Metabolic Rewiring and Altered Glial Differentiation in an iPSC-Derived Astrocyte Model Derived from a Nonketotic Hyperglycinemia Patient.

The pathophysiology of nonketotic hyperglycinemia (NKH), a rare neuro-metabolic disorder associated with severe brain malformations and life-threatening neurological manifestations, remains incompletely understood. Therefore, a valid human neural model is essential. We aimed to investigate the impact of GLDC gene variants, which cause NKH, on cellular fitness during the differentiation process of human induced pluripotent stem cells (iPSCs) into iPSC-derived astrocytes and to identify sustainable mechanisms capable of overcoming GLDC deficiency. We developed the GLDC27-FiPS4F-1 line and performed metabolomic, mRNA abundance, and protein analyses. This study showed that although GLDC27-FiPS4F-1 maintained the parental genetic profile, it underwent a metabolic switch to an altered serine-glycine-one-carbon metabolism with a coordinated cell growth and cell cycle proliferation response. We then differentiated the iPSCs into neural progenitor cells (NPCs) and astrocyte-lineage cells. Our analysis showed that GLDC-deficient NPCs had shifted towards a more heterogeneous astrocyte lineage with increased expression of the radial glial markers GFAP and GLAST and the neuronal markers MAP2 and NeuN. In addition, we detected changes in other genes related to serine and glycine metabolism and transport, all consistent with the need to maintain glycine at physiological levels. These findings improve our understanding of the pathology of nonketotic hyperglycinemia and offer new perspectives for therapeutic options.

Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined nonketotic hyperglycinemia and lipoate deficiency.

Maintaining protein lipoylation is vital for cell metabolism. The H-protein encoded by GCSH has a dual role in protein lipoylation required for bioenergetic enzymes including pyruvate dehydrogenase and 2-ketoglutarate dehydrogenase, and in the one-carbon metabolism through its involvement in glycine cleavage enzyme system, intersecting two vital roles for cell survival. Here, we report six patients with biallelic pathogenic variants in GCSH and a broad clinical spectrum ranging from neonatal fatal glycine encephalopathy to an attenuated phenotype of developmental delay, behavioral problems, limited epilepsy and variable movement problems. The mutational spectrum includes one insertion c.293-2_293-1insT, one deletion c.122_(228 + 1_229-1) del, one duplication of exons 4 and 5, one nonsense variant p.Gln76*and four missense p.His57Arg, p.Pro115Leu and p.Thr148Pro and the previously described p.Met1?. Via functional studies in patient's fibroblasts, molecular modeling, expression analysis in GCSH knockdown COS7 cells and yeast, and in vitro protein studies, we demonstrate for the first time that most variants identified in our cohort produced a hypomorphic effect on both mitochondrial activities, protein lipoylation and glycine metabolism, causing combined deficiency, whereas some missense variants affect primarily one function only. The clinical features of the patients reflect the impact of the GCSH changes on any of the two functions analyzed. Our analysis illustrates the complex interplay of functional and clinical impact when pathogenic variants affect a multifunctional protein involved in two metabolic pathways and emphasizes the value of the functional assays to select the treatment and investigate new personalized options.

Integrative Approach to Predict Severity in Nonketotic Hyperglycinemia.

