RARE DISEASE
Glycine encephalopathy
Glycine encephalopathy
Glycine encephalopathy
Synonyms: NKA, Non-ketotic hyperglycinemia
Synonyms: NKA, Non-ketotic hyperglycinemia
Synonyms: NKA, Non-ketotic hyperglycinemia
Drug discovery
2
drugs
With orphan designations
Overview
Glycine encephalopathy (GE), also called nonketotic hyperglycinemia, is an autosomal recessive disorder of glycine metabolism caused by defects in the glycine cleavage system (GLDC 70%, AMT 20%). It manifests with glycine accumulation in tissues, leading to neonatal lethargy, hypotonia, seizures, apnea, and progressive encephalopathy. Diagnosis requires elevated CSF-to-plasma glycine ratio (>0.08) and genetic testing. Prognosis is typically poor, with severe neurodevelopmental impairment in most cases [1][6][14].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
124 drug discovery papers about Glycine encephalopathy, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
124 drug discovery papers about Glycine encephalopathy, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-06-01 | Corrected Version: Sodium Benzoate, A Metabolite of Cinnamon and A Food Additive, Improves Cognitive Functions in Mice After Controlled Cortical Impact Injury.
Traumatic brain injury (TBI) is a major health concern, sometimes leading to long-term neurological disability, especially in children, young adults, and war veterans. Although the research investigators and clinicians have applied different treatment strategies or neurosurgical procedures to solve this health issue, we are still in need of effective therapy to halt the pathogenesis of brain injury. Earlier we have reported that sodium benzoate (NaB), a metabolite of cinnamon and a Food and Drug Administration-approved drug against urea cycle disorders and glycine encephalopathy, protects neurons in animal models of Parkinson's disease and Alzheimer's disease. This study was undertaken to examine the therapeutic efficacy of NaB in controlled cortical impact (CCI)-induced preclinical mouse model of TBI. Oral treatment with NaB, but not sodium formate (NaFO), was found to decrease the activation of microglia and astrocytes and inhibits the expression of inducible nitric oxide synthase (iNOS) in hippocampus and cortex of CCI-insulted mice. Further, administration of NaB also reduced the vascular damage and decreased the size of lesion cavity in the brain of CCI-induced mice. Importantly, NaB-treated mice showed significant improvements in memory and locomotor functions as well as displayed substantial reduction in depression like behaviors. These results delineate a novel neuroprotective property of NaB, highlighting its possible therapeutic importance in TBI.
2026-04-30 | Variants in glycine decarboxylase activate catabolic mechanisms of mitochondrial energy metabolism in the brain.
Brain energy metabolism is produced from glucose by mitochondrial oxidative phosphorylation. Variants in the mitochondrial enzyme glycine decarboxylase (GLDC) cause a rare neurological disease, nonketotic hyperglycinemia, with expected hallmarks of brain glycine elevation and responsiveness to folate deficiency but the consequences for energy mechanisms remain unknown. We find that brains of young-attenuated mutant mice show a 1.5-fold increase in glycine and no change in folate responsiveness. They are, however, reduced > 5-fold in GLDC, indicate decrease in the mitochondrial lipoyl-transfer protein GCSH and lipoylation of the pyruvate dehydrogenase complex as well as rise in signatures of astrocyte mitochondrial β-oxidation of fatty acids proportionate to mutation severity and activation of pyruvate dehydrogenase. Together these data reveal a novel GLDC mechanism that regulates catabolic mitochondrial energy processes in both attenuated and severe brain disease and suggest new targets in energy metabolism to treat nonketotic hyperglycinemia.
2026-04-12 | Clinical and laboratory outcomes of ketogenic versus glycine-restricted diet in nonketotic hyperglycinemia: A comparative study.
This study aimed to compare the clinical, biochemical, and nutritional outcomes of classical nonketotic hyperglycinemia (NKH) patients treated with a ketogenic diet (KD) versus a glycine-restricted diet (GRD). This retrospective study included patients with classical nonketotic hyperglycinemia treated with either a KD (n = 8) or a GRD (n = 6). Seizure frequency, seizure scores, antiepileptic drug (AED) use, motor function (GMFCS-E&R), swallowing difficulties, plasma glycine levels, and nutritional parameters were evaluated before and after dietary treatment. Baseline characteristics did not differ significantly between groups. Post-treatment assessments showed no significant differences in GMFCS scores, swallowing function, or plasma glycine levels. However, KD resulted in significantly reduced seizure frequency and seizure scores, and decreased AED use compared with GRD. Within-group analysis showed significant seizure control in the KD group, whereas seizure frequency increased in the GRD group. An increase in LDL cholesterol was observed in KD group, as expected; other nutritional parameters remained stable. Mortality was similarly high in both groups. Neither diet altered biochemical parameters or motor outcomes. However, KD provided better seizure control compared to GRD, supporting its role as a useful adjunctive therapy in NKH.
2026-01-28 | A Nonketotic Hyperglycinemia Mouse Shows Wide-Ranging Biochemical Consequences of Elevated Glycine, Reduced Folate One-Carbon Charging, and Serine Deficiency.
