Neonatal Epileptic Encephalopathy Due to Glutaminase Deficiency

Mendelian MONDO:0032678 Pathograph 10 Show in embeddings browser hereditary disease inborn error of metabolism Epileptic Encephalopathy

The severe, neonatal-onset end of the GLS glutaminase-deficiency spectrum: an autosomal recessive inborn error of amino acid metabolism caused by biallelic loss-of-function variants in GLS, the gene encoding phosphate-activated glutaminase. Because glutaminase hydrolyzes glutamine to glutamate, complete enzyme deficiency both blocks glutamine catabolism — so glutamine accumulates in blood and cerebrospinal fluid — and removes the neuronal route to glutamate, the principal excitatory neurotransmitter of the central nervous system. Affected neonates present in the first days of life with therapy-refractory seizures and status epilepticus on a burst-suppression EEG, respiratory insufficiency requiring ventilation, and structural brain abnormalities (simplified gyral pattern, diffuse volume loss, cerebral edema, and cystic lesions resembling those of urea cycle defects). Outcome is usually death in the neonatal period or progression to a persistent vegetative state, though at least one reported patient survived to age six. Named "developmental and epileptic encephalopathy, 71" (DEE71) in OMIM/MONDO and "neonatal epileptic encephalopathy due to glutaminase deficiency" in Orphanet, this entity sits under the MONDO grouping class glutaminase deficiency (MONDO:0600001) alongside spastic ataxia-dysarthria due to glutaminase deficiency (MONDO:0034146). It is allelic to, but clinically and mechanistically distinct from, the milder repeat-expansion form Global Developmental Delay, Progressive Ataxia, and Elevated Glutamine (MONDO:0032733 / OMIM 618412), and from the mechanistically opposite de novo gain-of-function (hypermorphic) GLS disorder characterized by glutamate excess (MONDO:0032685 / OMIM 618339).

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1
Definitions
1
Inheritance
10
Pathophys.
13
Phenotypes
2
Hypotheses
2
Gaps
10
Pathograph
1
Genes
2
Medical Actions
3
References
🏷

Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE
ICIMD (Inherited Metabolic Disorders)
glu gln and asp asn
📘

Definitions

1
Biochemical-plus-genetic diagnosis of neonatal glutaminase deficiency
Suspect this entity in a neonate with therapy-refractory seizures on a burst-suppression EEG and respiratory insufficiency whose plasma and cerebrospinal-fluid amino acids show elevated glutamine (with increased serum alanine) but a normal ammonia — a urea-cycle-like profile without hyperammonemia — particularly when brain MRI shows cystic lesions or a simplified gyral pattern. Confirmation is by demonstrating biallelic loss-of-function GLS variants. Unlike the repeat-expansion form, the coding lesions of this entity are detectable by exome sequencing.
DIAGNOSTIC_CRITERIA GLS glutaminase deficiency (biallelic coding loss-of-function form)
Show evidence (2 references)
PMID:41865506 SUPPORT Human Clinical
"biochemical features characteristic of urea cycle disorders, while ammonia levels remained within the normal range"
Establishes the discriminating biochemical signature — urea-cycle-like amino acids with normal ammonia — on which the diagnostic suspicion rests.
PMID:39559284 SUPPORT Human Clinical
"access to exome sequencing is a significant advantage in developing countries"
Confirms that exome sequencing is the diagnostic modality for this coding form, in contrast to the repeat-expansion form that exome misses.
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Autosomal recessive; affected infants carry biallelic loss-of-function GLS variants, either homozygous (consanguineous or founder families) or compound heterozygous.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:30575854 SUPPORT Human Clinical
"We identified a novel autosomal recessive neurometabolic disorder of loss of function of glutaminase that leads to lethal early neonatal encephalopathy."
States the autosomal recessive inheritance of the disorder.
◈

