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 son of Kurdish, consanguineous parents (cousin marriage) presented from the first day of life with initially focal and later generalized attacks of epileptic seizures and a severe generalized muscular hypotonia. Urinary excretion of 3-hydroxyisovalerate and of 3-methylcrotonylglycine was persistently increased. Diagnosis of isolated biotin-resistant 3-methylcrotonyl-CoA carboxylase deficiency was confirmed in cultured fibroblasts. Psychomotor retardation was progressive, seizures and marked EEG abnormalities persisted. Treatment with leucine and protein-resistricted diet under hospital control did not significantly improve these conditions. The patient died from a cardiac and circulatory failure after a prolonged epileptic attack, with bronchial aspiration. The non-responsiveness of our patient to therapy and the fatal outcome indicate the existence of a severe neonatal variant of this otherwise rather benign genetic enzyme deficiency.
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PMID:Isolated biotin-resistant deficiency of 3-methylcrotonyl-CoA carboxylase presenting as a clinically severe form in a newborn with fatal outcome. 129 82

Several childhood multisystem disorders with prominent ophthalmological manifestations have been ascribed to the malfunction of the peroxisome, a subcellular organelle. The peroxisomal disorders have been divided into three groups: 1) those that result from defective biogenesis of the peroxisome (Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum's disease); 2) those that result from multiple enzyme deficiencies (rhizomelic chondrodysplasia punctata); and 3) those that result from a single enzyme deficiency (X-linked adrenoleukodystrophy, primary hyperoxaluria type 1). Zellweger syndrome, the most lethal of the three peroxisomal biogenesis disorders, causes infantile hypotonia, seizures, and death within the first year. Ophthalmic manifestations include corneal opacification, cataract, glaucoma, pigmentary retinopathy and optic atrophy. Neonatal adrenoleukodystrophy and infantile Refsum's disease appear to be genetically distinct, but clinically, biochemically, and pathologically similar to Zellweger syndrome, although milder. Rhizomelic chondrodysplasia punctata, a peroxisomal disorder which results from at least two peroxisomal enzyme deficiencies, presents at birth with skeletal abnormalities and patients rarely survive past one year of age. The most prominent ocular manifestation consists of bilateral cataracts. X-linked (childhood) adrenoleukodystrophy, results from a deficiency of a single peroxisomal enzyme, presents in the latter part of the first decade with behavioral, cognitive and visual deterioration. The vision loss results from demyelination of the entire visual pathway, but the outer retina is spared. Primary hyperoxaluria type 1 manifests parafoveal subretinal pigment proliferation. Classical Refsum's disease may also be a peroxisomal disorder, but definitive evidence is lacking. Early identification of these disorders, which may depend on recognizing the ophthalmological findings, is critical for prenatal diagnosis, treatment, and genetic counselling.
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PMID:The peroxisome and the eye. 171 72

Glycerol kinase deficiency occurs either as a relatively benign isolated enzyme deficiency, or as part of a syndrome resulting from a microdeletion in the p21 region of the X chromosome associated with congenital adrenal hypoplasia and/or Duchenne muscular dystrophy. Developmental delay is a consistent feature of the microdeletion syndrome but not of the isolated enzyme defect. We report a case of isolated glycerol kinase deficiency in a neonate presenting with hypotonia, apnea, mild developmental delay, and glyceroluria, without evidence of adrenal insufficiency or myopathy. A mild communicating hydrocephalus was noted on magnetic resonance imaging brain scan. It is important, therefore, to exclude glyceroluria in infants being investigated for apnea and hypotonia.
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PMID:Isolated glycerol kinase deficiency in a neonate. 751 7

