[Clinical and molecular genetic characteristics of nonketotic hyperglycinemia].
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ABSTRACT:
SUBMITTER: Li HF
PROVIDER: S-EPMC7390138 | biostudies-literature | 2017 Mar
REPOSITORIES: biostudies-literature
Publications
[Clinical and molecular genetic characteristics of nonketotic hyperglycinemia].
Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics 20170301 3
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Project description:Nonketotic hyperglycinemia (NKH) is a rare, inborn error of metabolism. In this case report, a Chinese male infant was diagnosed with NKH caused by GLDC gene mutation. The clinical characteristics and genetic diagnosis were reported. The infant presented with an onset of early metabolic encephalopathy and Ohtahara syndrome. Both blood and urinary levels of metabolites were in the normal range. Brain MRI images indicated a poor development of corpus callosum, and a burst suppression pattern was found in the EEG. Results of target gene sequencing technology combined with multiplex ligation-dependent probe amplification (MLPA) indicated a heterozygous missense mutation of c.1786 C>T (p.R596X) in maternal exon 15 and a loss of heterozygosity of 4-15 exon gross deletions in paternal GLDC gene. These definite pathogenic mutations confirmed the diagnosis of NKH. The infant's clinical condition was not improved after treatment with adreno-cortico-tropic-hormone, topiramate and dextromethorphan, and he finally died at 4 months of age. Patients with NKH often exhibit complicated clinical phenotypes and are lack of specific symptoms. NKH could be diagnosed by metabolic screening and molecular genetic analysis.
| S-EPMC7390153 | biostudies-literature
Project description:BackgroundNonketotic hyperglycinemia (NKH) is a rare autosomal recessive genetic disorder of abnormal glycine metabolism caused by insufficient activity of the glycine cleavage enzyme system. Glycine is believed to function mainly as an inhibitory neurotransmitter, but it can also act as a co-agonist of the N-methyl-D-aspartate (NMDA) receptor. The accumulation of a large amount of glycine in the brain leads to neuronal and axonal injury via overactivation of NMDA receptors located in the hippocampus, cerebral cortex, olfactory bulb, and cerebellum and to stimulation of the inhibitory function of glycine receptors located in the spinal cord and brain stem, resulting in central apnea, hiccups, and hypotonia in the early stage of the disease.Case summaryThe child described in this report had typical clinical manifestations of NKH, such as hiccups, disturbance of consciousness, hypotonia, and convulsions, within the first week after birth. Whole-exome genetic testing revealed that the child had a compound heterozygous mutation, namely, c.395C>A (p.S132X) and c.2182G>A (p.G728R), in the GLDC gene, and he was diagnosed with NKH. For treatment, we administered an oral levetiracetam solution and added topiramate and prednisone for epilepsy control, but the epilepsy remained uncontrollable. Ketogenic diet therapy was started at 6 mo of age, his seizures were significantly reduced, and there were no obvious adverse reactions during ketogenic treatment. Furthermore, we found that with the development of the disease, high levels of serum glycine decreased or even disappeared without intervention, and as the disease progressed, the corpus callosum became dysplastic.ConclusionThis case shows that plasma glycine levels cannot be used to evaluate the prognosis of NKH, that the development of the corpus callosum can be affected by NKH, and that a ketogenic diet may be effective for seizure control in NKH patients.
| S-EPMC9372859 | biostudies-literature
Project description:ObjectiveNonketotic hyperglycinemia is a neurometabolic disorder characterized by intellectual disability, seizures, and spasticity. Patients with attenuated nonketotic hyperglycinemia make variable developmental progress. Predictive factors have not been systematically assessed.MethodsWe reviewed 124 patients stratified by developmental outcome for biochemical and molecular predictive factors. Missense mutations were expressed to quantify residual activity using a new assay.ResultsPatients with severe nonketotic hyperglycinemia required multiple anticonvulsants, whereas patients with developmental quotient (DQ) > 30 did not require anticonvulsants. Brain malformations occurred mainly in patients with severe nonketotic hyperglycinemia (71%) but rarely in patients with attenuated nonketotic hyperglycinemia (7.5%). Neonatal presentation did not correlate with outcome, but age at onset ≥ 4 months was associated with attenuated nonketotic hyperglycinemia. Cerebrospinal fluid (CSF) glycine levels and CSF:plasma glycine ratio correlated inversely with DQ; CSF glycine > 230 μM indicated severe outcome and CSF:plasma glycine ratio ≤ 0.08 predicted attenuated outcome. The glycine index correlated strongly with outcome. Molecular analysis identified 99% of mutant alleles, including 96 novel mutations. Mutations near the active cleft of the P-protein maintained stable protein levels. Presence of 1 mutation with residual activity was necessary but not sufficient for attenuated outcome; 2 such mutations conferred best outcome. Divergent outcomes for the same genotype indicate a contribution of other genetic or nongenetic factors.InterpretationAccurate prediction of outcome is possible in most patients. A combination of 4 factors available neonatally predicted 78% of severe and 49% of attenuated patients, and a score based on mutation severity predicted outcome with 70% sensitivity and 97% specificity.
