient treatment includes levocarnitine and carbohydrate supplementation, antipyretics for fever, and antiemetics for occasional vomiting. Acute inpatient treatment includes high-calorie fluids, insulin as needed, intravenous or oral levocarnitine (100-200 mg/kg/day), evaluation of muscle and liver involvement by measuring serum creatine kinase concentration and liver transaminases, and evaluation by cardiologist with EKG and echocardiogram for cardiomyopathy.

Surveillance: Monitor plasma carnitine concentration frequently until levels reach normal range; once levels reach normal range, measure three times a year during infancy and early childhood, twice a year in older children, and annually in adults. Assess growth and development at each visit throughout childhood. Neuropsychological testing and quality of life assessment as needed. EKG and echocardiogram annually during childhood and less frequently in adulthood.

Agents/circumstances to avoid: Fasting longer than age-appropriate periods; catabolic illness; inadequate calorie provision during other stressors.

Evaluation of relatives at risk: Evaluation of all sibs of any age by molecular genetic testing if the SLC22A5 pathogenic variants in the family are known or measurement of plasma-free carnitine concentration to identify as early as possible those who would benefit from institution of treatment and preventive measures.

Pregnancy management: Pregnant women with PCD require close monitoring of plasma carnitine levels and increased carnitine supplementation as needed to maintain plasma carnitine levels in the normal range.

Genetic counseling: PCD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an SLC22A5 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the SLC22A5 pathogenic variants have been identified in an affected family member, molecular genetic carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.