Nonketotic hyperglycinemia is a severe neonatal epileptic encephalopathy caused by deficient glycine cleavage enzyme activity, for which currently no effective treatment exists. Incomplete understanding of brain biochemistry represents a major knowledge gap to develop new treatments. We examined the biochemistry in blood, liver, cortex, hippocampus, and cerebellum of a mouse model homozygous for the Gldc variant p.Ala394Val. Glycine was increased in all compartments and caused increased brain neurotoxic metabolites guanidinoacetate and methylglyoxal, and also N-acetylglycine and cystathionine. The glycine extruding transporter Slc6a20 was increased. There was reduced one-carbon folate charging with secondarily reduced methionine in the cortex, and reduced alternative one-carbon donors L-serine and formate. Serine deficiency was associated with reduced amounts of sphingosine, sphingomyelin, and ceramide species important for myelination, but not phosphatidylserines. There was a region-specific deficiency of D-serine in the cortex and hippocampus. This difference, also present in humans, was strain- and age-related, most evident in young J129X1/SvJ mice, reflecting symptomatology. There was no evidence of oxidative stress or a bioenergetic defect. The biochemistry of the nonketotic hyperglycinemia mouse model can be traced to three components: increased glycine, reduced folate one-carbon charging, and decreased L- and D-serine. These changes will need to be addressed in new therapeutic approaches.
2026-01-01 | Novel Approach to Perioperative Management of a Child with Nonketotic Hyperglycinemia
Nonketotic hyperglycinemia is a rare condition that requires a specialized approach. Perioperative management remains uncertain due to both the rarity of the disease and the limited literature available. A 7-year-old girl was admitted for a surgical dental procedure. She remained fasting for 6 hours without receiving any intravenous dextrose-containing fluids. Oral dexmedetomidine at a dose of 4 mcg/kg was selected for premedication. Sevoflurane was used as the sole agent for both induction and maintenance of anesthesia. The patient awakened 20 minutes after the discontinuation of sevoflurane. In this case, we emphasize that the use of dexmedetomidine for premedication may reduce preoperative anxiety and the potential for postoperative delirium. Furthermore, preoperative glycine concentrations are likely proportional to the duration of awakening. To avoid prolonged emergence, the use of Bispectral Index monitoring is recommended. Additionally, it has been shown that preoperative fasting without intravenous fluid supplementation can be safe.
proteins
2025-10-30 | Clinical Evaluation and Outcome of Patients with Severe Non-ketotic Hyperglycinemia: Single Center Experience
Introduction:Severe non-ketotic hyperglycinemia may present with clinical signs such as lethargy, hypotonia, apnea, hiccups and persistent convulsions in the newborn period.It is aimed to be determin e the clinical characteristics, treatments, cranial MRI and EEG findings, prognoses of patients with non-ketotic hyperglycinemia in this study. Materials and Methods:Eight patients with severe non-ketotic hyperglycinemia who were followed between January 2016 and November 2024 were included in the study.Initial clinical findings, la boratory results, EEG findings, MRI and MRS findings, molecular genetic analyses, drugs, dietary treatments, treatment results and prognosis were evaluated from patient hospital files.Results: Levels of plasma and cerebrospinal fluid glycine were 868.3 259.0 mol/l and 137.7 36.0 mol/l, respectively.The ratio between cerebrospinal fluid and plasma glycine was above 0.08 in all eight patients.Cerebrospinal fluid/plasma glycine ratio was measured after treatment in three patients.Although a decrease in cerebrospinal fluid glycine levels was observed in two patients, no decrease was detected in cerebrospinal fluid/plasma glycine ratio after treatment.Seizure frequency decreased during periods of mild elev ated glycine levels in seven patients.Although plasma glycine levels remained normal in one patient, seizures continued in this patient.The c.1784dupT mutation was identified as a novel mutation in GLDC gene.Six patients died, two patients live with severe neurodevelopmental problems. Conclusions:Non-ketotic hyperglycinemia is a life-threatening inborn error of amino acid metabolism.Although CSF and plasma glycine levels are reduced with medication, unfortunately seizures decrease but continue.We observed that seizures may continue even when plasma glycine levels are normal.Currently, there is no specific treatment for non -ketotic hyperglycinemia.However, new potential curative therapies should be explored for this debilitating disorder, particularly for its severe form.
2011-06-01 | Glycine cleavage enzyme complex: Molecular cloning and expression of the H-protein cDNA from cultured human skin fibroblasts
The human H-protein is one of four essential components (H-, L-, P-, and T-proteins) of the mammalian glycine cleavage enzyme complex and its function is involved in the pathogenesis and diagnosis of glycine encephalopathy. A transcript corresponding to the glycine cleavage H-protein functional gene was isolated from cultured human skin fibroblasts along with a transcript for a putative processed pseudogene on chromosome 2q33.3. Sequence analysis of the fibroblast H-protein functional gene transcript showed complete identity to that reported from human liver. The H-protein cDNA was subsequently cloned with a hexahistidine affinity tag in the Pichia pastoris plasmid vector pPICZαA and recombined into the yeast genome downstream of the alcohol oxidase promoter for methanol-induced expression. The recombinant H-protein was secreted into the culture medium and purified to homogeneity using a one-step nickel-nitrilotriacetic acid resin column. Approximately 4 mg of homogeneous H-protein was obtained from 1 L of culture medium. Since the attachment of a lipoic acid prosthetic group is required for H-protein function, we have expressed and purified E. coli lipoate protein ligase and succeeded in lipoylating H-protein, converting the apo-H-protein to the functional holo-H-protein. A lipoamide dehydrogenase assay was performed to confirm that the apo-H-protein was inactive, whereas the holo-H-protein was approximately 2.3-fold more active than free lipoic acid as a hydrogen donor in driving the reaction. The availability of copious amounts of human recombinant H-protein by using Pichia pastoris expression and affinity purification will facilitate the elucidation of the structure and function of the H-protein and its relationship to the P-, T-, and L-proteins in the glycine cleavage enzyme complex. In view of the fact that there is no detectable glycine cleavage enzyme activity in human skin fibroblasts, we speculate that a plausible function of the H-protein is to interact with the L-protein, which is also part of the l-ketoglutarate dehydrogenase complex present in fibroblasts.
antibodies
2026-07-22 | Individualized repetitive intravenous immunoglobulin therapy for a 79-year-old patient with GlyR antibody-positive PERM: a case report and literature review.
Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a rare, life-threatening variant of stiff-person spectrum disorder that is primarily associated with anti-glycine receptor (GlyR) antibodies. Although advanced age and intensive care unit admission have been associated with poor outcomes for patients with GlyR antibody-positive PERM, detailed management strategies for elderly patients with multiple comorbidities remain limited. We report the successful individualized management of a 79-year-old male with glycine receptor 1 (GlyR1) antibody-positive PERM, who is among the oldest reported survivors of severe PERM. The patient initially presented with paroxysmal limb spasms, which were misattributed to spinal degeneration and a minor thalamic infarction. The subsequent development of a prominent startle response, respiratory failure, and autonomic instability prompted an autoimmune evaluation, confirming the presence of anti-GlyR1 antibodies in both serum and cerebrospinal fluid. High-dose corticosteroid pulse therapy was avoided because of an active pulmonary infection and comorbidity-related safety concerns. Intravenous immunoglobulin (IVIg) was selected as the initial immunomodulatory therapy, while plasma exchange was deferred and later discontinued after a single session because of procedure-related complications and hemodynamic instability. The patient received three sequential courses of IVIg; in addition, a single 20-mg subcutaneous dose of ofatumumab was administered as individualized off-label sequential/salvage immunotherapy. A major clinical improvement, including a reduction in spasms, successful extubation, antibody seroconversion, and excellent functional recovery with a modified Rankin scale (mRS) score of 1, occurred after repeated IVIg courses. At the 12-month follow-up, the patient remained clinically stable and had sustained negative GlyR1 antibody results. This case report highlights the importance of the early recognition of stimulus-sensitive spasms and the startle response in elderly patients with misleading age-related imaging findings. These findings also suggest that repeated IVIg courses may represent a feasible salvage strategy when conventional immunotherapies are limited, but the independent therapeutic contribution of ofatumumab remains uncertain. Serial GlyR1 antibody titers may be useful for monitoring the treatment response, although this result requires confirmation in larger studies.
2017-04-11 | Focal status epilepticus and progressive dyskinesia: A novel phenotype for glycine receptor antibody-mediated neurological disease in children.
Antibody-associated disorders of the central nervous system are increasingly recognised in adults and children. Some are known to be paraneoplastic, whereas in others an infective trigger is postulated. They include disorders associated with antibodies to N-methyl-d-aspartate receptor (NMDAR), voltage-gated potassium channel-complexes (VGKC-complex), GABAB receptor or glycine receptor (GlyR). With antibodies to NMDAR or VGKC-complexes, distinct clinical patterns are well characterised, but as more antibodies are discovered, the spectra of associated disorders are evolving. GlyR antibodies have been detected in patients with progressive encephalopathy with rigidity and myoclonus (PERM), or stiff man syndrome, both rare but disabling conditions. We report a case of a young child with focal seizures and progressive dyskinesia in whom GlyR antibodies were detected. Anticonvulsants and immunotherapy were effective in treating both the seizures and movement disorder with good neurological outcome and with a decline in the patient's serum GlyR-Ab titres. Glycine receptor antibodies are associated with focal status epilepticus and seizures, encephalopathy and progressive dyskinesia and should be evaluated in autoimmune encephalitis.
2014-09-23 | Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes.
The clinical associations of glycine receptor antibodies have not yet been described fully. We identified prospectively 52 antibody-positive patients and collated their clinical features, investigations and immunotherapy responses. Serum glycine receptor antibody endpoint titres ranged from 1:20 to 1:60 000. In 11 paired samples, serum levels were higher than (n = 10) or equal to (n = 1) cerebrospinal fluid levels; there was intrathecal synthesis of glycine receptor antibodies in each of the six pairs available for detailed study. Four patients also had high glutamic acid decarboxylase antibodies (>1000 U/ml), and one had high voltage-gated potassium channel-complex antibody (2442 pM). Seven patients with very low titres (<1:50) and unknown or alternative diagnoses were excluded from further study. Three of the remaining 45 patients had newly-identified thymomas and one had a lymphoma. Thirty-three patients were classified as progressive encephalomyelitis with rigidity and myoclonus, and two as stiff person syndrome; five had a limbic encephalitis or epileptic encephalopathy, two had brainstem features mainly, two had demyelinating optic neuropathies and one had an unclear diagnosis. Four patients (9%) died during the acute disease, but most showed marked improvement with immunotherapies. At most recent follow-up, (2-7 years, median 3 years, since first antibody detection), the median modified Rankin scale scores (excluding the four deaths) decreased from 5 at maximal severity to 1 (P < 0.0001), but relapses have occurred in five patients and a proportion are on reducing steroids or other maintenance immunotherapies as well as symptomatic treatments. The glycine receptor antibodies activated complement on glycine receptor-transfected human embryonic kidney cells at room temperature, and caused internalization and lysosomal degradation of the glycine receptors at 37°C. Immunoglobulin G antibodies bound to rodent spinal cord and brainstem co-localizing with monoclonal antibodies to glycine receptor-α1. Ten glycine receptor antibody positive samples were also identified in a retrospective cohort of 56 patients with stiff person syndrome and related syndromes. Glycine receptor antibodies are strongly associated with spinal and brainstem disorders, and the majority of patients have progressive encephalomyelitis with rigidity and myoclonus. The antibodies demonstrate in vitro evidence of pathogenicity and the patients respond well to immunotherapies, contrasting with earlier studies of this syndrome, which indicated a poor prognosis. The presence of glycine receptor antibodies should help to identify a disease that responds to immunotherapies, but these treatments may need to be sustained, relapses can occur and maintenance immunosuppression may be required.
gene therapies
2026-01-12 | The History and Nosology of the Glycine Disorders: A Framework for Clinicians.
