Classic Nonketotic Hyperglycinemia Research Articles

Glycine disrupts myelin, glutamatergic neurotransmission, and redox homeostasis in a neonatal model for non ketotic hyperglycinemia

Non ketotic hyperglycinemia (NKH) is an inborn error of glycine metabolism caused by mutations in the genes encoding glycine cleavage system proteins. Classic NKH has a neonatal onset, and patients present with severe neurodegeneration. Although glycine accumulation has been implicated in NKH pathophysiology, the exact mechanisms underlying the neurological damage and white matter alterations remain unclear. We investigated the effects of glycine in the brain of neonatal rats and MO3.13 oligodendroglial cells. Glycine decreased myelin basic protein (MBP) and myelin-associated glycoprotein (MAG) in the corpus callosum and striatum of rats on post-natal day (PND) 15. Glycine also reduced neuroglycan 2 (NG2) and N-methyl-d-aspartate receptor subunit 1 (NR1) in the cerebral cortex and striatum on PND15. Moreover, glycine reduced striatal glutamate aspartate transporter 1 (GLAST) content and neuronal nucleus (NeuN), and increased glial fibrillary acidic protein (GFAP) on PND15. Glycine also increased DCFH oxidation and malondialdehyde levels and decreased GSH concentrations in the cerebral cortex and striatum on PND6, but not on PND15. Glycine further reduced viability but did not alter DCFH oxidation and GSH levels in MO3.13 cells after 48- and 72-h incubation. These data indicate that impairment of myelin structure and glutamatergic system and induction of oxidative stress are involved in the neuropathophysiology of NKH.

Caracterización clínica, bioquímica e imagenológica en una cohorte de pacientes diagnosticados con hiperglicinemia no cetósica clásica: estudio ambispectivo 2000-2014, Medellín, Colombia

Introducción: La hiperglicinemia no cetósica (HGNC) es un error innato del metabolismo del grupo de las aminoacidopatías, de carácter autosómico recesivo, causado por un defecto en el sistema de clivaje de la glicina. Es una entidad rara y no se conoce su incidencia en Colombia.
 Objetivo:Describir características clínicas, bioquímica e imagenológicas en una cohorte de pacientes diagnosticados con hiperglicinemia no cetósica clásica
 Materiales y métodos: Estudio de tipo descriptivo, ambispectivo, en el periodo enero 2000-2014, en varios centros de Medellín.
 Resultados: Se incluyeron 20 pacientes que cumplían criterios de inclusión, de los 35 pacientes que cumplían con el criterio de búsqueda, en su mayoría de sexo femenino y con un Apgar adecuado al nacer. El promedio de inicio de los síntomas fue de 2,6 días; somnolencia, hipoactividad, apnea, convulsiones y singulto fueron los principales síntomas, y las convulsiones de tipo focal las más frecuentes. La relación glicina LCR/plasma en promedio fue 0,42. El patrón estallido-supresión en el electroencefalograma y la ausencia o retraso en la mielinización de la sustancia blanca supratentorial en la resonancia magnética fueron hallazgos comunes.
 Conclusión: La HGNC es frecuente en nuestro medio, por lo cual es necesario que se disponga de pruebas bioquímicas y moleculares necesarias para diagnóstico oportuno, manejo integral y asesoría genética.

Genotypic and phenotypic features in Turkish patients with classic nonketotic hyperglycinemia.

