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:
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.
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.
2026-07-22 | 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.
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.
Access all drug discovery papers and probability of success in trials forecasts:
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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 |
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