Mechanistic Hypotheses

2
Glutamate Deficiency (Loss-of-Function) Model
glutamate_deficiency ALTERNATIVE
Evidence balance 1 support
Because glutaminase produces glutamate — the principal excitatory neurotransmitter and the precursor of GABA — from astrocyte-derived glutamine, complete glutaminase deficiency is proposed to deprive neurons of glutamate and so disturb excitatory and inhibitory neurotransmission, producing the refractory seizures and the failure of central respiratory regulation. This was the framing of the original report. Its weakness is that it does not readily account for the cerebral edema and the cystic brain lesions.
Pathograph links
Impaired Glutamine Catabolism and Glutamine Accumulation -> Impaired Glutamatergic Neurotransmission INDIRECT UNKNOWN INTERMEDIATES Loss of neuronal glutamate synthesis impairs glutamatergic signaling.
Impaired Glutamatergic Neurotransmission -> Neonatal Epileptic Encephalopathy INDIRECT UNKNOWN INTERMEDIATES Disturbed excitatory/inhibitory balance contributes to refractory seizures.
Impaired Glutamatergic Neurotransmission -> Central Respiratory Failure INDIRECT UNKNOWN INTERMEDIATES Loss of glutamatergic signaling in brainstem respiratory networks is proposed to underlie the respiratory insufficiency.
Show evidence (1 reference)
PMID:30575854 SUPPORT Human Clinical
"We theorize that the potential reduction of glutamate and the excess of glutamine were a probable cause of the described physiological and structural abnormalities of the central nervous system."
The original authors advance reduced glutamate as a probable cause, but explicitly as a theory and jointly with glutamine excess — so it supports the model only partially.
Glutamine Accumulation Neurotoxicity Model
glutamine_neurotoxicity EMERGING
Evidence balance 1 support
The alternative model holds that accumulated glutamine is itself the neurotoxic species, by the astrocytic-osmolyte route established in hepatic encephalopathy and urea cycle defects. In this entity it is supported by elevated cerebrospinal-fluid glutamine, a urea-cycle-like amino acid profile with normal ammonia, and brain MRI cystic lesions resembling those of urea cycle defects. It accounts for the cerebral edema that the glutamate-deficiency model does not. The two models are not mutually exclusive, and the original report invoked both.
Pathograph links
Impaired Glutamine Catabolism and Glutamine Accumulation -> Glutamine Neurotoxicity INDIRECT UNKNOWN INTERMEDIATES Accumulated glutamine exerts a direct neurotoxic effect.
Glutamine Neurotoxicity -> Structural Brain Injury INDIRECT UNKNOWN INTERMEDIATES Glutamine-driven osmotic stress contributes to cerebral edema and volume loss.
Show evidence (1 reference)
PMID:41865506 SUPPORT Human Clinical
"The biochemical and clinical findings in our patients support a key role for elevated glutamine in the neuropathogenesis"
Directly supports elevated glutamine as a key driver of the neuropathogenesis.
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Discussions and Knowledge Gaps