Despite its simple chemical structure, glycine plays a complex role in the body. The glycine cleavage system regulates brain glycine levels and is a key one-carbon donor to folate. Its metabolism is tightly integrated with that of serine. In addition to its biochemical role, glycine functions as a neurotransmitter and neuromodulator. Primary defects in the glycine cleavage system have long been known to cause human disease with a primarily neurological phenotype, and this was labelled as 'nonketotic hyperglycinaemia' in 1968. With increasing availability of molecular testing, many additional genetic conditions became apparent, as well as non-genetic factors that cause hyperglycinaemia. There is now a much greater appreciation of the marked clinical impact of this heterogeneity. The previous terminology of 'classical' and 'atypical' nonketotic hyperglycinaemia does not adequately address these numerous genetic aetiologies, nor does it account for the phenotypic spectrum within individual genetic disorders. We provide here a clinically relevant classification of the glycine encephalopathies, based on the underlying genetic aetiology and its relation to the glycine cleavage system. Characteristic clinical and biochemical features of each condition, as well as non-genetic phenocopies that cause hyperglycinaemia, are discussed in detail. This provides a readily usable framework for clinicians when faced with a patient with elevated glycine levels.
2026-01-06 | Nonketotic Hyperglycinemia in Central and Appalachian Kentucky.
Nonketotic hyperglycinemia (NKH) is a rare genetic disorder with a global incidence of 0.4 to 1.3 per 100 000 live births with regional variation. We sought to estimate the regional birth incidence and describe the clinical and genetic features of NKH in central and Appalachian Kentucky. Fifteen patients met standard diagnostic criteria for NKH; 13 were born in Kentucky, yielding an estimated birth incidence of 2.53 per 100 000 live births (13/513 419; 95% CI 1.35-4.33). Of those with available genetic data (n = 9), 8 carried GLDC variants, with 6 having the c.1166C>T (p.A389V) variant. We found a higher incidence of NKH in central and Appalachian Kentucky compared to global estimates, with local enrichment of the p.A389V variant. These findings highlight the need for clinician awareness and further research to inform regional screening and management.
2025-07-28 | Possible Founder Effect of Glycine Encephalopathy: Evidence of a GLDC c.2714T>G (p.Val905Gly) Common Variant in the Paisa Community Based in Cali, Colombia.
Non-ketotic hyperglycinemia (NKH) is a rare autosomal recessive disorder caused by defects in the mitochondrial glycine cleavage system, most commonly involving variants in GLDC. Clinical presentation is heterogeneous, ranging from severe neonatal encephalopathy with intractable epilepsy to attenuated forms with variable neurodevelopmental outcomes. We conducted a comprehensive clinical, biochemical, molecular, and genealogical analysis of eight Colombian patients with NKH, all of whom shared ancestry from the Paisa population. All patients were born at term after uncomplicated pregnancies and presented in the neonatal period with hypotonia, lethargy, feeding difficulties, and treatment-resistant seizures. Elevated glycine levels were detected in plasma for all patients and cerebrospinal fluid in three cases. Molecular testing identified the same homozygous GLDC variant (NM_000170.3:c.2714 T>G; p.Val905Gly) in all individuals. Although no consanguinity was reported, shared surname and regional ancestry suggested intra- and interfamilial isonymy, raising the possibility of a founder effect. Clinical outcomes varied despite the implementation of early supportive interventions. This is the first report of a recurrent GLDC variant in Colombian patients, supporting a potential founder effect in the Paisa population. These findings highlight the importance of regional genetic studies in enhancing diagnostic precision and guiding population-specific strategies for rare disease management.
2025-05-30 | Clinical and genetic characterization of neonatal non-ketotic hyperglycinemia: a rare case with SLC6A9 gene mutation
Nonketotic hyperglycinemia (NKH) is a rare autosomal recessive disorder caused by mutations in the glycine cleavage system (GCS), leading to glycine accumulation in cerebrospinal fluid (CSF) and plasma, with an increased CSF-to-plasma glycine ratio. Typically presenting in the neonatal period, symptoms include lethargy, poor feeding, hypotonia, seizures, and encephalopathy, often resulting in severe neurological impairment. Early diagnosis is vital but challenging due to the rarity and nonspecific nature of symptoms, especially in populations with high consanguinity rates. We report a neonate born to consanguineous parents who developed severe encephalopathy within 48 hours of birth despite normal antenatal and perinatal findings. The infant exhibited poor feeding, seizures, and worsening neurological status. NKH was confirmed by elevated CSF glycine levels and genetic analysis identifying a novel SLC6A9 mutation. This case highlights the importance of considering NKH in neonatal encephalopathy and the need for genetic testing and counseling in at-risk groups.
2025-03-31 | Gene therapy prevents disease and death from non-ketotic hyperglycinemia
Abstract Genetic defects in glycine decarboxylase (GLDC) cause non-ketotic hyperglycinemia (NKH), a rare and frequently fatal neurometabolic disease, which lacks FDA-approved therapies. We characterized CRISPR Cas9-edited humanized mice expressing a prevalent clinical mutation after administration with a single intraperitoneal dose of a novel recombinant of adeno-associated viral vector 9 expressing GLDC (rAAV9-GLDC). Long term biological activity of rAAV9-GLDC was first validated by assessment of its systemic efficacy over five and ten months in mice. Access of rAAV9 to the brain was confirmed by tracking green fluorescent protein (GFP) after a single intraperitoneal dose of rAAV9-GFP. Over five months, control ‘mock’ treated GFP-mice showed reduction in astrocytes but not microglia, oligodendrocytes or neurons in the brain. 37% of these animals suffered long term neurological disease and/or death. rAAV9-GLDC boosts astrogenesis without triggering an inflammatory response and confers 100% protection against disease progression and fatality due to NKH.
other
2024-01-29 | Metabolic Rewiring and Altered Glial Differentiation in an iPSC-Derived Astrocytes 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 neuronal 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. The 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. 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 and offer new perspectives for therapeutic options.
small molecules
2026-06-01 | Corrected Version: Sodium Benzoate, A Metabolite of Cinnamon and A Food Additive, Improves Cognitive Functions in Mice After Controlled Cortical Impact Injury.
