Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1762617 (weakness)
 37,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In hospitalized patients rhabdomyolysis is an important clinical entity, leading to myoglobinuria and acute renal failure in 8-25% of cases. When common causes of rhabdomyolysis, such as crush, trauma, infections, and drug abuse are excluded, inherited disorders of energy metabolism, in particular lipid metabolism, should be considered. Carnitine palmitoyltransferase (CPT) II deficiency is a common disorder of mitochondrial lipid oxidation. There are two distinct clinical forms: a severe and usually fatal infantile form and a benign classical muscular form. Usually, patients with CPT II deficiency present with episodic myoglobinuria, muscle cramps and weakness prompted by strenuous exercise or prolonged fasting. Liver and cardiac dysfunction are rarely seen and indicate severe disease. Most affected patients are males, although CPT II deficiency shows an autosomal recessive mode of inheritance. The human CPT II gene has been cloned, sequenced and localised to chromosome 1p32. Several mutations have been detected in the human gene which differ in the remaining enzyme activity and may explain the heterogeneity in the clinical picture of this disorder. Diagnosis is by muscle biopsy. Normally, light microscopy shows no pathological findings, and diagnosis must be established by biochemical and molecular methods. In our report on two typical cases we set out to promote knowledge of this disorder and discuss the diagnostic approach, which requires a specialised laboratory.
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PMID:[Rhabdomyolysis in carnitine palmitoyltransferase II deficiency: developments in pathophysiology, diagnosis and therapy]. 969 38

Carnitine is a conditionally essential metabolite that plays a critical role in cell physiology by participating in transesterification reactions and preventing organic acid accumulation. A number of disease states are characterized by carnitine depletion that may lead to metabolic and clinical disturbances. In maintenance hemodialysis, carnitine is lost through dialytic membranes, leading in selected patients to carnitine depletion with a relative increase of the esterified forms. Carnitine supplementation after or during dialysis counteracts such alterations and may be associated with some clinical benefits. Recent meta-analyses of the literature indicate that carnitine supplementation in hemodialysis patients may improve the hematological status (allowing a reduction of the requirement for erythropoietin), the exercise tolerance, the plasma lipid profile, and the intradialytic symptoms. In addition, carnitine supplementation may improve cardiac functions, protein metabolism, and insulin resistance. Carnitine supplementation has been recently approved by the US Food and Drug Administration not only for the treatment, but also for the prevention of carnitine depletion in dialysis patients. Furthermore, clinical guidelines developed by both American and European nephrological societies suggest that a trial with carnitine supplementation could be recommended in selected dialysis patients who do not adequately respond to standard therapy for certain conditions, such as severe and persistent muscle cramps or hypotension during dialysis, lack of energy affecting quality of life, skeletal muscle weakness or myopathy, cardiomyopathy, and anemia of uremia unresponsive to or requiring large doses of erythropoietin.
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PMID:Carnitine metabolism in uremia. 1157 25

Primary systemic carnitine deficiency or carnitine uptake defect (OMIM 212140) is a potentially lethal, autosomal recessive disorder characterized by progressive infantile-onset cardiomyopathy, weakness, and recurrent hypoglycemic hypoketotic encephalopathy, which is highly responsive to L-carnitine therapy. Molecular analysis of the SLC22A5 (OCTN2) gene, encoding the high-affinity carnitine transporter, was done in 11 affected individuals by direct nucleotide sequencing of polymerase chain reaction products from all 10 exons. Carnitine uptake (at Km of 5 microM) in cultured skin fibroblasts ranged from 1% to 20% of normal controls. Eleven mutations (delF23, N32S, and one 11-bp duplication in exon 1; R169W in exon 3; a donor splice mutation [IVS3+1 G > A] in intron 3; frameshift mutations in exons 5 and 6; Y401X in exon 7; T440M, T468R and S470F in exon 8) are described. There was no correlation between residual uptake and severity of clinical presentation, suggesting that the wide phenotypic variability is likely related to exogenous stressors exacerbating carnitine deficiency. Most importantly, strict compliance with carnitine from birth appears to prevent the phenotype.
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PMID:Novel OCTN2 mutations: no genotype-phenotype correlations: early carnitine therapy prevents cardiomyopathy. 1221 Mar 23

Carnitine, gamma-trimethyl-beta-hydroxybutyrobetaine, is a small molecule widely present in all cells from prokaryotic to eukaryotic. It is an important element in the beta-oxidation of fatty acids. A lack of carnitine in hemodialysis patients is caused by insufficient carnitine synthesis and particularly by the loss through dialytic membranes, leading in some patients to carnitine depletion with a relative increase of esterified forms. The authors found a decrease in plasma-triglyceride and increase of high-density lipoprotein cholesterol (HDL-Chol) in dialysis patients during carnitine treatment. Many studies have shown that L-carnitine supplementation leads to improvements in several complications seen in uremic patients, including cardiac complications, impaired exercise and functional capacities, muscle symptoms, increased symptomatic intradialytic hypotension, and erythropoietin-resistant anemia, normalizing the reduced carnitine palmitoyl transferase activity in red cells. In addition, carnitine supplementation may improve protein metabolism and insulin resistance. Recently, carnitine supplementation has been approved by the US Food and Drug Administration not only for the treatment, but also for the prevention of carnitine depletion in dialysis patients. Regular carnitine supplementation in hemodialysis patients can improve their lipid metabolism, protein nutrition, antioxidant status, and anemia requiring large doses of erythropoietin, It also may reduce the incidence of intradialytic muscle cramps, hypotension, asthenia, muscle weakness, and cardiomyopathy.
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PMID:Carnitine and hemodialysis. 1261 67

