Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026827 (hypotonia)
 5,860 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Secondary carnitine deficiency in a patient with glutaric acidaemia type II, due to deficient ETF-dehydrogenase activity, is described. The patient responded clinically to a pharmacological dose of riboflavin and a restricted protein diet. In the second year of her life she developed more frequent and severe exacerbations during intercurrent infections from which she did not fully recover. Hypotonia and marked ataxia persisted. Plasma carnitine was entirely complexed as acylcarnitine with no free carnitine detected. Retrospective evaluation of several frozen urine specimens obtained since the age of 10 months revealed undetectable free carnitine with elevated acylcarnitine levels. Marked clinical improvement was observed following L-carnitine supplementation. The hypotonia and ataxia disappeared. The frequency and the severity of the exacerbations were noticeably decreased. The role of L-carnitine in preventing the accumulation of acyl-CoA compounds in inborn errors of organic acid metabolism is further emphasized by this patient. The necessity to evaluate free carnitine, acylcarnitine and acyl/free ratio in the assessment, follow-up and management of patients with inborn errors of organic acid metabolism is discussed.
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PMID:The importance of recognizing secondary carnitine deficiency in organic acidaemias: case report in glutaric acidaemia type II. 246 19

l-Carnitine occurs naturally as an essential cofactor of fatty acid metabolism which is synthesised endogenously or obtained from dietary sources. In patients with primary carnitine deficiencies, which may be life-threatening, and some secondary deficiencies such as organic acidurias, the exogenously administered compound is clearly beneficial: by abolishing hypotonia, motor skills are improved, as are muscle weakness and wasting. In preliminary clinical trials in patients with ischaemic cardiac disease, therapy with l-carnitine has shown beneficial effects on myocardial function and metabolism and has improved exercise tolerance in patients with angina pectoris-findings which require further substantiation in larger controlled studies. Moreover, while some interesting evidence suggests that l-carnitine may find potential use in such diverse conditions as carnitine deficiencies secondary to prolonged total parenteral nutrition supplementation or chronic haemodialysis, hyperlipidaemias and the prevention of toxicity induced by anthracyclines and valproate, such findings must be regarded as preliminary. Exogenously administered l-carnitine is very well tolerated. Thus, while its role in primary deficiencies is established, with its profile of negligible toxicity l-carnitine is worthy of further investigation to more clearly define its therapeutic applications in a variety of conditions which may be indirectly related to alterations in fatty acid metabolism.
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PMID:l-Carnitine. A preliminary review of its pharmacokinetics, and its therapeutic use in ischaemic cardiac disease and primary and secondary carnitine deficiencies in relationship to its role in fatty acid metabolism. 330 9

The prognosis of patients with cardiomyopathy associated with hypocarnitinemia is uncertain. Cardiac hemodynamics, histologic findings and response to oral L-carnitine therapy were retrospectively evaluated in 11 children with cardiomyopathy associated with abnormal carnitine metabolism. Three had systemic carnitine deficiency, two familial hypocarnitinemia with neutropenia, three transient neonatal hypocarnitinemia and three a carnitine insufficiency syndrome. Six had a hypertrophic and five a dilated cardiomyopathy. Hypotonia was present in seven (64%). The cardiothoracic ratio was greater than 0.60 in eight (73%). The most frequent abnormality on the electrocardiogram was ST-T wave inversion in the left precordial leads with various degrees of left ventricular hypertrophy. Echocardiographically, two patients with hypertrophic cardiomyopathy had decreased left ventricular function and two patients with dilated cardiomyopathy had increased thickness of the left ventricular wall. Histologic evaluation (two autopsies and one endomyocardial biopsy) revealed striking lipid accumulation within hypertrophied myocytes. Six of eight patients on carnitine replacement therapy had improvement echocardiographically during a 3 month to 2 year follow-up period. In summary, both hypertrophic and dilated cardiomyopathy can result from abnormal carnitine metabolism. The determination of plasma carnitine concentrations and fatty acid metabolism by-products should be performed in all patients with either form of cardiomyopathy of unknown etiology because carnitine supplementation may lead to improvement.
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PMID:Cardiac manifestations in disorders of fat and carnitine metabolism in infancy. 336 6

