Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

Eight novel mutations were found in the P-protein (glycine decarboxylase) gene (GLDC) of the glycine cleavage system (EC 2.1.1.10) by screening five exons of the gene in patients with glycine encephalopathy (NKH). The mutations identified were of eight single base changes: a one-base deletion 1054del A, a splice site mutation IVS18-2A-->G and six amino acid substitutions A283P, A313P, P329T, R410K, P700A, and G762R.
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PMID:Novel mutations in the P-protein (glycine decarboxylase) gene in patients with glycine encephalopathy (non-ketotic hyperglycinemia). 1212 39

A defect in the P-protein component of the glycine cleavage system has been the most frequent abnormality found in patients with glycine encephalopathy (NKH). In a retrospective study of a more specific group of NKH patients, however, we found that >50% had T-protein mutations. The patients studied had one or more of the following unusual biochemical findings: residual glycine cleavage system activity in liver assayed by the standard method or a newly developed micromethod, residual glycine cleavage system activity in lymphoblasts, and/or increased amniotic fluid glycine/serine ratio with a normal amniotic fluid glycine level in prenatal diagnosis. The selected patients had a much higher incidence of T-protein defects than expected in the general NKH patient population. We report, here, three novel mutations and five polymorphisms in the T-protein gene, PCR/restriction enzyme methods for one mutation (R296H) and two polymorphisms (E211K and R318R), and an estimation of their frequency in normal controls. The co-occurrence of the polymorphism E211K with the mutation R320H in patients with a severe phenotype is discussed.
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PMID:Molecular genetic and potential biochemical characteristics of patients with T-protein deficiency as a cause of glycine encephalopathy (NKH). 1294 42

Glycine encephalopathy (GE) (non-ketotic hyperglycinemia) is an autosomal recessive neurometabolic disease caused by defective activity of the glycine cleavage system. Clinically, patients present usually in the neonatal period with hypotonia, encephalopathy, hiccups and breath arrests with or without overt seizures. GE is considered rare, but its incidence is relatively high in several geographical areas around the world. We report a novel mutation causing GE in six extended Arab families, all from a small suburban village (population 5,000). A methionine to threonine change in the initiation codon of the glycine decarboxylase gene led to markedly reduced glycine decarboxylase mRNA levels and abolished glycine cleavage system activity.
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PMID:A single nucleotide substitution that abolishes the initiator methionine codon of the GLDC gene is prevalent among patients with glycine encephalopathy in Jerusalem. 1586 13

Glycine encephalopathy, or nonketotic hyperglycinaemia (NKH; Mckusick 238300) is a severe autosomal recessive disease due to a defect in the glycine cleavage system (GCS), which is a complex of four subunits: P-, T-, H- and L-proteins. A P-protein (glycine decarboxylase or GLDC) deficiency was reported in about 80% of NKH patients. We performed mutation analysis of the complete coding sequence of the GLDC gene in 28 unrelated patients with neonatal NKH using denaturing high-performance liquid chromatography (DHPLC) and sequencing. Forty different gene alterations were identified, confirming the large molecular heterogeneity of the GLDC gene. Eighteen alterations were clearly disease-causing: two large deletions, four one-base deletions (c.28delC, c.1175delC, c.2186delC, c.2422delA), one 1-base insertion (c.1002_1003insT), one 4-base insertion (c.1285_1286insCAAA), one insertion/deletion (c.2153_2155delinsTCCTGGTTTA), five nonsense mutations (p.E153X, p.R236X, p.E270X, p.R337X, p.R424X) and four splice site mutations (c.861+1G > T, c.1402-1C > G, c.2316-1G > A, c.2919+1G > A). Additionally, we identified one intronic mutation outside the consensus splice sites (c.2838+5G > A) and 21 nucleotide substitutions leading to amino acid change (including three previously described mutations: p.T269M, p.R461Q, p.G771R), the pathogenicity of which should be confirmed by expression studies (p.S132W, p.Y138F, p.G171A, p.T187K, p.R212K, p.T269M, p.R373W, p.I440N, p.R461Q, p.N533Y, p.C644F, p.H651R, p.V705M, p.N732K, p.G771R, p.H775R, p.T830M, p.A841P, p.D880V, p.S957P and p.R966G). Mutation analysis allowed us to identify sequence alterations in both alleles for 19 patients and in one allele for 7 patients One patient was carrying three mutations (p.Y138F, p.T269M and p.E153X) and one patient was carrying two amino acid substitutions on the same allele (p.V705M and p.R212K) and an unidentified mutation on the other allele. No mutation could be found in two patients, suggesting possible defects in the H-protein or gene alterations that could not be identified by our technique. The potential use of genotype determination for prenatal diagnosis is emphasized.
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PMID:Genetic heterogeneity of the GLDC gene in 28 unrelated patients with glycine encephalopathy. 1660 80