Traumatic brain injury (TBI) is a major health concern, sometimes leading to long-term neurological disability, especially in children, young adults, and war veterans. Although the research investigators and clinicians have applied different treatment strategies or neurosurgical procedures to solve this health issue, we are still in need of effective therapy to halt the pathogenesis of brain injury. Earlier we have reported that sodium benzoate (NaB), a metabolite of cinnamon and a Food and Drug Administration-approved drug against urea cycle disorders and glycine encephalopathy, protects neurons in animal models of Parkinson's disease and Alzheimer's disease. This study was undertaken to examine the therapeutic efficacy of NaB in controlled cortical impact (CCI)-induced preclinical mouse model of TBI. Oral treatment with NaB, but not sodium formate (NaFO), was found to decrease the activation of microglia and astrocytes and inhibits the expression of inducible nitric oxide synthase (iNOS) in hippocampus and cortex of CCI-insulted mice. Further, administration of NaB also reduced the vascular damage and decreased the size of lesion cavity in the brain of CCI-induced mice. Importantly, NaB-treated mice showed significant improvements in memory and locomotor functions as well as displayed substantial reduction in depression like behaviors. These results delineate a novel neuroprotective property of NaB, highlighting its possible therapeutic importance in TBI.
2026-04-30 | Variants in glycine decarboxylase activate catabolic mechanisms of mitochondrial energy metabolism in the brain.
Brain energy metabolism is produced from glucose by mitochondrial oxidative phosphorylation. Variants in the mitochondrial enzyme glycine decarboxylase (GLDC) cause a rare neurological disease, nonketotic hyperglycinemia, with expected hallmarks of brain glycine elevation and responsiveness to folate deficiency but the consequences for energy mechanisms remain unknown. We find that brains of young-attenuated mutant mice show a 1.5-fold increase in glycine and no change in folate responsiveness. They are, however, reduced > 5-fold in GLDC, indicate decrease in the mitochondrial lipoyl-transfer protein GCSH and lipoylation of the pyruvate dehydrogenase complex as well as rise in signatures of astrocyte mitochondrial β-oxidation of fatty acids proportionate to mutation severity and activation of pyruvate dehydrogenase. Together these data reveal a novel GLDC mechanism that regulates catabolic mitochondrial energy processes in both attenuated and severe brain disease and suggest new targets in energy metabolism to treat nonketotic hyperglycinemia.
2026-04-12 | Clinical and laboratory outcomes of ketogenic versus glycine-restricted diet in nonketotic hyperglycinemia: A comparative study.
This study aimed to compare the clinical, biochemical, and nutritional outcomes of classical nonketotic hyperglycinemia (NKH) patients treated with a ketogenic diet (KD) versus a glycine-restricted diet (GRD). This retrospective study included patients with classical nonketotic hyperglycinemia treated with either a KD (n = 8) or a GRD (n = 6). Seizure frequency, seizure scores, antiepileptic drug (AED) use, motor function (GMFCS-E&R), swallowing difficulties, plasma glycine levels, and nutritional parameters were evaluated before and after dietary treatment. Baseline characteristics did not differ significantly between groups. Post-treatment assessments showed no significant differences in GMFCS scores, swallowing function, or plasma glycine levels. However, KD resulted in significantly reduced seizure frequency and seizure scores, and decreased AED use compared with GRD. Within-group analysis showed significant seizure control in the KD group, whereas seizure frequency increased in the GRD group. An increase in LDL cholesterol was observed in KD group, as expected; other nutritional parameters remained stable. Mortality was similarly high in both groups. Neither diet altered biochemical parameters or motor outcomes. However, KD provided better seizure control compared to GRD, supporting its role as a useful adjunctive therapy in NKH.
2026-01-28 | A Nonketotic Hyperglycinemia Mouse Shows Wide-Ranging Biochemical Consequences of Elevated Glycine, Reduced Folate One-Carbon Charging, and Serine Deficiency.
Nonketotic hyperglycinemia is a severe neonatal epileptic encephalopathy caused by deficient glycine cleavage enzyme activity, for which currently no effective treatment exists. Incomplete understanding of brain biochemistry represents a major knowledge gap to develop new treatments. We examined the biochemistry in blood, liver, cortex, hippocampus, and cerebellum of a mouse model homozygous for the Gldc variant p.Ala394Val. Glycine was increased in all compartments and caused increased brain neurotoxic metabolites guanidinoacetate and methylglyoxal, and also N-acetylglycine and cystathionine. The glycine extruding transporter Slc6a20 was increased. There was reduced one-carbon folate charging with secondarily reduced methionine in the cortex, and reduced alternative one-carbon donors L-serine and formate. Serine deficiency was associated with reduced amounts of sphingosine, sphingomyelin, and ceramide species important for myelination, but not phosphatidylserines. There was a region-specific deficiency of D-serine in the cortex and hippocampus. This difference, also present in humans, was strain- and age-related, most evident in young J129X1/SvJ mice, reflecting symptomatology. There was no evidence of oxidative stress or a bioenergetic defect. The biochemistry of the nonketotic hyperglycinemia mouse model can be traced to three components: increased glycine, reduced folate one-carbon charging, and decreased L- and D-serine. These changes will need to be addressed in new therapeutic approaches.
