Impaired Skin Fibroblast Carnitine Uptake in Primary Systemic Carnitine Deficiency Manifested by Childhood Carnitine-Responsive Cardiomyopathy (original) (raw)
Related papers
Chronic cardiomyopathy and weakness or acute coma in children with a defect in carnitine uptake
Annals of Neurology, 1991
A defect in intracellular uptake of carnitine has been identified in patients with severe carnitine deficiency. To define the clinical manifestations of this disorder, the presenting features of 15 affected infants and children were examined. Progressive cardiomyopathy, with or without chronic muscle weakness, was the most common presentation (median age of onset, 3 years). Other patients presented with episodes of fasting hypoglycemia during the first 2 years of life before cardiomyopathy had become apparent. A defect in carnitine uptake was demonstrable in fibroblasts and leukocytes from patients. The defect also appears to be expressed in muscle and kidney. Concentrations of plasma carnitine and rates of carnitine uptake in parents were intermediate between affected patients and normal control subjects, consistent with recessive inheritance. Early recognition and treatment with high doses of oral carnitine may be life-saving in this disorder of fatty acid oxidation.
The Journal of Pediatrics, 1982
We studied a boy who presented at age 3 89 years with cardiomegaly, a distinctive electrocardiogram, and a history of a brother dying with cardiomyopathy. From age 3 89 to 5 years, cardiac disease progressed, resulting in intractable congestive heart failure. Skeletal muscle weakness developed and a muscle biopsy showed lipid myopathy. Muscle and plasma earnitine were reduced to 2 and 10% of the normal mean values, respectively. Therapy with L-carnitine (174 mg/kg/day) was begun at age 5 89 years and continued to the present (age 6 89 years). The cardiac disease has resolved and the muscle strength has returned to normal. Plasma carnitine concentrations have risen to the low-normal range, while urinary carnitine excretion has increased to values which are 30 times normal. The renal clearance of carnitine exceeds normal at all plasma concentrations and plasma carnitine values do not change acutely after an oral carnitine load. These results suggest that there is a distinct form of carnitine deficiency which presents as cardiomyopathy and may be successfully treated with L-carnitine. A defect in renal and possibly gastrointestinal transport of carnitine is a likely cause of this patient's disorder.
Renal Handling of Carnitine in Secondary Carnitine Deficiency Disorders
Pediatric Research, 1993
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Journal of Inherited Metabolic Disease, 1995
One of the mechanisms by which chronic valproic acid (VPA) therapy induces serum and tissue depletion of camitine in normal controls is through inhibition of plasmalemmal carnitine uptake . To determine the effect of VPA on proven heterozygotes for the plasmalemmal carnitine transporter defect, we studied this system in cultured human skin fibroblasts with reduced gma x for the canfitine transporter using L-pH]carnitine. There was en exponential dose-dependent decrease in carnitine uptake with increasing VPA concentrations and the relative inhibitory effect was the same for all three carnitine concentrations for a given cell line. Importantly, the lower the maximal velocity of carnitine uptake of the heterozygore, the lower the number of carnitine transporters and the lower the camitine uptake per given concentration of VPA. The degree of inhibition was also directly proportional to the time of VPA preincubation up to a specifc maximal saturation time. The maximal effect of VPA exposure time was reached by 10 days in the control cell line and by 3 days in the two heterozygote lines, probably reflecting earlier saturation. We conclude that patients who are heterozygous for the plasmalemmal camitine transporter defect are at increased risk for VPA-associated serum and tissue depletion of carnitine through inhibition of plasmalemmal carnitine uptake.
The Syndrome of Carnitine Deficiency: Morphological and Metabolic Correlations in Two Cases
Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 1978
SUMMARY:Two cases of systemic carnitine deficiency are described. In both patients, carnitine concentration was lower than normal in serum and muscle tissue. In the first case, the illness began at age 35; the clinical manifestations were only muscular. In the second case, the illness began in childhood; there were intermittent episodes of hepatic enlargement and coma. An excessive lipid content was present in muscle tissue, especially in type I fibers, of both cases, and in the liver of the second patient. Ultrastructural studies of muscle tissue revealed important changes of mitochondria.During muscular exercise, aerobic and anaerobic metabolism were in vestigated. For a given relative work intensity, these patients showed abnormally high blood lactic acid concentration and lactic acid/pyruvic acid ratios. These data, together with the morphological alterations observed in mitochondria, suggest an impaired function of the respiratory chain, leading to a shift of the red/ox potenti...
