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Systemic primary carnitine deficiency

Orpha number ORPHA158
Synonym(s) CUD
Carnitine transporter defect
Carnitine uptake deficiency
Deficiency of plasma-membrane carnitine transporter
PCD
Primary systemic carnitine deficiency
Prevalence 1-9 / 100 000
Inheritance
  • Autosomal recessive
Age of onset Neonatal/infancy
ICD-10
  • E71.3
OMIM
UMLS -
MeSH -
MedDRA -
SNOMED CT -

Summary

Systemic primary carnitine deficiency (SPCD) is a potentially lethal disorder of fatty acid oxidation characterized classically by early childhood onset cardiomyopathy often with weakness and hypotonia, failure to thrive and recurrent hypoglycemic hypoketotic seizures and/or coma.

The 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.

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 gastoenteritis 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.

SPCD is caused by mutations in the SLC22A5 gene on chromosome 5q23.3 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 is not available, glucose is consumed (resulting in hypoglycemia) and fat released from the adispose tissue which accumulates in the liver, heart and skeletal muscle (leading to hepatic steatosis and lipid myopathy).

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, and Spain.

Differential diagnoses include other fat oxidation defects such as medium chain acyl-CoA dehydrogenase deficiency and very long chain acyl-CoA dehydrogenase deficiency (see these terms).

SPCD is an autosomal recessive disorder and genetic counseling can be offered to families with a known mutation.

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.

The prognosis is extremely good as long as oral carnitine supplementation is maintained.

Expert reviewer(s)

  • Dr Simon OLPIN

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Detailed information

Emergency guidelines
  • EN (2008,pdf)
Review article
  • EN (2012)
Clinical genetics review
  • EN (2014)
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