Systemic primary carnitine deficiency (ORPHA:158)
A rare disorder of carnitine cycle and carnitine transport that is characterized classically by early childhood onset cardiomyopathy often with weakness and hypotonia, failure to thrive and recurrent hypoglycemic hypoketotic seizures and/or coma.
Epidemiology
Systemic primary carnitine deficiency (SPCD) exact prevalence is unknown and varies depending on ethnicity. The estimated prevalence is 1/20,000 - 1/70,000 newborns in Europe and the USA while the estimated incidence in Japan is 1/40,000 births. In the Faroe Islands, the prevalence is 1/1,300 and the incidence is 1/720.
Clinical description
Disease onset typically occurs in infancy between the ages of 3 months to 2 years. Infants often present with hypoketotic hypoglycemia, poor feeding, irritability, lethargy, and hepatomegaly, triggered by fasting stress or common illnesses including gastroenteritis and respiratory tract infections. Roughly half of clinically presenting patients present with muscle hypotonia and progressive childhood cardiomyopathy leading to heart failure. Anemia is sometimes observed as carnitine plays a role in red blood cell metabolism. Adulthood presentation is associated with minor symptoms like fatigue and decreased stamina but dilated cardiomyopathy and arrhythmias and sudden cardiac death have also been reported. Asymptomatic adults are also described. During pregnancy, minor symptoms as well as cardiac arrhythmias can worsen.
Etiology
SPCD is caused by mutations in the SLC22A5 gene on chromosome 5q31.1 that encodes the plasma membrane sodium-dependent high affinity carnitine transporter (OCTN2) which is expressed in most tissues including cultured fibroblasts, lymphocytes, muscle, kidney, gut and heart. OCTN2 is necessary for L-carnitine transport across the plasma membrane and L-carnitine is necessary for transporting long chain fatty acids into the mitochondria for fatty acid oxidation. When fat cannot be used for fatty acid oxidation due to SPCD, glucose is consumed (resulting in hypoglycemia) and the fat released from adipose tissue accumulates in the liver, heart and skeletal muscle (leading to hepatic steatosis and lipid myopathy).
Diagnostic methods
Diagnosis is based on a finding of very low plasma free and total carnitine concentrations (<5-10 micromol/L) and confirmed by demonstrating significantly reduced carnitine transport in skin fibroblasts or biallelic pathogenic mutations in the SLC22A5 gene. There is lipid myopathy with microvesicular lipid accumulation found in the muscle and liver as well as elevated liver transaminases and hyperammonemia. A marked renal loss of carnitine even in the presence of very low plasma and tissue carnitine concentrations is also noted. Newborn screening is available in Austria, Denmark, Hungary, Iceland, Portugal, Spain and Israel.
Differential diagnosis
Differential diagnoses include other fat oxidation defects such as medium chain acyl-CoA dehydrogenase deficiency and very long chain acyl-CoA dehydrogenase deficiency.
Genetic counseling
SPCD is an autosomal recessive disorder and genetic counseling can be offered to families with a known mutation.
Management and treatment
Carnitine therapy is the standard treatment. Oral levocarnitine (L-carnitine) supplementation of 100-400 mg/kg/day in three divided doses is usually required. Oral carnitine treatment is required for lifelong treatment of the disease.
Prognosis
The prognosis is extremely good as long as oral carnitine supplementation is maintained.

                            Last update: 
                            May 2019


                            - Expert reviewer(s): 
                             Joanne CROFT  - Dr Simon OLPIN