2
Should the neonatal-onset lethal form of GLS glutaminase deficiency be a separate Disease entry from the milder repeat-expansion form (Global Developmental Delay, Progressive Ataxia, and Elevated Glutamine)?
INTERPRETATION RESOLVED neonatal-vs-gdpag-lump-split
Recent literature frames GLS glutaminase deficiency as a single disorder with a broad phenotypic spectrum, from early-onset global developmental delay to lethal early neonatal encephalopathy. Against that, the two ends carry distinct OMIM and MONDO identities (618328 / MONDO:0032678 versus 618412 / MONDO:0032733) and mechanistically distinct lesions: biallelic coding loss-of-function producing complete enzymatic deficiency (this entry) versus a noncoding 5' untranslated region GCA-repeat expansion producing only a partial deficiency.
Posed by curator Resolved 2026-08-07T00:00:00Z
Resolution: Curator decision: keep split, mirroring the decision already recorded on the repeat-expansion entry (raised by ai4c-reviewer on PR #7138). This entry is scoped to the biallelic coding loss-of-function form. The shared upstream mechanism is captured by both entries citing the same enzymatic chain, and the MONDO grouping class glutaminase deficiency (MONDO:0600001) is the natural anchor for a future dismech Grouping over the GLS entities.
Show evidence (1 reference)
PMID:41865506 SUPPORT Human Clinical
"Glutaminase deficiency has recently been identified as a novel inherited metabolic disorder with a broad phenotypic spectrum ranging from early-onset global developmental delay to lethal early neonatal encephalopathy"
Documents the spectrum framing that motivates the lump/split question; the curator resolution keeps the neonatal form as a distinct entry aligned to its own OMIM/MONDO identity.
Is "developmental and epileptic encephalopathy, 71" an appropriate primary label for this entity, given that the disorder is a metabolic glutaminase deficiency rather than a primary channelopathy-style DEE?
INTERPRETATION OPEN mondo-dee71-label-vs-mechanism
MONDO:0032678 carries the OMIM DEE-series label, which places the entity in a numbered epilepsy series and makes the metabolic mechanism invisible in the name. Orphanet:557064 instead calls it "neonatal epileptic encephalopathy due to glutaminase deficiency", which is mechanistically transparent; MONDO retains that as an exact synonym and classifies the term under both MONDO:0100062 (genetic developmental and epileptic encephalopathy) and MONDO:0600001 (glutaminase deficiency). This dismech entry uses the Orphanet phrasing as its name and preferred_term while binding term.label to the canonical MONDO label, per the repository convention that preferred_term may be more informative than the ontology label.
Posed by curator
⚙

