Impaired Skin Fibroblast Carnitine Uptake in Primary Systemic Carnitine Deficiency Manifested by Childhood Carnitine-Responsive Cardiomyopathy

Abstract

ABSTRACT. Evidence is emerging that primary systemic carnitine deficiency, a potentially lethal but eminently treatable inborn error of fatty acid oxidation, involves a cellular defect in the uptake of carnitine. We present four unrelated children with primary carnitine-responsive cardiomyopathy, weakness (with or without hypoketotic hypoglycemic encephalopathy), low serum and/or tissue carnitine concentrations, and severe renal carnitine leak. Dicarboxylic acids were absent in the urine of three children who were tested, and all four had a rapid and dramatic improvement in cardiac function, strength, and somatic growth after carnitine therapy. We studied carnitine uptake in cultured skin fibroblasts from all four children and seven of the eight healthy nonconsanguinous parents.[3H]~-carnitine uptake was evaluated in vitro under linear time kinetics. Substrate concentrations were varied from 0.1 to 1000 wM. Physiologic uptake was determined at carnitine concentrations between 0.1 and 50 wM. Nonspecific uptake was determined at a concentration of 10 mM. The four patients had negligible uptake throughout the physiologic range, implying a marked deficiency in the specific highaffinity, low-concentration, carrier-mediated uptake mechanism. At a concentration of 5 pmol/L, the mean velocity of uptake in the four patients was 2% of control values. Their parents showed intermediate maximal rates of carnitine uptake ranging from 13 to 44% of control V,,, values, but normal Km values, suggesting that the heterozygotes had a reduced number of normal functioning carnitine transporters. The observed reduction in V,,, values for the parents supports an autosomal recessive inheritance pattern and may be a more sensitive indicator of heterozygosity than serum carnitine concentrations. We conclude that carnitine uptake studies in cultured skin fibroblasts are important for diagnosis, screening of siblings and heterozygote parents, understanding pathogenesis, and investigating the molecular basis of this disease. Given the

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

“…This case's serum carnitine level was higher than other cases (6.76 mmol/L). Identification of mutations in siblings is critical because of the progressive and lethal nature of this disorder and the high incidence of sudden unexpected infant deaths unless there is early diagnosis and prompt therapeutic intervention (Stanley et al 1991;Tein et al 1990). Free carnitine levels in the plasma before initiation of therapy were 2.63 AE 1.92 mmol/L (N: 10-60), after a year of therapy free carnitine levels in the plasma raised to 16.62 AE 5.11 (N: 10-60) (p < 0.001).…”

“…After therapy all cases had increase in their hemoglobin levels. In the literature, anemia was noted in some cases of primary carnitine transporter deficiency (Cano et al 2008;Komlósi et al 2009;Lamhonwah et al 2002;Melegh et al 2004;Tein and Di Mauro 1992). Carnitine is known to have a role in red blood cell metabolism: it stabilizes the cellular membrane and raises the red blood cell osmotic resistance (Evangeliou and Vlassopoulos 2003).…”

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

“…jvs, juvenile visceral steatosis; FBP, fructose 1,6-bisphosphate; GOT, glutamic oxaloacetic transaminase; SDH, succinate dehydrogenase; NCP, non-collagen protein. [5][6][7]. Unexpectedly, there have been only a few reports that give the detail informations about the cardiomyopathy.…”

“…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.…”

Muscle Carnitine Repletion by Long-Term Carnitine Supplementation in Nephropathic Cystinosis

“…22). deficient transport at the level of the plasma membrane (23)(24)(25) or inner mitochondria1 membrane (26). excessive esterification by fatty acids that accumulate due to shortchain (27) or medium-chain (4) acyl-CoA dehydrogenase deficiency, binding by medications such as valproic acid (28) 4 Different rrom "low carnitine" mean at p = 0.036.…”