Nonketotic hyperglycinemia is an autosomal recessive inborn error of glycine metabolism, characterized by deficient activity of the glycine cleavage enzyme system. Classic nonketotic hyperglycinemia is caused by mutations or genomic changes in genes that encode the protein components of the glycine cleavage enzyme system. We aimed to investigate clinical, biochemical, radiological findings and molecular genetic data in ten Turkish patients with classic nonketotic hyperglycinemia.Ten Turkish patients who were diagnosed with classic nonketotic hyperglycinemia in a single center from 2013 to 2019 were included in this study. Their clinical, radiological, electrophysiological and laboratory data were collected retrospectively.Sixty percent of the patients were in neonatal group, while 40 % of the patients were infantile. There were no late-onset patients. 90 % of the patients had the severe form. All patients had developmental delay and seizures. Mortality ratio was 30 % in all groups and 50 % in the neonatal group, while no mortality was seen in infantile group. Median (range) values of cerebrospinal fluid (CSF) glycine levels, plasma glycine levels and CSF/plasma glycine ratios were 148 (15-320) µmol/L, 896 (87-1910) µmol/L, 0.17 (0.09-0.21) respectively. Diffuse hypomyelination and corpus callosum anomaly were the most common cranial MRI findings and multifocal epileptic activity and burst supression pattern were the most common electroencephalographic findings. Six patients had variants in GLDC gene and four in AMT gene; five novel variants including AMT gene deletion were detected. Prognosis was poor and treatment was not effective, especially in the severe form.Classic nonketotic hyperglycinemia causes high morbidity and mortality. Neonatal-onset disease was more common and severe than infantile-onset disease. The ratio of AMT gene variants might be higher in Turkey than other countries. AMT gene deletion also plays a role in the etiology of classic nonketotic hyperglycinemia.

New Pathogenic Mutations on GLDC gene leading to Classic Nonketotic Hyperglycinemia

New Pathogenic Mutations on GLDC gene leading to Classic Nonketotic Hyperglycinemia

Brain imaging in classic nonketotic hyperglycinemia: Quantitative analysis and relation to phenotype.

Patients with severe nonketotic hyperglycinemia (NKH) have absent psychomotor development and intractable epilepsy, whereas attenuated patients have variable psychomotor development and absent or treatable epilepsy; differences in brain magnetic resonance imaging (MRI) between phenotypes have not been reported. In a retrospective cross-sectional study, we reviewed 38 MRI studies from 24 molecularly proven NKH patients, and 2 transient NKH patients. Quantitative analyses included corpus callosum size, apparent diffusion coefficient, automated brain volumetric analysis, and glycine/creatine ratio by spectroscopy. All patients age <3 months had restricted diffusion in the posterior limb of the internal capsule, anterior brainstem, posterior tegmental tracts, and cerebellum, not present in transient NKH. In older infants, the pattern evolved and included generalized diffusion restriction in the supratentorial white matter, which quantitatively peaked between 3 and 12 months. No patient had absent corpus callosum or gyral malformation. The corpus callosum was relatively short in severe compared to attenuated phenotypes, and thin in severe cases only. The corpus callosum growth rate differed by severity; age-matched Z-scores of thickness worsened in severe cases only. Cerebral volume was decreased in the hippocampus, globus pallidus, cerebral cortex, thalamus, and cerebellum. Severe patients had greatest glycine/creatine ratios. In this study, no brain malformations were identified. The growth failure of the corpus callosum is worse in severe NKH, whereas the diffusion restriction pattern, reflecting microspongiosis, does not discriminate by phenotypic severity. NKH is therefore a disorder of brain growth best recognized in the corpus callosum, whereas spongiosis is not prognostic.

Correction: The genetic basis of classic nonketotic hyperglycinemia due to mutations in GLDC and AMT.

The original supplementary information included with this article contained several minor errors. Corrected Supplementary Information accompanies this corrigendum.

The genetic basis of classic nonketotic hyperglycinemia due to mutations in GLDC and AMT

The study's purpose was to delineate the genetic mutations that cause classic nonketotic hyperglycinemia (NKH). Genetic results, parental phase, ethnic origin, and gender data were collected from subjects suspected to have classic NKH. Mutations were compared with those in the existing literature and to the population frequency from the Exome Aggregation Consortium (ExAC) database. In 578 families, genetic analyses identified 410 unique mutations, including 246 novel mutations. 80% of subjects had mutations in GLDC. Missense mutations were noted in 52% of all GLDC alleles, most private. Missense mutations were 1.5 times as likely to be pathogenic in the carboxy terminal of GLDC than in the amino-terminal part. Intragenic copy-number variations (CNVs) in GLDC were noted in 140 subjects, with biallelic CNVs present in 39 subjects. The position and frequency of the breakpoint for CNVs correlated with intron size and presence of Alu elements. Missense mutations, most often recurring, were the most common type of disease-causing mutation in AMT. Sequencing and CNV analysis identified biallelic pathogenic mutations in 98% of subjects. Based on genotype, 15% of subjects had an attenuated phenotype. The frequency of NKH is estimated at 1:76,000. The 484 unique mutations now known in classic NKH provide a valuable overview for the development of genotype-based therapies.Genet Med 19 1, 104-111.

