Nonketotic Hyperglycinemia

Mendelian MONDO:0011612 Pathograph 31 Metabolic Disease Inborn Error of Metabolism

Nonketotic hyperglycinemia (NKH), also known as glycine encephalopathy, is a rare autosomal recessive inborn error of glycine metabolism caused by deficient activity of the mitochondrial glycine cleavage system (GCS). The GCS normally catabolizes glycine via decarboxylation and transfers a one-carbon unit to tetrahydrofolate to form 5,10-methylene-THF, supporting serine-glycine-one-carbon (SGOC) metabolism. Mutations in GLDC, AMT, or less commonly GCSH disrupt this pathway, producing systemic and CNS glycine accumulation and downstream one-carbon deficits. The disease is characterized biochemically by elevated glycine in blood and cerebrospinal fluid with an increased CSF-to-plasma glycine ratio. Clinical presentation ranges from severe neonatal encephalopathy with intractable seizures, apnea, and profound hypotonia to attenuated forms with variable developmental delay and behavioral phenotypes. Worldwide incidence is estimated at approximately 1 in 76,000, with higher prevalence in certain populations such as northern Finland (1 in 12,000).

Ask OpenScientist

Ask a research question about Nonketotic Hyperglycinemia. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

Mappings

Definitions

Inheritance

Histopathology

Differentials

Datasets

Trials

Models

References

Deep Research

🏷

Classifications

Harrison's Chapter

Mechanistic Nosology

◆

Subtypes

Classical neonatal nonketotic hyperglycinemia

Severe early-onset form presenting in the neonatal period with encephalopathy, seizures, hypotonia, and high early mortality.

Show evidence (1 reference)

PMID:39206282 SUPPORT Human Clinical

"nine patients died, eight in the"

Supports a severe neonatal subtype with high early mortality.

Attenuated nonketotic hyperglycinemia

Milder survivor form with persistent neurodevelopmental and behavioral manifestations, including variable intellectual disability and ADHD-like features.

Show evidence (1 reference)

PMID:38589924 SUPPORT Human Clinical

"Twelve children, age 6 to 21y, functioned at mild to"

Supports a later-surviving attenuated subtype with variable long-term neurodevelopmental outcomes.

⚙

Pathophysiology

Glycine cleavage system dysfunction

Pathogenic variants in glycine cleavage system genes reduce mitochondrial glycine-cleavage enzymatic function.

GLDC link AMT link GCSH link

glycine decarboxylation via glycine cleavage system link glycine catabolic process link amino acid metabolic process link

aminomethyltransferase activity link

Downstream

Systemic and CNS glycine accumulation Reduced glycine-cleavage flux causes glycine buildup in plasma and cerebrospinal fluid.

GCSH variant-driven lipoylation defects and bioenergetic failure GCSH variants affect the H-protein role in both glycine cleavage and mitochondrial protein lipoylation.

Show evidence (2 references)

PMID:39206282 SUPPORT Human Clinical

"Genetic analyses revealed four new variations and GLDC,"

Supports upstream genetic disruption of glycine cleavage system components in NKH.

PMID:36190515 PARTIAL In Vitro

"has a dual role in protein lipoylation required for bioenergetic"

Provides component-level mechanistic support for GCSH-linked variant NKH and lipoylation coupling.

Systemic and CNS glycine accumulation

Deficient glycine cleavage system activity leads to systemic and CNS glycine accumulation. In a Chinese cohort of 20 NKH patients, median CSF glycine was 135.2 umol/L and median plasma glycine was 998.2 umol/L, with a median CSF/plasma glycine ratio of 0.16. The diagnostic hallmark is a CSF-to-plasma glycine ratio greater than 0.08 (normal less than 0.04).

amino acid metabolic process link

Downstream

Plasma glycine Systemic glycine accumulation is measured clinically as elevated plasma glycine.

CSF glycine CNS glycine accumulation is measured as elevated cerebrospinal-fluid glycine.

CSF-to-plasma glycine ratio Concurrent CSF and plasma glycine elevation produces the increased diagnostic CSF-to-plasma ratio.

Serine-glycine-one-carbon metabolic disruption Excess glycine and reduced cleavage flux perturb one-carbon transfer metabolism.

NMDA receptor dysregulation and neurotransmission imbalance Elevated CNS glycine is hypothesized to perturb NMDA receptor signaling through the NMDA co-agonist site, although the net direction of receptor activity remains unresolved.

Lethargy CNS glycine accumulation drives neonatal metabolic encephalopathy with lethargy.

Muscular hypotonia CNS glycine accumulation and neonatal encephalopathy manifest with profound hypotonia.

Apnea Severe neonatal glycine encephalopathy can involve brainstem respiratory control and apnea.

Neonatal respiratory distress Apnea and shallow breathing in severe neonatal NKH can require ventilatory support.

Recurrent singultus Neonatal hiccups are a recognized presenting clue in glycine encephalopathy.

Show evidence (2 references)

PMID:39206282 SUPPORT Human Clinical

"were135.2 (range, 6.3-546.3) μmol/L, 998.2 (range,75-3,084) μmol/L, 0.16 (range,"

Provides quantitative biochemical data on glycine accumulation in NKH patients.

PMID:38474060 SUPPORT In Vitro

"disorder associated with severe brain malformations and life-threatening"

Confirms NKH as a neuro-metabolic disorder with severe neurological consequences.

Serine-glycine-one-carbon metabolic disruption

The GCS provides one-carbon units for folate-linked one-carbon metabolism. In patient-derived iPSC models, GLDC deficiency causes a metabolic switch to altered serine-glycine-one-carbon metabolism with coordinated cell-growth and cell-cycle responses, suggesting that NKH biology extends beyond simple glycine excitotoxicity.

astrocyte link

one-carbon metabolic process link folic acid metabolic process link

Downstream

Altered glial lineage differentiation in GLDC-deficient neural progenitors Patient-derived GLDC-deficient neural progenitors show altered glial lineage differentiation downstream of SGOC metabolic rewiring.

Show evidence (1 reference)

PMID:38474060 SUPPORT In Vitro

"metabolic switch to an altered serine-glycine-one-carbon metabolism with a"

Demonstrates SGOC metabolic rewiring in GLDC-deficient human iPSC models.

NMDA receptor dysregulation and neurotransmission imbalance

Excess glycine has historically been assumed to overactivate NMDA-type glutamatergic receptors through the NMDA co-agonist site. A 2024 expert reassessment notes that d-serine, another endogenous NMDA co-agonist, is markedly decreased in NKH and may instead contribute to underactivation, so the net direction of NMDA receptor signaling remains unresolved.

neuron link

glutamate receptor signaling pathway link

Downstream

Seizures NMDA receptor dysregulation is a plausible contributor to the high seizure burden in NKH, but the receptor overactivation model remains under reassessment.

EEG with burst suppression Severe neonatal glycine encephalopathy can manifest as burst-suppression EEG and epileptic encephalopathy.

Show evidence (1 reference)

PMID:39423724 SUPPORT Other

"excess glycine in nonketotic hyperglycinemia would result in overactivation of"

Describes glycine's role at the NMDA receptor co-agonist site.

Altered glial lineage differentiation in GLDC-deficient neural progenitors

GLDC-deficient iPSC-derived neural progenitors shift toward a heterogeneous astrocyte lineage with increased radial glial markers and unexpected neuronal marker expression, linking GLDC-related metabolic defects to altered neurodevelopment.

radial glial cell link

astrocyte differentiation link

Downstream

Global developmental delay Altered glial differentiation provides a plausible neurodevelopmental mechanism, and NKH survivor cohorts document developmental disorders.

Intellectual disability Altered neural/glial differentiation provides a plausible neurodevelopmental mechanism for the intellectual-disability phenotype in attenuated survivors.

Attention deficit hyperactivity disorder Attenuated NKH survivors show ADHD-like maladaptive behaviors as part of the neurodevelopmental phenotype.

Abnormal corpus callosum morphology NKH-associated disruption of neural development is reflected in corpus callosum dysplasia/hypogenesis on MRI.

Abnormal cerebral white matter morphology NKH-associated neurodevelopmental and metabolic injury includes white-matter abnormalities on MRI.

Show evidence (1 reference)

PMID:38474060 SUPPORT In Vitro

"shifted towards a more heterogeneous astrocyte lineage with increased expression"

Demonstrates altered glial differentiation in NKH cell models.

GCSH variant-driven lipoylation defects and bioenergetic failure

Pathogenic GCSH variants disrupt the H-protein role in mitochondrial protein lipoylation, producing combined NKH and lipoate deficiency with impaired bioenergetic enzyme function.

GCSH link

protein lipoylation link

mitochondrion link

Downstream

Global developmental delay GCSH-linked lipoylation and glycine-metabolism defects are associated with attenuated phenotypes that include developmental delay.

Show evidence (1 reference)

PMID:36190515 SUPPORT In Vitro

"has a dual role in protein lipoylation required for bioenergetic"

Functional evidence demonstrates the GCSH role in protein lipoylation required for bioenergetic enzymes.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Musculoskeletal 1

Muscular hypotonia FREQUENT Hypotonia (HP:0001252)

Show evidence (1 reference)

PMID:39206282 SUPPORT Human Clinical

"for admission with a history of seizures (15/20), lethargy (14/20), hypotonia"

Documents hypotonia in 55% of NKH patients in this cohort.

Nervous System 8

Seizures VERY_FREQUENT Seizure (HP:0001250)

Show evidence (1 reference)

PMID:39206282 SUPPORT Human Clinical

"for admission with a history of seizures (15/20), lethargy (14/20), hypotonia"

Quantifies seizure frequency at 75% in an NKH cohort.

Lethargy VERY_FREQUENT Lethargy (HP:0001254)

Show evidence (1 reference)

PMID:39206282 SUPPORT Human Clinical

"for admission with a history of seizures (15/20), lethargy (14/20), hypotonia"

Lethargy observed in 70% of NKH patients.

Global developmental delay VERY_FREQUENT Global developmental delay (HP:0001263)

Show evidence (2 references)

PMID:39206282 SUPPORT Human Clinical

"Among the nine survivors, varying developmental disorders were"

Developmental delay documented in NKH survivors.

PMID:38589924 SUPPORT Human Clinical

"Twelve children, age 6 to 21y, functioned at mild to"

Confirms intellectual disability across the spectrum in attenuated NKH.

Intellectual disability FREQUENT Intellectual disability (HP:0001249)

Show evidence (1 reference)

PMID:38589924 SUPPORT Human Clinical

"Twelve children, age 6 to 21y, functioned at mild to"

Directly documents intellectual disability levels in attenuated NKH.

Abnormal corpus callosum morphology FREQUENT Abnormal corpus callosum morphology (HP:0001273)

Show evidence (1 reference)

PMID:39206282 SUPPORT Human Clinical

"dysplasia of the corpus callosum (5/14)"

Documents corpus callosum dysplasia in 36% of NKH patients with MRI data.

Abnormal cerebral white matter morphology OCCASIONAL Abnormal cerebral white matter morphology (HP:0002500)

Show evidence (1 reference)

PMID:39206282 SUPPORT Human Clinical

"white matter abnormalities (3/14)"

White matter abnormalities in 21% of NKH patients with MRI.

EEG with burst suppression FREQUENT EEG with burst suppression (HP:0010851)

Show evidence (1 reference)

PMID:39206282 SUPPORT Human Clinical

"EEG evaluations showed anomalies such as burst suppression (4/8) and"

Burst suppression documented in 50% of NKH patients with EEG.

Attention deficit hyperactivity disorder FREQUENT Attention deficit hyperactivity disorder (HP:0007018)

Show evidence (2 references)

PMID:38589924 SUPPORT Human Clinical

"characteristics were present in more than two thirds of children."

Documents high ADHD-like behavior frequency in attenuated NKH.

PMID:38589924 SUPPORT Human Clinical

"dextromethorphan, but no significant relation between plasma glycine levels and"

Explores associations with dextromethorphan but not glycine levels.

Respiratory 2

Apnea FREQUENT Apnea (HP:0002104)

Show evidence (1 reference)

PMID:39206282 SUPPORT Human Clinical

"(11/20), apnea (9/20), and feeble sobbing (4/20)."

Apnea documented in 45% of NKH patients.

Neonatal respiratory distress FREQUENT Neonatal respiratory distress (HP:0002643)

Show evidence (1 reference)

PMID:39206282 SUPPORT Human Clinical

"(11/20), apnea (9/20), and feeble sobbing (4/20)."

Apnea in 45% of NKH patients supports neonatal respiratory distress as a frequent feature.

Constitutional 1

Recurrent singultus OCCASIONAL Recurrent singultus (HP:0100247)

Hiccups are frequently described in NKH case reports and reviews as an early presenting sign in neonates.

Show evidence (1 reference)

PMID:26962342 SUPPORT Human Clinical

"presented in neonatal life with hiccups"

Case series reports neonatal hiccups as a presenting feature before NKH diagnosis.

🧬

Genetic Associations

GLDC pathogenic variants (Pathogenic Variants)

Autosomal recessive

Show evidence (1 reference)

CGGV:assertion_14d991f3-25f3-40c9-aacd-c1a008d9eaea-2019-02-06T170000.000Z SUPPORT Other

ClinGen classifies the GLDC-glycine encephalopathy gene-disease relationship as definitive with autosomal recessive inheritance.

AMT pathogenic variants (Pathogenic Variants)

Autosomal recessive

Show evidence (1 reference)

CGGV:assertion_a85e1b07-b975-4c92-b592-7b3e8d35805a-2019-05-24T160000.000Z SUPPORT Other

ClinGen classifies the AMT-glycine encephalopathy gene-disease relationship as definitive with autosomal recessive inheritance.

GCSH pathogenic variants (variant NKH)

Autosomal recessive

Show evidence (2 references)

PMID:36190515 SUPPORT Human Clinical

"spectrum ranging from neonatal fatal glycine encephalopathy to an attenuated"

Documents pathogenic GCSH variants with broad clinical spectrum.

PMID:36190515 SUPPORT In Vitro

"lipoylation and glycine metabolism, causing combined deficiency, whereas some"

Demonstrates functional consequences of GCSH variants.