OBJECTIVE: Glycine encephalopathy, also known as nonketotic hyperglycinemia (NKH), is an inherited neurometabolic disorder with variable clinical course and severity, ranging from infantile epileptic encephalopathy to psychiatric disorders. A precise phenotypic characterization and an evaluation of predictive approaches are needed. METHODS: Longitudinal clinical and biochemical data of 25 individuals with NKH from the patient registry of the International Working Group on Neurotransmitter Related Disorders were studied with in silico analyses, pathogenicity scores, and molecular modeling of GLDC and AMT variants. RESULTS: Symptom onset (p < 0.01) and diagnosis occur earlier in life in severe NKH (p < 0.01). Presenting symptoms affect the age at diagnosis. Psychiatric problems occur predominantly in attenuated NKH. Onset age ≥ 3 months (66% specificity, 100% sensitivity, area under the curve [AUC] = 0.87) and cerebrospinal fluid (CSF)/plasma glycine ratio ≤ 0.09 (57% specificity, 100% sensitivity, AUC = 0.88) are sensitive indicators for attenuated NKH, whereas CSF glycine concentration ≥ 116.5µmol/l (100% specificity, 93% sensitivity, AUC = 0.97) and CSF/plasma glycine ratio ≥ 0.15 (100% specificity, 64% sensitivity, AUC = 0.88) are specific for severe forms. A ratio threshold of 0.128 discriminates the overlapping range. We present 10 new GLDC variants. Two mild variants resulted in attenuated, whereas 2 severe variants or 1 mild and 1 severe variant led to severe phenotype. Based on clinical, biochemical, and genetic parameters, we propose a severity prediction model. INTERPRETATION: This study widens the phenotypic spectrum of attenuated NKH and expands the number of pathogenic variants. The multiparametric approach provides a promising tool to predict disease severity, helping to improve clinical management strategies. ANN NEUROL 2022;92:292-303.

Genomic analyses of glycine decarboxylase neurogenic mutations yield a large-scale prediction model for prenatal disease.

Hundreds of mutations in a single gene result in rare diseases, but why mutations induce severe or attenuated states remains poorly understood. Defect in glycine decarboxylase (GLDC) causes Non-ketotic Hyperglycinemia (NKH), a neurological disease associated with elevation of plasma glycine. We unified a human multiparametric NKH mutation scale that separates severe from attenuated neurological disease with new in silico tools for murine and human genome level-analyses, gathered in vivo evidence from mice engineered with top-ranking attenuated and a highly pathogenic mutation, and integrated the data in a model of pre- and post-natal disease outcomes, relevant for over a hundred major and minor neurogenic mutations. Our findings suggest that highly severe neurogenic mutations predict fatal, prenatal disease that can be remedied by metabolic supplementation of dams, without amelioration of persistent plasma glycine. The work also provides a systems approach to identify functional consequences of mutations across hundreds of genetic diseases. Our studies provide a new framework for a large scale understanding of mutation functions and the prediction that severity of a neurogenic mutation is a direct measure of pre-natal disease in neurometabolic NKH mouse models. This framework can be extended to analyses of hundreds of monogenetic rare disorders where the underlying genes are known but understanding of the vast majority of mutations and why and how they cause disease, has yet to be realized.

GLYT1 encephalopathy: Further delineation of disease phenotype and discussion of pathophysiological mechanisms.

GLYT1 encephalopathy is a form of glycine encephalopathy caused by disturbance of glycine transport. The phenotypic spectrum of the disease has not yet been completely described, as only four unrelated families with the disorder have been reported to date. Common features of affected patients include neonatal hypotonia, respiratory failure, encephalopathy, myoclonic jerks, dysmorphic features, and musculoeskeletal anomalies. All reported affected patients harbor biallelic genetic variants in SLC6A9. SNP array together with Sanger sequencing were performed in a newborn with arthrogryposis and severe neurological impairment. The novel genetic variant c.997delC in SLC6A9 was detected in homozygous state in the patient. At protein level, the predicted change is p.(Arg333Alafs*3), which most probably results in a loss of protein function. The variant cosegregated with the disease in the family. A subsequent pregnancy with ultrasound anomalies was also affected. The proband presented the core phenotypic features of GLYT1 encephalopathy, but also a burst suppression pattern on the electroencephalogram, a clinical feature not previously associated with the disorder. Our results suggest that the appearance of this pattern correlates with higher cerebrospinal fluid glycine levels and cerebrospinal fluid/plasma glycine ratios. A detailed discussion on the possible pathophysiological mechanisms of the disorder is also provided.

Regulation of glycine metabolism by the glycine cleavage system and conjugation pathway in mouse models of non-ketotic hyperglycinemia.