The placental transport of carnitine is significant because the fetus cannot supply itself with adequate amounts of this nutrient. Carnitine deficiencies in infants can lead to symptoms ranging from muscle weakness to sudden infant death. Objectives of this study include the characterization of novel organic cation transporter 2 (OCTN2) function in the BeWo cell line and the inhibition of placental carnitine uptake by amphetamine derivatives. BeWo cells were seeded in 12- or 24-well tissue culture plates and incubated at 37 degrees C until monolayers were confluent. Uptake studies with radiolabeled L-carnitine and inhibitors in Hanks' balanced salt solution were carried out in the plates at 37 degrees C for 30 min. Uptake of L-carnitine in BeWo cells was Na(+)-dependent and saturable (K(m) = 9.8 +/- 2.4 microM, V(max) = 800 +/- 70 pmol/mg of protein/30 min) with a nonsaturable constant of 2.8 +/- 0.3 microl/mg of protein/30 min. Among the amphetamine analogs studied, IC(50) values ranged from 2.3 to 9.2 mM, and the inhibition of carnitine uptake was stronger for compounds having a methyl-substituted nitrogen atom. Lineweaver-Burk plots show that inhibition by tetraethylammonium and valproate was competitive; inhibition by ephedrine was not completely competitive. The observed kinetics, Western blot, and inhibition profiles indicate that high-affinity carnitine uptake in the BeWo cell line is mediated by OCTN2. Inhibition of carnitine transport by amphetamines potentially poses serious consequences for fetal development.
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PMID:Novel organic cation transporter 2-mediated carnitine uptake in placental choriocarcinoma (BeWo) cells. 1531 89

Carnitine is a small water-soluble molecule that is present in almost all animal species. It plays an indispensable role in fatty acid metabolism, where it is involved in the transport of activated fatty acids between different cellular compartments. Uremic patients, as well as patients with chronic renal failure, appear to have abnormal renal handling of carnitine leading to dyslipidemia, lethargy, muscular weakness, hypotension, cardiac dysfunction and arrhythmias, and recurrent cramps. It often is difficult to distinguish these symptoms from similar ones related to uremia and dialysis. Many investigators have advocated L-carnitine supplementation in an attempt to alleviate carnitine deficiencies, and good results from this therapy have been reported. Moreover, several studies have shown that L-carnitine supplementation improves the response to erythropoietin. Chronic inflammation is another particular aspect affecting these patients. Anti-inflammatory properties of L-carnitine in hemodialysis patients have been shown by our group. Treatment with L-carnitine (20 mg/kg, given intravenously at the end of each dialysis session for 6 mo), significantly decreased serum C-reactive protein (CRP) levels, a proinflammatory cytokine known to inhibit erythropoiesis. Moreover, data from published literature are indicative of L-carnitine modulation of the immune system by the activation of glucocorticoid receptors and the modulation of the transcription of glucocorticoid-responsive genes. Our study showed that in these patients, treatment with L-carnitine has been able to improve their body mass index, likely by promoting a positive protein balance. This aspect is strictly correlated with the status of insulin resistance, which is well described in patients with renal diseases. Many studies showed that carnitine allowed mitochondrial fatty acid usage to link to the rate of glucose usage, thus improving insulin resistance. In conclusion, clinical beneficial effects of L-carnitine treatment on patients suffering from renal diseases are supported by molecular evidence involving both inflammatory and metabolic aspects of the disease.
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PMID:Carnitine system in uremic patients: molecular and clinical aspects. 1549 Apr 12

A 45-year-old male patient had an episode of acute renal failure with myoglobinuria, myalgias, weakness, and markedly increased serum CK levels. Similar episodes had occurred in the past. Carnitine palmitoyl-transferase II (CPT II) deficiency was documented both biochemically and genetically. Interestingly, muscle biopsy also showed some ragged red fibers (RRF) and complete mitochondrial DNA (mtDNA) sequence disclosed a homoplasmic T3394C point mutation. This mutation is described in Leber's hereditary optic neuropathy (LHON) or in patients with diabetes mellitus.
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PMID:A case of CPT deficiency, homoplasmic mtDNA mutation and ragged red fibers at muscle biopsy. 1616 41