2026-01-01 | Novel Approach to Perioperative Management of a Child with Nonketotic Hyperglycinemia
Nonketotic hyperglycinemia is a rare condition that requires a specialized approach. Perioperative management remains uncertain due to both the rarity of the disease and the limited literature available. A 7-year-old girl was admitted for a surgical dental procedure. She remained fasting for 6 hours without receiving any intravenous dextrose-containing fluids. Oral dexmedetomidine at a dose of 4 mcg/kg was selected for premedication. Sevoflurane was used as the sole agent for both induction and maintenance of anesthesia. The patient awakened 20 minutes after the discontinuation of sevoflurane. In this case, we emphasize that the use of dexmedetomidine for premedication may reduce preoperative anxiety and the potential for postoperative delirium. Furthermore, preoperative glycine concentrations are likely proportional to the duration of awakening. To avoid prolonged emergence, the use of Bispectral Index monitoring is recommended. Additionally, it has been shown that preoperative fasting without intravenous fluid supplementation can be safe.
proteins
2025-10-30 | Clinical Evaluation and Outcome of Patients with Severe Non-ketotic Hyperglycinemia: Single Center Experience
Introduction:Severe non-ketotic hyperglycinemia may present with clinical signs such as lethargy, hypotonia, apnea, hiccups and persistent convulsions in the newborn period.It is aimed to be determin e the clinical characteristics, treatments, cranial MRI and EEG findings, prognoses of patients with non-ketotic hyperglycinemia in this study. Materials and Methods:Eight patients with severe non-ketotic hyperglycinemia who were followed between January 2016 and November 2024 were included in the study.Initial clinical findings, la boratory results, EEG findings, MRI and MRS findings, molecular genetic analyses, drugs, dietary treatments, treatment results and prognosis were evaluated from patient hospital files.Results: Levels of plasma and cerebrospinal fluid glycine were 868.3 259.0 mol/l and 137.7 36.0 mol/l, respectively.The ratio between cerebrospinal fluid and plasma glycine was above 0.08 in all eight patients.Cerebrospinal fluid/plasma glycine ratio was measured after treatment in three patients.Although a decrease in cerebrospinal fluid glycine levels was observed in two patients, no decrease was detected in cerebrospinal fluid/plasma glycine ratio after treatment.Seizure frequency decreased during periods of mild elev ated glycine levels in seven patients.Although plasma glycine levels remained normal in one patient, seizures continued in this patient.The c.1784dupT mutation was identified as a novel mutation in GLDC gene.Six patients died, two patients live with severe neurodevelopmental problems. Conclusions:Non-ketotic hyperglycinemia is a life-threatening inborn error of amino acid metabolism.Although CSF and plasma glycine levels are reduced with medication, unfortunately seizures decrease but continue.We observed that seizures may continue even when plasma glycine levels are normal.Currently, there is no specific treatment for non -ketotic hyperglycinemia.However, new potential curative therapies should be explored for this debilitating disorder, particularly for its severe form.
2011-06-01 | Glycine cleavage enzyme complex: Molecular cloning and expression of the H-protein cDNA from cultured human skin fibroblasts
The human H-protein is one of four essential components (H-, L-, P-, and T-proteins) of the mammalian glycine cleavage enzyme complex and its function is involved in the pathogenesis and diagnosis of glycine encephalopathy. A transcript corresponding to the glycine cleavage H-protein functional gene was isolated from cultured human skin fibroblasts along with a transcript for a putative processed pseudogene on chromosome 2q33.3. Sequence analysis of the fibroblast H-protein functional gene transcript showed complete identity to that reported from human liver. The H-protein cDNA was subsequently cloned with a hexahistidine affinity tag in the Pichia pastoris plasmid vector pPICZαA and recombined into the yeast genome downstream of the alcohol oxidase promoter for methanol-induced expression. The recombinant H-protein was secreted into the culture medium and purified to homogeneity using a one-step nickel-nitrilotriacetic acid resin column. Approximately 4 mg of homogeneous H-protein was obtained from 1 L of culture medium. Since the attachment of a lipoic acid prosthetic group is required for H-protein function, we have expressed and purified E. coli lipoate protein ligase and succeeded in lipoylating H-protein, converting the apo-H-protein to the functional holo-H-protein. A lipoamide dehydrogenase assay was performed to confirm that the apo-H-protein was inactive, whereas the holo-H-protein was approximately 2.3-fold more active than free lipoic acid as a hydrogen donor in driving the reaction. The availability of copious amounts of human recombinant H-protein by using Pichia pastoris expression and affinity purification will facilitate the elucidation of the structure and function of the H-protein and its relationship to the P-, T-, and L-proteins in the glycine cleavage enzyme complex. In view of the fact that there is no detectable glycine cleavage enzyme activity in human skin fibroblasts, we speculate that a plausible function of the H-protein is to interact with the L-protein, which is also part of the l-ketoglutarate dehydrogenase complex present in fibroblasts.
antibodies
2026-07-22 | Individualized repetitive intravenous immunoglobulin therapy for a 79-year-old patient with GlyR antibody-positive PERM: a case report and literature review.
Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a rare, life-threatening variant of stiff-person spectrum disorder that is primarily associated with anti-glycine receptor (GlyR) antibodies. Although advanced age and intensive care unit admission have been associated with poor outcomes for patients with GlyR antibody-positive PERM, detailed management strategies for elderly patients with multiple comorbidities remain limited. We report the successful individualized management of a 79-year-old male with glycine receptor 1 (GlyR1) antibody-positive PERM, who is among the oldest reported survivors of severe PERM. The patient initially presented with paroxysmal limb spasms, which were misattributed to spinal degeneration and a minor thalamic infarction. The subsequent development of a prominent startle response, respiratory failure, and autonomic instability prompted an autoimmune evaluation, confirming the presence of anti-GlyR1 antibodies in both serum and cerebrospinal fluid. High-dose corticosteroid pulse therapy was avoided because of an active pulmonary infection and comorbidity-related safety concerns. Intravenous immunoglobulin (IVIg) was selected as the initial immunomodulatory therapy, while plasma exchange was deferred and later discontinued after a single session because of procedure-related complications and hemodynamic instability. The patient received three sequential courses of IVIg; in addition, a single 20-mg subcutaneous dose of ofatumumab was administered as individualized off-label sequential/salvage immunotherapy. A major clinical improvement, including a reduction in spasms, successful extubation, antibody seroconversion, and excellent functional recovery with a modified Rankin scale (mRS) score of 1, occurred after repeated IVIg courses. At the 12-month follow-up, the patient remained clinically stable and had sustained negative GlyR1 antibody results. This case report highlights the importance of the early recognition of stimulus-sensitive spasms and the startle response in elderly patients with misleading age-related imaging findings. These findings also suggest that repeated IVIg courses may represent a feasible salvage strategy when conventional immunotherapies are limited, but the independent therapeutic contribution of ofatumumab remains uncertain. Serial GlyR1 antibody titers may be useful for monitoring the treatment response, although this result requires confirmation in larger studies.
2017-04-11 | Focal status epilepticus and progressive dyskinesia: A novel phenotype for glycine receptor antibody-mediated neurological disease in children.
Antibody-associated disorders of the central nervous system are increasingly recognised in adults and children. Some are known to be paraneoplastic, whereas in others an infective trigger is postulated. They include disorders associated with antibodies to N-methyl-d-aspartate receptor (NMDAR), voltage-gated potassium channel-complexes (VGKC-complex), GABAB receptor or glycine receptor (GlyR). With antibodies to NMDAR or VGKC-complexes, distinct clinical patterns are well characterised, but as more antibodies are discovered, the spectra of associated disorders are evolving. GlyR antibodies have been detected in patients with progressive encephalopathy with rigidity and myoclonus (PERM), or stiff man syndrome, both rare but disabling conditions. We report a case of a young child with focal seizures and progressive dyskinesia in whom GlyR antibodies were detected. Anticonvulsants and immunotherapy were effective in treating both the seizures and movement disorder with good neurological outcome and with a decline in the patient's serum GlyR-Ab titres. Glycine receptor antibodies are associated with focal status epilepticus and seizures, encephalopathy and progressive dyskinesia and should be evaluated in autoimmune encephalitis.
2014-09-23 | Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes.
The clinical associations of glycine receptor antibodies have not yet been described fully. We identified prospectively 52 antibody-positive patients and collated their clinical features, investigations and immunotherapy responses. Serum glycine receptor antibody endpoint titres ranged from 1:20 to 1:60 000. In 11 paired samples, serum levels were higher than (n = 10) or equal to (n = 1) cerebrospinal fluid levels; there was intrathecal synthesis of glycine receptor antibodies in each of the six pairs available for detailed study. Four patients also had high glutamic acid decarboxylase antibodies (>1000 U/ml), and one had high voltage-gated potassium channel-complex antibody (2442 pM). Seven patients with very low titres (<1:50) and unknown or alternative diagnoses were excluded from further study. Three of the remaining 45 patients had newly-identified thymomas and one had a lymphoma. Thirty-three patients were classified as progressive encephalomyelitis with rigidity and myoclonus, and two as stiff person syndrome; five had a limbic encephalitis or epileptic encephalopathy, two had brainstem features mainly, two had demyelinating optic neuropathies and one had an unclear diagnosis. Four patients (9%) died during the acute disease, but most showed marked improvement with immunotherapies. At most recent follow-up, (2-7 years, median 3 years, since first antibody detection), the median modified Rankin scale scores (excluding the four deaths) decreased from 5 at maximal severity to 1 (P < 0.0001), but relapses have occurred in five patients and a proportion are on reducing steroids or other maintenance immunotherapies as well as symptomatic treatments. The glycine receptor antibodies activated complement on glycine receptor-transfected human embryonic kidney cells at room temperature, and caused internalization and lysosomal degradation of the glycine receptors at 37°C. Immunoglobulin G antibodies bound to rodent spinal cord and brainstem co-localizing with monoclonal antibodies to glycine receptor-α1. Ten glycine receptor antibody positive samples were also identified in a retrospective cohort of 56 patients with stiff person syndrome and related syndromes. Glycine receptor antibodies are strongly associated with spinal and brainstem disorders, and the majority of patients have progressive encephalomyelitis with rigidity and myoclonus. The antibodies demonstrate in vitro evidence of pathogenicity and the patients respond well to immunotherapies, contrasting with earlier studies of this syndrome, which indicated a poor prognosis. The presence of glycine receptor antibodies should help to identify a disease that responds to immunotherapies, but these treatments may need to be sustained, relapses can occur and maintenance immunosuppression may be required.
gene therapies
2026-01-12 | The History and Nosology of the Glycine Disorders: A Framework for Clinicians.
Despite its simple chemical structure, glycine plays a complex role in the body. The glycine cleavage system regulates brain glycine levels and is a key one-carbon donor to folate. Its metabolism is tightly integrated with that of serine. In addition to its biochemical role, glycine functions as a neurotransmitter and neuromodulator. Primary defects in the glycine cleavage system have long been known to cause human disease with a primarily neurological phenotype, and this was labelled as 'nonketotic hyperglycinaemia' in 1968. With increasing availability of molecular testing, many additional genetic conditions became apparent, as well as non-genetic factors that cause hyperglycinaemia. There is now a much greater appreciation of the marked clinical impact of this heterogeneity. The previous terminology of 'classical' and 'atypical' nonketotic hyperglycinaemia does not adequately address these numerous genetic aetiologies, nor does it account for the phenotypic spectrum within individual genetic disorders. We provide here a clinically relevant classification of the glycine encephalopathies, based on the underlying genetic aetiology and its relation to the glycine cleavage system. Characteristic clinical and biochemical features of each condition, as well as non-genetic phenocopies that cause hyperglycinaemia, are discussed in detail. This provides a readily usable framework for clinicians when faced with a patient with elevated glycine levels.
