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)

The disorders of peroxisomal beta-oxidation, which have been well characterised at the molecular level, include defects of acyl-CoA oxidase, defects of the D-bifunctional protein (D-BP) (including specific defects of its enoyl-CoA hydratase and D-3-hydroxyacyl-CoA dehydrogenase components), defects of the very-long-chain fatty acid (VLCFA)-CoA importer [X-linked adrenoleukodystrophy (ALD)] and alpha-methylacyl-CoA racemase deficiency. A survey of the clinical consequences of these defects indicates that defects in the acyl-CoA oxidase and D-BP can produce neonatal hypotonia, seizures in early infancy, retinopathy and progressive neurological dysfunction with leukodystrophy on imaging. Defects in the VLCFA-CoA importer and in the racemase do not produce disease until a long time after the neonatal period. However, again the clinical picture is dominated by neurological disease: impaired cognitive function with leukodystrophy in childhood X-linked ALD and retinopathy and neuropathy in racemase deficiency. It is difficult to escape the conclusion that defective peroxisomal beta-oxidation has effects (such as impaired neuronal migration in the developing brain), which are more serious than those produced by the accumulation of substrates (VLCFAs, pristanic acid) alone.
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PMID:Clinical consequences of defects in peroxisomal beta-oxidation. 1135 71

The clinical, neuroradiological, neuropathological and biochemical findings in a patient with optico-cochleo-dentate degeneration (OCDD; OMIM 258700) are presented in a severe case succumbing at the age of 4 years. The electron microscopic and biochemical data showed for the first time that OCDD may occur as the phenotypic expression of D-bifunctional protein deficiency, i.e., a peroxisomal disorder. The boy was born as the first child of healthy, consanguineous parents of Turkish origin. No other family members were affected. The main clinical symptoms consisted of muscle hypotonia ("floppy infant"), generalized epileptic fits, hypacusis, rotatory nystagmus, insufficient pupillary reactions, and mental retardation. Fibroblast cultures revealed D-bifunctional protein deficiency. Neuropathological examination displayed moderate frontoparietal and insular microgyria, and atrophy of the cerebellum. Loss of neurons was severe in the granular layer, the Purkinje cell band of the cerebellum, and rather complete in the dentate nucleus. A corresponding loss of myelinated fibers associated with characteristic periodic acid-Schiff-positive macrophages was most prominent in the white matter of the cerebellum. There was additional severe loss of myelinated fibers in the central portions of the optic nerve, reduction of the nerve fiber density in the cochlear nerve, and reduction of myelinated nerve fibers by about 80-90% in the sural nerve, which has not been studied in previous cases. At the electron microscopic level, characteristic inclusions mainly in perivascular macrophages and astrocytes were the most prominent finding. The inclusions usually showed a bilaminar structure, whereas trilaminar structures, typically seen in adrenoleukodystrophy, and multilaminar structures were less frequently seen.
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PMID:Optico-cochleo-dentate degeneration associated with severe peripheral neuropathy and caused by peroxisomal D-bifunctional protein deficiency. 1523 8

Neonatal adrenoleukodystrophy constitutes a distinct genetic disorder of autosomal recessive inheritance, and is distinguishable from the cerebro-hepato-renal syndrome of Zellweger and X-linked juvenile adrenoleukodystrophy, although all three conditions store very long chain fatty acids. Abnormal clinical features in neonatal adrenoleukodystrophy are generally present at birth, and include muscle hypotonia, severe psychomotor retardation, and failure to thrive. These infants are generally blind and deaf, with seizures developing during their first few weeks. A retinopathic "leopard spot" is common, and should help identify this disorder. The brains of four infants who died of neonatal adrenoleukodystrophy were biochemically analyzed for complex lipids, including cholesterol, cholesterol esters, total phospholipids, total galactolipids, and gangliosides. Additional analyses included the separation and identification of very long chain fatty acids and various forms of brain plasmalogen. Analyses of brains with neonatal adrenoleukodystrophy revealed the chemical identification of at least two stored lipid products. Very long chain fatty acids are present, especially in cholesterol esters, and vinyl ether ethanolamine plasmalogens are markedly elevated. The storage of vinyl ether plasmalogen in brains of infants dying of neonatal adrenoleukodystrophy clearly distinguishes them from those with cerebro-hepato-renal syndrome of Zellweger, which fail to synthesize plasmalogens.
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PMID:Neonatal adrenoleukodystrophy: a clinical, pathologic, and biochemical study. 2304 13