💊

Treatments

Sodium benzoate therapy

Action: nitrogen scavenger therapy Ontology label: pharmacotherapy MAXO:0000058

Agent: sodium benzoate ↗

Sodium benzoate is the mainstay of glycine reduction therapy in NKH. Benzoate conjugates with glycine and is excreted in urine as hippurate, thereby lowering plasma glycine. Clinical targets commonly aim for plasma glycine approximately 120-300 umol/L.

Mechanism Target:

INHIBITS Systemic and CNS glycine accumulation — Sodium benzoate is used as glycine-reduction therapy to lower accumulated glycine.

Show evidence (2 references)

PMID:36471344 SUPPORT Human Clinical

"Current glycine reduction therapy"

The abstract frames current NKH treatment as glycine-reduction therapy.

PMID:36471344 SUPPORT Human Clinical

"uses high doses of sodium benzoate."

The adjacent abstract text identifies high-dose sodium benzoate as the current glycine-reduction therapy.

Show evidence (2 references)

PMID:36471344 SUPPORT Human Clinical

"uses high doses of sodium benzoate."

Establishes sodium benzoate as standard glycine reduction therapy.

PMID:36471344 SUPPORT Human Clinical

"to benzoate monotherapy by on average 28%."

Provides quantitative data on benzoate therapy effectiveness as comparator.

Ketogenic diet

Action: dietary intervention MAXO:0000088

The ketogenic diet is used as an alternative glycine-lowering strategy. In a multi-center series, six infants switching from high-dose benzoate to KD with low-dose benzoate showed approximately 28% lower plasma glycine, reduced brain glycine by MRS, and seizure reduction in half of patients. KD promotes glycine use as a gluconeogenic substrate.

Mechanism Target:

INHIBITS Systemic and CNS glycine accumulation — Ketogenic diet is used as a glycine-lowering intervention and produced lower plasma glycine than benzoate monotherapy in the reported series.

Show evidence (1 reference)

PMID:36471344 SUPPORT Human Clinical

"a more consistent reduction in plasma glycine levels than high-dose benzoate"

The study conclusion supports ketogenic diet as a glycine-lowering treatment.

Show evidence (2 references)

PMID:36471344 SUPPORT Human Clinical

"to benzoate monotherapy by on average 28%."

Demonstrates KD effectiveness for glycine reduction.

PMID:36471344 SUPPORT Human Clinical

"a more consistent reduction in plasma glycine levels than high-dose benzoate"

Supports KD as an effective glycine reduction strategy.

NMDA antagonist therapy (dextromethorphan/ketamine)

Action: pharmacotherapy MAXO:0000058

Agent: dextromethorphan ↗ ketamine ↗

NMDA receptor antagonists such as dextromethorphan and ketamine have been used to counteract presumed NMDA receptor overactivation by excess glycine. However, a 2024 expert reassessment finds insufficient evidence of added therapeutic benefit beyond glycine reduction strategies, and notes potential adverse behavioral effects. Controlled clinical studies have never been performed.

Mechanism Target:

MODULATES NMDA receptor dysregulation and neurotransmission imbalance — Dextromethorphan and ketamine target NMDA receptor signaling, but evidence for clinical benefit in NKH is insufficient and the mechanism is under reassessment.

Show evidence (1 reference)

PMID:39423724 PARTIAL Other

"NMDA-type receptor antagonists in"

The reassessment identifies the treatment class as NMDA-type receptor antagonists while concluding that clinical benefit remains unproven.

Show evidence (3 references)

PMID:39423724 PARTIAL Other

"dextromethorphan or ketamine in nonketotic hyperglycinemia has not been"

Expert reassessment finds no clear evidence of therapeutic benefit.

PMID:39423724 PARTIAL Other

"nonketotic hyperglycinemia should be reevaluated, particularly in light of"

Recommends reevaluation of NMDA antagonist use due to potential adverse effects.

PMID:38589924 PARTIAL Human Clinical

"dextromethorphan, but no significant relation between plasma glycine levels and"

Dextromethorphan use associated with maladaptive behaviors in attenuated NKH.

Anticonvulsant therapy

Action: antiepileptic drug therapy Ontology label: anticonvulsant agent therapy MAXO:0000167

Antiepileptic drugs are used for seizure management in NKH. Sodium valproate is specifically contraindicated because it increases both CSF and plasma glycine levels, potentially worsening seizures. Vigabatrin should also be avoided, particularly in attenuated NKH with West syndrome, because GeneReviews reports rapid loss of function with its use. Appropriate anticonvulsant selection is critical in NKH management.

Target Phenotypes: Seizure ↗

Show evidence (2 references)

PMID:39206282 PARTIAL Human Clinical

"for admission with a history of seizures (15/20)"

High seizure frequency (75%) supports the need for anticonvulsant therapy, though the snippet does not specify which anticonvulsants are used.

PMID:20301531 SUPPORT Other

"vigabatrin, which has resulted in rapid loss of function when used to treat seizures, particularly in those with attenuated NKH who have West syndrome."

GeneReviews explicitly lists vigabatrin as an agent to avoid in NKH seizure management.

Supportive care

Action: supportive care MAXO:0000950

Comprehensive supportive care including ventilatory support for apnea, feeding support, developmental therapies, and monitoring for metabolic decompensation. NKH neonates frequently require intensive care. Long-term care includes management of neurodevelopmental disability.

Target Phenotypes: Apnea ↗ Neonatal respiratory distress ↗ Global developmental delay ↗

Show evidence (1 reference)

PMID:26962342 SUPPORT Human Clinical

"apneic episodes requiring ventilatory support"

Case-series infants with NKH required ventilatory support because of apnea.

Genetic counseling

Action: genetic counseling MAXO:0000079

Genetic counseling is indicated for families with NKH given the autosomal recessive inheritance, 25% recurrence risk, and the availability of molecular genetic testing. Prenatal diagnosis is possible when familial variants are known.

Mechanism Target:

GLDC pathogenic variants — Counseling is anchored to biallelic GLDC pathogenic variants and supports recurrence-risk counseling and prenatal diagnosis when familial variants are known.

Show evidence (1 reference)

PMID:26962342 SUPPORT Human Clinical

"genetic counseling and prenatal diagnosis can be offered at the subsequent"

Case-series authors state that early recognition enables genetic counseling and prenatal diagnosis.

AMT pathogenic variants — Counseling is anchored to autosomal recessive glycine-cleavage gene variants, including AMT, and supports recurrence-risk counseling.

Show evidence (1 reference)

CGGV:assertion_a85e1b07-b975-4c92-b592-7b3e8d35805a-2019-05-24T160000.000Z SUPPORT Other

ClinGen supports autosomal recessive AMT-related glycine encephalopathy as a counseling target.

GCSH pathogenic variants (variant NKH) — Counseling also covers variant NKH caused by autosomal recessive GCSH pathogenic variants.

Show evidence (1 reference)

PMID:36190515 SUPPORT Human Clinical

"spectrum ranging from neonatal fatal glycine encephalopathy to an attenuated"

GCSH variant series documents the heritable variant NKH spectrum relevant to counseling.

Show evidence (1 reference)

PMID:40225406 SUPPORT Human Clinical

"crucial guidance for both the patient's clinical management and family's"

Demonstrates the value of molecular diagnosis for genetic counseling in NKH families.

🔬

Biochemical Markers

Plasma glycine (INCREASED)

Context: Elevated plasma glycine is a hallmark biochemical finding in NKH. In a Chinese cohort, median plasma glycine was 998.2 umol/L (range 75-3084). Target on treatment is approximately 120-300 umol/L.

Pathograph Readouts

Readout Of Systemic and CNS glycine accumulation Positive Diagnostic

Elevated plasma glycine reports systemic glycine accumulation from impaired glycine cleavage.

Show evidence (1 reference)

PMID:39206282 SUPPORT Human Clinical

"were135.2 (range, 6.3-546.3) μmol/L, 998.2 (range,75-3,084) μmol/L, 0.16 (range,"

Cohort data quantify plasma glycine as part of the diagnostic biochemical profile.

Show evidence (1 reference)

PMID:39206282 SUPPORT Human Clinical

"were135.2 (range, 6.3-546.3) μmol/L, 998.2 (range,75-3,084) μmol/L, 0.16 (range,"

Quantifies plasma glycine elevation in NKH patients.

CSF glycine (INCREASED)

Context: CSF glycine is markedly elevated in NKH patients. Median CSF glycine was 135.2 umol/L (range 6.3-546.3) in a Chinese cohort. The CSF-to-plasma glycine ratio is the key diagnostic marker, with values above 0.08 considered diagnostic (normal below 0.04).

Pathograph Readouts

Readout Of Systemic and CNS glycine accumulation Positive Diagnostic

Elevated CSF glycine reports CNS glycine accumulation and supports NKH diagnosis.

Show evidence (1 reference)

PMID:39206282 SUPPORT Human Clinical

"were135.2 (range, 6.3-546.3) μmol/L, 998.2 (range,75-3,084) μmol/L, 0.16 (range,"

Cohort data quantify CSF glycine as part of the diagnostic biochemical profile.

Show evidence (1 reference)

PMID:39206282 SUPPORT Human Clinical

"were135.2 (range, 6.3-546.3) μmol/L, 998.2 (range,75-3,084) μmol/L, 0.16 (range,"

Documents CSF glycine elevation and diagnostic CSF/plasma ratio.

CSF-to-plasma glycine ratio (INCREASED)

Context: The CSF-to-plasma glycine ratio is the hallmark diagnostic biomarker for NKH. Values above 0.08 are diagnostic (normal below 0.04). In a Chinese cohort, the median ratio was 0.16 (range 0.03-0.60). This ratio reflects the CNS burden of glycine accumulation and is more diagnostically specific than absolute glycine levels alone.

Pathograph Readouts

Readout Of Systemic and CNS glycine accumulation Positive Diagnostic

Increased CSF-to-plasma glycine ratio reports disproportionate CNS glycine accumulation.

Show evidence (1 reference)

PMID:39206282 SUPPORT Human Clinical

"were135.2 (range, 6.3-546.3) μmol/L, 998.2 (range,75-3,084) μmol/L, 0.16 (range,"

Cohort data report the CSF/plasma glycine ratio as part of the diagnostic biochemical profile.

Show evidence (1 reference)

PMID:39206282 SUPPORT Human Clinical

"were135.2 (range, 6.3-546.3) μmol/L, 998.2 (range,75-3,084) μmol/L, 0.16 (range,"

Provides the key diagnostic ratio data for NKH.

D-serine (DECREASED)

Context: D-serine, an alternative endogenous NMDA receptor co-agonist, is markedly decreased in NKH. This may contribute to underactivation of NMDA-type glutamatergic receptors and complicates the assumption that NMDA receptors are simply overactivated.

Pathograph Readouts

Readout Of NMDA receptor dysregulation and neurotransmission imbalance Negative

Lower D-serine tracks with the underactivation component of the revised NMDA-receptor model in NKH.

Show evidence (1 reference)

PMID:39423724 SUPPORT Other

"markedly decreased in nonketotic hyperglycinemia."

The reassessment identifies decreased D-serine as mechanistically relevant to NMDA receptor signaling in NKH.

Show evidence (1 reference)

PMID:39423724 SUPPORT Other

"markedly decreased in nonketotic hyperglycinemia."

Documents d-serine deficiency in NKH challenging the NMDA overactivation model.

{ }

Source YAML

click to show

name: Nonketotic Hyperglycinemia
category: Mendelian
creation_date: '2026-02-23T00:00:00Z'
updated_date: '2026-05-18T13:09:45Z'
synonyms:
- Glycine encephalopathy
- NKH
- Glycine cleavage system deficiency
- GCE deficiency
description: 'Nonketotic hyperglycinemia (NKH), also known as glycine encephalopathy, is a rare autosomal recessive inborn error of glycine metabolism caused by deficient activity of the mitochondrial glycine cleavage system (GCS). The GCS normally catabolizes glycine via decarboxylation and transfers a one-carbon unit to tetrahydrofolate to form 5,10-methylene-THF, supporting serine-glycine-one-carbon (SGOC) metabolism. Mutations in GLDC, AMT, or less commonly GCSH disrupt this pathway, producing systemic and CNS glycine accumulation and downstream one-carbon deficits. The disease is characterized biochemically by elevated glycine in blood and cerebrospinal fluid with an increased CSF-to-plasma glycine ratio. Clinical presentation ranges from severe neonatal encephalopathy with intractable seizures, apnea, and profound hypotonia to attenuated forms with variable developmental delay and behavioral phenotypes. Worldwide incidence is estimated at approximately 1 in 76,000, with higher prevalence in certain populations such as northern Finland (1 in 12,000).

  '
disease_term:
  preferred_term: glycine encephalopathy
  term:
    id: MONDO:0011612
    label: glycine encephalopathy
classifications:
  harrisons_chapter:
  - classification_value: hereditary disease
  - classification_value: nervous system disorder
  mechanistic_category:
  - classification_value: mitochondrial disease
parents:
- Metabolic Disease
- Inborn Error of Metabolism
prevalence:
- population: Global live births
  percentage: 0.4-1.3 per 100,000 live births
  notes: >-
    Contemporary regional study cited a global incidence range of roughly 1 in
    250,000 to 1 in 77,000 live births, underscoring the rarity of NKH outside
    founder populations.
  evidence:
  - reference: PMID:41493948
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "0.4 to 1.3 per 100 000 live births with regional variation."
    explanation: This recent regional epidemiology study explicitly states the current global incidence range for NKH.
- population: Northern Finland live births
  percentage: 1 in 12,000
  notes: >-
    Classic Finnish study demonstrated strong geographic enrichment in northern
    Finland relative to the broader Finnish incidence of 1 in 55,000 newborns.
  evidence:
  - reference: PMID:445864
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "1:12,000."
    explanation: This founder-population study provides the classic high-incidence estimate for northern Finland.
has_subtypes:
- name: Classical neonatal nonketotic hyperglycinemia
  description: 'Severe early-onset form presenting in the neonatal period with encephalopathy, seizures, hypotonia, and high early mortality.

    '
  evidence:
  - reference: PMID:39206282
    reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "nine patients died, eight in the"
    explanation: Supports a severe neonatal subtype with high early mortality.
- name: Attenuated nonketotic hyperglycinemia
  description: 'Milder survivor form with persistent neurodevelopmental and behavioral manifestations, including variable intellectual disability and ADHD-like features.