Glycine abundance is modulated in a tissue-specific manner by use in biosynthetic reactions, catabolism by the glycine cleavage system (GCS), and excretion via glycine conjugation. Dysregulation of glycine metabolism is associated with multiple disorders including epilepsy, developmental delay, and birth defects. Mutation of the GCS component glycine decarboxylase (GLDC) in non-ketotic hyperglycinemia (NKH) causes accumulation of glycine in body fluids, but there is a gap in our knowledge regarding the effects on glycine metabolism in tissues. Here, we analysed mice carrying mutations in Gldc that result in severe or mild elevations of plasma glycine and model NKH. Liver of Gldc-deficient mice accumulated glycine and numerous glycine derivatives, including multiple acylglycines, indicating increased flux through reactions mediated by enzymes including glycine-N-acyltransferase and arginine: glycine amidinotransferase. Levels of dysregulated metabolites increased with age and were normalised by liver-specific rescue of Gldc expression. Brain tissue exhibited increased abundance of glycine, as well as derivatives including guanidinoacetate, which may itself be epileptogenic. Elevation of brain tissue glycine occurred even in the presence of only mildly elevated plasma glycine in mice carrying a missense allele of Gldc. Treatment with benzoate enhanced hepatic glycine conjugation thereby lowering plasma and tissue glycine. Moreover, administration of a glycine conjugation pathway intermediate, cinnamate, similarly achieved normalisation of liver glycine derivatives and circulating glycine. Although exogenous benzoate and cinnamate impact glycine levels via activity of glycine-N-acyltransferase, that is not expressed in brain, they are sufficient to lower levels of glycine and derivatives in brain tissue of treated Gldc-deficient mice.

Large scale analyses of genotype-phenotype relationships of glycine decarboxylase mutations and neurological disease severity.

Monogenetic diseases provide unique opportunity for studying complex, clinical states that underlie neurological severity. Loss of glycine decarboxylase (GLDC) can severely impact neurological development as seen in non-ketotic hyperglycinemia (NKH). NKH is a neuro-metabolic disorder lacking quantitative predictors of disease states. It is characterized by elevation of glycine, seizures and failure to thrive, but glycine reduction often fails to confer neurological benefit, suggesting need for alternate tools to distinguish severe from attenuated disease. A major challenge has been that there are 255 unique disease-causing missense mutations in GLDC, of which 206 remain entirely uncharacterized. Here we report a Multiparametric Mutation Score (MMS) developed by combining in silico predictions of stability, evolutionary conservation and protein interaction models and suitable to assess 251 of 255 mutations. In addition, we created a quantitative scale of clinical disease severity comprising of four major disease domains (seizure, cognitive failure, muscular and motor control and brain-malformation) to comprehensively score patient symptoms identified in 131 clinical reports published over the last 15 years. The resulting patient Clinical Outcomes Scores (COS) were used to optimize the MMS for biological and clinical relevance and yield a patient Weighted Multiparametric Mutation Score (WMMS) that separates severe from attenuated neurological disease (p = 1.2 e-5). Our study provides understanding for developing quantitative tools to predict clinical severity of neurological disease and a clinical scale that advances monitoring disease progression needed to evaluate new treatments for NKH.

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.

Why does hyperglycinemia exhibit so grave brain anomalies and so severe neurological symptoms?

Nonketotic-hyperglycinemia (NKH) is an autosomal recessive disorder associated with grave brain malformations and severe neurological symptoms, and also characterized by accumulation of a large amount of glycine in body fluids. NKH is caused by an inherited deficiency of the glycine cleavage system (GCS), which is the main system to degrade glycine in mammalians. These severe symptoms and grave bran malformations are not normally observed in the other amino acid metabolic disorders, suggesting that GCS should have unknown pivotal roles in brain development and function. Interestingly, GCS is indispensable in supplying proliferating cells with 5,10-methylenetetrahydrofolate as a one-carbon donor, which is essential for the synthesis of DNA in cell proliferation. Since GCS is expressed intensely and ubiquitously in the neuroepithelium, the lack of GCS might greatly impair the proliferation of neural stem cells. On the other hand, this system is also very important to regulate extracellular glycine concentrations. Since glycine is an important neurotransmitter, which binds to both glycine receptors and NMDA receptors, high glycine concentrations caused by the deficiency of GCS might cause the aberrant neurotransmission in the patient brains. Considering these unique two faces of GCS functions, proliferation disturbance and aberrant neurotransmission are intricately mixed in the developing brain, leading to the grave brain malformations and sever neurological symptoms.