Pathophysiology

10
Biallelic GLS Loss-of-Function Variants
The primary genomic lesion is a biallelic (homozygous or compound heterozygous) coding loss-of-function lesion in GLS. Reported alleles include the frameshift p.(Asp232Glufs*2), the nonsense p.(Gln81*), the missense p.(Arg272Lys), and the homozygous missense variants p.(Gly392Arg) and p.(Leu344Pro). Unlike the noncoding 5' untranslated region GCA-repeat expansion that causes the milder repeat-expansion form, these coding lesions are detectable by exome sequencing.
Downstream
Complete Phosphate-Activated Glutaminase Deficiency Biallelic loss-of-function alleles abolish glutaminase activity.
Show evidence (2 references)
PMID:30575854 SUPPORT Human Clinical
"We identified a homozygous frameshift variant p.(Asp232Glufs*2) in GLS in the first family, as well as compound heterozygous variants p.(Gln81*) and p.(Arg272Lys) in GLS in the second family."
Documents the causal biallelic coding GLS lesions in the two originally reported families.
PMID:41865506 SUPPORT Human Clinical
"Exome sequencing identified a homozygous, unreported missense variant in GLS"
Documents two further homozygous missense GLS lesions in a second cohort of neonatal-onset patients.
Complete Phosphate-Activated Glutaminase Deficiency
Biallelic loss-of-function alleles produce a complete deficiency of phosphate-activated glutaminase, the mitochondrial enzyme (EC 3.5.1.2) that hydrolyzes glutamine to glutamate and ammonia. This is the primary enzymatic defect. The completeness of the enzymatic block distinguishes this entity from the partial/relative deficiency of the repeat-expansion form and is the proximate reason for the far more severe, neonatal-onset phenotype.
glutaminase activity GO:0004359 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves glutaminase activity (GO:0004359), qualified as loss of function. GO:0004359 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
Downstream
Impaired Glutamine Catabolism and Glutamine Accumulation Loss of glutaminase activity blocks hydrolysis of glutamine to glutamate.
Organelle Stress and Mitochondrial Bioenergetic Failure Loss of the glutaminase-supplied anaplerotic route into the TCA cycle is associated with organelle stress and impaired mitochondrial respiration in patient fibroblasts.
Show evidence (2 references)
PMID:30575854 SUPPORT Human Clinical
"All 3 variants probably lead to a loss of function and thus glutaminase deficiency."
Establishes loss of glutaminase function as the enzymatic consequence of the identified GLS variants.
PMID:41865506 SUPPORT In Vitro
"Functional studies of patient fibroblasts and recombinantly expressed mutant glutaminase protein, demonstrated a complete glutaminase deficiency."
Confirms by direct functional assay in patient fibroblasts and recombinant protein that the enzymatic deficiency is complete, not partial.
Impaired Glutamine Catabolism and Glutamine Accumulation
With glutaminase activity abolished, hydrolysis of glutamine to glutamate fails, so glutamine accumulates in blood and cerebrospinal fluid while the glutaminase-dependent route to glutamate is lost. The biochemical profile — elevated glutamine and alanine with normal ammonia — mimics that of a urea cycle disorder and is the diagnostic clue.
Glutamate Deficiency (Loss-of-Function) Model Glutamine Accumulation Neurotoxicity Model
L-glutamine catabolic process GO:0006543 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased L-glutamine catabolic process (GO:0006543). GO:0006543 is a biological process from the Gene Ontology. ↓ DECREASED L-glutamate biosynthetic process GO:0097054 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased L-glutamate biosynthetic process (GO:0097054). GO:0097054 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Glutamine Neurotoxicity Accumulated glutamine exerts a direct neurotoxic effect. Glutamine Accumulation Neurotoxicity Model
Impaired Glutamatergic Neurotransmission Loss of neuronal glutamate synthesis impairs glutamatergic signaling. Glutamate Deficiency (Loss-of-Function) Model
Show evidence (2 references)
PMID:30575854 SUPPORT Human Clinical
"Indeed, glutamine was increased in affected children"
Documents glutamine accumulation as the direct biochemical consequence of the glutaminase block.
PMID:41865506 SUPPORT Human Clinical
"elevated glutamine concentrations in cerebrospinal fluid and increased serum alanine and glutamine levels, biochemical features characteristic of urea cycle disorders, while ammonia levels remained within the normal range"
Documents the urea-cycle-like biochemical signature (high glutamine and alanine, normal ammonia) produced by the glutaminase block.
Glutamine Neurotoxicity
Accumulated glutamine is held to be directly neurotoxic, by the same route that operates in hepatic encephalopathy and urea cycle defects, where glutamine taken up by astrocytes acts as an osmolyte and drives astrocytic swelling and cerebral edema. In glutaminase deficiency this model is supported by elevated cerebrospinal-fluid glutamine together with brain MRI cystic lesions that resemble those of urea cycle defects — and it explains the cerebral edema, which a pure glutamate-deficiency model does not.
Glutamine Accumulation Neurotoxicity Model
astrocyte CL:0000127 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves astrocyte (CL:0000127). CL:0000127 is a cell type from the Cell Ontology. neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
Downstream
Structural Brain Injury Glutamine-driven osmotic stress contributes to cerebral edema and volume loss. Glutamine Accumulation Neurotoxicity Model
Show evidence (2 references)
PMID:41865506 SUPPORT Human Clinical
"support a key role for elevated glutamine in the neuropathogenesis of both glutaminase-deficient patients and individuals with hepatic encephalopathy and/or urea cycle defects"
Directly supports glutamine accumulation as a driver of the neuropathology, linking it to the established glutamine-mediated injury of hepatic encephalopathy and urea cycle defects.
PMID:41865506 SUPPORT Human Clinical
"brain magnetic resonance imaging revealed cystic lesions resembling the neuroimaging findings typically observed in patients with urea cycle defects"
The urea-cycle-defect-like neuroimaging phenotype is the structural correlate predicted by a glutamine-osmolyte mechanism.
Impaired Glutamatergic Neurotransmission