| S-EPMC4767401 | biostudies-literature
Project description:PurposeNeonatal nonketotic hyperglycinemia is an autosomal recessive inborn disorder of glycine metabolism in which large quantities of glycine accumulate in all body tissues. It is characterized by a progressive lethargy, hypotonia, myoclonic jerks, and early death secondary to respiratory problems. As a result of early diagnosis and treatment protocols, more patients survive the critical neonatal period with profound mental retardation, delayed developmental milestones, seizures, and spasticity. There are no reports about the orthopaedic manifestations of neonatal nonketotic hyperglycinemia. The purpose of this study is to evaluate the musculoskeletal findings of neonatal nonketotic hyperglycinemia.MethodsThis is a retrospective IRB-approved study of all patients in our Orthopaedic and Genetics Clinics with the diagnosis of neonatal nonketotic hyperglycinemia during a 10-year period. Demographic, clinical, and imaging data were analyzed.ResultsTwelve patients with neonatal nonketotic hyperglycinemia were evaluated, with a mean age of 7 years and 2 months (range: 5 months to 21 years). Seven were male and five were female. Eleven patients (92 %) have evidence of progressive early-onset neuromuscular scoliosis with a mean Cobb angle of 55° (range: 30-95°). Five children (42 %) presented evidence of progressive hip dislocation secondary to spasticity. All the patients have severe multiple joint contractures.ConclusionNeonatal nonketotic hyperglycinemia is a rare metabolic disorder presented in the past as a lethal condition. Recent advances in early diagnosis and neonatal care improve overall outcome. As pediatric orthopaedic surgeons, we need to establish treatment based on update information of the disease and probability to improve quality of life.
| S-EPMC3400000 | biostudies-literature
Project description:Nonketotic hyperglycinemia (NKH) is an autosomal recessive hereditary disease caused by a defect in the glycine cleavage system and is classified into typical and atypical NKH. Atypical NKH has complex manifestations and is difficult to diagnose in clinical practice. This article reports a family of NKH. The parents had normal phenotypes, and the older brother and the younger sister developed this disease in the neonatal period. The older brother manifested as intractable epilepsy, severe spastic diplegia, intellectual disability, an increased level of glycine in blood and cerebrospinal fluid, an increased glycine/creatinine ratio in urine, and an increased ratio of glycine concentration in cerebrospinal fluid and blood. The younger sister manifested as delayed language development, ataxia, chorea, mental and behavior disorders induced by pyrexia, hypotonia, an increased level of glycine in cerebrospinal fluid, and an increased ratio of glycine concentration in cerebrospinal fluid and blood. High-throughput sequencing found a maternal missense mutation, c.3006C>G (p.C1002W), and a paternal nonsense mutation, c.1256C>G (p.S419X), in the GLDC gene in both patients. These two mutations were thought to be pathogenic mutations by a biological software. H293T cells transfected with these two mutants of the GLDC gene had a down-regulated activity of glycine decarboxylase. NKH has various phenotypes, and high-throughput sequencing helps to make a confirmed diagnosis. Atypical NKH is associated with the downregulated activity of glycine decarboxylase caused by gene mutations.
| S-EPMC7389275 | biostudies-literature
Project description:Nonketotic hyperglycinemia, also known as glycine encephalopathy (OMIM #605899), is an autosomal recessive disorder of glycine metabolism resulting from a defect in the glycine cleavage system. We report two novel mutations of the glycine decarboxylase (GLDC) gene observed in a compound heterozygous state in a neonate of mixed Maori and Caucasian parentage: c.395C>T p.(Ser132Leu) in exon 3, and c.256-?_334+?del p.(Ser86Valfs*119), resulting in an out-of-frame deletion of exon 2. Additionally, we describe our experience of implementing the ketogenic diet, alongside standard pharmacological therapy, and highlight its potential therapeutic benefit in severe nonketotic hyperglycinemia, particularly in seizure management.