Non-ketotic hyperglycinaemia (NKH), or glycine encephalopathy, is an autosomal recessive neurometabolic disease caused by defective activity of the glycine cleavage system. Up to 80% of NKH cases are caused by mutations in the P protein encoded by the glycine decarboxylase (GLDC) gene. GLDC deletions were identified in approximately 20% of NKH mutant alleles and resulted in a severe neonatal form of the disease. Given the difficult management of NKH caused by GLDC deletion, it was decided to adopt a preventative approach in a family with a history of this disease by using preimplantation genetic diagnosis (PGD). In this family, there is a deletion in the 5' UTR (untranslated region) up to the third intron of GLDC. PGD was carried out using multiple displacement amplification (MDA) and fluorescent polymerase chain reaction (PCR). This resulted in a singleton pregnancy after transfer of three unaffected embryos. Post-natal DNA testing of the newborn confirmed the PGD result. This is the first report of a successful PGD cycle intended to prevent the occurrence of NKH in a family with a history of the disease. The use of MDA coupled with fluorescent PCR is a very encouraging strategy leading to both low allele drop-out (2/40) and failure of amplification (0/40) rates.
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PMID:Delivery of a normal baby after preimplantation genetic diagnosis for non-ketotic hyperglycinaemia. 1854 3

Early myoclonic encephalopathy presents neonatally with fragmented myoclonus and a suppression-burst electroencephalography pattern. We describe a newborn boy with early myoclonic encephalopathy caused by nonketotic hyperglycinemia. He presented with severe hypotonia, progressive apneic episodes, and erratic myoclonus. Screening of deletions in GLDC, using the multiplex ligation-dependent probe amplification method, and a (13)C breath test confirmed the diagnosis of nonketotic hyperglycinemia. Treatment with the N-methyl-d-aspartate receptor antagonist ketamine exerted dramatic suppressive effects on his seizures, and ameliorated his clinical status.
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PMID:Nonketotic hyperglycinemia: proposal of a diagnostic and treatment strategy. 2069 48

Nonketotic hyperglycinemia (OMIM #605899), also known as glycine encephalopathy, is an autosomal recessive disorder of glycine metabolism caused by a defect in the glycine cleavage system. A term neonate developed progressive lethargy, muscular hypotonia, and respiratory insufficiency on day 2 after birth, but no overt clinical seizures. Amplitude-integrated electroencephalography indicated a continuous burst-suppression pattern. The diagnosis of nonketotic hyperglycinemia was made biochemically and was confirmed by genetic studies, which revealed two missense mutations (one not previously described) within the glycine decarboxylase gene, GLDC. Nonketotic hyperglycinemia should be incorporated into the differential diagnosis of neonatal hypotonia, to avoid an erroneous diagnosis of sepsis or hypoxic ischemic injury. Amplitude-integrated electroencephalography may be helpful in the initial assessment of severely sick and hypotonic neonates without overt clinical seizures, and may direct further diagnostic evaluation.
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PMID:A novel missense mutation in a neonate with nonketotic hyperglycinemia. 2093 83