2026-01-06 | Nonketotic Hyperglycinemia in Central and Appalachian Kentucky.
Nonketotic hyperglycinemia (NKH) is a rare genetic disorder with a global incidence of 0.4 to 1.3 per 100 000 live births with regional variation. We sought to estimate the regional birth incidence and describe the clinical and genetic features of NKH in central and Appalachian Kentucky. Fifteen patients met standard diagnostic criteria for NKH; 13 were born in Kentucky, yielding an estimated birth incidence of 2.53 per 100 000 live births (13/513 419; 95% CI 1.35-4.33). Of those with available genetic data (n = 9), 8 carried GLDC variants, with 6 having the c.1166C>T (p.A389V) variant. We found a higher incidence of NKH in central and Appalachian Kentucky compared to global estimates, with local enrichment of the p.A389V variant. These findings highlight the need for clinician awareness and further research to inform regional screening and management.
2025-07-28 | Possible Founder Effect of Glycine Encephalopathy: Evidence of a GLDC c.2714T>G (p.Val905Gly) Common Variant in the Paisa Community Based in Cali, Colombia.
Non-ketotic hyperglycinemia (NKH) is a rare autosomal recessive disorder caused by defects in the mitochondrial glycine cleavage system, most commonly involving variants in GLDC. Clinical presentation is heterogeneous, ranging from severe neonatal encephalopathy with intractable epilepsy to attenuated forms with variable neurodevelopmental outcomes. We conducted a comprehensive clinical, biochemical, molecular, and genealogical analysis of eight Colombian patients with NKH, all of whom shared ancestry from the Paisa population. All patients were born at term after uncomplicated pregnancies and presented in the neonatal period with hypotonia, lethargy, feeding difficulties, and treatment-resistant seizures. Elevated glycine levels were detected in plasma for all patients and cerebrospinal fluid in three cases. Molecular testing identified the same homozygous GLDC variant (NM_000170.3:c.2714 T>G; p.Val905Gly) in all individuals. Although no consanguinity was reported, shared surname and regional ancestry suggested intra- and interfamilial isonymy, raising the possibility of a founder effect. Clinical outcomes varied despite the implementation of early supportive interventions. This is the first report of a recurrent GLDC variant in Colombian patients, supporting a potential founder effect in the Paisa population. These findings highlight the importance of regional genetic studies in enhancing diagnostic precision and guiding population-specific strategies for rare disease management.
2025-05-30 | Clinical and genetic characterization of neonatal non-ketotic hyperglycinemia: a rare case with SLC6A9 gene mutation
Nonketotic hyperglycinemia (NKH) is a rare autosomal recessive disorder caused by mutations in the glycine cleavage system (GCS), leading to glycine accumulation in cerebrospinal fluid (CSF) and plasma, with an increased CSF-to-plasma glycine ratio. Typically presenting in the neonatal period, symptoms include lethargy, poor feeding, hypotonia, seizures, and encephalopathy, often resulting in severe neurological impairment. Early diagnosis is vital but challenging due to the rarity and nonspecific nature of symptoms, especially in populations with high consanguinity rates. We report a neonate born to consanguineous parents who developed severe encephalopathy within 48 hours of birth despite normal antenatal and perinatal findings. The infant exhibited poor feeding, seizures, and worsening neurological status. NKH was confirmed by elevated CSF glycine levels and genetic analysis identifying a novel SLC6A9 mutation. This case highlights the importance of considering NKH in neonatal encephalopathy and the need for genetic testing and counseling in at-risk groups.
2025-03-31 | Gene therapy prevents disease and death from non-ketotic hyperglycinemia
Abstract Genetic defects in glycine decarboxylase (GLDC) cause non-ketotic hyperglycinemia (NKH), a rare and frequently fatal neurometabolic disease, which lacks FDA-approved therapies. We characterized CRISPR Cas9-edited humanized mice expressing a prevalent clinical mutation after administration with a single intraperitoneal dose of a novel recombinant of adeno-associated viral vector 9 expressing GLDC (rAAV9-GLDC). Long term biological activity of rAAV9-GLDC was first validated by assessment of its systemic efficacy over five and ten months in mice. Access of rAAV9 to the brain was confirmed by tracking green fluorescent protein (GFP) after a single intraperitoneal dose of rAAV9-GFP. Over five months, control ‘mock’ treated GFP-mice showed reduction in astrocytes but not microglia, oligodendrocytes or neurons in the brain. 37% of these animals suffered long term neurological disease and/or death. rAAV9-GLDC boosts astrogenesis without triggering an inflammatory response and confers 100% protection against disease progression and fatality due to NKH.
other
2024-01-29 | Metabolic Rewiring and Altered Glial Differentiation in an iPSC-Derived Astrocytes 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 neuronal 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. The 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. 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 and offer new perspectives for therapeutic options.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
2 orphan drug designations for Glycine encephalopathy.
2 orphan drug designations for Glycine encephalopathy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
glyceryl tribenzoate | small molecules | FDA | 2019-10-15 | — | Liberyx Therapeutics Limited |
Benzoic acid, sodium salt | small molecules | EMA | 2002-09-11 | — | Ethicare GmbH |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.