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)

A lethal carbamylphosphate synthetase (CPS: EC 6.3.4.16) deficiency (McKusick 23730) was found in a newborn girl; who presented on the second day of life with acute hyperammonaemia, hypotonia, seizures and who died in a coma 6 days after birth. The activity of the mitochondrial urea cycle enzymes, CPS and ornithine transcarbamylase (OTC: EC 2.1.3.3) were measured on a needle biopsy sample taken from liver and showed that CPS was 1.4% of the normal mean (0.09 nmol/min/mg protein) whereas OTC activity was normal (110 nmol/min/mg protein). Immunological analysis of the liver sample showed no detectable immunoreactive CPS and confirmed the presence of normal levels of OTC. RNA was extracted from postmortem liver and in vitro translation experiments showed that there was no translatable CPS mRNA and confirmed that no CPS protein was synthesized in this child. The absence of translatable mRNA is explicable in terms of a genetic defect which results in a failure to synthesize mRNA for CPS, or synthesis of a defective form of mRNA which is not translated.
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PMID:A carbamylphosphate synthetase deficiency with no detectable immunoreactive enzyme and no translatable mRNA. 643 91

The clinical and biochemical findings in a patient with the inherited disease so called hyperammonemia type II are presented. The patient was a male who had the first abnormal symptoms of tremors and continuous crying at 35 hours of age and exhibited a rapid clinical course dying 62 hours after birth. Rejection of food, respiratory problems, hypotonia and tonic-clonic convulsions were other outstanding clinical symptoms observed. Withdrawal of the feedings and initiation of a perfusion did not improve the clinical picture. Biochemical studies in samples of blood, urine and CSF revealed the presence of high concentrations of ammonia, alanine, glutamine and orotic acid. Final diagnosis was achieved when post mortem liver ornithine transcarbamylase activity was found to be lower than 6% with respect to that of adequate controls. Carbamyl phosphate synthetase, another urea cycle enzyme measured, was within normal limits of activity.
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PMID:[Neonatal hyperammonemia due to ornithine transcarbamylase deficiency (author's transl)]. 711 19

Ornithine transcarbamylase (OTC) deficiency, the most common inborn error of the urea cycle, shows X-linked inheritance with frequent new mutations. Using polymerase chain reaction (PCR) amplification of the individual exons including adjacent intron sequences followed by direct sequencing of the amplimers we identified four new mutations affecting donor splice sites of introns 2, 5, 6, and 8. The mutation at the first position of intron 2 was a G to A exchange associated with acute neonatal hyperammonemia in a male patient at the age of 5 months. A G to C substitution in intron 5 was detected in a boy who developed 2 days after birth hypotonia, and respiratory distress, followed by severe hyperammonemia and terminal coma. The intron 6 mutation, a G to T substitution, was detected in a girl presenting with first episodes of vomiting and agitation at the age of 2 months. The mutation in intron 8, also a G to T transition, caused fatal hyperammonemia and early death at the age of 15 days in a male patient. We present four donor splice site mutations resulting in severe neonatal or very early onset of the disease in three boys and in one female patient. As the GT dinucleotide of the 5' donor splice site is invariant and required for correct splicing the described mutations may lead to improperly spliced mRNAs and aberrant gene products.
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PMID:Identification of four novel splice site mutations in the ornithine transcarbamylase gene. 856 55

Congenital ornithine transcarbamylase (OTC) deficiency in humans results in failure to thrive, hypotonia, seizures and mental retardation. Neuropathologic evaluation reveals significant cerebral cortical atrophy, delayed myelination and Alzheimer type II astrocytosis. Using an animal model of congenital OTC deficiency, the sparse fur (spf) mouse, studies reveal convincing evidence of a loss of forebrain cholinergic neurons in this condition. Evidence includes (i) reduced activities of the cholinergic nerve terminal enzyme choline acetyltransferase (ChAT), (ii) a 25% loss of ChAT immunostaining, (iii) reduced high affinity transport of [3H]choline by cortical synaptosomes and (iv) a selective reduction in densities of presynaptic muscarinic M2 binding sites, in spf mouse brain compared to controls. A partial correction of the cholinergic deficit was observed following treatment with acetyl-L-carnitine. Possible mechanisms responsible for cholinergic neuronal loss in congenital OTC deficiency include decreased synthesis of the ChAT substrate acetyl CoA, impaired cerebral energy metabolism and NMDA receptor-mediated excitotoxicity. Loss of forebrain cholinergic neurons is consistent with the severe cognitive impairment characteristic of congenital OTC deficiency.
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PMID:Evidence for forebrain cholinergic neuronal loss in congenital ornithine transcarbamylase deficiency. 1088 42

BACKGROUND The urea cycle converts amino acids to urea and is excreted by the kidneys. Ornithine carbamoyltransferase (OTC) deficiency is a rare X-linked urea cycle disorder which results in hyperammonemia. Diagnosis is made based on a clinical presentation of poor feeding, hypotonia, biochemical profile, and genetic testing. Another genetic cause for hyperammonemia is hyperammonia hyperinsulinemia (HAHI) syndrome. A mutation coding for glutamate dehydrogenase (GDH) results in increased alpha-keto glutarate and ATP, triggering the secretion of pancreatic insulin. However, unlike OTC deficiency, these patients are asymptomatic but do have symptoms of hypoglycemia. The purpose of this article is to present the case of a 66-year-old woman with an unusual late-onset of OTC deficiency compounded with an underlying HAHI syndrome with co-disease management. CASE REPORT A 66-year-old female with a history significant for transient ischemic attack (TIA) and urea cycle disorder was admitted for new adverse symptoms. Further evaluation revealed hyperammonemia and hypoglycemia. Despite standard previous treatment for her underlying urea cycle disorder, high ammonia levels and hypoglycemia persisted. The contradicting values with continued hypoglycemia regardless of dextrose treatment was suspicious for underlying HAHI. Further genetic testing during her admission revealed a deletion in GLUD-1 gene concurrent with diagnosis of HAHI. After co-diagnosis was established, effective management required medications for both disorders in concordance with dietary restriction. CONCLUSIONS This is an extremely rare case of OTC deficiency, with a vague presentation in an elderly female. Exploring compounding genetic disorders in the presence of one that is already established and early recognition are crucial for prompt diagnosis and management.
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PMID:Management of Ornithine Carbamoyltransferase Deficiency with Underlying Hyperammonia Hyperinsulinemia Syndrome. 3133 45