Nonketotic hyperglycinemia (NKH), or glycine encephalopathy, is an autosomal recessive disorder caused by a defect in the glycine cleavage enzyme system. In neonatal-onset NKH, patients manifest lethargy, hypotonia, apnea, and intractable epileptic seizures that are not specific to this disease. We experienced a 6-year-old girl with spastic quadriplegia, intractable epilepsy, and mental retardation, all initially regarded as sequelae of neonatal meningitis. The seizure frequency was transiently increased when valproate was started. Head MRI revealed progressive brain atrophy and white matter loss with high intensity signals on T2-weighted and diffusion-weighted images, which prompted us to conduct further metabolic workups. High glycine levels led us to suspect NKH, and we confirmed this diagnosis by the non-invasive, (13)C-glycine breath test. DNA sequencing revealed novel Leu885Pro/Trp897Cys mutations in the glycine decarboxylase gene that were transmitted from both parents. Sodium benzoate and dextromethorphan dramatically decreased her hypertonicity. Our case shows that paradoxical increases in seizure frequency following valproate can be a clue for a diagnosis of NKH, and that a correct diagnosis of NKH can greatly alter the quality of life in such patients.
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PMID:Paradoxical increase in seizure frequency with valproate in nonketotic hyperglycinemia. 2131 84

Glycine encephalopathy (GE), also known as non-ketotic hyperglycinemia, is a life-threatening metabolic disease caused by inherited deficiency of the glycine cleavage system (GCS). GE is characterized by accumulation of a large amount of glycine in serum and cerebrospinal fluids. In typical cases with GE, coma, profound hypotonia, and intractable seizures develop within several days of life. Patients with atypical symptoms may have delayed or missed diagnosis because of non-specific symptoms. It is sometimes problematic to confirm the diagnosis of GE since it requires either invasive liver biopsy for measurement of GCS activity or exhaustive mutational screening of three GCS genes, GLDC, AMT, and GCSH. We herein describe two novel laboratory tests for diagnosis of GE, [1-(13)C]glycine breath test and the multiplex ligation-dependent probe amplification (MLPA) for detection of large deletions in GLDC. The [1-(13)C]glycine breath test has been developed for noninvasive enzymatic diagnosis of GE. Because the GCS generates CO(2) by degradation of glycine, the GCS activity could be evaluated in vivo by measurement of exhaled (13)CO(2) after administration of a stable isotope, [1-(13)C]glycine. The MLPA has been developed for improvement in mutation detection rate in GE: Deletions involving multiple GDLC exons are prevalent among GE patients, but cannot be detected by the exon-sequencing analysis. Two novel diagnosis methods would facilitate diagnosis of hyperglycinemic patients as having GE.
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PMID:Two novel laboratory tests facilitating diagnosis of glycine encephalopathy (nonketotic hyperglycinemia). 2147 Aug 5

Non ketotic hyperglycinemia is a rare inborn error of glycine metabolism due to deficient activity of glycine cleavage system, a multienzymatic complex consisting of four protein subunits: the P-protein, the H-protein, the T-protein and the L-protein. The neonatal form of non ketotic hyperglycinemia presents in the first days of life with encephalopathy, seizures, multifocal myoclonus and characteristic "hiccups". Rapid progression may lead to intractable seizures, coma and respiratory failure requiring mechanical ventilation. Clinical trial with scavenges drugs decreasing glycine levels such as sodium benzoate, and with drugs reducing NMDA receptors excitatory properties, such as ketamine and dextromethorphan, have been tried but the outcome is usually poor; antiepileptic therapy, moreover, is unable to control epileptic seizures. Ketogenic diet has been successfully tried for refractory epilepsy in pediatric patients. We report three cases affected by neonatal non ketotic hyperglycinemia and early myoclonic encephalopathy treated with ketogenic diet. In our patients ketogenic diet, in association with standard pharmacological therapy, determined dramatic reduction of seizures and improved quality of life.
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PMID:Ketogenic diet in early myoclonic encephalopathy due to non ketotic hyperglycinemia. 2226 Oct 77


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