We report a 4-year-old girl heterozygous for X-linked adrenoleukodystrophy (ALD) who displayed dopa-responsive motor symptoms and was subsequently diagnosed with sepiapterin reductase deficiency (SPR; OMIM 182125). Her father and paternal uncle had known ALD, and she was found to have elevated plasma very long chain fatty acids and a mutation in the ABCD1 gene. She had language delay, severe hypotonia and abnormal eye movements and responded dramatically to a trial of levodopa (4 mg/kg per day). Two mutations within the gene for sepiapterin reductase were found and cultured skin fibroblasts demonstrated near zero activity of the enzyme. This case illustrates the importance of treatment trials that may give rise to biochemical clues to the underlying diagnosis, and the need to continue to search for diagnoses despite a misleading family history.
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PMID:Levodopa response reveals sepiapterin reductase deficiency in a female heterozygote with adrenoleukodystrophy. 2343 Aug 77

Zellweger syndrome (ZS) is a severe manifestation of disease within the spectrum of peroxisome biogenesis disorders that includes neonatal adrenoleukodystrophy, infantile Refsum disease, and rhizomelic chondroplasia punctata. Patients with ZS present in the neonatal period with a characteristic phenotype of distinctive facial stigmata, pronounced hypotonia, poor feeding, hepatic dysfunction, and often seizures and boney abnormalities. In patients with ZS, a mutation in one of the PEX genes coding for a peroxin (a peroxisome assembly protein) creates functionally incompetent organelles causing an accumulation of very long chain fatty acids (VLCFA), among other complications. Despite an absence of treatment options, prompt diagnosis of ZS is important for providing appropriate symptomatic care, definitive genetic testing, and counseling regarding family planning.
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PMID:Child neurology: Zellweger syndrome. 2367 47

Pipecolic acid (PA) levels are increased in severe metabolic disorders of the central nervous system such as Zellweger syndrome, infantile Refsum disease, neonatal adrenoleukodystrophy and hyperlysinemia. The affected individuals present progressive neurological dysfunction, hypotonia and growth retardation. The mechanisms of brain damage of these disorders remain poorly understood. Since PA catabolism can produce H2O2 by oxidases, oxidative stress may be a possible mechanism involved in the pathophysiology of these diseases. Lipoic acid (LA) is considered an efficient antioxidant and has been shown to prevent oxidative stress in experimental models of many disorders of the neurologic system. Considering that to our knowledge no study investigated the role of PA on oxidative stress, in the present work we investigated the in vitro effects of PA on some oxidative stress parameters and evaluated the LA efficacy against possible pro-oxidant effects of PA in cerebral cortex of 14-day-old rats. The activities of catalase (CAT), glutathione peroxidase (GPx), glucose 6-phosphate dehydrogenase (G6PD), and glutathione S-transferase (GST) along with reduced glutathione (GSH) content were significantly decreased, while superoxide dismutase (SOD) activity and thiobarbituric acid-reactive substances (TBA-RS) were significantly enhanced by PA. LA was able to prevent these effects by improving the activity of antioxidant enzymes, increasing GSH content and reducing TBA-RS. In contrast, glutathione reductase and 6-phosphogluconate dehydrogenase activities and sulfhydryl content were not affected. Taken together, it may be presumed that PA in vitro elicits oxidative stress and LA is able to prevent these effects.
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PMID:Pipecolic acid induces oxidative stress in vitro in cerebral cortex of young rats and the protective role of lipoic acid. 2433 30

We present a 9-year-old boy with X-linked cerebral adrenoleukodystrophy (X-linked ALD) and previous umbilical cord transplant who required general anaesthesia. An anaesthetic plan for each individual should be tailored to ensure the best possible anaesthetic care for these patients. The anaesthetic considerations include mental retardation, seizure disorder, hypotonia, liver function abnormalities, gastro-oesophageal reflux, impaired adrenocortical function and immunosuppression. Pre-operative sedation should be avoided because of hypotonia of the pharyngeal muscles. Anti-convulsants are continued, and potentially epileptogenic anaesthetic agents are avoided. The patient was intubated using a modified rapid sequence induction with a head up position of 30 degrees. Four other cases have been reported in literature. Nevertheless, there is still no established anaesthetic management for these patients, and total intravenous anaesthesia can be considered as a safe and alternative method of anaesthesia. To the best of our knowledge, this is the first reported use of total intravenous anaesthesia with propofol and remifentanil in a case of cerebral adrenoleukodystrophy, and with a favourable outcome.
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PMID:Anaesthesia for a child with adrenoleukodystrophy: A case report and review of the literature. 2470 Sep 3


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