In a 4.5-month-old boy presenting with marked muscular hypotonia in the neonatal period, hepatomegaly, cardiac hypertrophy, recurrent hypoglycemia, metabolic acidosis, and secondary carnitine deficiency, there was a considerable urinary excretion of 3-methylglutaconic and 3-methylglutaric acid. Estimation of 3-methylglutaconyl-CoA hydratase, 3-hydroxy-3-methylglutaryl-CoA lyase and initial enzymatic steps of cholesterol biosynthesis in cultured fibroblasts and in different tissues postmortem revealed no enzyme deficiency. Analyses of the respiratory chain in postmortem tissues demonstrated severe impairment of complex I (NADH ubiquinone oxidoreductase) and complex IV (cytochrome c oxidase) activities in skeletal muscle and reduced complex IV activity in heart.
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PMID:Multiple respiratory chain abnormalities associated with hypertrophic cardiomyopathy and 3-methylglutaconic aciduria. 769 3

We describe four infants with a novel subtype of an isolated deficiency of one of the peroxisomal beta-oxidation enzymes with detectable enzyme protein. The patients showed characteristic clinical and biochemical abnormalities, including hypotonia, psychomotor retardation, hepatomegaly, typical facial appearance, accumulation of very-long-chain fatty acids, and decreased lignoceric acid oxidation. However, beta-oxidation enzyme proteins were detected by immunoblot analyses, and large peroxisomes were identified by immunofluorescence staining. In order to identify the underlying defect in these patients, complementation analysis was introduced using fibroblasts from these patients and patients with an established deficiency of either acyl-CoA oxidase or bifunctional enzyme, as identified by immunoblotting. In the complementing combinations, fused cells showed increased lignoceric acid oxidation, resistance against 1-pyrene dodecanoic acid/UV selection, and normalization of the size and the distribution of peroxisomes. The results indicate that two patients with a more severe clinical course were suffering from bifunctional enzyme deficiency and that the other two infants, who were siblings and had a less severe clinical presentation, were the first patients with acyl-CoA oxidase deficiency with detectable enzyme protein.
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PMID:Novel subtype of peroxisomal acyl-CoA oxidase deficiency and bifunctional enzyme deficiency with detectable enzyme protein: identification by means of complementation analysis. 827 68

We report on three cases of Corticosterone Methyl Oxidase Typ II deficiency in two siblings and one boy. All three children were presented with typical symptoms of a saltlosing syndrome (vomiting, poor drinking, weight loss, hypotonia). Hyponatremia and hyperkalemia, low plasma aldosterone concentrations when related to high plasma-renin-activities suggested deficiency in the final steps of aldosterone biosynthesis. Variable degrees of enzyme deficiency and no relation of biochemical findings to the clinical symptoms were observed. Clinical symptoms became less severe with age. Diagnosis of CMO II-deficiency was established by an abnormal high ratio of 18-hydroxycorticosterone to aldosterone, by measurement of their precursors and metabolites in plasma and urine. In one sibling negative values may have been caused by suppression of the renin-angiotensin-system due to high sodium replacement therapy.
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PMID:[Variability of corticosterone methyl oxidase (type II) deficiency. Presentation of three case reports]. 835 May 92

We describe a 6 1/2-year-old-girl presenting with a unique phenotype and dihydroxyacetonephosphate acyltransferase (DHAP-AT) deficiency (1.6% of control activity in cultured fibroblasts), a peroxisomal enzyme deficiency which was reported previously to cause rhizomelic chondroplasia punctata (RCDP). Her phenotype is less severe than that seen in classical RCDP, and is notable for short stature, microcataracts, normal limbs, mild hypotonia, and severe mental retardation. Epiphyseal stippling is present. This patient illustrates the variability of peroxisomal disorders whereby a specific defect in peroxisomal plasmalogen synthesis may lead to several phenotypes. Her case also suggests that children presenting with deficient growth, developmental delay, and epiphyseal stippling should be screened carefully for peroxisomal disorders, with measurement of plasmalogens in addition to very long chain fatty acids.
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PMID:Developmental delay and growth failure caused by a peroxisomal disorder, dihydroxyacetonephosphate acyltransferase (DHAP-AT) deficiency. 984 43