    '
  evidence:
  - reference: PMID:38589924
    reference_title: "The behavioral phenotype of children and adolescents with attenuated non-ketotic hyperglycinemia, intermediate to good subtype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twelve children, age 6 to 21y, functioned at mild to"
    explanation: Supports a later-surviving attenuated subtype with variable long-term neurodevelopmental outcomes.
pathophysiology:
- name: Glycine cleavage system dysfunction
  description: 'Pathogenic variants in glycine cleavage system genes reduce mitochondrial glycine-cleavage enzymatic function.

    '
  genes:
  - preferred_term: GLDC
    term:
      id: hgnc:4313
      label: GLDC
  - preferred_term: AMT
    term:
      id: hgnc:473
      label: AMT
  - preferred_term: GCSH
    term:
      id: hgnc:4208
      label: GCSH
  biological_processes:
  - preferred_term: glycine decarboxylation via glycine cleavage system
    term:
      id: GO:0019464
      label: glycine decarboxylation via glycine cleavage system
  - preferred_term: glycine catabolic process
    term:
      id: GO:0006546
      label: glycine catabolic process
  - preferred_term: amino acid metabolic process
    term:
      id: GO:0006520
      label: amino acid metabolic process
  molecular_functions:
  - preferred_term: aminomethyltransferase activity
    term:
      id: GO:0004047
      label: aminomethyltransferase activity
  evidence:
  - reference: PMID:39206282
    reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analyses revealed four new variations and GLDC,"
    explanation: Supports upstream genetic disruption of glycine cleavage system components in NKH.
  - reference: PMID:36190515
    reference_title: "Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined nonketotic hyperglycinemia and lipoate deficiency."
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: "has a dual role in protein lipoylation required for bioenergetic"
    explanation: Provides component-level mechanistic support for GCSH-linked variant NKH and lipoylation coupling.
  downstream:
  - target: Systemic and CNS glycine accumulation
    description: Reduced glycine-cleavage flux causes glycine buildup in plasma and cerebrospinal fluid.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40225406
      reference_title: "The precise molecular diagnosis of novel GLDC compound heterozygous variants highlights the benefits for a Chinese family with nonketotic hyperglycinemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "resulting in elevated glycine concentration in plasma and cerebrospinal fluid."
      explanation: Directly links the inborn glycine-metabolism error in NKH to elevated glycine in plasma and CSF.
  - target: GCSH variant-driven lipoylation defects and bioenergetic failure
    description: GCSH variants affect the H-protein role in both glycine cleavage and mitochondrial protein lipoylation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36190515
      reference_title: "Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined nonketotic hyperglycinemia and lipoate deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "lipoylation and glycine metabolism, causing combined deficiency, whereas some"
      explanation: Functional studies show combined protein lipoylation and glycine metabolism deficiency from GCSH variants.
- name: Systemic and CNS glycine accumulation
  description: 'Deficient glycine cleavage system activity leads to systemic and CNS glycine accumulation. In a Chinese cohort of 20 NKH patients, median CSF glycine was 135.2 umol/L and median plasma glycine was 998.2 umol/L, with a median CSF/plasma glycine ratio of 0.16. The diagnostic hallmark is a CSF-to-plasma glycine ratio greater than 0.08 (normal less than 0.04).

    '
  biological_processes:
  - preferred_term: amino acid metabolic process
    term:
      id: GO:0006520
      label: amino acid metabolic process
  chemical_entities:
  - preferred_term: glycine
    term:
      id: CHEBI:15428
      label: glycine
    modifier: INCREASED
  evidence:
  - reference: PMID:39206282
    reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "were135.2 (range, 6.3-546.3) μmol/L, 998.2 (range,75-3,084) μmol/L, 0.16 (range,"
    explanation: Provides quantitative biochemical data on glycine accumulation in NKH patients.
  - reference: PMID:38474060
    reference_title: "Metabolic Rewiring and Altered Glial Differentiation in an iPSC-Derived Astrocyte Model Derived from a Nonketotic Hyperglycinemia Patient."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "disorder associated with severe brain malformations and life-threatening"
    explanation: Confirms NKH as a neuro-metabolic disorder with severe neurological consequences.
  downstream:
  - target: Plasma glycine
    description: Systemic glycine accumulation is measured clinically as elevated plasma glycine.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39206282
      reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "were135.2 (range, 6.3-546.3) μmol/L, 998.2 (range,75-3,084) μmol/L, 0.16 (range,"
      explanation: Patient cohort data quantify the elevated plasma glycine component of systemic accumulation.
  - target: CSF glycine
    description: CNS glycine accumulation is measured as elevated cerebrospinal-fluid glycine.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39206282
      reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "were135.2 (range, 6.3-546.3) μmol/L, 998.2 (range,75-3,084) μmol/L, 0.16 (range,"
      explanation: Patient cohort data quantify CSF glycine as part of the biochemical accumulation phenotype.
  - target: CSF-to-plasma glycine ratio
    description: Concurrent CSF and plasma glycine elevation produces the increased diagnostic CSF-to-plasma ratio.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39206282
      reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "were135.2 (range, 6.3-546.3) μmol/L, 998.2 (range,75-3,084) μmol/L, 0.16 (range,"
      explanation: The same patient series reports CSF glycine, plasma glycine, and the increased CSF/plasma ratio.
  - target: Serine-glycine-one-carbon metabolic disruption
    description: Excess glycine and reduced cleavage flux perturb one-carbon transfer metabolism.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - GLDC-deficient glycine-cleavage flux
    evidence:
    - reference: PMID:38474060
      reference_title: "Metabolic Rewiring and Altered Glial Differentiation in an iPSC-Derived Astrocyte Model Derived from a Nonketotic Hyperglycinemia Patient."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "metabolic switch to an altered serine-glycine-one-carbon metabolism with a"
      explanation: GLDC-deficient patient-derived cells show SGOC rewiring downstream of impaired glycine metabolism.
  - target: NMDA receptor dysregulation and neurotransmission imbalance
    description: Elevated CNS glycine is hypothesized to perturb NMDA receptor signaling through the NMDA co-agonist site, although the net direction of receptor activity remains unresolved.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - glycine NMDA co-agonist signaling
    evidence:
    - reference: PMID:39423724
      reference_title: "The role of NMDA-receptor type glutamatergic antagonists dextromethorphan or ketamine in the treatment of nonketotic hyperglycinemia: A critical reassessment."
      supports: PARTIAL
      evidence_source: OTHER
      snippet: "excess glycine in nonketotic hyperglycinemia would result in overactivation of"
      explanation: Expert reassessment identifies excess glycine at the NMDA co-agonist site as the historical mechanism while cautioning that net receptor activation is not proven.
  - target: Lethargy
    description: CNS glycine accumulation drives neonatal metabolic encephalopathy with lethargy.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - glycine-associated neonatal encephalopathy
    evidence:
    - reference: PMID:39206282
      reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "for admission with a history of seizures (15/20), lethargy (14/20), hypotonia"
      explanation: Patient cohort data list lethargy among common presenting manifestations of NKH.
  - target: Muscular hypotonia
    description: CNS glycine accumulation and neonatal encephalopathy manifest with profound hypotonia.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - glycine-associated neonatal encephalopathy
    evidence:
    - reference: PMID:39206282
      reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "for admission with a history of seizures (15/20), lethargy (14/20), hypotonia"
      explanation: Patient cohort data list hypotonia among common presenting manifestations of NKH.
  - target: Apnea
    description: Severe neonatal glycine encephalopathy can involve brainstem respiratory control and apnea.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - brainstem dysfunction in neonatal encephalopathy
    evidence:
    - reference: PMID:39206282
      reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "(11/20), apnea (9/20), and feeble sobbing (4/20)."
      explanation: Patient cohort data report apnea among presenting manifestations of NKH.
  - target: Neonatal respiratory distress
    description: Apnea and shallow breathing in severe neonatal NKH can require ventilatory support.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - brainstem dysfunction in neonatal encephalopathy
    evidence:
    - reference: PMID:26962342
      reference_title: "Nonketotic hyperglycinemia case series."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "apneic episodes requiring ventilatory support"
      explanation: Case-series infants with NKH required ventilatory support because of apnea.
  - target: Recurrent singultus
    description: Neonatal hiccups are a recognized presenting clue in glycine encephalopathy.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - brainstem and diaphragmatic irritability in neonatal encephalopathy
    evidence:
    - reference: PMID:26962342
      reference_title: "Nonketotic hyperglycinemia case series."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "presented in neonatal life with hiccups"
      explanation: Case series directly reports neonatal hiccups as a presenting manifestation before NKH diagnosis.
- name: Serine-glycine-one-carbon metabolic disruption
  description: 'The GCS provides one-carbon units for folate-linked one-carbon metabolism. In patient-derived iPSC models, GLDC deficiency causes a metabolic switch to altered serine-glycine-one-carbon metabolism with coordinated cell-growth and cell-cycle responses, suggesting that NKH biology extends beyond simple glycine excitotoxicity.

    '
  biological_processes:
  - preferred_term: one-carbon metabolic process
    term:
      id: GO:0006730
      label: one-carbon metabolic process
  - preferred_term: folic acid metabolic process
    term:
      id: GO:0046655
      label: folic acid metabolic process
  cell_types:
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  evidence:
  - reference: PMID:38474060
    reference_title: "Metabolic Rewiring and Altered Glial Differentiation in an iPSC-Derived Astrocyte Model Derived from a Nonketotic Hyperglycinemia Patient."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "metabolic switch to an altered serine-glycine-one-carbon metabolism with a"
    explanation: Demonstrates SGOC metabolic rewiring in GLDC-deficient human iPSC models.
  downstream:
  - target: Altered glial lineage differentiation in GLDC-deficient neural progenitors
    description: Patient-derived GLDC-deficient neural progenitors show altered glial lineage differentiation downstream of SGOC metabolic rewiring.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - GLDC-deficient neural progenitor metabolic rewiring
    evidence:
    - reference: PMID:38474060
      reference_title: "Metabolic Rewiring and Altered Glial Differentiation in an iPSC-Derived Astrocyte Model Derived from a Nonketotic Hyperglycinemia Patient."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "shifted towards a more heterogeneous astrocyte lineage with increased expression"
      explanation: The iPSC model links GLDC-deficient metabolic rewiring to altered glial differentiation.
- name: NMDA receptor dysregulation and neurotransmission imbalance
  description: 'Excess glycine has historically been assumed to overactivate NMDA-type glutamatergic receptors through the NMDA co-agonist site. A 2024 expert reassessment notes that d-serine, another endogenous NMDA co-agonist, is markedly decreased in NKH and may instead contribute to underactivation, so the net direction of NMDA receptor signaling remains unresolved.

    '
  biological_processes:
  - preferred_term: glutamate receptor signaling pathway
    term:
      id: GO:0007215
      label: glutamate receptor signaling pathway
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:39423724
    reference_title: "The role of NMDA-receptor type glutamatergic antagonists dextromethorphan or ketamine in the treatment of nonketotic hyperglycinemia: A critical reassessment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "excess glycine in nonketotic hyperglycinemia would result in overactivation of"
    explanation: Describes glycine's role at the NMDA receptor co-agonist site.
  downstream:
  - target: Seizures
    description: NMDA receptor dysregulation is a plausible contributor to the high seizure burden in NKH, but the receptor overactivation model remains under reassessment.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39423724
      reference_title: "The role of NMDA-receptor type glutamatergic antagonists dextromethorphan or ketamine in the treatment of nonketotic hyperglycinemia: A critical reassessment."
      supports: PARTIAL
      evidence_source: OTHER
      snippet: "excess glycine in nonketotic hyperglycinemia would result in overactivation of"
      explanation: Provides the mechanistic rationale for connecting glycine/NMDA signaling to neurologic manifestations while acknowledging uncertainty.
    - reference: PMID:39206282
      reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "for admission with a history of seizures (15/20), lethargy (14/20), hypotonia"
      explanation: Patient cohort data document seizures as a frequent NKH manifestation.
  - target: EEG with burst suppression
    description: Severe neonatal glycine encephalopathy can manifest as burst-suppression EEG and epileptic encephalopathy.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - neonatal epileptic encephalopathy
    evidence:
    - reference: PMID:39206282
      reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "EEG evaluations showed anomalies such as burst suppression (4/8) and"
      explanation: Patient cohort data report burst-suppression EEG among NKH electrophysiologic findings.
- name: Altered glial lineage differentiation in GLDC-deficient neural progenitors
  description: 'GLDC-deficient iPSC-derived neural progenitors shift toward a heterogeneous astrocyte lineage with increased radial glial markers and unexpected neuronal marker expression, linking GLDC-related metabolic defects to altered neurodevelopment.