Nonketotic hyperglycinemia: Clinical range and outcome of a rare neurometabolic disease in a single-center.

BACKGROUND: Nonketotic hyperglycinemia (NKH) is an autosomal recessive severe life-threatening catostrophic metabolic disorder. MATERIALS AND METHODS: The present study was conducted in a tertiary reference center in Turkey for six years period. The accurate diagnosis of six NKH patients was based on clinical history of the patients, neurological examinations, seizure semiology, serial electroencephalography (EEG) recordings, neuroimaging findings, metabolic tests and genetic analysis. RESULTS: The common clinical findings were hypotonia with severe head lag, poor feeding, poor sucking, and intractable seizures. The starting age of the symptoms was between birth and 45 days of age (median: 8 days). The starting age of the seizures was between 30 min of age and 45 days of age (median: 18 days). The age of accurate diagnosis was between 1 month of age and 5.5 months of age (mean: 3.75 ±â€¯1.69 months). The cerebrospinal fluid (CSF) to plasma GLY ratio of the patients was between 0.031 and 0.21 (median: 0.16). The EEG patterns of the patients were suppression-burst, hypsarrhythmia, multifocal epileptic activity, and right centro-occipital epileptic activity on admission. The neuroimaging findings were diffuse hypomyelination, corpus callosum (CC) hypoplasia, CC agenesis and brainstem hypoplasia on the magnetic resonance imaging and glycine peak was evidenced on magnetic resonance spectroscopy. Four of the patients were mutation-positive. CONCLUSIONS: If a child is encephalopathic and/or hypotonic with severe head lag, early evaluation of the EEG records should be made even without a history of clinical seizures. The disease has a heterogenous course and the clinical outcome depends on the mutation type.

Glycine Administration Alters MAPK Signaling Pathways and Causes Neuronal Damage in Rat Brain: Putative Mechanisms Involved in the Neurological Dysfunction in Nonketotic Hyperglycinemia.

High glycine (GLY) levels have been suggested to induce neurotoxic effects in the central nervous system of patients with nonketotic hyperglycinemia (NKH). Since the mechanisms involved in the neuropathophysiology of NKH are not totally established, we evaluated the effect of a single intracerebroventricular administration of GLY on the content of proteins involved in neuronal damage and inflammatory response, as well as on the phosphorylation of the MAPK p38, ERK1/2, and JNK in rat striatum and cerebral cortex. We also examined glial fibrillary acidic protein (GFAP) staining, a marker of glial reactivity. The parameters were analyzed 30 min or 24 h after GLY administration. GLY decreased Tau phosphorylation in striatum and cerebral cortex 30 min and 24 h after its administration. On the other hand, synaptophysin levels were decreased in striatum at 30 min and in cerebral cortex at 24 h after GLY injection. GLY also decreased the phosphorylation of p38, ERK1/2, and JNK 30 min after its administration in both brain structures. Moreover, GLY-induced decrease of p38 phosphorylation in striatum was attenuated by N-methyl-D-aspartate receptor antagonist MK-801. In contrast, synuclein, NF-κB, iκB, inducible nitric oxide synthase and nitrotyrosine content, and GFAP immunostaining were not altered by GLY infusion. It may be presumed that the decreased phosphorylation of MAPK associated with alterations of markers of neuronal injury induced by GLY may contribute to the neurological dysfunction observed in NKH.

Nonketotic hyperglycinemia: spectrum of imaging findings with emphasis on diffusion-weighted imaging.