We studied the clinical spectrum associated with secondary plasma carnitine deficiency in 51 pediatric patients. Forty-three patients had total plasma carnitine values below 20 mumol/L and an additional eight patients had total values above 20 mumol/L but had low free plasma carnitine levels. The clinical presentation in the patients with total plasma carnitine deficiency included hypotonia (34 of 43), failure to thrive (27 of 43), recurrent infections (27 of 43), encephalopathy (six of 43), nonketotic hypoglycemia (seven of 43), and cardiomyopathy (nine of 43). Of the eight patients with low free and elevated esterified carnitine levels, the signs and symptoms at presentation included hypotonia (six of eight), recurrent infections (six of eight), failure to thrive (six of eight), encephalopathy (three of eight), nonketotic hypoglycemia (one of eight), and cardiomyopathy (one of eight). All patients were treated with L-carnitine. Treatment time varied from one month to 24 months (average, four months). A subjective improvement in muscle tone was seen in 24 of 38 patients, 22 of 33 patients showed acceleration of incremental growth, and infection frequency appeared to decrease in 18 of 33 patients. After therapy, the echocardiograms of all patients with cardiomyopathy normalized. There were no further hypoglycemic episodes. Of the nine patients with encephalopathy, eight showed improvement in their mental status. Three patients died of complications of their primary disorder. In our experience, secondary plasma carnitine deficiency is a common pediatric finding. The presence of failure to thrive, recurrent infections, hypotonia, encephalopathy, cardiomyopathy, or nonketotic hypoglycemia requires investigation of carnitine status.
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PMID:Plasma carnitine deficiency. Clinical observations in 51 pediatric patients. 357 91

An 18-month-old boy presented with general hypotonia, decreased muscle strength, retarded motor development and stunted growth. The excretion of dicarboxylic acids was enhanced. EMG was normal. A muscle biopsy revealed a lipid storage myopathy. Oral daily supplementation with 2 g D, L-carnitine resulted in: (1) an increase of the growth velocity; (2) increased muscle strength, and (3) a decrease in the lipid fraction of the fibre volume. The carnitine content of the muscle biopsied prior to treatment appeared to be normal.
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PMID:Successful carnitine treatment in a non-carnitine-deficient lipid storage myopathy. 744 3

We report 27 children, aged 14 months to 9 years, who had megalencephaly, hypotonia, proximal muscle weakness, speech and motor delay, and increased intracellular lipid (myoliposis) in needle muscle biopsy specimens. The patients had many features of the Ruvalcaba-Myhre-Smith syndrome, and in 17 families we confirmed the autosomal dominant inheritance pattern previously suggested. Muscle carnitine content was low in all 11 patients and all 4 affected relatives tested. All 27 probands were treated with oral L-carnitine; a clinical response was noted in 17. We speculate that myoliposis may be found in other disorders with megalencephaly and muscle symptoms. In such cases, muscle carnitine deficiency should be considered. The reason for the reduced muscle carnitine content is not known.
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PMID:Dominantly inherited megalencephaly, muscle weakness, and myoliposis: a carnitine-deficient myopathy within the spectrum of the Ruvalcaba-Myhre-Smith syndrome. 832 Jun 28

A series of 9 infants, ranging in age from 3 months to 5 years (average: 2 years), suffered from idiopathic myopathic carnitine deficiency presenting as hypotonia and motor delay. Secondary carnitine deficiency was eliminated by appropriate tests. Muscle carnitine concentration ranged from 2.3-7.1 nmol/mg non-collagen protein (NCP; average: 4.87 nmol/mg NCP; normal: 22 +/- 6 nmol/mg NCP). Lipid accumulation in muscle was observed in 2 of 8 patients. Therapy with L-carnitine (100 mg/kg/day in most patients) was given with clinical and laboratory follow-up 6 months later. In 7 of 9 patients, muscle tone and motor function improved. Muscle carnitine concentration increased to a range of 2.7-23.4 nmol/mg (average: 12.27 nmol/mg). In some patients the muscle carnitine content multiplied by a factor of 3-4, but carnitine concentration reached the normal range in only 2 patients. Most infants with idiopathic carnitine deficiency did benefit from 6 months of therapy; however, in order to achieve full recovery the duration of therapy should probably continue for longer periods, with a dose of not less than 100 mg/kg/day.
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PMID:Infantile idiopathic myopathic carnitine deficiency: treatment with L-carnitine. 845 98