P85 – 2818: Nonketotic hyperglycinemia: A cause of severe epileptic encephalopathy and hypotonia in children

Objective Nonketotic hyperglycinemia is an autosomal recessive metabolic disorder characterized by the accumulation of glycine in all body tissues especially the central nervous system. It is considered a rare disorder, but the exact worldwide incidence is not known. Methods In this report, we present 5 cases of classical nonketotic hyperglycinemia referred to our pediatric hospital. These patients were diagnosed in the last three months in our center in the capital city of Turkey. The patients' common findings were severe hypotonia, head lag, poor sucking and intractable seizures. Only one patient had hiccups in the neonatal period. The other 4 patients had flexor and mixed spasms. The patient with hiccups developed asymmetric tonic spasms after 1 month. All patients were taking multiple antiepileptic drugs for their seizures before the diagnosis. All the patients' cerebrospinal fluid to plasma glycine ratio was over 0.08 at the diagnosis. The initial ratio of the patient with hiccups was 0.031 (over 0.02), but the second evaluation ratio was over 0.08. 2 of 5 patients are mutation positive. The first patient's mutations in the AMT gene are p.E211K homozygous and p.R320H heterozygous. The other patient's mutation in the GLDC gene is p.D880E heterozygous. The other 3 patients' mutation analyses are on research. 4/5 patients have also been evaluated with MRS consolidating the diagnosis. Results All of the 5 patients were seizure free after Na benzoate treatment for a while. Conclusion We speculate that glycine encephalopathy is not a rare neurometabolic disorder in our ethnical geography. We should be aware of this disorder if the baby is severe hypotonic and should early evaluate EEG records even without clinical seizures. We offer that cerebrospinal fluid to plasma glycine ratio should be evaluated more than once if there is a strong clinical suspicion. Nonketotic hyperglycinemia is an autosomal recessive metabolic disorder characterized by the accumulation of glycine in all body tissues especially the central nervous system. It is considered a rare disorder, but the exact worldwide incidence is not known. In this report, we present 5 cases of classical nonketotic hyperglycinemia referred to our pediatric hospital. These patients were diagnosed in the last three months in our center in the capital city of Turkey. The patients' common findings were severe hypotonia, head lag, poor sucking and intractable seizures. Only one patient had hiccups in the neonatal period. The other 4 patients had flexor and mixed spasms. The patient with hiccups developed asymmetric tonic spasms after 1 month. All patients were taking multiple antiepileptic drugs for their seizures before the diagnosis. All the patients' cerebrospinal fluid to plasma glycine ratio was over 0.08 at the diagnosis. The initial ratio of the patient with hiccups was 0.031 (over 0.02), but the second evaluation ratio was over 0.08. 2 of 5 patients are mutation positive. The first patient's mutations in the AMT gene are p.E211K homozygous and p.R320H heterozygous. The other patient's mutation in the GLDC gene is p.D880E heterozygous. The other 3 patients' mutation analyses are on research. 4/5 patients have also been evaluated with MRS consolidating the diagnosis. All of the 5 patients were seizure free after Na benzoate treatment for a while. We speculate that glycine encephalopathy is not a rare neurometabolic disorder in our ethnical geography. We should be aware of this disorder if the baby is severe hypotonic and should early evaluate EEG records even without clinical seizures. We offer that cerebrospinal fluid to plasma glycine ratio should be evaluated more than once if there is a strong clinical suspicion.

