Primary Carnitine Deficiency Due to a Failure of Carnitine Transport in Kidney, Muscle, and Fibroblasts

Treem, William R.; Stanley, Charles A.; Finegold, David N.; Hale, Daniel E.; Coates, Paul M.

doi:10.1056/nejm198811173192006

Cited by 283 publications

(146 citation statements)

References 32 publications

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“…In primary systemic carnitine deficiency (CDSP, OMIM 212140), caused by mutations in the SLC22A5 gene encoding OCTN2, proximal tubular reabsorption of carnitine is impaired, indicating that OCTN2 is the most important transporter for renal carnitine reabsorption Rahbeeni et al, 2002;Seth et al, 1999;Wang et al, 1999). Clinical findings in patients with primary carnitine deficiency, in particular myopathy, cardiomyopathy, hepatomegaly and failure to thrive, result from low tissue carnitine levels Treem et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

The plasma carnitine concentration regulates renal OCTN2 expression and carnitine transport in rats

Schürch

Todesco

Nováková

et al. 2010

European Journal of Pharmacology

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Previous findings in rats and in human vegetarians suggest that the plasma carnitine concentration and/or carnitine ingestion may influence the renal reabsorption of carnitine. We tested this hypothesis in rats with secondary carnitine deficiency following treatment with N-trimethyl-hydrazine-3-propionate (THP) for 2 weeks and rats treated with excess L-carnitine for 2 weeks. Compared to untreated control rats, treatment with THP was associated with an approximately 70% decrease in plasma carnitine and with a 74% decrease in the skeletal muscle carnitine content. In contrast, treatment with Lcarnitine increased plasma carnitine levels by 80% and the skeletal muscle carnitine content by 50%. Treatment with L-carnitine affected neither the activity of carnitine transport into isolated renal brush border membrane vesicles, nor renal mRNA expression of the carnitine transporter OCTN2. In contrast, in carnitine deficient rats, carnitine transport into isolated brush border membrane vesicles was increased 1.9-fold compared to untreated control rats. Similarly, renal mRNA expression of OCTN2 increased by a factor of 1.7 in carnitine deficient rats, whereas OCTN2 mRNA expression remained unchanged in gut, liver or skeletal muscle. Our study supports the hypothesis that a decrease in the carnitine plasma and/or glomerular filtrate concentration increases renal expression and activity of OCTN2.

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Section: Introductionmentioning

confidence: 99%

The plasma carnitine concentration regulates renal OCTN2 expression and carnitine transport in rats

Schürch

Todesco

Nováková

et al. 2010

European Journal of Pharmacology

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“…Many cases of human systemic carnitine deficiency have been reported [4][5][6][7]. Recently, more than 20 cases of human systemic carnitine deficiency have been shown to have a defect of carnitine uptake into cultured fibroblasts and are suspected to have impaired renal conservation of carnitine.…”

Section: Introductionmentioning

confidence: 99%

Cardiac hypertrophy in juvenile visceral steatosis (jvs) mice with systemic carnitine deficiency

et al. 1993

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We have reported the clinical and biochemical findings in juvenile visceral steatosis (jvs) mice with systemic carnitine deficiency. This paper is the first report about cardiomyopathy injvs mice. Adult jvs mice (at the age of 2 3 months) show cardiac hypertrophy which is caused by enlargement of the cardiac muscle cell associated with increases of non-collagen protein and DNA content. Carnitine administration (2 mg/head, twice a day, from 1 month of age) significantly suppresses the cardiac hypertrophy, showing that carnitine deficiency plays an important role in the development of the cardiac hypertrophy. The discovery of cardiac hypertrophy in carnitine-deficient jvs mice will lead to clarification of the pathophysiology of cardiomyopathy in systemic carnitine deficiency in human beings.Cardiac hypertrophy; Systemic carnitine deficiency; Animal model; Juvenile visceral steatosis mice

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“…The disease frequency is ranging from 1:40,000 to 1:120,000 newborns in different parts of the world and is possibly the second most frequent disorder of fatty oxidation after medium chain acyl CoA dehydrogenase deficiency (Koizumi et al 1999;Wilcken et al 2001Wilcken et al , 2003. Studies in cultured fibroblasts from affected patients established that the primary defect in SCD involves the sodium-dependent high-affinity transporter situated in the plasmalemmal membrane (Tein et al 1996;Treem et al 1988). The same transporter is also involved in the renal reabsorption of carnitine, thus explaining the excessive renal waste of carnitine in SCD patients.…”

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confidence: 99%

“…In patients with SCD, the key to the diagnosis is the measurement of plasma carnitine levels that are extremely decreased (free carnitine <5 mM, controls 25-50 mM), and low renal uptake of carnitine (Cano et al 2008;Scaglia et al 1998;Treem et al 1988). Diagnosis can be confirmed by demonstrating reduced carnitine transport in skin fibroblasts from the patient or by mutation analyses of the SLC22A5 gene (Cano et al 2008).…”

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confidence: 99%

Identification of Mutations and Evaluation of Cardiomyopathy in Turkish Patients with Primary Carnitine Deficiency

et al. 2011

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Primary systemic carnitine deficiency (SCD) is an autosomal recessive disorder caused by defective cellular carnitine transport. Patients usually present with predominant metabolic or cardiac manifestations. SCD is caused by mutations in the organic cation/carnitine transporter OCTN2 (SLC22A5) gene. Mutation analysis of SLC22A5 gene was carried out in eight Turkish patients from six families. Six patients presented with signs and symptoms of heart failure, cardiomyopathy, and low plasma carnitine levels, five of them with concurrent anemia. A patient with dilated cardiomyopathy had also facial dysmorphia, microcephaly, and developmental delay. Tandem MS analyses in siblings of the patients revealed two more cases with low plasma carnitine levels. SCD diagnosis was confirmed in these two cases by mutation screening. These two cases were asymptomatic but echocardiography revealed left ventricular dilatation in one of them. Carnitine treatment was started before the systemic signs and symptoms developed in these patients. Mean value of serum carnitine levels of the patients was 2.63 AE 1.92 mmol/L at the time of diagnosis. After 1 year of treatment, carnitine values increased to 16.62 AE 5.11 (p < 0.001) and all responded to carnitine supplementation clinically.

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Primary Carnitine Deficiency Due to a Failure of Carnitine Transport in Kidney, Muscle, and Fibroblasts

Cited by 283 publications

References 32 publications

The plasma carnitine concentration regulates renal OCTN2 expression and carnitine transport in rats

The plasma carnitine concentration regulates renal OCTN2 expression and carnitine transport in rats

Cardiac hypertrophy in juvenile visceral steatosis (jvs) mice with systemic carnitine deficiency

Identification of Mutations and Evaluation of Cardiomyopathy in Turkish Patients with Primary Carnitine Deficiency

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