PURPOSE: The purpose of this study was to explore brain abnormalities in nonketotic hyperglycinemia (NKH) using diffusion-weighted imaging (DWI) and when feasible, diffusion tensor imaging (DTI) and tractography. METHODS: Seven patients with confirmed diagnosis of NKH (8 days-2 years) underwent brain MRI. Conventional T1 and T2WI were acquired in all patients, DWI in six and DTI and tractography in two (4 months and 2 years). Measurements of fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD) and Trace from eight white matter regions were compared between the two patients and age-matched controls. Tractography of corpus callosum, superior longitudinal fasciculus and corticospinal tracts was performed with extraction of their FA and diffusivity indices. RESULTS: MRI showed nonspecific brain atrophy in three children. Corpus callosum atrophy was found as a part of these atrophic changes. Cerebellar vermian hypoplasia and supratentorial hydrocephalus were seen in one patient. The topographic distribution of diffusion restriction was different among patients. The affected white matter regions were not predominantly following the expected areas of myelination according to patients' age. Deep grey matter nuclei were affected in one patient. DTI revealed lower FA with higher RD in most of the measured white matter regions and tracts. These changes were more appreciated in the 2-year-old patient. However, Trace was higher in the 2-year-old patient and lower in the 4-month-old one. The extracted tracts were decreased in volume. CONCLUSION: DWI, DTI and tractography with FA and diffusivity measurements can give insights into white matter microstructural alterations that can occur in NKH.

Nonketotic hyperglycinemia: Functional assessment of missense variants in GLDC to understand phenotypes of the disease.

The rapid analysis of genomic data is providing effective mutational confirmation in patients with clinical and biochemical hallmarks of a specific disease. This is the case for nonketotic hyperglycinemia (NKH), a Mendelian disorder causing seizures in neonates and early-infants, primarily due to mutations in the GLDC gene. However, understanding the impact of missense variants identified in this gene is a major challenge for the application of genomics into clinical practice. Herein, a comprehensive functional and structural analysis of 19 GLDC missense variants identified in a cohort of 26 NKH patients was performed. Mutant cDNA constructs were expressed in COS7 cells followed by enzymatic assays and Western blot analysis of the GCS P-protein to assess the residual activity and mutant protein stability. Structural analysis, based on molecular modeling of the 3D structure of GCS P-protein, was also performed. We identify hypomorphic variants that produce attenuated phenotypes with improved prognosis of the disease. Structural analysis allows us to interpret the effects of mutations on protein stability and catalytic activity, providing molecular evidence for clinical outcome and disease severity. Moreover, we identify an important number of mutants whose loss-of-functionality is associated with instability and, thus, are potential targets for rescue using folding therapeutic approaches.

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

PURPOSE: The study's purpose was to delineate the genetic mutations that cause classic nonketotic hyperglycinemia (NKH). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Mutation in SLC6A9 encoding a glycine transporter causes a novel form of non-ketotic hyperglycinemia in humans.

Glycine cleavage system (GCS) catalyzes the degradation of glycine and disruption of its components encoded by GLDC, AMT and GCSH are the only known causes of glycine encephalopathy, also known as non-ketotic hyperglycinemia (NKH). In this report, we describe a consanguineous family with one child who presented with NKH, but harbored no pathogenic variants in any of the three genes linked to this condition. Whole-exome sequencing revealed a novel homozygous missense variant in exon 9 of SLC6A9 NM_201649.3: c.1219 A>G (p.Ser407Gly) that segregates with the disease within the family. This variant replaces the highly conserved S407 in the ion-binding site of this glycine transporter and is predicted to disrupt its function. In murine model, knockout of Slc6a9 is associated with equivalent phenotype of NKH, namely respiratory distress and hypotonia. This is the first demonstration that mutation of the glycine transporter can be associated with NKH in humans.

Susceptibility weighted imaging features of nonketotic hyperglycemia: unusual cause of hemichorea-hemiballismus.

Nonketotic hyperglycemia has been described as a metabolic cause of Hemiballism-hemichorea (HB-HC), especially in elderly patients with poorly controlled diabetes. Pathophysiology is not known yet. MRI features tend to be hyperintense in the putamen on T1-weighted images. We present conventional MRI with diffusion weighted imaging (DWI) and susceptibility weighted imaging (SWI) features of two cases with nonketotic hyperglycemia. T1 hyperintensity without diffusion restriction on DWI and minimal putaminal hypointensity without phase shift on SWI were compatible with either pathological mineralization or petechial microhemorrhage or protein denaturation. In the type 2 diabetic patients with HC-HB, conventional MRI together with SWI and DWI will guide to clinician to plan treatment approach.

Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5.

Patients with nonketotic hyperglycinemia and deficient glycine cleavage enzyme activity, but without mutations in AMT, GLDC or GCSH, the genes encoding its constituent proteins, constitute a clinical group which we call 'variant nonketotic hyperglycinemia'. We hypothesize that in some patients the aetiology involves genetic mutations that result in a deficiency of the cofactor lipoate, and sequenced genes involved in lipoate synthesis and iron-sulphur cluster biogenesis. Of 11 individuals identified with variant nonketotic hyperglycinemia, we were able to determine the genetic aetiology in eight patients and delineate the clinical and biochemical phenotypes. Mutations were identified in the genes for lipoate synthase (LIAS), BolA type 3 (BOLA3), and a novel gene glutaredoxin 5 (GLRX5). Patients with GLRX5-associated variant nonketotic hyperglycinemia had normal development with childhood-onset spastic paraplegia, spinal lesion, and optic atrophy. Clinical features of BOLA3-associated variant nonketotic hyperglycinemia include severe neurodegeneration after a period of normal development. Additional features include leukodystrophy, cardiomyopathy and optic atrophy. Patients with lipoate synthase-deficient variant nonketotic hyperglycinemia varied in severity from mild static encephalopathy to Leigh disease and cortical involvement. All patients had high serum and borderline elevated cerebrospinal fluid glycine and cerebrospinal fluid:plasma glycine ratio, and deficient glycine cleavage enzyme activity. They had low pyruvate dehydrogenase enzyme activity but most did not have lactic acidosis. Patients were deficient in lipoylation of mitochondrial proteins. There were minimal and inconsistent changes in cellular iron handling, and respiratory chain activity was unaffected. Identified mutations were phylogenetically conserved, and transfection with native genes corrected the biochemical deficiency proving pathogenicity. Treatments of cells with lipoate and with mitochondrially-targeted lipoate were unsuccessful at correcting the deficiency. The recognition of variant nonketotic hyperglycinemia is important for physicians evaluating patients with abnormalities in glycine as this will affect the genetic causation and genetic counselling, and provide prognostic information on the expected phenotypic course.

Characteristic MRI findings in neonatal nonketotic hyperglycinemia due to sequence changes in GLDC gene encoding the enzyme glycine decarboxylase.

Neonatal metabolic encephalopathy may be related to electrolyte imbalances, endocrine dysfunction, or inborn errors of metabolism. The metabolic encephalopathies are always a diagnostic challenge to the neonatologist and pediatricians. This is more so because the signs and symptoms of are nonspecific and are often similar to those with other neonatal emergencies. Clinical suspicion of neonatal encephalopathy should be considered in any infant exhibiting an abnormal level of consciousness, seizures, tone and reflex abnormalities, apnea, aspiration, and feeding difficulties. A definitive diagnosis is frequently not possible during the neonatal care unit or emergency department. But the proper initial management based on the probable diagnosis can be life-saving or reduce neurologic sequelae. In the case of inborn errors of metabolism, imaging may play a vital role either in limiting the differential diagnosis or yet times pointing towards the specific diagnosis or error of metabolism. We report DWI-ADC changes on MRI in the acute stages of neonatal nonketotic hyperglycinemia (NKH) due to sequence changes in GLDC gene.

Diagnostic tools of metabolic and structural brain disturbances in neonatal non-ketotic hyperglycinemia.

Non-ketotic hyperglycinemia (NKH) is a rare autosomal recessive disorder of glycine metabolism. We report a newborn case of NKH and discuss the effects of this rare disease on brain metabolism and structure together with amplitude-integrated electroencephalography, cranial magnetic resonance and magnetic resonance spectroscopy findings which are very rarely reported together so far.