A Known and a Novel Mutation in the Glycine Decarboxylase Gene in a Newborn with Classic Nonketotic Hyperglycinemia

A term neonate displayed typical features of nonketotic hyperglycinemia (NKH). Conventional magnetic resonance imaging showed corpus callosum hypoplasia and increased signal intensity of the white matter. Magnetic resonance proton spectroscopy revealed high cerebral glycine levels. The liquor/plasma glycine ratio was increased. Genetic testing detected a known and a novel mutation in the glycine decarboxylase gene, leading to the classic form of glycine encephalopathy. Prenatal genetic testing in the subsequent pregnancy showed that this fetus was not affected. As features of neonatal NKH may not be very specific, recognition of the disease may be difficult. An overview of clinical, electroencephalography, and neuroimaging findings is given in this article.

Nonketotic Hyperglycinemia

Nonketotic hyperglycinemia is a rare metabolic disorder with severe, frequently fatal, neurologic manifestations. Reliable and accurate diagnosis depends on careful interpretation of laboratory findings. The clinical suspicion should lead to determination of glycine in plasma and cerebrospinal fluid. Amino acid analysis presents diagnostic values for classic nonketotic hyperglycinemia, but it also should be performed in suspected cases of atypical nonketotic hyperglycinemia and in children with seizures, failure to thrive, behavior problems, and uncoordinated movements. Clinical assessment should be reinforced by demonstration of elevated cerebrospinal fluid-to-plasma glycine ratio. Confirmatory diagnosis requires enzymatic and genetic investigation of glycine cleavage system. An early diagnosis, though not affecting clinical outcome, allows proper genetic counseling, with the possibility of prenatal diagnosis. We report 3 cases of nonketotic hyperglycinemia, 2 typical neonatal and 1 atypical, diagnosed in Pediatric Hospital of Coimbra, Portugal, and investigated at Laboratory of Biochemical Genetics in 2004 to 2010 (incidence 1:47 455; prevalence 1:782 951).

Proteomic analysis in cerebrospinal fluid of patients with atypical nonketotic hyperglycinemia and pulmonary hypertension – A pilot study

A variant phenotype of nonketotic hyperglycinemia has been described by our group associated with pulmonary hypertension. The aim of this study is to investigate the cerebrospinal fluid proteomes to get an insight into this neurodegenerative process producing leukoencephalopathy with white matter spongiform degeneration. DIGE and MALDI-TOF-TOF analyses were performed to carry out the proteomic study of four patients against three normal controls and one additional control of a classical nonketotic hyperglycinemia. The differential proteomic analysis showed a displacement of some series of spots toward the acidic side. The shifted proteins showed a high degree of carbonylation and increased methionine sulfoxidation was found in cystatin C and in vitamin-D-binding protein. These findings in addition to the increase of serum malondialdehyde concentration provide evidence of an oxidative stress in the patients under study, which is probably systemic rather than mainly confined to the CNS. The similarities of our findings with those found in other neurodegenerative diseases suggest that oxidative damage is commonly involved in these pathologies. DIGE technology improves the 2-D PAGE differential analysis and it is suitable in proteomic studies with a small number of cases.

Nonketotic hyperglycinemia in Suleimaniah Children’s Hospital, Riyadh, Saudi Arabia

Nonketotic hyperglycinemia in Suleimaniah Children’s Hospital, Riyadh, Saudi Arabia

Transient nonketotic hyperglycinemia: two case reports and literature review

Transient nonketotic hyperglycinemia is characterized by clinical and biochemical findings similar to those seen in classic nonketotic hyperglycinemia. Abnormalities in amino acids are partially or completely resolved in a period ranging from days to months. Almost all patients with the classic form of nonketotic hyperglycinemia survive with severe neurologic sequela, whereas most of the patients with the transient form exhibit normal development. Therefore, distinguishing the transient form of nonketotic hyperglycinemia from classic nonketotic hyperglycinemia is important to predict outcome of the patients. Transient nonketotic hyperglycinemia has been reported in only seven neonates. This article adds two cases to the transient nonketotic hyperglycinemia and reviews the relevant literature. Common clinical features were determined, and presence of miotic pupils was stressed.