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Query: UMLS:C0085584 (encephalopathy)
 18,178 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Propionic acidemia occasionally produces a toxic encephalopathy resembling Reye syndrome, indicating disruption of mitochondrial metabolism. Understanding the mitochondrial effect of propionate might clarify the pathophysiology. Liver mitochondria are inhibited by propionate (5 mM) while muscle mitochondria are not. Preincubation is required to inhibit liver mitochondria, suggesting that propionate is metabolized to propionyl CoA. Liver and skeletal muscle mitochondria incubated with [1-14C]propionate contain similar quantities of matrix isotope and release comparable [14C]CO2. However, only liver mitochondria accumulated significant propionyl CoA, which was largely (68%) synthesized from propionate. Carnitine reduced the level of liver matrix propionyl CoA. Inhibition of respiratory control ratios by propionate correlated with propionyl CoA levels. These results support the hypothesis that acyl CoA esters are toxic and that carnitine exerts its protective effect by converting acyl CoA esters to acylcarnitine esters.
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PMID:Propionate mitochondrial toxicity in liver and skeletal muscle: acyl CoA levels. 188 30

Carnitine deficiency syndromes manifest as metabolic encephalopathy, lipid storage myopathy, or cardiomyopathy. Impairment of long-chain fatty acid metabolism and failure of energy production affect tissues reliant on oxidative metabolism. The accumulation of toxic fatty acyl derivatives impedes gluconeogenesis and urea cycle function which, in turn, causes hypoketotic hypoglycemia, transaminase elevations, and hyperammonemia. Oxidation of accumulated fatty acids through an alternative pathway, omega-oxidation, produces dicarboxylic aciduria. Carnitine must be transported into skeletal muscle. Myopathic carnitine deficiency occurs when this transport mechanism is defective. Most systemic carnitine deficiencies are secondary to other disorders that promote excretion of carnitine as acylcarnitine; however, primary systemic carnitine deficiency, likely due to impaired renal conservation of carnitine, also occurs.
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PMID:Carnitine deficiency syndromes. 218 42

Carnitine deficiency can be defined as a decrease of intracellular carnitine, leading to an accumulation of acyl-CoA esters and an inhibition of acyl-transport via the mitochondrial inner membrane. This may cause disease by the following processes. A. Inhibition of the mitochondrial oxidation of long-chain fatty acids during fasting causes heart or liver failure. The latter may cause encephalopathy by hypoketonaemia, hypoglycaemia and hyperammonaemia. B. Increased acyl-CoA esters inhibit many enzymes and carriers. Long-chain acyl-CoA affects mitochondrial oxidative phosphorylation at the adenine nucleotide carrier, and also inhibits other mitochondrial enzymes such as glutamate dehydrogenase, carnitine acetyltransferase and NAD(P) transhydrogenase. C. Accumulation of triacylglycerols in organs increases stress susceptibility by an exaggerated response to hormonal stimuli. D. Decreased mitochondrial acetyl-export lowers acetylcholine synthesis in the nervous system. Primary carnitine deficiency can be defined as a genetic defect in the transport or biosynthesis of carnitine. Until now only defects at the level of carnitine transport have been discovered. The most severe form of primary carnitine deficiency is the consequence of a lesion of the carnitine transport protein in the brush border membrane of the renal tubules. This defect causes cardiomyopathy or hepatic encephalopathy usually in combination with skeletal myopathy. In a patient with cardiomyopathy and without myopathy, we found that carnitine transport at the level of the small intestinal epithelial brush border was also inhibited. The patient was cured by carnitine supplementation. Muscle carnitine increased, but remained too low. This suggests that carnitine transport in muscle is also inhibited. Carnitine transport in fibroblasts was normal, which disagrees with literature reports for similar patients.
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PMID:Primary carnitine deficiency. 219 96

A 20-year-old woman had systemic carnitine deficiency. Biochemical studies of cultured fibroblasts, skeletal muscle mitochondria, and fluids showed no evidence of other disease that might deplete tissue carnitine stores. Carnitine supplementation produced a dramatic improvement in her clinical condition: she gained weight and strength and recovered brain function, which had deteriorated slightly after repeated episodes of encephalopathy. Lipid droplets disappeared from skeletal muscle and plasma, and muscle carnitine content rose from low to normal values. On treatment, she excreted less carnitine than controls. This form of systemic carnitine deficiency may be due to defective carnitine biosynthesis.
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PMID:Systemic carnitine deficiency: clinical, biochemical, and morphological cure with L-carnitine. 653 2

