Carnitine Uptake Defect

Other Names

CUD

Carnitine uptake deficiency

Carnitine transporter deficiency

Systemic carnitine deficiency (SCD)

Primary carnitine deficiency

Diagnosis Coding

Disorder Category

A fatty acid oxidation disorder

Screening

Overview

Carnitine uptake deficieny (CUD) results in urinary carnitine wasting and systemic and intracellular carnitine deficiency. The latter results in an intramitochondrial defect in the beta-oxidation of fatty acids that impairs energy production and causes accumulation of free fatty acids. The increased reliance on fat metabolism for energy production during prolonged fasting and/or periods of increased energy demands (fever, stress, lack of sleep) may cause metabolic crises in patients with carnitine deficiency. Mutations in the SLC22A5 gene cause CUD. This gene is responsible for making a protein called OCTN2 that transports carnitine into cells.

Incidence

Approximately 1 in 40,000 [Koizumi: 1999], with about 1% of the normal US population being heterozygous (carriers) for this condition [Amat: 2008]

Inheritance

Autosomal recessive

Prenatal Testing

DNA testing possible by amniocentesis or chorionic villus sampling (CVS) if both disease causing mutations of an affected family member have been identified. Gunctional assay (carnitine transport) possible by amniocentesis or CVS.

Other Testing

Genetic testing is possible for at-risk family members if both disease causing mutations of an affected family member have been identified.

Clinical Characteristics

With treatment prior to metabolic crises, outcomes should be normal. Treatment may reverse pre-existing cardiomyopathy and muscle weakness, but not developmental delay. Without treatment, symptoms may begin between birth and three years of age or, in the myopathic form, symptoms usually begin before seven years and may not include metabolic crisis episodes or hypoglycemia. Some children remain asymptomatic for life. Patients are at risk of sudden death from arrhythmia at any age.

Inital signs and symptoms may include:

• poor appetite
• vomiting
• irritability
• lethargy
• hypoketotic hypoglycemia
• sudden death
• lab findings:
  • anemia
  • metabolic acidosis
  • hypoglycemia

Subsequent finding include:

• muscle weakness
• cardiomyopathy
• cardiac arrhythmia
• hepatomegaly
• seizures and
• brain injury from hypoglycemia

Treatment consists of carnitine supplementation. Mothers with primary carnitine deficiency can be identified by newborn screening of their unaffected infant.[Schimmenti: 2007]

Follow-up Testing after Positive Screen

Plasma and urine carnitine analysis (the latter to measure urinary carnitine reabsorption), carnitine transporter functional analysis in fibroblasts and/or SLC22A5 gene sequencing.

Primary Care Management

Specialty Care Collaboration

Initial consultation and ongoing collaboration if the child is affected. A dietician may work with the family to devise an optimal approach to dietary management. Genetic counseling for the family.

Resources

Authors

Page Bibliography

Amat di San Filippo C, Taylor MR, Mestroni L, Botto LD, Longo N.
Cardiomyopathy and carnitine deficiency.
Mol Genet Metab.. 2008;94(2):162-166.
Carnitine is essential for the transfer of long-chain fatty acids across the mitochondrial membrane for subsequent beta-oxidation. Study results indicate heterozygosity for primary carnitine deficiency is not more frequent in patients with unselected types of cardiomyopathy and is unlikely to be an important cause of cardiomyopathy in humans.

Koizumi A, Nozaki J, Ohura T, Kayo T, Wada Y, Nezu J, Ohashi R, Tamai I, Shoji Y, Takada G, Kibira S, Matsuishi T, Tsuji A.
Genetic epidemiology of the carnitine transporter OCTN2 gene in a Japanese population and phenotypic characterization in Japanese pedigrees with primary systemic carnitine deficiency.
Hum Mol Genet. 1999;8(12):2247-54. PubMed abstract

Schimmenti LA, Crombez EA, Schwahn BC, Heese BA, Wood TC, Schroer RJ, Bentler K, Cederbaum S, Sarafoglou K, McCann M, Rinaldo P, Matern D, di San Filippo CA, Pasquali M, Berry SA, Longo N.
Expanded newborn screening identifies maternal primary carnitine deficiency.
Mol Genet Metab. 2007;90(4):441-5. PubMed abstract
Primary carnitine deficiency impairs fatty acid oxidation and can result in hypoglycemia, hepatic encephalopathy, cardiomyopathy and sudden death. Given the lifetime risk of morbidity or sudden death, identification of adult patients with primary carnitine deficiency is an added benefit of expanded newborn screening programs.

Schulze A, Lindner M, Kohlmuller D, Olgemoller K, Mayatepek E, Hoffmann GF.
Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications.
Pediatrics. 2003;111(6 Pt 1):1399-406. PubMed abstract