Neuronal glutaminase supplies glutamate — the principal excitatory neurotransmitter of the central nervous system and the precursor of GABA — from astrocyte-derived glutamine via the glutamate-glutamine cycle. Complete glutaminase deficiency is proposed to deprive neurons of this route, disturbing excitatory and downstream inhibitory neurotransmission and contributing to the refractory seizures and to the failure of central respiratory regulation.
Glutamate Deficiency (Loss-of-Function) Model
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology. astrocyte CL:0000127 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves astrocyte (CL:0000127). CL:0000127 is a cell type from the Cell Ontology.
glutamate secretion, neurotransmission GO:0061535 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased glutamate secretion, neurotransmission (GO:0061535). GO:0061535 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Neonatal Epileptic Encephalopathy Disturbed excitatory/inhibitory balance contributes to refractory seizures. Glutamate Deficiency (Loss-of-Function) Model
Central Respiratory Failure Loss of glutamatergic signaling in brainstem respiratory networks is proposed to underlie the respiratory insufficiency. Glutamate Deficiency (Loss-of-Function) Model
Show evidence (2 references)
PMID:30575854 SUPPORT Human Clinical
"The GLS gene encodes glutaminase (Enzyme Commission 3.5.1.2), which plays a major role in the conversion of glutamine into glutamate, the main excitatory neurotransmitter of the central nervous system."
Establishes the enzymatic role of GLS in supplying glutamate, the neurotransmitter whose loss underpins this arm of the model.
PMID:30575854 SUPPORT Human Clinical
"We theorize that the potential reduction of glutamate and the excess of glutamine were a probable cause of the described physiological and structural abnormalities of the central nervous system."
The authors advance reduced glutamate as a probable contributor, but explicitly frame it as a theory rather than a demonstrated mechanism — hence PARTIAL.
Organelle Stress and Mitochondrial Bioenergetic Failure
Patient-derived fibroblasts show a broad cell-biological phenotype beyond the amino acid disturbance: nuclear dysmorphism, lysosomal dysfunction with glycogen accumulation, endoplasmic reticulum stress, Golgi disruption, and mitochondrial fragmentation, accompanied by impaired mitochondrial respiratory function. This is consistent with loss of the glutaminase-derived anaplerotic supply of glutamate to alpha-ketoglutarate and the TCA cycle, and adds a bioenergetic dimension to the neurotransmitter-centred models.
fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
response to endoplasmic reticulum stress GO:0034976 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased response to endoplasmic reticulum stress (GO:0034976). GO:0034976 is a biological process from the Gene Ontology. ↑ INCREASED mitochondrial fission GO:0000266 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased mitochondrial fission (GO:0000266). GO:0000266 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Structural Brain Injury Bioenergetic failure is proposed to compound the neuronal injury, though the fibroblast findings are not themselves a measurement in brain.
Show evidence (1 reference)
PMID:41865506 SUPPORT In Vitro
"patient-derived fibroblasts exhibited pronounced ultrastructural abnormalities, including nuclear dysmorphisms, lysosomal dysfunction with glycogen accumulation, ER stress, Golgi disruption, and mitochondrial fragmentation, along with altered cellular bioenergetics characterized by impaired..."
Documents the organelle-stress and bioenergetic phenotype in patient fibroblasts.
Neonatal Epileptic Encephalopathy
Therapy-refractory seizures beginning in the first days of life, with status epilepticus and a burst-suppression EEG pattern — the defining clinical syndrome of this entity.
Downstream
Neonatal Death or Persistent Vegetative State The encephalopathy is usually lethal in the neonatal period.
Show evidence (1 reference)
PMID:30575854 SUPPORT Human Clinical
"lethal, therapy-refractory early neonatal seizures with status epilepticus and suppression bursts"
Documents the refractory neonatal seizure phenotype with status epilepticus and burst suppression.
Central Respiratory Failure
Respiratory insufficiency requiring ventilatory support, with apnea, is a cardinal and often terminal feature. The original report singles out respiratory regulation as one of the physiological functions for which GLS is required.
Downstream
Neonatal Death or Persistent Vegetative State Respiratory failure is a proximate cause of neonatal death.
Show evidence (1 reference)
PMID:30575854 SUPPORT Human Clinical
"This inborn error of metabolism underlines the importance of GLS for appropriate glutamine homeostasis and respiratory regulation, signal transduction, and survival."
Identifies respiratory regulation as a GLS-dependent physiological function that fails in this disorder.
Structural Brain Injury
Structural brain abnormalities comprise a simplified gyral pattern, diffuse volume loss, cerebral edema, and cystic lesions resembling those seen in urea cycle defects. The simplified gyral pattern implies a prenatal, developmental component to the injury, not purely postnatal seizure-related damage.
Downstream
Neonatal Death or Persistent Vegetative State Severe structural brain injury underlies the poor neurological outcome.
Show evidence (1 reference)
PMID:30575854 SUPPORT Human Clinical
"simplified gyral structures, diffuse volume loss of the brain, and cerebral edema"
Documents the structural brain abnormalities of the disorder.
Neonatal Death or Persistent Vegetative State
Outcome is death within the neonatal period in the originally reported families, or progression to a persistent vegetative state; survival beyond infancy is exceptional but documented.
Show evidence (2 references)
PMID:30575854 SUPPORT Human Clinical
"A total of 4 infants from 2 unrelated families, each of whom died less than 40 days after birth, were included."
Documents the lethal neonatal outcome in all four originally reported infants.
PMID:41865506 SUPPORT Human Clinical
"progressing to either a persistent vegetative state or early death"
Documents the two outcome trajectories in a second cohort.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Neonatal Epileptic Encephalopathy Due to Glutaminase Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