    '
  biological_processes:
  - preferred_term: astrocyte differentiation
    term:
      id: GO:0048708
      label: astrocyte differentiation
  cell_types:
  - preferred_term: radial glial cell
    term:
      id: CL:0000681
      label: radial glial cell
  evidence:
  - reference: PMID:38474060
    reference_title: "Metabolic Rewiring and Altered Glial Differentiation in an iPSC-Derived Astrocyte Model Derived from a Nonketotic Hyperglycinemia Patient."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "shifted towards a more heterogeneous astrocyte lineage with increased expression"
    explanation: Demonstrates altered glial differentiation in NKH cell models.
  downstream:
  - target: Global developmental delay
    description: Altered glial differentiation provides a plausible neurodevelopmental mechanism, and NKH survivor cohorts document developmental disorders.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38474060
      reference_title: "Metabolic Rewiring and Altered Glial Differentiation in an iPSC-Derived Astrocyte Model Derived from a Nonketotic Hyperglycinemia Patient."
      supports: PARTIAL
      evidence_source: IN_VITRO
      snippet: "shifted towards a more heterogeneous astrocyte lineage with increased expression"
      explanation: Cell-model evidence links NKH metabolic defects to altered neural lineage differentiation.
    - reference: PMID:39206282
      reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Among the nine survivors, varying developmental disorders were"
      explanation: Human cohort data document developmental disorders among NKH survivors.
  - target: Intellectual disability
    description: Altered neural/glial differentiation provides a plausible neurodevelopmental mechanism for the intellectual-disability phenotype in attenuated survivors.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38474060
      reference_title: "Metabolic Rewiring and Altered Glial Differentiation in an iPSC-Derived Astrocyte Model Derived from a Nonketotic Hyperglycinemia Patient."
      supports: PARTIAL
      evidence_source: IN_VITRO
      snippet: "shifted towards a more heterogeneous astrocyte lineage with increased expression"
      explanation: Cell-model evidence supports altered neural lineage differentiation downstream of GLDC deficiency.
    - reference: PMID:38589924
      reference_title: "The behavioral phenotype of children and adolescents with attenuated non-ketotic hyperglycinemia, intermediate to good subtype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Twelve children, age 6 to 21y, functioned at mild to"
      explanation: Human attenuated-NKH cohort documents mild-to-severe intellectual disability.
  - target: Attention deficit hyperactivity disorder
    description: Attenuated NKH survivors show ADHD-like maladaptive behaviors as part of the neurodevelopmental phenotype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38474060
      reference_title: "Metabolic Rewiring and Altered Glial Differentiation in an iPSC-Derived Astrocyte Model Derived from a Nonketotic Hyperglycinemia Patient."
      supports: PARTIAL
      evidence_source: IN_VITRO
      snippet: "shifted towards a more heterogeneous astrocyte lineage with increased expression"
      explanation: Cell-model evidence links GLDC deficiency to altered neural lineage differentiation.
    - reference: PMID:38589924
      reference_title: "The behavioral phenotype of children and adolescents with attenuated non-ketotic hyperglycinemia, intermediate to good subtype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "characteristics were present in more than two thirds of children."
      explanation: Human attenuated-NKH cohort documents frequent ADHD-like behavioral characteristics.
  - target: Abnormal corpus callosum morphology
    description: NKH-associated disruption of neural development is reflected in corpus callosum dysplasia/hypogenesis on MRI.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38474060
      reference_title: "Metabolic Rewiring and Altered Glial Differentiation in an iPSC-Derived Astrocyte Model Derived from a Nonketotic Hyperglycinemia Patient."
      supports: PARTIAL
      evidence_source: IN_VITRO
      snippet: "disorder associated with severe brain malformations and life-threatening"
      explanation: Patient-derived neural model frames NKH as associated with severe brain malformations.
    - reference: PMID:39206282
      reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "dysplasia of the corpus callosum (5/14)"
      explanation: Patient cohort data document corpus callosum dysplasia on MRI.
  - target: Abnormal cerebral white matter morphology
    description: NKH-associated neurodevelopmental and metabolic injury includes white-matter abnormalities on MRI.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38474060
      reference_title: "Metabolic Rewiring and Altered Glial Differentiation in an iPSC-Derived Astrocyte Model Derived from a Nonketotic Hyperglycinemia Patient."
      supports: PARTIAL
      evidence_source: IN_VITRO
      snippet: "disorder associated with severe brain malformations and life-threatening"
      explanation: Patient-derived neural model frames NKH as associated with severe brain malformations.
    - reference: PMID:39206282
      reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "white matter abnormalities (3/14)"
      explanation: Patient cohort data document white-matter abnormalities on MRI.
- name: GCSH variant-driven lipoylation defects and bioenergetic failure
  description: 'Pathogenic GCSH variants disrupt the H-protein role in mitochondrial protein lipoylation, producing combined NKH and lipoate deficiency with impaired bioenergetic enzyme function.

    '
  genes:
  - preferred_term: GCSH
    term:
      id: hgnc:4208
      label: GCSH
  biological_processes:
  - preferred_term: protein lipoylation
    term:
      id: GO:0009249
      label: protein lipoylation
  locations:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  evidence:
  - reference: PMID:36190515
    reference_title: "Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined nonketotic hyperglycinemia and lipoate deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "has a dual role in protein lipoylation required for bioenergetic"
    explanation: Functional evidence demonstrates the GCSH role in protein lipoylation required for bioenergetic enzymes.
  downstream:
  - target: Global developmental delay
    description: GCSH-linked lipoylation and glycine-metabolism defects are associated with attenuated phenotypes that include developmental delay.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36190515
      reference_title: "Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined nonketotic hyperglycinemia and lipoate deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "phenotype of developmental delay, behavioral problems, limited epilepsy and"
      explanation: Human GCSH variant cases include attenuated phenotypes with developmental delay.
phenotypes:
- name: Seizures
  frequency: VERY_FREQUENT
  description: 'Seizures are among the most common presenting features of NKH, occurring in 75% of patients in a Chinese cohort (15/20). EEG evaluations show burst suppression and hypsarrhythmia patterns. Seizures are attributed to both NMDA receptor dysregulation and direct glycine toxicity.

    '
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:39206282
    reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "for admission with a history of seizures (15/20), lethargy (14/20), hypotonia"
    explanation: Quantifies seizure frequency at 75% in an NKH cohort.
- name: Muscular hypotonia
  frequency: FREQUENT
  description: 'Profound hypotonia is a cardinal feature of neonatal NKH, observed in 55% of patients in a Chinese cohort and nearly universally in severe neonatal presentations.

    '
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:39206282
    reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "for admission with a history of seizures (15/20), lethargy (14/20), hypotonia"
    explanation: Documents hypotonia in 55% of NKH patients in this cohort.
- name: Lethargy
  frequency: VERY_FREQUENT
  description: 'Lethargy and decreased alertness are frequent early signs, present in 70% of patients (14/20) in a Chinese cohort, reflecting severe CNS glycine toxicity.

    '
  phenotype_term:
    preferred_term: Lethargy
    term:
      id: HP:0001254
      label: Lethargy
  evidence:
  - reference: PMID:39206282
    reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "for admission with a history of seizures (15/20), lethargy (14/20), hypotonia"
    explanation: Lethargy observed in 70% of NKH patients.
- name: Apnea
  frequency: FREQUENT
  description: 'Central apnea is a life-threatening feature of neonatal NKH, present in 45% of patients (9/20) in a Chinese cohort. It reflects brainstem glycinergic receptor dysfunction and severe metabolic encephalopathy.

    '
  phenotype_term:
    preferred_term: Apnea
    term:
      id: HP:0002104
      label: Apnea
  evidence:
  - reference: PMID:39206282
    reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "(11/20), apnea (9/20), and feeble sobbing (4/20)."
    explanation: Apnea documented in 45% of NKH patients.
- name: Global developmental delay
  frequency: VERY_FREQUENT
  description: 'Varying degrees of developmental delay are near-universal among NKH survivors, ranging from mild delay in attenuated forms to severe intellectual disability in classical neonatal NKH.

    '
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:39206282
    reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the nine survivors, varying developmental disorders were"
    explanation: Developmental delay documented in NKH survivors.
  - reference: PMID:38589924
    reference_title: "The behavioral phenotype of children and adolescents with attenuated non-ketotic hyperglycinemia, intermediate to good subtype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twelve children, age 6 to 21y, functioned at mild to"
    explanation: Confirms intellectual disability across the spectrum in attenuated NKH.
- name: Intellectual disability
  frequency: FREQUENT
  description: 'In attenuated NKH, children function at mild to severe intellectual disability levels. In classical NKH, profound intellectual disability is expected in survivors.

    '
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:38589924
    reference_title: "The behavioral phenotype of children and adolescents with attenuated non-ketotic hyperglycinemia, intermediate to good subtype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twelve children, age 6 to 21y, functioned at mild to"
    explanation: Directly documents intellectual disability levels in attenuated NKH.
- name: Abnormal corpus callosum morphology
  frequency: FREQUENT
  description: 'Structural brain abnormalities including dysplasia or hypogenesis of the corpus callosum are a recognized feature of NKH, observed in 36% of patients with available MRI data (5/14) in a Chinese cohort.

    '
  phenotype_term:
    preferred_term: Abnormal corpus callosum morphology
    term:
      id: HP:0001273
      label: Abnormal corpus callosum morphology
  evidence:
  - reference: PMID:39206282
    reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: dysplasia of the corpus callosum (5/14)
    explanation: Documents corpus callosum dysplasia in 36% of NKH patients with MRI data.
- name: Abnormal cerebral white matter morphology
  frequency: OCCASIONAL
  description: 'White matter abnormalities are detected on brain MRI in NKH patients, observed in 21% of those with imaging data (3/14).

    '
  phenotype_term:
    preferred_term: Abnormal cerebral white matter morphology
    term:
      id: HP:0002500
      label: Abnormal cerebral white matter morphology
  evidence:
  - reference: PMID:39206282
    reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: white matter abnormalities (3/14)
    explanation: White matter abnormalities in 21% of NKH patients with MRI.
- name: EEG with burst suppression
  frequency: FREQUENT
  description: 'Burst suppression pattern on EEG is a characteristic finding in severe neonatal NKH, observed in half of patients with EEG data (4/8) in a Chinese cohort.

    '
  phenotype_term:
    preferred_term: EEG with burst suppression
    term:
      id: HP:0010851
      label: EEG with burst suppression
  evidence:
  - reference: PMID:39206282
    reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EEG evaluations showed anomalies such as burst suppression (4/8) and"
    explanation: Burst suppression documented in 50% of NKH patients with EEG.
- name: Attention deficit hyperactivity disorder
  frequency: FREQUENT
  description: 'In the attenuated form of NKH, maladaptive behaviors with ADHD-like characteristics are present in more than two-thirds of children. These behaviors were significantly related to female sex and to dextromethorphan use but not to plasma glycine levels.

    '
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:38589924
    reference_title: "The behavioral phenotype of children and adolescents with attenuated non-ketotic hyperglycinemia, intermediate to good subtype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characteristics were present in more than two thirds of children."
    explanation: Documents high ADHD-like behavior frequency in attenuated NKH.
  - reference: PMID:38589924
    reference_title: "The behavioral phenotype of children and adolescents with attenuated non-ketotic hyperglycinemia, intermediate to good subtype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dextromethorphan, but no significant relation between plasma glycine levels and"
    explanation: Explores associations with dextromethorphan but not glycine levels.
- name: Neonatal respiratory distress
  frequency: FREQUENT
  description: 'Respiratory failure and distress requiring ventilatory support are common in severe neonatal NKH, reflecting brainstem glycinergic dysfunction. Eight of nine deaths in a Chinese cohort occurred in the neonatal period.

    '
  phenotype_term:
    preferred_term: Neonatal respiratory distress
    term:
      id: HP:0002643
      label: Neonatal respiratory distress
  evidence:
  - reference: PMID:39206282
    reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "(11/20), apnea (9/20), and feeble sobbing (4/20)."
    explanation: Apnea in 45% of NKH patients supports neonatal respiratory distress as a frequent feature.
- name: Recurrent singultus
  frequency: OCCASIONAL
  description: 'Hiccups are a recognized clinical feature of NKH, particularly in the neonatal period, and may reflect brainstem irritability from glycine excess.

    '
  phenotype_term:
    preferred_term: Recurrent singultus
    term:
      id: HP:0100247
      label: Recurrent singultus
  notes: Hiccups are frequently described in NKH case reports and reviews as an early presenting sign in neonates.
  evidence:
  - reference: PMID:26962342
    reference_title: "Nonketotic hyperglycinemia case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presented in neonatal life with hiccups"
    explanation: Case series reports neonatal hiccups as a presenting feature before NKH diagnosis.
biochemical:
- name: Plasma glycine
  presence: INCREASED
  context: 'Elevated plasma glycine is a hallmark biochemical finding in NKH. In a Chinese cohort, median plasma glycine was 998.2 umol/L (range 75-3084). Target on treatment is approximately 120-300 umol/L.

    '
  biomarker_term:
    preferred_term: glycine
    term:
      id: CHEBI:15428
      label: glycine
  readouts:
  - target: Systemic and CNS glycine accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated plasma glycine reports systemic glycine accumulation from impaired glycine cleavage.
    evidence:
    - reference: PMID:39206282
      reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "were135.2 (range, 6.3-546.3) μmol/L, 998.2 (range,75-3,084) μmol/L, 0.16 (range,"
      explanation: Cohort data quantify plasma glycine as part of the diagnostic biochemical profile.
  evidence:
  - reference: PMID:39206282
    reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "were135.2 (range, 6.3-546.3) μmol/L, 998.2 (range,75-3,084) μmol/L, 0.16 (range,"
    explanation: Quantifies plasma glycine elevation in NKH patients.
- name: CSF glycine
  presence: INCREASED
  context: 'CSF glycine is markedly elevated in NKH patients. Median CSF glycine was 135.2 umol/L (range 6.3-546.3) in a Chinese cohort. The CSF-to-plasma glycine ratio is the key diagnostic marker, with values above 0.08 considered diagnostic (normal below 0.04).

    '
  biomarker_term:
    preferred_term: glycine
    term:
      id: CHEBI:15428
      label: glycine
  readouts:
  - target: Systemic and CNS glycine accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated CSF glycine reports CNS glycine accumulation and supports NKH diagnosis.
    evidence:
    - reference: PMID:39206282
      reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "were135.2 (range, 6.3-546.3) μmol/L, 998.2 (range,75-3,084) μmol/L, 0.16 (range,"
      explanation: Cohort data quantify CSF glycine as part of the diagnostic biochemical profile.
  evidence:
  - reference: PMID:39206282
    reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "were135.2 (range, 6.3-546.3) μmol/L, 998.2 (range,75-3,084) μmol/L, 0.16 (range,"
    explanation: Documents CSF glycine elevation and diagnostic CSF/plasma ratio.
- name: CSF-to-plasma glycine ratio
  presence: INCREASED
  context: 'The CSF-to-plasma glycine ratio is the hallmark diagnostic biomarker for NKH. Values above 0.08 are diagnostic (normal below 0.04). In a Chinese cohort, the median ratio was 0.16 (range 0.03-0.60). This ratio reflects the CNS burden of glycine accumulation and is more diagnostically specific than absolute glycine levels alone.

    '
  readouts:
  - target: Systemic and CNS glycine accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Increased CSF-to-plasma glycine ratio reports disproportionate CNS glycine accumulation.
    evidence:
    - reference: PMID:39206282
      reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "were135.2 (range, 6.3-546.3) μmol/L, 998.2 (range,75-3,084) μmol/L, 0.16 (range,"
      explanation: Cohort data report the CSF/plasma glycine ratio as part of the diagnostic biochemical profile.
  evidence:
  - reference: PMID:39206282
    reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "were135.2 (range, 6.3-546.3) μmol/L, 998.2 (range,75-3,084) μmol/L, 0.16 (range,"
    explanation: Provides the key diagnostic ratio data for NKH.
- name: D-serine
  presence: DECREASED
  context: 'D-serine, an alternative endogenous NMDA receptor co-agonist, is markedly decreased in NKH. This may contribute to underactivation of NMDA-type glutamatergic receptors and complicates the assumption that NMDA receptors are simply overactivated.