The in vivo oxidation of fatty acids (FA) of different chain length was investigated in three patients with documented mitochondrial FA oxidation disorders: one patient with mild multiple acyl-CoA dehydrogenase deficiency (MADM), one with medium chain acyl-CoA dehydrogenase deficiency (MCAD), and one with carnitine palmitoyltransferase I deficiency (CPT I). Breath tests were performed after oral administration of 1-13C butyric. 1-13C octanoic, and 1-13C palmitic acids. 13C/12C ratio in the expired oxidative end product CO2 was measured. The cumulative 13C elimination was calculated and expressed as a percentage of the administered dose. In the MADM patient the influence of carnitine therapy (or deprivation) on the utilization of 1-13C palmitic acid was also examined. In the MCAD and CPT I patients, the 1-13C butyric, 1-13C octanoic and 1-13C palmitic acids in vivo oxidation were similar to five healthy controls. In the MADM patient, the oxidation of 1-13C butyric and 1-13C octanoic acids were normal, whereas the metabolism of 1-13C palmitic acid ranged from 33% of 66% of controls. In this patient the serum carnitine level decreased from 60 to 27 mumol/l without carnitine supplementation. Clinically there was mild hypotonia. 1-13C palmitic acid oxidation compared to controls was 50%. After 2 further weeks of carnitine deprivation the serum carnitine was 10-15 mumol/l. Clinically he was very hypotonic and had a large liver. 1-13C Palmitic acid oxidation was 33%. After 6 weeks of readministration of carnitine (L-carnitine 100 mg/kg/day p.o.) the serum carnitine was 60 mumol/l and the patient was in good clinical condition. 1-13C palmitic acid oxidation was 66% compared to controls. Our study implies that this simple fatty acid breath test is not of diagnostic use for detection of enzymatic defects in FA oxidation disorders. The carnitine dependent 1-13C palmitic acid oxidation indicates that this test might be of some value in cases with primary or secondary carnitine deficiencies.
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PMID:In vivo stable isotope studies in three patients affected with mitochondrial fatty acid oxidation disorders: limited diagnostic use of 1-13C fatty acid breath test using bolus technique. 926 22

Ornithine Transcarbamylase (OTC) is a key urea cycle enzyme. Congenital OTC deficiencies in humans result in hyperammonemia and a spectrum of neurological symptoms including hypotonia, seizures and mental retardation. Neuropathologic evaluation reveals cerebral atrophy, ventricular enlargement and Alzheimer type II astrocytosis. Using an animal model of congenital OTC deficiency, the sparse fur (spf) mouse, recent studies have revealed significant alterations of cholinergic, serotoninergic and glutamatergic neurotransmitter systems. Possible pathophysiologic mechanisms responsible for neuronal cell loss in OTC deficiency include a deficit in cerebral energy metabolism, and glutamate excitotoxicity. Therapy continues to rely on alternative substrate administration including sodium benzoate and sodium phenylacetate. Experimental evidence suggests that acetyl-L-carnitine and glutamate (NMDA) receptor antagonists could be potentially useful therapeutic agents. Liver transplantation is effective in many patients and recent experimental studies using adenoviral vectors suggest that gene therapy may ultimately be useful in the treatment of congenital OTC deficiency.
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PMID:Ornithine transcarbamylase deficiency: pathogenesis of the cerebral disorder and new prospects for therapy. 934 66

Glutaric aciduria type I (GA1) is a preventable cause of acute brain damage in early childhood, leading to a severe dystonic-dyskinetic disorder that is similar to cerebral palsy and ranges from extreme hypotonia to choreoathetosis to rigidity with spasticity. Degeneration of the putamen and caudate typically occurs between 6 and 18 months of age and is probably linked to changes in metabolic demand caused by normal maturational changes and superimposed catabolic stress. Recognition of this biochemical disorder before the brain has been injured is essential to outcome. Diagnosis depends upon the recognition of relatively non-specific physical findings such as hypotonia, irritability and macrocephaly, and on performance of urine organic acid quantification by gas chromatography--mass spectrometry or selective searches of urine or blood specimens by tandem mass spectrometry for glutarylcarnitine. The diagnosis may also be suggested by characteristic findings on neuroimaging. In selected patients diagnosis can only be reached by enzyme assay. Specific current management by the authors of this paper includes pharmacological doses of L-carnitine, as well as dietary protein restriction. Metabolic decompensation must be treated aggressively to avoid permanent brain damage. Multicentre studies are needed to establish best methods of diagnosis and optimal therapy of this disorder.
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PMID:Diagnosis and management of glutaric aciduria type I. 970 May 90


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