Carnitine transport and fatty acid oxidation
Biochimica et biophysica acta, 2016
Carnitine is essential for the transfer of long-chain fatty acids across the inner mitochondrial membrane for subsequent β-oxidation. It can be synthesized by the body or assumed with the diet from meat and dairy products. Defects in carnitine biosynthesis do not routinely result in low plasma carnitine levels. Carnitine is accumulated by the cells and retained by kidneys using OCTN2, a high affinity organic cation transporter specific for carnitine. Defects in the OCTN2 carnitine transporter results in autosomal recessive primary carnitine deficiency characterized by decreased intracellular carnitine accumulation, increased losses of carnitine in the urine, and low serum carnitine levels. Patients can present early in life with hypoketotic hypoglycemia and hepatic encephalopathy, or later in life with skeletal and cardiac myopathy or sudden death from cardiac arrhythmia, usually triggered by fasting or catabolic state. This disease responds to oral carnitine that, in pharmacologica...
Carnitine metabolism and inborn errors
Journal of Inherited Metabolic Disease, 1984
Current knowledge of the metabolic role, biosynthesis, cellular uptake, excretion and turnover of carnitine is reviewed. The clinical spectrum and possible aetiology ofthe primary muscle and primary systemic carnitine deficiency syndromes are considered and the various genetic defects of intermediary metabolism which can give rise to secondary carnitine deficiency are indicated. CARNITINE METABOLISM L-Carnitine,~-hydroxy-y-N-trimethylammonium butyrate, is ubiquitous in cells of higher animals. The primary function of the molecule is to transfer long chain fatty acids across the inner mitochondrial membrane (Fritz, 1968). Cytosolic long chain fatty acids are activated to their coenzyme A (CoA) esters by fatty acyl-CoA synthetase (EC 6.2.1.3). The activated long chain fatty acids thus formed are transesterified to L-carnitine by carnitine palmitoyltransferase I (EC 2.3.1.21), an enzyme located on the external surface of the inner mitochondrial membrane (Hoppel, 1982). Transfer of the long chain fatty acylcarnitine esters across the inner mitochondrial membrane is mediated by acylcarnitine translocase (Pande and Parvin, 1976). Subsequently, long chain fatty acyl-CoA is regenerated by the action of carnitine palmitoyltransferase II on the matrix side of the inner mitochondrial membrane (Hoppel, 1982). The fatty acyl-CoA undergoes~-oxidation, and carnitine returns to the cytosol. Carnitine may also function in other metabolic processes (Bieber et al., 1982). These include (1) facilitation of branched chain ex-keto acid oxidation, (2) shuttling of acyl moieties chain-shortened by~ oxidation out of hepatic peroxisomes and (3) modulation of the acyl-CoA/CoASH ratio in mammalian cells. L-Carnitine is synthesized endogenously from lysine and methionine (Tanphaichitr and Broquist, 1973; Wolf and Berger, 1961) via the intermediates c-N-trimethyllysine (Tanphaichitr and Broquist, 1973),~-hydroxy+ N-trimethyllysine (Henderson et aI., 1982), c-trimethylaminobutyraldehyde (Henderson et ai., 1982), and ybutyrobetaine (Bremer, 1962). In humans, the final reaction, hydroxylation of y-butyrobetaine, occurs in liver, kidney and brain but not in cardiac or skeletal muscle (Rebouche and Engel, 1980a, b). In mammalian systems, the initial step in synthesis involves methylation of protein-bound lysine to c-N-trimethyllysine which becomes available for carnitine synthesis on pl'oteolysis (LaBadie et al., 1976). The biosynthetic enzymes are cytosolic except c-N-trimethyllysine hydroxylase which is mitochondrial. Ascorbate, Fez +, Oz and ex-ketoglutarate are required for optimal activity of c-Ntrimethyllysine hydroxylase (Henderson et ai., 1982) and y-butyrobetaine hydroxylase (EC 1.14.11.1) (Lindstedt and Lindstedt, 1970). Pyridoxine is a cofactor for the aldolase which cleaves c-N-trimethyllysine into y
Primary carnitine deficiency is a life‐long disease
JIMD Reports
Primary carnitine deficiency is a rare autosomal recessive disease associated with acute hypoketotic hypoglycaemia, cardiomyopathy and sudden cardiac death. Effective treatment with carnitine supplementation is available. An 18 months old boy, who presented with cardiomyopathy was diagnosed with primary carnitine deficiency, and carnitine supplementation resulted in a full recovery. At age 13 years, he discontinued his medication and at 20 years, he discontinued clinical monitoring. Nine years later, age 29, he presented with heart failure and atrial fibrillation and was admitted to an intensive care unit, where he was treated with furosemide, enoximone and intravenous carnitine supplementation, this lead to improved cardiac function within 2 weeks, and with continued oral carnitine supplements, his left ventricular ejection fraction normalised. The last 8 years were uneventful and he continued to attend his regular follow‐up visits at a specialised metabolic outpatient clinic. We r...