    '
  biomarker_term:
    preferred_term: D-serine
    term:
      id: CHEBI:16523
      label: D-serine
  readouts:
  - target: NMDA receptor dysregulation and neurotransmission imbalance
    relationship: READOUT_OF
    direction: NEGATIVE
    interpretation: Lower D-serine tracks with the underactivation component of the revised NMDA-receptor model in NKH.
    evidence:
    - reference: PMID:39423724
      reference_title: "The role of NMDA-receptor type glutamatergic antagonists dextromethorphan or ketamine in the treatment of nonketotic hyperglycinemia: A critical reassessment."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "markedly decreased in nonketotic hyperglycinemia."
      explanation: The reassessment identifies decreased D-serine as mechanistically relevant to NMDA receptor signaling in NKH.
  evidence:
  - reference: PMID:39423724
    reference_title: "The role of NMDA-receptor type glutamatergic antagonists dextromethorphan or ketamine in the treatment of nonketotic hyperglycinemia: A critical reassessment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "markedly decreased in nonketotic hyperglycinemia."
    explanation: Documents d-serine deficiency in NKH challenging the NMDA overactivation model.
genetic:
- name: GLDC pathogenic variants
  gene_term:
    preferred_term: GLDC
    term:
      id: hgnc:4313
      label: GLDC
  association: Pathogenic Variants
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:39206282
      reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "INTRODUCTION: Nonketotic hyperglycinemia (NKH) is a rare, life-threatening"
      explanation: NKH is established as an autosomal recessive genetic disorder.
    - reference: PMID:40225406
      reference_title: "The precise molecular diagnosis of novel GLDC compound heterozygous variants highlights the benefits for a Chinese family with nonketotic hyperglycinemia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "rare inherited disease caused by an inborn error of glycine metabolism,"
      explanation: Confirms NKH as an inherited disease with biallelic variants.
  features: 'GLDC encodes glycine decarboxylase (P-protein) of the glycine cleavage system. GLDC variants account for approximately 65-80% of classical NKH cases. In a Chinese cohort, GLDC variants were found in 65% (13/20) of patients. Novel compound heterozygous variants continue to expand the mutational spectrum.

    '
  evidence:
  - reference: CGGV:assertion_14d991f3-25f3-40c9-aacd-c1a008d9eaea-2019-02-06T170000.000Z
    reference_title: "GLDC / glycine encephalopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "GLDC | HGNC:4313 | glycine encephalopathy | MONDO:0011612 | AR | Definitive"
    explanation: ClinGen classifies the GLDC-glycine encephalopathy gene-disease relationship as definitive with autosomal recessive inheritance.
- name: AMT pathogenic variants
  gene_term:
    preferred_term: AMT
    term:
      id: hgnc:473
      label: AMT
  association: Pathogenic Variants
  inheritance:
  - name: Autosomal recessive
  features: 'AMT encodes aminomethyltransferase (T-protein) of the glycine cleavage system. AMT variants account for approximately 20-35% of NKH cases. In a Chinese cohort, AMT variants were found in 35% (7/20) of patients.

    '
  evidence:
  - reference: CGGV:assertion_a85e1b07-b975-4c92-b592-7b3e8d35805a-2019-05-24T160000.000Z
    reference_title: "AMT / glycine encephalopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "AMT | HGNC:473 | glycine encephalopathy | MONDO:0011612 | AR | Definitive"
    explanation: ClinGen classifies the AMT-glycine encephalopathy gene-disease relationship as definitive with autosomal recessive inheritance.
- name: GCSH pathogenic variants (variant NKH)
  gene_term:
    preferred_term: GCSH
    term:
      id: hgnc:4208
      label: GCSH
  inheritance:
  - name: Autosomal recessive
  features: 'GCSH encodes the H-protein, a multifunctional lipoyl carrier protein with dual roles in glycine cleavage and mitochondrial lipoylation. Pathogenic GCSH variants cause combined NKH and lipoate deficiency (variant NKH) with a broad clinical spectrum from neonatal fatal glycine encephalopathy to attenuated phenotypes with developmental delay. Most variants produce a hypomorphic effect on both protein lipoylation and glycine metabolism.

    '
  evidence:
  - reference: PMID:36190515
    reference_title: "Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined nonketotic hyperglycinemia and lipoate deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "spectrum ranging from neonatal fatal glycine encephalopathy to an attenuated"
    explanation: Documents pathogenic GCSH variants with broad clinical spectrum.
  - reference: PMID:36190515
    reference_title: "Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined nonketotic hyperglycinemia and lipoate deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "lipoylation and glycine metabolism, causing combined deficiency, whereas some"
    explanation: Demonstrates functional consequences of GCSH variants.
treatments:
- name: Sodium benzoate therapy
  description: 'Sodium benzoate is the mainstay of glycine reduction therapy in NKH. Benzoate conjugates with glycine and is excreted in urine as hippurate, thereby lowering plasma glycine. Clinical targets commonly aim for plasma glycine approximately 120-300 umol/L.

    '
  treatment_term:
    preferred_term: nitrogen scavenger therapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: sodium benzoate
      term:
        id: CHEBI:113455
        label: sodium benzoate
  evidence:
  - reference: PMID:36471344
    reference_title: "Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "uses high doses of sodium benzoate."
    explanation: Establishes sodium benzoate as standard glycine reduction therapy.
  - reference: PMID:36471344
    reference_title: "Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "to benzoate monotherapy by on average 28%."
    explanation: Provides quantitative data on benzoate therapy effectiveness as comparator.
  target_mechanisms:
  - target: Systemic and CNS glycine accumulation
    treatment_effect: INHIBITS
    description: Sodium benzoate is used as glycine-reduction therapy to lower accumulated glycine.
    evidence:
    - reference: PMID:36471344
      reference_title: "Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Current glycine reduction therapy"
      explanation: The abstract frames current NKH treatment as glycine-reduction therapy.
    - reference: PMID:36471344
      reference_title: "Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "uses high doses of sodium benzoate."
      explanation: The adjacent abstract text identifies high-dose sodium benzoate as the current glycine-reduction therapy.
- name: Ketogenic diet
  description: 'The ketogenic diet is used as an alternative glycine-lowering strategy. In a multi-center series, six infants switching from high-dose benzoate to KD with low-dose benzoate showed approximately 28% lower plasma glycine, reduced brain glycine by MRS, and seizure reduction in half of patients. KD promotes glycine use as a gluconeogenic substrate.

    '
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
  evidence:
  - reference: PMID:36471344
    reference_title: "Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "to benzoate monotherapy by on average 28%."
    explanation: Demonstrates KD effectiveness for glycine reduction.
  - reference: PMID:36471344
    reference_title: "Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a more consistent reduction in plasma glycine levels than high-dose benzoate"
    explanation: Supports KD as an effective glycine reduction strategy.
  target_mechanisms:
  - target: Systemic and CNS glycine accumulation
    treatment_effect: INHIBITS
    description: Ketogenic diet is used as a glycine-lowering intervention and produced lower plasma glycine than benzoate monotherapy in the reported series.
    evidence:
    - reference: PMID:36471344
      reference_title: "Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a more consistent reduction in plasma glycine levels than high-dose benzoate"
      explanation: The study conclusion supports ketogenic diet as a glycine-lowering treatment.
- name: NMDA antagonist therapy (dextromethorphan/ketamine)
  description: 'NMDA receptor antagonists such as dextromethorphan and ketamine have been used to counteract presumed NMDA receptor overactivation by excess glycine. However, a 2024 expert reassessment finds insufficient evidence of added therapeutic benefit beyond glycine reduction strategies, and notes potential adverse behavioral effects. Controlled clinical studies have never been performed.

    '
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: dextromethorphan
      term:
        id: CHEBI:4470
        label: dextromethorphan
    - preferred_term: ketamine
      term:
        id: CHEBI:6121
        label: ketamine
  evidence:
  - reference: PMID:39423724
    reference_title: "The role of NMDA-receptor type glutamatergic antagonists dextromethorphan or ketamine in the treatment of nonketotic hyperglycinemia: A critical reassessment."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "dextromethorphan or ketamine in nonketotic hyperglycinemia has not been"
    explanation: Expert reassessment finds no clear evidence of therapeutic benefit.
  - reference: PMID:39423724
    reference_title: "The role of NMDA-receptor type glutamatergic antagonists dextromethorphan or ketamine in the treatment of nonketotic hyperglycinemia: A critical reassessment."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "nonketotic hyperglycinemia should be reevaluated, particularly in light of"
    explanation: Recommends reevaluation of NMDA antagonist use due to potential adverse effects.
  - reference: PMID:38589924
    reference_title: "The behavioral phenotype of children and adolescents with attenuated non-ketotic hyperglycinemia, intermediate to good subtype."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "dextromethorphan, but no significant relation between plasma glycine levels and"
    explanation: Dextromethorphan use associated with maladaptive behaviors in attenuated NKH.
  target_mechanisms:
  - target: NMDA receptor dysregulation and neurotransmission imbalance
    treatment_effect: MODULATES
    description: Dextromethorphan and ketamine target NMDA receptor signaling, but evidence for clinical benefit in NKH is insufficient and the mechanism is under reassessment.
    evidence:
    - reference: PMID:39423724
      reference_title: "The role of NMDA-receptor type glutamatergic antagonists dextromethorphan or ketamine in the treatment of nonketotic hyperglycinemia: A critical reassessment."
      supports: PARTIAL
      evidence_source: OTHER
      snippet: "NMDA-type receptor antagonists in"
      explanation: The reassessment identifies the treatment class as NMDA-type receptor antagonists while concluding that clinical benefit remains unproven.
- name: Anticonvulsant therapy
  description: 'Antiepileptic drugs are used for seizure management in NKH. Sodium valproate is specifically contraindicated because it increases both CSF and plasma glycine levels, potentially worsening seizures. Vigabatrin should also be avoided, particularly in attenuated NKH with West syndrome, because GeneReviews reports rapid loss of function with its use. Appropriate anticonvulsant selection is critical in NKH management.

    '
  treatment_term:
    preferred_term: antiepileptic drug therapy
    term:
      id: MAXO:0000167
      label: anticonvulsant agent therapy
  evidence:
  - reference: PMID:39206282
    reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "for admission with a history of seizures (15/20)"
    explanation: High seizure frequency (75%) supports the need for anticonvulsant therapy, though the snippet does not specify which anticonvulsants are used.
  - reference: PMID:20301531
    reference_title: "Nonketotic Hyperglycinemia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "vigabatrin, which has resulted in rapid loss of function when used to treat seizures, particularly in those with attenuated NKH who have West syndrome."
    explanation: GeneReviews explicitly lists vigabatrin as an agent to avoid in NKH seizure management.
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  notes: Sodium valproate is contraindicated as it increases glycine levels and worsens seizures. Vigabatrin should also be avoided because it can cause rapid loss of function in attenuated NKH with West syndrome.
- name: Supportive care
  description: 'Comprehensive supportive care including ventilatory support for apnea, feeding support, developmental therapies, and monitoring for metabolic decompensation. NKH neonates frequently require intensive care. Long-term care includes management of neurodevelopmental disability.

    '
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_phenotypes:
  - preferred_term: Apnea
    term:
      id: HP:0002104
      label: Apnea
  - preferred_term: Neonatal respiratory distress
    term:
      id: HP:0002643
      label: Neonatal respiratory distress
  - preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:26962342
    reference_title: "Nonketotic hyperglycinemia case series."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "apneic episodes requiring ventilatory support"
    explanation: Case-series infants with NKH required ventilatory support because of apnea.
  notes: High neonatal mortality (9/20 in one cohort, 8 in the neonatal period) underscores the need for intensive supportive care including ventilatory support and monitoring.
- name: Genetic counseling
  description: 'Genetic counseling is indicated for families with NKH given the autosomal recessive inheritance, 25% recurrence risk, and the availability of molecular genetic testing. Prenatal diagnosis is possible when familial variants are known.

    '
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  target_mechanisms:
  - target: GLDC pathogenic variants
    description: Counseling is anchored to biallelic GLDC pathogenic variants and supports recurrence-risk counseling and prenatal diagnosis when familial variants are known.
    evidence:
    - reference: PMID:26962342
      reference_title: "Nonketotic hyperglycinemia case series."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "genetic counseling and prenatal diagnosis can be offered at the subsequent"
      explanation: Case-series authors state that early recognition enables genetic counseling and prenatal diagnosis.
  - target: AMT pathogenic variants
    description: Counseling is anchored to autosomal recessive glycine-cleavage gene variants, including AMT, and supports recurrence-risk counseling.
    evidence:
    - reference: CGGV:assertion_a85e1b07-b975-4c92-b592-7b3e8d35805a-2019-05-24T160000.000Z
      reference_title: "AMT / glycine encephalopathy (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "AMT | HGNC:473 | glycine encephalopathy | MONDO:0011612 | AR | Definitive"
      explanation: ClinGen supports autosomal recessive AMT-related glycine encephalopathy as a counseling target.
  - target: GCSH pathogenic variants (variant NKH)
    description: Counseling also covers variant NKH caused by autosomal recessive GCSH pathogenic variants.
    evidence:
    - reference: PMID:36190515
      reference_title: "Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined nonketotic hyperglycinemia and lipoate deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "spectrum ranging from neonatal fatal glycine encephalopathy to an attenuated"
      explanation: GCSH variant series documents the heritable variant NKH spectrum relevant to counseling.
  evidence:
  - reference: PMID:40225406
    reference_title: "The precise molecular diagnosis of novel GLDC compound heterozygous variants highlights the benefits for a Chinese family with nonketotic hyperglycinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "crucial guidance for both the patient's clinical management and family's"
    explanation: Demonstrates the value of molecular diagnosis for genetic counseling in NKH families.
diagnosis:
- name: Newborn screening
  description: 'NKH diagnosis should be considered for neonates presenting with seizures, hypotonia, lethargy, and apnea. Biochemical screening using plasma and CSF glycine levels with CSF-to-plasma ratio calculation is the standard diagnostic approach. Early diagnosis enables timely intervention.