Carnitine is a metabolic cofactor which is essential for normal fatty acid metabolism. Patients with chronic kidney disease on dialysis have been shown both to suffer from disordered fatty acid metabolism and to have a significant deficiency in plasma and tissue carnitine. Aberrant fatty acid metabolism has been associated with a number of cellular abnormalities such as increased mitochondrial permeability (a promoter of apoptosis), insulin resistance, and enhanced generation of free radicals. These cellular abnormalities have, in turn, been correlated with pathological clinical conditions common in dialysis patients including cardiomyopathy with attendant hypotension and resistance to the therapeutic effect of recombinant human erythropoietin (EPO). In 1999, the Food and Drug Administration approved levocarnitine injection for the prevention and treatment of carnitine deficiency in patients on dialysis based on documentation of free plasma carnitine levels in dialysis patients similar to other serious carnitine deficiency states for which treatment was required. Data analysis performed by expert panels convened by both the American Association of Kidney Patients and, subsequently, the National Kidney Foundation recommended a trial of levocarnitine therapy for specific subsets of dialysis patients including those with EPO resistance, dialysis-related hypotension, cardiomyopathy and muscle weakness. In 2003, the Centers for Medicare and Medicaid services convened a Medical Advisory Committee which established reimbursement on a national level for carnitine-deficient dialysis patients who had either dialysis-related hypotension or EPO resistance. Recently, a correlation between reductions in hospitalization rates of dialysis patients receiving levocarnitine therapy has been demonstrated in a large retrospective study. Despite data-based recommendations and national reimbursement, only a small minority of dialysis patients have been prescribed a therapeutic trial of levocarnitine. Whereas the reasons for the reluctance of nephrologists to prescribe this therapeutic trial are unclear, possible explanations include a lack of appreciation of the pivotal role played by carnitine in cellular metabolism and the strength of evidence for a substantial deficiency of carnitine in dialysis patients, an underestimation of the prognostic import of EPO resistance and dialysis-related hypotension, inadequate dissemination of the clinical trial data supporting the use of levocarnitine in dialysis patients, and the heterogeneous clinical response of dialysis patients to levocarnitine therapy. Difficulties in documenting both initial eligibility and evidence of improvement as a result of therapy may also be a contributing factor. This paper discusses the biological role of carnitine and its particular relevance to dialysis patients. Clinical trial data concerning an effect of therapy on EPO resistance and dialysis-related hypotension are summarized along with a discussion of the logic behind the use of levocarnitine in dialysis. Finally, the difficulties posed by a reimbursement policy based on clinical as opposed to laboratory endpoints and a heterogeneous response to therapy are addressed.
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PMID:Debate forum: levocarnitine therapy is rational and justified in selected dialysis patients. 1636 53

Carnitine is an essential co-factor in fatty acid metabolism. Carnitine deficiency can impair fatty acid oxidation, rarely leading to hyperammonemia and encephalopathy. We present the case of a 35-year-old woman who developed acute mental status changes, asterixis, and diffuse muscle weakness. Her ammonia level was elevated at 276 microg/dL. Traditional ammonia-reducing therapies were initiated, but proved ineffective. Pharmacologic, microbial, and autoimmune causes for the hyperammonemia were excluded. The patient was severely malnourished and her carnitine level was found to be extremely low. After carnitine supplementation, ammonia levels normalized and the patient's mental status returned to baseline. In the setting of refractory hyperammonemia, this case illustrates how careful investigation may reveal a treatable condition.
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PMID:Hyperammonemic encephalopathy caused by carnitine deficiency. 1808 Jan 67

At present, long-chain fatty acid oxidation (FAO) defects are diagnosed in a number of countries by newborn screening using tandem mass spectrometry. In the majority of cases, affected newborns are asymptomatic at time of diagnosis and acute clinical presentations can be avoided by early preventive measures. Because evidence-based studies on management of long-chain FAO defects are lacking, we carried out a retrospective analysis of 75 patients from 18 metabolic centres in Germany, Switzerland, Austria and the Netherlands with special regard to treatment and disease outcome. Dietary treatment is effective in many patients and can prevent acute metabolic derangements and prevent or reverse severe long-term complications such as cardiomyopathy. However, 38% of patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency had intermittent muscle weakness and pain despite adhering to therapy. Seventy-six per cent of patients with disorders of the mitochondrial trifunctional protein (TFP)-complex including long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, had long-term myopathic symptoms. Of these, 21% had irreversible peripheral neuropathy and 43% had retinopathy. The main principle of treatment was a fat-reduced and fat-modified diet. Fat restriction differed among patients with different enzyme defects and was strictest in disorders of the TFP-complex. Patients with a medium-chain fat-based diet received supplementation of essential long-chain fatty acids. l-Carnitine was supplemented in about half of the patients, but in none of the patients with VLCAD deficiency identified by newborn screening. In summary, in this cohort the treatment regimen was adapted to the severity of the underlying enzyme defect and thus differed among the group of long-chain FAO defects.
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PMID:Management and outcome in 75 individuals with long-chain fatty acid oxidation defects: results from a workshop. 1939 38


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