| S-EPMC4999328 | biostudies-literature
Project description:Nonketotic hyperglycinemia (NKH) is caused by deficient glycine cleavage enzyme activity and characterized by elevated brain glycine. Metabolism of glycine is connected enzymatically to serine through serine hydroxymethyltransferase and shares transporters with serine and threonine. We aimed to evaluate changes in serine and threonine in NKH patients, and relate this to clinical outcome severity. Age-related reference values were developed for cerebrospinal fluid (CSF) serine and threonine from 274 controls, and in a cross-sectional study compared to 61 genetically proven NKH patients, categorized according to outcome. CSF d-serine and l-serine levels were stereoselectively determined in seven NKH patients and compared to 29 age-matched controls. In addition to elevated CSF glycine, NKH patients had significantly decreased levels of CSF serine and increased levels of CSF threonine, even after age-adjustment. The CSF serine/threonine ratio discriminated between NKH patients and controls. The CSF glycine/serine aided in discrimination between severe and attenuated neonates with NKH. Over all ages, the CSF glycine, serine and threonine had moderate to fair correlation with outcome classes. After age-adjustment, only the CSF glycine level provided good discrimination between outcome classes. In untreated patients, d-serine was more reduced than l-serine, with a decreased d/l-serine ratio, indicating a specific impact on d-serine metabolism. We conclude that in NKH the elevation of glycine is accompanied by changes in l-serine, d-serine and threonine, likely reflecting a perturbation of the serine shuttle and metabolism, and of one-carbon metabolism. This provides additional guidance on diagnosis and prognosis, and opens new therapeutic avenues to be explored.
| S-EPMC9543955 | biostudies-literature
Project description:The crystal structure of the P-protein of the glycine cleavage system from Thermus thermophilus HB8 has been determined. This is the first reported crystal structure of a P-protein, and it reveals that P-proteins do not involve the alpha(2)-type active dimer universally observed in the evolutionarily related pyridoxal 5'-phosphate (PLP)-dependent enzymes. Instead, novel alphabeta-type dimers associate to form an alpha(2)beta(2) tetramer, where the alpha- and beta-subunits are structurally similar and appear to have arisen by gene duplication and subsequent divergence with a loss of one active site. The binding of PLP to the apoenzyme induces large open-closed conformational changes, with residues moving up to 13.5 A. The structure of the complex formed by the holoenzyme bound to an inhibitor, (aminooxy)acetate, suggests residues that may be responsible for substrate recognition. The molecular surface around the lipoamide-binding channel shows conservation of positively charged residues, which are possibly involved in complex formation with the H-protein. These results provide insights into the molecular basis of nonketotic hyperglycinemia.
| S-EPMC1142568 | biostudies-literature
Project description:Background: Nonketotic hyperglycinemia is a metabolic disease with autosomal recessive inheritance due to the glycine cleavage system (GCS) defect leading to the accumulation of glycine that causes severe and fatal neurological symptoms in the neonatal period. Methods: Genomic DNA was extracted from the peripheral blood of the female proband and her family members. The AMT variation was detected in the patient by whole-exome sequencing (WES), and the variant was validated by Sanger sequencing. Results: The WES showed that there were novel compound heterozygous frameshift variations c.977delA (p.Glu326Glyfs*12) and c.982_983insG (p.Ala328Glyfs*22) in exon eight of the AMT gene (NM_000481.4) in the proband. Genetic analysis showed that the former was inherited from the mother, and the latter was inherited from the father. Conclusion: We report the novel compound heterozygous variation of the AMT gene in a Chinese girl with NKH by WES, which has never been reported previously. Our case expanded the AMT gene mutation spectrum, further strengthened the understanding of NKH, and deepened the genetic and clinical heterogeneity of the disease. However, the study of treatment and prognosis is still our future challenge and focus.
| S-EPMC9133660 | biostudies-literature
Project description:The glycine cleavage system H protein (GCSH) is an integral part of the glycine cleavage system with its additional involvement in the synthesis and transport of lipoic acid. We hypothesize that pathogenic variants in GCSH can cause variant nonketotic hyperglycinemia (NKH), a heterogeneous group of disorders with findings resembling a combination of severe NKH (elevated levels of glycine in plasma and CSF, progressive lethargy, seizures, severe hypotonia, no developmental progress, early death) and mitochondriopathies (lactic acidosis, leukoencephalopathy and Leigh-like lesions on MRI). We herein report three individuals from two unrelated Indian families with clinical, biochemical, and radiological findings of variant NKH, harboring a biallelic start loss variant, c.1A > G in GCSH.
| S-EPMC9990824 | biostudies-literature