    '
  evidence:
  - reference: PMID:39206282
    reference_title: "Natural history and outcome of nonketotic hyperglycinemia in China."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "diagnosis should be considered for neonates presenting specific symptoms. The"
    explanation: Supports the importance of early NKH detection and standardized diagnostic protocols.
notes: 'NKH pathophysiology is increasingly recognized as multifactorial, extending beyond simple glycine neurotoxicity to encompass serine-glycine-one-carbon metabolic disruption, altered glial differentiation, and in variant NKH (GCSH mutations) bioenergetic failure from impaired lipoylation. MRI and EEG abnormalities may be more reliable prognostic indicators than biochemical glycine levels. The benefit of NMDA receptor antagonist therapy is under critical reassessment. Recent iPSC-based disease modeling has opened new avenues for understanding and potentially treating the metabolic and neurodevelopmental dimensions of NKH beyond glycine reduction alone.

  '
references:
- reference: PMID:20301531
  title: "Nonketotic Hyperglycinemia."
  tags:
  - GeneReviews
  findings: []
- reference: PMID:39206282
  title: "Natural history and outcome of nonketotic hyperglycinemia in China."
  findings: []
- reference: PMID:38589924
  title: "The behavioral phenotype of children and adolescents with attenuated non-ketotic hyperglycinemia, intermediate to good subtype."
  findings: []
- reference: PMID:36190515
  title: "Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined nonketotic hyperglycinemia and lipoate deficiency."
  findings: []
- reference: PMID:40225406
  title: "The precise molecular diagnosis of novel GLDC compound heterozygous variants highlights the benefits for a Chinese family with nonketotic hyperglycinemia."
  findings: []
- reference: PMID:38474060
  title: "Metabolic Rewiring and Altered Glial Differentiation in an iPSC-Derived Astrocyte Model Derived from a Nonketotic Hyperglycinemia Patient."
  findings: []
- reference: PMID:39423724
  title: "The role of NMDA-receptor type glutamatergic antagonists dextromethorphan or ketamine in the treatment of nonketotic hyperglycinemia: A critical reassessment."
  findings: []
- reference: PMID:36471344
  title: "Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels."
  findings: []
- reference: PMID:26962342
  title: "Nonketotic hyperglycinemia case series."
  findings: []
- reference: PMID:41493948
  title: "Nonketotic Hyperglycinemia in Central and Appalachian Kentucky."
  findings: []
- reference: PMID:445864
  title: "Nonketotic hyperglycinemia. A genetic study of 13 Finnish families."
  findings: []
- reference: CGGV:assertion_14d991f3-25f3-40c9-aacd-c1a008d9eaea-2019-02-06T170000.000Z
  title: "GLDC / glycine encephalopathy (Definitive)"
  findings: []
- reference: CGGV:assertion_a85e1b07-b975-4c92-b592-7b3e8d35805a-2019-05-24T160000.000Z
  title: "AMT / glycine encephalopathy (Definitive)"
  findings: []

📚

References & Deep Research

References

PMID:20301531

Nonketotic Hyperglycinemia.

No top-level findings curated for this source.

PMID:39206282

Natural history and outcome of nonketotic hyperglycinemia in China.

No top-level findings curated for this source.

PMID:38589924

The behavioral phenotype of children and adolescents with attenuated non-ketotic hyperglycinemia, intermediate to good subtype.

No top-level findings curated for this source.

PMID:36190515

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

No top-level findings curated for this source.

PMID:40225406

The precise molecular diagnosis of novel GLDC compound heterozygous variants highlights the benefits for a Chinese family with nonketotic hyperglycinemia.

No top-level findings curated for this source.

PMID:38474060

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

No top-level findings curated for this source.

PMID:39423724

The role of NMDA-receptor type glutamatergic antagonists dextromethorphan or ketamine in the treatment of nonketotic hyperglycinemia: A critical reassessment.

No top-level findings curated for this source.

PMID:36471344

Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels.

No top-level findings curated for this source.

PMID:26962342

Nonketotic hyperglycinemia case series.

No top-level findings curated for this source.

PMID:41493948

Nonketotic Hyperglycinemia in Central and Appalachian Kentucky.

No top-level findings curated for this source.

PMID:445864

Nonketotic hyperglycinemia. A genetic study of 13 Finnish families.

No top-level findings curated for this source.

CGGV:assertion_14d991f3-25f3-40c9-aacd-c1a008d9eaea-2019-02-06T170000.000Z

GLDC / glycine encephalopathy (Definitive)

No top-level findings curated for this source.

CGGV:assertion_a85e1b07-b975-4c92-b592-7b3e8d35805a-2019-05-24T160000.000Z

AMT / glycine encephalopathy (Definitive)

No top-level findings curated for this source.

Deep Research

Falcon ▸

Disease Pathophysiology Research Template

Edison Scientific Literature 30 citations 2026-02-23T23:32:16.743315

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Pathophysiology Research Template

Target Disease

Disease Name: Nonketotic Hyperglycinemia
MONDO ID: (if available)
Category: Genetic

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Nonketotic Hyperglycinemia. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

What are the primary pathophysiological mechanisms?
What molecular pathways are dysregulated?
What cellular processes are affected?

2. Key Molecular Players

Genes/Proteins: Which genes are causally involved or implicated?
Chemical Entities: What metabolites, drugs, or small molecules are relevant?
Cell Types: Which cell types are primarily affected?
Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

What biological processes (GO terms) are disrupted?
Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

Where in the cell do key processes occur?
Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

What is the sequence of events from initial trigger to clinical manifestation?
Are there distinct stages or phases?

6. Phenotypic Manifestations

What are the key clinical phenotypes?
How do they relate to the underlying mechanisms?

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic claims
Prioritize recent reviews and landmark papers
Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Title: Pathophysiology of Nonketotic Hyperglycinemia (NKH; Glycine Encephalopathy)

Publication window emphasized: 2023–2024 (with selected 2022 supportive clinical implementation data where needed).

Disease concept, definitions, and current understanding

1.1 Definition and nosology Nonketotic hyperglycinemia (NKH), also called glycine encephalopathy, is a rare autosomal recessive inborn error of glycine metabolism caused by deficient activity of the mitochondrial glycine cleavage system (GCS)/glycine cleavage enzyme (GCE). It is characterized biochemically by elevated glycine in blood and cerebrospinal fluid (CSF), with an increased CSF:plasma glycine ratio as a hallmark diagnostic feature. (nyhan2023nonketotichyperglycinemia pages 1-2, zhou2024naturalhistoryand pages 1-2, hirtum2024thebehavioralphenotype pages 1-2)

A commonly cited diagnostic hallmark is an increased CSF:plasma glycine ratio “> 0.08; normal < 0.04”. (nyhan2023nonketotichyperglycinemia pages 1-2)

Clinical categorization is used along two axes: • Age of onset: neonatal/classical (0–4 weeks), infantile (5 weeks–2 years), and late-onset (>2 years). (zhou2024naturalhistoryand pages 1-2) • Severity/outcome: severe (“classic”) versus attenuated (sometimes subdivided by developmental quotient into poor/intermediate/good). (hirtum2024thebehavioralphenotype pages 1-2)

1.2 Core biochemical lesion The GCS normally catabolizes glycine via decarboxylation and transfers a one-carbon unit to tetrahydrofolate (THF) to form 5,10-methylene-THF, thereby supporting serine–glycine–one-carbon (SGOC) metabolism. In NKH, GLDC or AMT mutations (and less commonly GCSH or lipoylation pathway defects) reduce this flux, producing systemic and CNS glycine accumulation and downstream one-carbon deficits. (arribascarreira2024metabolicrewiringand pages 1-2)

Core pathophysiology: molecular and cellular mechanisms

2.1 Primary mechanisms: glycine accumulation + one-carbon product deficiency A recent expert reassessment emphasizes that NKH pathophysiology should be conceptualized as both (i) excess glycine (upstream of the enzymatic block) and (ii) deficiency of 5,10-methylene-tetrahydrofolate (downstream product), with “multifold” adverse effects. (hove2024theroleof pages 3-5)

2.2 Neurotransmission dysregulation: NMDA and glycine receptors Excess glycine has long been hypothesized to overactivate NMDA receptors because glycine is an endogenous agonist at the NMDA receptor allosteric (co-agonist) site; thus, glycine elevation was proposed to “result in increased activation… leading to seizures, and through neuronal apoptosis to cell death,” motivating NMDA-antagonist trials with dextromethorphan or ketamine. (hove2024theroleof pages 1-3)

However, newer mechanistic interpretation is nuanced: d-serine is also a major NMDA co-agonist and is reduced in NKH brain/CSF, likely due to reduced l-serine availability and inhibition of serine racemase by glycine; this could yield NMDA underactivation depending on region/developmental stage. A 2024 reassessment states that direct experimental evidence for net NMDA over- vs under-activation “has not been explored to date.” (hove2024theroleof pages 1-3)

In parallel, glycine acts at inhibitory strychnine-sensitive glycine receptors, especially in spinal cord and brainstem; a 2024 iPSC-based NKH model review highlights glycine action “on both NMDA receptors in the cortex and glycine receptors in the spinal cord and brain stem neurons,” consistent with mixed excitatory/inhibitory and respiratory network effects (e.g., apnea). (arribascarreira2024metabolicrewiringand pages 1-2)

2.3 SGOC metabolic disruption: nucleotide, redox, and epigenetic consequences The SGOC axis provides one-carbon units for synthesis of amino acids, nucleotides, and phospholipids and for epigenetic remodeling. Disruption of SGOC metabolism is therefore a plausible contributor to neurodevelopmental pathology beyond excitotoxicity. (arribascarreira2024metabolicrewiringand pages 1-2)

A 2024 patient-derived GLDC-deficient iPSC-to-astrocyte study provides direct cellular evidence of SGOC rewiring: • GLDC-deficient cells exhibited a “metabolic switch to an altered serine–glycine–one-carbon metabolism” with a “coordinated cell growth and cell cycle proliferation response.” (arribascarreira2024metabolicrewiringand pages 1-2) • They reported impaired mitochondrial one-carbon enzymes (SHMT2, MTHFD2) with compensatory increases in cytosolic SHMT1/MTHFD1, consistent with shifted subcellular one-carbon partitioning. (arribascarreira2024metabolicrewiringand pages 13-14) • They observed “nearly 50% decline in the levels of nucleotide metabolites,” reduced proliferative capacity, increased quiescence/senescence signals, and that such rewiring “could influence cell fate during the differentiation process.” (arribascarreira2024metabolicrewiringand pages 13-14, arribascarreira2024metabolicrewiringand pages 14-16) • Redox stress was implicated by a “substantial decrease in glutathione levels,” suggesting compromised antioxidant buffering and increased ROS burden. (arribascarreira2024metabolicrewiringand pages 14-16)

2.4 Glial biology and neurodevelopment: altered astrocyte-lineage differentiation The same 2024 iPSC-based model directly supports a glial contribution to disease biology: • During differentiation, GLDC-deficient neural progenitor cells “shifted towards a more heterogeneous astrocyte lineage” with increased radial glial markers (GFAP, GLAST) and unexpected neuronal marker expression (MAP2, NeuN). (arribascarreira2024metabolicrewiringand pages 1-2, arribascarreira2024metabolicrewiringand pages 14-16) • Functional transporter changes were detected, including increased glycine uptake and upregulation of glycine transporters (GLYT1/GLYT2) in patient-derived astrocyte-lineage cells. (arribascarreira2024metabolicrewiringand pages 9-13) These findings link GLDC deficiency to altered glial differentiation and neurotransmitter handling, which may shape excitability and developmental trajectories. (arribascarreira2024metabolicrewiringand pages 14-16, arribascarreira2024metabolicrewiringand pages 9-13)

2.5 Mitochondrial bioenergetics and lipoylation: “variant NKH” mechanisms A major 2023 advance is the definition of “variant NKH” caused by defects in protein lipoylation that secondarily disrupt the GCS and key mitochondrial dehydrogenases. The GCSH-encoded H-protein is “moonlighting”: it is required for glycine cleavage and is a mitochondrial lipoate carrier/donor in lipoate biogenesis and transfer. (arribascarreira2023pathogenicvariantsingcshencoding pages 2-3, arribascarreira2023pathogenicvariantsingcshencoding pages 1-2)

Mechanistically, the H-protein cycle depicts how H-protein donates lipoyl groups to bioenergetic enzymes (PDH E2 subunit DLAT; 2-ketoglutarate dehydrogenase E2 subunit DLST) and also participates in glycine degradation by the GCS. (arribascarreira2023pathogenicvariantsingcshencoding media 0157c767)

Functionally, patient cell data show that pathogenic GCSH variants can cause “strongly reduced lipoylated proteins of the E2 subunits of PDH (DLAT) and 2-KGDH (DLST)” and reduced PDH activities, directly linking NKH phenotypes to mitochondrial energy metabolism. (arribascarreira2023pathogenicvariantsingcshencoding pages 5-5)

2.6 Putative additional toxic mediators: oxidative stress and guanidinoacetate An expert 2024 synthesis lists oxidative stress, direct glycine toxicity, elevation of neurotoxic metabolites such as guanidinoacetate, and secondary neurotransmitter disturbances (e.g., d-serine deficiency) as part of the multifactorial biochemical landscape of NKH. (hove2024theroleof pages 3-5)

Consistent with this, the 2024 iPSC model reports AGAT upregulation and increased arginine absorption compatible with increased guanidinoacetate synthesis as a glycine “exit” route, providing a mechanistic bridge between glycine overload and neurotoxic guanidino compounds. (arribascarreira2024metabolicrewiringand pages 14-16)

Key molecular players (knowledge-base oriented)

3.1 Causal genes and protein complex Core GCS genes/proteins (HGNC symbols): • GLDC (glycine decarboxylase; “P-protein/GCSP”) (arribascarreira2024metabolicrewiringand pages 1-2, hirtum2024thebehavioralphenotype pages 1-2) • AMT (aminomethyltransferase; “T-protein/GCST”) (arribascarreira2024metabolicrewiringand pages 1-2, hirtum2024thebehavioralphenotype pages 1-2) • GCSH (H-protein; lipoyl carrier; “moonlighting” in lipoylation) (arribascarreira2024metabolicrewiringand pages 1-2, arribascarreira2023pathogenicvariantsingcshencoding pages 2-3) • DLD (L-protein; dihydrolipoamide dehydrogenase) (arribascarreira2024metabolicrewiringand pages 1-2)