A 9-year-old girl was referred to our hospital after recurrent episodes of hypoglycemia, altered consciousness and persistent vomiting without acetonemia or myopathic symptoms. Other pertinent laboratory data included elevated BUN, hyperammonemia and very low levels of triglycerides with elevated free fatty acids. The patient was born from unaffected but related parents (second cousins) and the illness was previously diagnosed as Reye encephalopathy. Recurrence of similar attacks suggested an underlying metabolic disorder. Several syndromes of impaired FFA beta oxidation were taken into account and discarded successively after laboratory investigations: systemic carnitine deficiency, Medium and Long Chain Acyl-CoA Dehydrogenase deficiency and Multiple Acyl CoA Dehydrogenation deficiency (Glutaric aciduria, Ethylmalonic-adipic aciduria and riboflavin-responsive multiple acyl CoA dehydrogenation deficiency). Urinary and hematic gas-chromatography and Mass-Spectrometry show no abnormality in Medium Chain fatty acids and in C6-C10 dicarboxylic acids. Carnitine plasma concentrations (both total and free) were above normal levels while in urine acetyl carnitine was low in respect to longer acyclic radicals. Among metabolic defects located at the level of hepatic fatty acid oxidation, only Carnitine Transferase deficiency can explain this peculiar mosaic of data (precursors of the blocked reaction are elevated in blood whereas lack of the metabolites derived uniquely from this reaction explains all the clinical manifestations).
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PMID:[Non-ketotic hypoglycemia caused by carnitine palmitoyl transferase 1 deficiency]. 848 29

Carnitine is an essential cofactor for oxidation of mitochondrial fatty acids. Carnitine deficiency results in failure of energy production by mitochondria and leads to metabolic encephalopathy, lipid-storage myopathy, and cardiomyopathy. The juvenile visceral steatosis (JVS) mouse, an animal model of systematic carnitine deficiency, inherits the JVS phenotype in autosomal recessive fashion, through a mutant allele mapped to mouse chromosome 11. As a step toward identifying the gene responsible for JVS by positional cloning, we attempted to refine the jvs locus in the mouse by detailed linkage analysis with 13 microsatellite markers, using 190 backcross progeny. Among the 13 loci tested, 5 (defined by markers D11Mit24, D11Mit111, D11Nds9, D11Mit86, and D11Mit23) showed no recombination, with a maximum lod score of 52.38. Our results implied that the jvs gene can be sought on mouse chromosome 11 within a genetic distance no greater than about 1.6 cM.
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PMID:Definition of the locus responsible for systemic carnitine deficiency within a 1.6-cM region of mouse chromosome 11 by detailed linkage analysis. 866 Sep 78

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

A clinical survey of Japanese patients with mitochondrial fatty acid beta-oxidation and related disorders (FAODs) was performed with questionnaires sent to 187 institutions, where inborn errors of metabolism could be managed in Japan, including a search of related literature published between 1985 and 2000. Sixty-four patients with ten types of FAODs were found. Carnitine palmitoyltransferase 2 deficiency and glutaric aciduria type 2 were most common (17 and 14 patients, respectively). As of 2000, there were no patients with medium-chain acyl-CoA dehydrogenase deficiency, which is common in Caucasians. Age at onset was under 2 years in 38 (59%) of the patients. Eight (13%) patients had neonatal onset. Twenty-one (55%) of the 38 children with an initial attack under 2 years of age had acute encephalopathy or a Reye syndrome-like illness. Half of the patients presented within 2 years of birth died or were handicapped. On the other hand, 19 (79%) of the 24 with onset after 2 years of age had muscle symptoms and 23 (96%) of the 24 grew and developed normally. Though the precise incidence of FAODs in Japan is still unknown, as a consequence of the development of diagnostic procedures the number of FAOD cases being diagnosed appears to have increased. Mass screening for FAODs during the neonatal period will greatly aid in prevention of attacks and related effects.
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PMID:A survey of Japanese patients with mitochondrial fatty acid beta-oxidation and related disorders as detected from 1985 to 2000. 1242 13

Valproic acid (VPA) is a broad-spectrum antiepileptic drug and is usually well tolerated, but rare serious complications may occur in some patients receiving VPA chronically, including haemorrhagic pancreatitis, bone marrow suppression, VPA-induced hepatotoxicity (VHT) and VPA-induced hyperammonaemic encephalopathy (VHE). Some data suggest that VHT and VHE may be promoted by carnitine deficiency. Acute VPA intoxication also occurs as a consequence of intentional or accidental overdose and its incidence is increasing, because of use of VPA in psychiatric disorders. Although it usually results in mild central nervous system depression, serious toxicity and even fatal cases have been reported. Several studies or isolated clinical observations have suggested the potential value of oral L-carnitine in reversing carnitine deficiency or preventing its development as well as some adverse effects due to VPA. Carnitine supplementation during VPA therapy in high-risk patients is now recommended by some scientific committees and textbooks, especially paediatricians. L-carnitine therapy could also be valuable in those patients who develop VHT or VHE. A few isolated observations also suggest that L-carnitine may be useful in patients with coma or in preventing hepatic dysfunction after acute VPA overdose. However, these issues deserve further investigation in controlled, randomized and probably multicentre trials to evaluate the clinical value and the appropriate dosage of L-carnitine in each of these conditions.
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PMID:Science review: carnitine in the treatment of valproic acid-induced toxicity - what is the evidence? 1627 30

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


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