A 15-month-old girl with severe hemolytic anemia and progressive respiratory failure is presented. She was well until the age of six months when she developed a pulmonary infection. During the next six months, she had frequent respiratory infections and her paleness became evident. At the age of 12 months, she was observed to have easy fatigability and muscle weakness, and she received her first blood transfusion. She was referred to our hospital at the age of 15 months. The physical examination revealed a malnourished girl with hypotonia, nystagmus, generalized muscle weakness and severe breathing difficulty requiring ventilatory support The hemoglobin (Hb) was 9.7 g/dl; hematocrit (Hct) 29%, mean corpuscular volume (MCV) 101 fl and reticulocyte count 15%. Peripheral blood smear revealed macrocytosis and stomatocytosis (30% of the red cells) and polychromasia. Sweat chloride test was 90 and 94 mEq/L on two separate occasions. The serum vitamin E level was 0.26 mg/dl (N: 0.44-0.68). She was found to be heterozygous for factor V Leiden mutation. Although malnutrition, low serum vitamin E and elevated sweat chloride test were suggestive of cystic fibrosis, this diagnosis failed to account for all the findings in the patient. A search for a red cell enzyme deficiency revealed that the red cell triosephosphate isomerase (TPI) activity was low. DNA analysis showed the 315 G-C (105 Glu-Asp) TPI mutation, thus confirming the diagnosis of TPI deficiency.
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PMID:Triosephosphate isomerase deficiency with elevated sweat chloride test: report of a case. 1119 50

We report the first case of isolated biotin resistant 3-methylcrotonyl-CoA carboxylase (MCC) deficiency in Argentina. The diagnosis was established at 14 months of age by urinary organic-acid analysis and confirmed by enzyme assay in fibroblasts. The patient suffered from severe psychomotor retardation, hypotonia, areflexia, and failure to thrive, and died unexpectedly at 3 years 4 months of life. Brain MRI at 14 months showed signals of the white matter on cerebral T2-weighted, which were indicative of confluent and multiple foci of leukodystrophy, a pattern not previously described in this entity. In addition, high levels of oxypurines were detected in cerebrospinal fluid. This might be related to energetic consequences of the enzyme deficiency in the brain. This case extends the phenotype of isolated MCC deficiency in infancy and suggests this entity should be considered to be one of the possible causes of "metabolic leukodystrophies."
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PMID:Leukodystrophy and CSF purine abnormalities associated with isolated 3-methylcrotonyl-CoA carboxylase deficiency. 1189 4

Canavan disease (CD) is an inherited leukodystrophy, caused by aspartoacylase (ASPA) deficiency, and accumulation of N-acetylaspartic acid (NAA) in the brain. The gene for ASPA has been cloned and more than 40 mutations have been described, with two founder mutations among Ashkenazi Jewish patients. Screening of Ashkenazi Jews for these two common mutations revealed a high carrier frequency, approximately 1/40, so that programs for carrier testing are currently in practice. The enzyme deficiency in CD interferes with the normal hydrolysis of NAA, which results in disruption of myelin and spongy degeneration of the white matter of the brain. The clinical features of the disease are macrocephaly, head lag, progressive severe mental retardation, and hypotonia in early life, which later changes to spasticity. A knockout mouse for CD has been generated, and used to study the pathophysiological basis for CD. Findings from the knockout mouse indicate that this monogenic trait leads to a series of genomic interaction in the brain. Changes include low levels of glutamate and GABA. Microarray expression analysis showed low level of expression of GABA-A receptor (GABRA6) and glutamate transporter (EAAT4). The gene Spi2, a gene involved in apoptosis and cell death, showed high level of expression. Such complexity of gene interaction results in the phenotype, the proteome, with spongy degeneration of the brain and neurological impairment of the mouse, similar to the human counterpart. Aspartoacylase gene transfer trial in the mouse brain using adenoassociated virus (AAV) as a vector are encouraging showing improved myelination and decrease in spongy degeneration in the area of the injection and also beyond that site.
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PMID:Canavan disease: a monogenic trait with complex genomic interaction. 1456 59


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