Lipoylation/bioenergetic links: • LIAS, LIPT1 (lipoate synthesis/transfer; pathway context) (arribascarreira2023pathogenicvariantsingcshencoding pages 2-3) • DLAT (PDH E2), DLST (2-KGDH E2) (arribascarreira2023pathogenicvariantsingcshencoding pages 5-5, arribascarreira2023pathogenicvariantsingcshencoding media 0157c767)

SGOC and associated metabolic rewiring observed in patient-derived models: • SHMT1/SHMT2, MTHFD1/MTHFD2; PHGDH, PSAT1, PSPH; SRR (serine racemase); SLC6A9 (GlyT1), SLC6A5 (GlyT2); GFAP, SLC1A3 (GLAST); AGAT (GATM). (arribascarreira2024metabolicrewiringand pages 13-14, arribascarreira2024metabolicrewiringand pages 14-16, arribascarreira2024metabolicrewiringand pages 9-13)

3.2 Key chemical entities / metabolites (CHEBI-aligned) • Glycine (diagnostic and toxic mediator) (zhou2024naturalhistoryand pages 1-2, hirtum2024thebehavioralphenotype pages 1-2) • THF / 5,10-methylene-THF (downstream one-carbon product deficiency concept) (arribascarreira2024metabolicrewiringand pages 1-2, hove2024theroleof pages 3-5) • l-serine / d-serine (NMDA co-agonist biology; d-serine reduced in NKH) (hove2024theroleof pages 1-3) • Lipoic acid (cofactor biology via GCSH) (arribascarreira2024metabolicrewiringand pages 1-2, arribascarreira2023pathogenicvariantsingcshencoding pages 2-3) • Glutathione (redox buffering decreased in GLDC-deficient iPSC model) (arribascarreira2024metabolicrewiringand pages 14-16) • Guanidinoacetate (neurotoxic metabolite implicated) (arribascarreira2024metabolicrewiringand pages 14-16, hove2024theroleof pages 3-5) • Hippurate (benzoate conjugation product for glycine excretion) (hirtum2024thebehavioralphenotype pages 1-2, yuan2025theprecisemolecular pages 3-4)

Cellular components and subcellular localization Key processes localize to: • Mitochondria: GCS complex, lipoylation cycle (H-protein), PDH/2-KGDH lipoylation, mitochondrial one-carbon enzymes (e.g., SHMT2/MTHFD2) (arribascarreira2024metabolicrewiringand pages 1-2, arribascarreira2023pathogenicvariantsingcshencoding pages 2-3) • Cytosol: compensatory one-carbon flux (SHMT1/MTHFD1 upregulation in GLDC-deficient cells) (arribascarreira2024metabolicrewiringand pages 13-14) • Plasma membrane: glycine/glutamate transporters (GLYT1/2, GLAST) in patient-derived astrocytes (arribascarreira2024metabolicrewiringand pages 9-13)
Disease progression and stages (sequence of events)

5.1 Typical clinical sequence (severe neonatal form) Many patients present within hours to days after birth with poor feeding, profound hypotonia, apnea, hiccups, and severe myoclonic seizures progressing rapidly to coma. Survivors often develop intractable seizures and intellectual disability. (nyhan2023nonketotichyperglycinemia pages 1-2)

5.2 Heterogeneity and attenuated courses Attenuated NKH can present neonatally or later and can include treatable/absent epilepsy and variable developmental progress. In attenuated/intermediate-to-good cohorts, ADHD-like maladaptive behaviors occur frequently (reported in >2/3). (hirtum2024thebehavioralphenotype pages 1-2)

Phenotypic manifestations and links to mechanisms (HP-aligned)

Key phenotypes observed across cohorts and consistent with the mechanistic landscape include: • Developmental and epileptic encephalopathy / seizures / status epilepticus (NMDA/glycine receptor dysregulation; metabolic toxicity) (zhou2024naturalhistoryand pages 1-2, hove2024theroleof pages 5-6) • Hypotonia and lethargy (global metabolic/neurotransmitter disruption) (zhou2024naturalhistoryand pages 1-2) • Apnea/respiratory failure (brainstem glycinergic signaling and severe neonatal encephalopathy) (zhou2024naturalhistoryand pages 1-2, arribascarreira2024metabolicrewiringand pages 1-2) • Structural brain abnormalities including corpus callosum dysplasia/hypogenesis and white matter abnormalities (neurodevelopmental and metabolic mechanisms; possibly SGOC/epigenetic and glial differentiation effects) (zhou2024naturalhistoryand pages 1-2, nyhan2023nonketotichyperglycinemia pages 1-2) • Behavioral dysregulation (ADHD-like features) in attenuated NKH (mechanisms unclear; association with dextromethorphan use reported) (hirtum2024thebehavioralphenotype pages 1-2)

Recent developments (2023–2024 prioritized)

7.1 2024: Human cell models implicate SGOC rewiring and glial differentiation defects Patient-derived GLDC-deficient iPSC-to-astrocyte differentiation revealed: altered serine–glycine–one-carbon metabolism, reduced nucleotide pools, reduced glutathione (redox stress), altered proliferation/cell cycle, and a shift toward heterogeneous astrocyte/radial glial phenotypes with transporter changes. These findings provide a mechanistic bridge between the enzymatic defect and neurodevelopmental phenotypes beyond “glycine excitotoxicity.” (arribascarreira2024metabolicrewiringand pages 13-14, arribascarreira2024metabolicrewiringand pages 14-16)

7.2 2024: Expert reassessment challenges simplistic NMDA-overactivation model A 2024 critical reassessment highlights that d-serine deficiency complicates the assumption that elevated glycine necessarily overactivates NMDA receptors, and notes the lack of direct experimental proof for net NMDA over- vs under-activation in NKH models/organoids. (hove2024theroleof pages 1-3)

7.3 2023: “Variant NKH” via GCSH moonlighting links NKH to lipoate/PDH/2-KGDH defects Identification of pathogenic GCSH variants causing combined NKH and lipoate deficiency expands disease biology from a single metabolic block to coupled bioenergetic failure via impaired lipoylation of PDH/2-KGDH E2 subunits. (arribascarreira2023pathogenicvariantsingcshencoding pages 2-3, arribascarreira2023pathogenicvariantsingcshencoding pages 5-5)

Current applications and real-world implementations

8.1 Diagnostics (biochemical + genetic) Biochemical diagnosis uses plasma and CSF glycine and CSF:plasma glycine ratio; a commonly cited cutoff is ratio >0.08 (normal <0.04). (nyhan2023nonketotichyperglycinemia pages 1-2, zhou2024naturalhistoryand pages 1-2)

Recent cohort statistics (China; Frontiers in Neurology, published 14 Aug 2024, https://doi.org/10.3389/fneur.2024.1440883): median CSF glycine 135.2 μmol/L (range 6.3–546.3), median plasma glycine 998.2 μmol/L (range 75–3084), median CSF/plasma ratio 0.16 (range 0.03–0.60). (zhou2024naturalhistoryand pages 1-2)

Genetic confirmation commonly identifies GLDC and AMT variants; in the 2024 China cohort, GLDC variants were observed in 65% (13/20) and AMT in 35% (7/20). (zhou2024naturalhistoryand pages 1-2)

8.2 Standard-of-care: glycine reduction Sodium benzoate is a mainstay to lower glycine. In attenuated NKH management descriptions, benzoate “conjugates with glycine and is excreted in the urine as hippurate.” (hirtum2024thebehavioralphenotype pages 1-2)

Clinical targets commonly aim for plasma glycine ~120–300 μM. (hirtum2024thebehavioralphenotype pages 1-2, shelkowitz2022ketogenicdietas pages 1-2)

8.3 Dietary implementation: ketogenic diet (KD) KD is used clinically as an additional glycine-lowering strategy, described mechanistically as using glycine as a gluconeogenic precursor. (hirtum2024thebehavioralphenotype pages 1-2)

In a multi-center retrospective series (published 12 Dec 2022; https://doi.org/10.1186/s13023-022-02581-6), six infants switching from high-dose benzoate to KD + low-dose benzoate had ~28% lower plasma glycine on KD vs benzoate monotherapy; brain glycine by MRS was reduced but not normalized; half had seizure reduction. (shelkowitz2022ketogenicdietas pages 1-2)

8.4 Symptom-targeted neurotransmission modulation: dextromethorphan and ketamine NMDA antagonists (dextromethorphan, ketamine) are used in practice, often for refractory neonatal seizures/status epilepticus. (hove2024theroleof pages 5-6)

Evidence quality is limited. A 2024 expert review states: “Controlled clinical studies of dextromethorphan or ketamine… have never been done,” and “Today insufficient evidence exists to consider it a proven primary treatment.” (hove2024theroleof pages 1-3)

Safety and implementation considerations include complex pharmacology of dextromethorphan and potential behavioral effects in attenuated NKH cohorts, and concerns about chronic ketamine use. (hove2024theroleof pages 1-3, hirtum2024thebehavioralphenotype pages 1-2)

8.5 Medication cautions Sodium valproate is commonly discouraged because it “increases both CSF and plasma glycine level, leading to worsening of seizures.” (nyhan2023nonketotichyperglycinemia pages 2-3)

Natural history, epidemiology, and recent statistics

9.1 Incidence A 2024 NKH cohort paper cites worldwide incidence ~1/76,000 and higher prevalence in northern Finland (1:12,000), and Taiwan incidence 7.2/1,000,000. (zhou2024naturalhistoryand pages 1-2)

9.2 Symptom frequencies and outcomes (2024 cohort statistics) In the 2024 China series (n=20), 85% were neonatal-onset and 15% infantile-onset. Presenting features included seizures (15/20), lethargy (14/20), hypotonia (11/20), apnea (9/20). (zhou2024naturalhistoryand pages 1-2)

Outcome data were available for 18 cases: 9 died, with 8 deaths in the neonatal period; survivors had varying developmental disorders. The authors conclude glycine measures do not reliably predict prognosis, whereas MRI/EEG abnormalities may indicate poor outlook. (zhou2024naturalhistoryand pages 1-2)

Ontology-oriented annotation sets (starter mappings)

10.1 Genes/proteins (HGNC) • GLDC; AMT; GCSH; DLD; DLAT; DLST (arribascarreira2024metabolicrewiringand pages 1-2, arribascarreira2023pathogenicvariantsingcshencoding pages 5-5)

10.2 Candidate disrupted GO biological processes (examples) • Glycine catabolic process / glycine cleavage (GCS function) (arribascarreira2024metabolicrewiringand pages 1-2) • One-carbon metabolic process / folate-mediated one-carbon metabolism (5,10-methylene-THF generation; SGOC flux) (arribascarreira2024metabolicrewiringand pages 1-2) • Mitochondrial protein lipoylation (GCSH moonlighting; PDH/2-KGDH lipoylation) (arribascarreira2023pathogenicvariantsingcshencoding pages 2-3, arribascarreira2023pathogenicvariantsingcshencoding pages 5-5) • Regulation of cell cycle / cellular proliferation (iPSC model: proliferation/quiescence shifts) (arribascarreira2024metabolicrewiringand pages 14-16) • Response to oxidative stress / glutathione metabolic process (reduced glutathione) (arribascarreira2024metabolicrewiringand pages 14-16)

10.3 Cellular components (GO CC; examples) • Mitochondrial matrix / mitochondrion (GCS complex; lipoylation; mitochondrial one-carbon enzymes) (arribascarreira2024metabolicrewiringand pages 1-2, arribascarreira2023pathogenicvariantsingcshencoding pages 2-3) • Cytosol (compensatory cytosolic one-carbon enzymes) (arribascarreira2024metabolicrewiringand pages 13-14) • Plasma membrane transporter complexes (GLYT1/2, GLAST changes) (arribascarreira2024metabolicrewiringand pages 9-13)

10.4 Cell types (CL; examples) • Astrocyte-lineage cells / iPSC-derived astrocytes (altered differentiation and transport) (arribascarreira2024metabolicrewiringand pages 9-13) • Radial glia / neural progenitor cells (shift in lineage markers; proposed relevance of GCS expression in radial glia) (arribascarreira2024metabolicrewiringand pages 14-16)

10.5 Anatomy (UBERON; examples) • Brain/CNS, including cortex (NMDA co-agonism), brainstem/spinal cord (glycinergic receptor biology), white matter/basal ganglia regions affected on MRI/MRS (arribascarreira2024metabolicrewiringand pages 1-2, zhou2024naturalhistoryand pages 1-2) • Liver, kidney, lung as GCS-active tissues in adults (arribascarreira2024metabolicrewiringand pages 1-2)

10.6 Phenotypes (HP; examples) • Seizures, burst suppression/hypsarrhythmia (EEG) (zhou2024naturalhistoryand pages 1-2) • Hypotonia, lethargy, apnea (zhou2024naturalhistoryand pages 1-2) • Developmental delay/intellectual disability; behavioral abnormalities (hyperactivity/ADHD-like) (hirtum2024thebehavioralphenotype pages 1-2) • Corpus callosum abnormalities; white matter abnormalities (zhou2024naturalhistoryand pages 1-2)

Evidence items (selected, with URLs and dates)

A. Natural history/outcomes cohort • Zhou et al., “Natural history and outcome of nonketotic hyperglycinemia in China,” Frontiers in Neurology, published 14 Aug 2024. https://doi.org/10.3389/fneur.2024.1440883 (zhou2024naturalhistoryand pages 1-2)

B. Mechanistic human cellular model • Arribas-Carreira et al., “Metabolic Rewiring and Altered Glial Differentiation in an iPSC-Derived Astrocyte Model Derived from a Nonketotic Hyperglycinemia Patient,” Int J Mol Sci, published 28 Feb 2024. https://doi.org/10.3390/ijms25052814 (arribascarreira2024metabolicrewiringand pages 1-2, arribascarreira2024metabolicrewiringand pages 14-16)

C. Variant NKH / lipoylation biology • Arribas-Carreira et al., “Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined nonketotic hyperglycinemia and lipoate deficiency,” Human Molecular Genetics, published 2023 (issue dated Oct 2023). https://doi.org/10.1093/hmg/ddac246 (arribascarreira2023pathogenicvariantsingcshencoding pages 2-3, arribascarreira2023pathogenicvariantsingcshencoding pages 5-5) • Key pathway schematic image (Figure 1: H-protein cycle) (arribascarreira2023pathogenicvariantsingcshencoding media 0157c767)

D. Expert reassessment of NMDA antagonist therapy • Van Hove, “The role of NMDA-receptor type glutamatergic antagonists dextromethorphan or ketamine in the treatment of nonketotic hyperglycinemia: A critical reassessment,” Molecular Genetics and Metabolism, Nov 2024. https://doi.org/10.1016/j.ymgme.2024.108594 (hove2024theroleof pages 1-3, hove2024theroleof pages 3-5)

E. Attenuated phenotype and treatment framing • Van Hirtum et al., “The behavioral phenotype of children and adolescents with attenuated non-ketotic hyperglycinemia,” Orphanet J Rare Dis, Apr 2024. https://doi.org/10.1186/s13023-024-03172-3 (hirtum2024thebehavioralphenotype pages 1-2)

Gaps and expert interpretation

Despite mechanistic plausibility and widespread off-label clinical use of NMDA antagonists, the best available expert review (2024) concludes that controlled trials have not been done and evidence is insufficient to designate dextromethorphan/ketamine as proven primary therapies; by contrast, glycine reduction (benzoate and/or KD) has accumulating observational evidence for improved alertness and seizure control. (hove2024theroleof pages 1-3)

Recent iPSC-based disease modeling supports that NKH pathophysiology plausibly includes (and may substantially depend on) SGOC-driven limitations in nucleotide/redox metabolism and altered glial differentiation, suggesting that future therapies may need to target both neurotransmission and metabolic/one-carbon/bioenergetic biology. (arribascarreira2024metabolicrewiringand pages 14-16)

References

(nyhan2023nonketotichyperglycinemia pages 1-2): W. L. Nyhan, Georg F. Hoffmann, A. Al-aqeel, and B. Barshop. Nonketotic hyperglycinemia. Atlas of Inherited Metabolic Diseases, Jul 2023. URL: https://doi.org/10.1201/b15310-25, doi:10.1201/b15310-25. This article has 33 citations.
(zhou2024naturalhistoryand pages 1-2): Zhizi Zhou, Yanna Cai, Xiuzhen Li, Zongcai Liu, Minzhi Peng, Yunting Lin, Xiaojian Mao, Chunhua Zeng, Li Liu, and Wen Zhang. Natural history and outcome of nonketotic hyperglycinemia in china. Frontiers in Neurology, Aug 2024. URL: https://doi.org/10.3389/fneur.2024.1440883, doi:10.3389/fneur.2024.1440883. This article has 3 citations and is from a peer-reviewed journal.
(hirtum2024thebehavioralphenotype pages 1-2): Liesbet D. F. M. Van Hirtum, Tine Van Damme, Johan L. K. Van Hove, and Jean G. Steyaert. The behavioral phenotype of children and adolescents with attenuated non-ketotic hyperglycinemia, intermediate to good subtype. Orphanet Journal of Rare Diseases, Apr 2024. URL: https://doi.org/10.1186/s13023-024-03172-3, doi:10.1186/s13023-024-03172-3. This article has 4 citations and is from a peer-reviewed journal.
(arribascarreira2024metabolicrewiringand pages 1-2): Laura Arribas-Carreira, Margarita Castro, Fernando García, Rosa Navarrete, Irene Bravo-Alonso, Francisco Zafra, Magdalena Ugarte, Eva Richard, Belén Pérez, and Pilar Rodríguez-Pombo. Metabolic rewiring and altered glial differentiation in an ipsc-derived astrocyte model derived from a nonketotic hyperglycinemia patient. International Journal of Molecular Sciences, 25:2814, Feb 2024. URL: https://doi.org/10.3390/ijms25052814, doi:10.3390/ijms25052814. This article has 4 citations.
(hove2024theroleof pages 3-5): Johan L.K. Van Hove. The role of nmda-receptor type glutamatergic antagonists dextromethorphan or ketamine in the treatment of nonketotic hyperglycinemia: a critical reassessment. Molecular Genetics and Metabolism, 143(3):108594, Nov 2024. URL: https://doi.org/10.1016/j.ymgme.2024.108594, doi:10.1016/j.ymgme.2024.108594. This article has 8 citations and is from a peer-reviewed journal.
(hove2024theroleof pages 1-3): Johan L.K. Van Hove. The role of nmda-receptor type glutamatergic antagonists dextromethorphan or ketamine in the treatment of nonketotic hyperglycinemia: a critical reassessment. Molecular Genetics and Metabolism, 143(3):108594, Nov 2024. URL: https://doi.org/10.1016/j.ymgme.2024.108594, doi:10.1016/j.ymgme.2024.108594. This article has 8 citations and is from a peer-reviewed journal.
(arribascarreira2024metabolicrewiringand pages 13-14): Laura Arribas-Carreira, Margarita Castro, Fernando García, Rosa Navarrete, Irene Bravo-Alonso, Francisco Zafra, Magdalena Ugarte, Eva Richard, Belén Pérez, and Pilar Rodríguez-Pombo. Metabolic rewiring and altered glial differentiation in an ipsc-derived astrocyte model derived from a nonketotic hyperglycinemia patient. International Journal of Molecular Sciences, 25:2814, Feb 2024. URL: https://doi.org/10.3390/ijms25052814, doi:10.3390/ijms25052814. This article has 4 citations.
(arribascarreira2024metabolicrewiringand pages 14-16): Laura Arribas-Carreira, Margarita Castro, Fernando García, Rosa Navarrete, Irene Bravo-Alonso, Francisco Zafra, Magdalena Ugarte, Eva Richard, Belén Pérez, and Pilar Rodríguez-Pombo. Metabolic rewiring and altered glial differentiation in an ipsc-derived astrocyte model derived from a nonketotic hyperglycinemia patient. International Journal of Molecular Sciences, 25:2814, Feb 2024. URL: https://doi.org/10.3390/ijms25052814, doi:10.3390/ijms25052814. This article has 4 citations.
(arribascarreira2024metabolicrewiringand pages 9-13): Laura Arribas-Carreira, Margarita Castro, Fernando García, Rosa Navarrete, Irene Bravo-Alonso, Francisco Zafra, Magdalena Ugarte, Eva Richard, Belén Pérez, and Pilar Rodríguez-Pombo. Metabolic rewiring and altered glial differentiation in an ipsc-derived astrocyte model derived from a nonketotic hyperglycinemia patient. International Journal of Molecular Sciences, 25:2814, Feb 2024. URL: https://doi.org/10.3390/ijms25052814, doi:10.3390/ijms25052814. This article has 4 citations.
(arribascarreira2023pathogenicvariantsingcshencoding pages 2-3): Laura Arribas-Carreira, Cristina Dallabona, Michael A Swanson, Joseph Farris, Elsebet Østergaard, Konstantinos Tsiakas, Maja Hempel, Cecile Aquaviva-Bourdain, Stefanos Koutsoukos, Nicholas V Stence, Martina Magistrati, Elaine B Spector, Kathryn Kronquist, Mette Christensen, Helena G Karstensen, René G Feichtinger, Melanie T Achleitner, J Lawrence Merritt II, Belén Pérez, Magdalena Ugarte, Stephanie Grünewald, Anthony R Riela, Natalia Julve, Jean-Baptiste Arnoux, Kasturi Haldar, Claudia Donnini, René Santer, Allan M Lund, Johannes A Mayr, Pilar Rodriguez-Pombo, and Johan L K Van Hove. Pathogenic variants ingcshencoding the moonlighting h-protein cause combined nonketotic hyperglycinemia and lipoate deficiency. Human Molecular Genetics, 32(6):917-933, Oct 2023. URL: https://doi.org/10.1093/hmg/ddac246, doi:10.1093/hmg/ddac246. This article has 16 citations and is from a domain leading peer-reviewed journal.
(arribascarreira2023pathogenicvariantsingcshencoding pages 1-2): Laura Arribas-Carreira, Cristina Dallabona, Michael A Swanson, Joseph Farris, Elsebet Østergaard, Konstantinos Tsiakas, Maja Hempel, Cecile Aquaviva-Bourdain, Stefanos Koutsoukos, Nicholas V Stence, Martina Magistrati, Elaine B Spector, Kathryn Kronquist, Mette Christensen, Helena G Karstensen, René G Feichtinger, Melanie T Achleitner, J Lawrence Merritt II, Belén Pérez, Magdalena Ugarte, Stephanie Grünewald, Anthony R Riela, Natalia Julve, Jean-Baptiste Arnoux, Kasturi Haldar, Claudia Donnini, René Santer, Allan M Lund, Johannes A Mayr, Pilar Rodriguez-Pombo, and Johan L K Van Hove. Pathogenic variants ingcshencoding the moonlighting h-protein cause combined nonketotic hyperglycinemia and lipoate deficiency. Human Molecular Genetics, 32(6):917-933, Oct 2023. URL: https://doi.org/10.1093/hmg/ddac246, doi:10.1093/hmg/ddac246. This article has 16 citations and is from a domain leading peer-reviewed journal.
(arribascarreira2023pathogenicvariantsingcshencoding media 0157c767): Laura Arribas-Carreira, Cristina Dallabona, Michael A Swanson, Joseph Farris, Elsebet Østergaard, Konstantinos Tsiakas, Maja Hempel, Cecile Aquaviva-Bourdain, Stefanos Koutsoukos, Nicholas V Stence, Martina Magistrati, Elaine B Spector, Kathryn Kronquist, Mette Christensen, Helena G Karstensen, René G Feichtinger, Melanie T Achleitner, J Lawrence Merritt II, Belén Pérez, Magdalena Ugarte, Stephanie Grünewald, Anthony R Riela, Natalia Julve, Jean-Baptiste Arnoux, Kasturi Haldar, Claudia Donnini, René Santer, Allan M Lund, Johannes A Mayr, Pilar Rodriguez-Pombo, and Johan L K Van Hove. Pathogenic variants ingcshencoding the moonlighting h-protein cause combined nonketotic hyperglycinemia and lipoate deficiency. Human Molecular Genetics, 32(6):917-933, Oct 2023. URL: https://doi.org/10.1093/hmg/ddac246, doi:10.1093/hmg/ddac246. This article has 16 citations and is from a domain leading peer-reviewed journal.
(arribascarreira2023pathogenicvariantsingcshencoding pages 5-5): Laura Arribas-Carreira, Cristina Dallabona, Michael A Swanson, Joseph Farris, Elsebet Østergaard, Konstantinos Tsiakas, Maja Hempel, Cecile Aquaviva-Bourdain, Stefanos Koutsoukos, Nicholas V Stence, Martina Magistrati, Elaine B Spector, Kathryn Kronquist, Mette Christensen, Helena G Karstensen, René G Feichtinger, Melanie T Achleitner, J Lawrence Merritt II, Belén Pérez, Magdalena Ugarte, Stephanie Grünewald, Anthony R Riela, Natalia Julve, Jean-Baptiste Arnoux, Kasturi Haldar, Claudia Donnini, René Santer, Allan M Lund, Johannes A Mayr, Pilar Rodriguez-Pombo, and Johan L K Van Hove. Pathogenic variants ingcshencoding the moonlighting h-protein cause combined nonketotic hyperglycinemia and lipoate deficiency. Human Molecular Genetics, 32(6):917-933, Oct 2023. URL: https://doi.org/10.1093/hmg/ddac246, doi:10.1093/hmg/ddac246. This article has 16 citations and is from a domain leading peer-reviewed journal.
(yuan2025theprecisemolecular pages 3-4): Fang Yuan, Xiaozhen Song, Rongrong Yin, Xiaoping Lan, Jingjing Sun, Xiaojun Tang, Wuhen Xu, Shaohua Hu, Man Xiao, Hong Zhang, Wenhao Weng, Yuanfeng Zhang, and Shengnan Wu. The precise molecular diagnosis of novel gldc compound heterozygous variants highlights the benefits for a chinese family with nonketotic hyperglycinemia. Jun 2025. URL: https://doi.org/10.1016/j.ymgmr.2025.101209, doi:10.1016/j.ymgmr.2025.101209. This article has 1 citations.
(hove2024theroleof pages 5-6): Johan L.K. Van Hove. The role of nmda-receptor type glutamatergic antagonists dextromethorphan or ketamine in the treatment of nonketotic hyperglycinemia: a critical reassessment. Molecular Genetics and Metabolism, 143(3):108594, Nov 2024. URL: https://doi.org/10.1016/j.ymgme.2024.108594, doi:10.1016/j.ymgme.2024.108594. This article has 8 citations and is from a peer-reviewed journal.
(shelkowitz2022ketogenicdietas pages 1-2): Emily Shelkowitz, Russell P. Saneto, Walla Al-Hertani, Charlotte M. A. Lubout, Nicholas V. Stence, Mark S. Brown, Patrick Long, Diana Walleigh, Julie A. Nelson, Francisco E. Perez, Dennis W. W. Shaw, Emma J. Michl, and Johan L. K. Van Hove. Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels. Orphanet Journal of Rare Diseases, Dec 2022. URL: https://doi.org/10.1186/s13023-022-02581-6, doi:10.1186/s13023-022-02581-6. This article has 19 citations and is from a peer-reviewed journal.
(nyhan2023nonketotichyperglycinemia pages 2-3): W. L. Nyhan, Georg F. Hoffmann, A. Al-aqeel, and B. Barshop. Nonketotic hyperglycinemia. Atlas of Inherited Metabolic Diseases, Jul 2023. URL: https://doi.org/10.1201/b15310-25, doi:10.1201/b15310-25. This article has 33 citations.

Ask OpenScientist

OpenScientist Report

Classifications

Subtypes

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Treatments

Biochemical Markers

Source YAML

References & Deep Research

References

Deep Research

Disease Pathophysiology Research Template

Target Disease

Research Objectives

Required Information

1. Core Pathophysiology

2. Key Molecular Players

3. Biological Processes (for GO annotation)

4. Cellular Components

5. Disease Progression

6. Phenotypic Manifestations

Citation Requirements

Output Format