13
Metabolism 2
Cerebral edema HP:0002181 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral edema (HP:0002181). HP:0002181 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30575854 SUPPORT Human Clinical
"simplified gyral structures, diffuse volume loss of the brain, and cerebral edema"
Documents cerebral edema.
Hyperglutaminemia HP:0003217 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperglutaminemia (HP:0003217). HP:0003217 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30575854 SUPPORT Human Clinical
"Indeed, glutamine was increased in affected children"
Documents elevated glutamine in affected infants.
Nervous System 2
EEG with burst suppression HP:0010851 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is EEG with burst suppression (HP:0010851). HP:0010851 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41865506 SUPPORT Human Clinical
"neonatal onset refractory burst-suppression epileptic encephalopathy and respiratory failure"
Documents the burst-suppression EEG pattern in the second reported cohort.
Cerebral atrophy HP:0002059 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral atrophy (HP:0002059). HP:0002059 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30575854 SUPPORT Human Clinical
"simplified gyral structures, diffuse volume loss of the brain, and cerebral edema"
Documents diffuse cerebral volume loss.
Respiratory 2
Respiratory failure HP:0002878 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Respiratory failure (HP:0002878). HP:0002878 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41865506 SUPPORT Human Clinical
"neonatal onset refractory burst-suppression epileptic encephalopathy and respiratory failure"
Documents respiratory failure as a presenting feature.
Apnea HP:0002104 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Apnea (HP:0002104). HP:0002104 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39559284 SUPPORT Human Clinical
"neonatal encephalopathy characterized by refractory seizures and significant apnea resulting from glutaminase deficiency"
Documents significant apnea in a further reported neonate.
Other 7
Neonatal seizures VERY_FREQUENT HP:0032807 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neonatal seizure (HP:0032807), qualified as temporality acute. HP:0032807 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (1 reference)
PMID:30575854 SUPPORT Human Clinical
"4 children who each had lethal, therapy-refractory early neonatal seizures with status epilepticus and suppression bursts"
All four originally reported infants had refractory early neonatal seizures, supporting a VERY_FREQUENT frequency band (4/4).
Status epilepticus HP:0002133 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Status epilepticus (HP:0002133). HP:0002133 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30575854 SUPPORT Human Clinical
"early neonatal seizures with status epilepticus and suppression bursts"
Documents status epilepticus in the reported infants.
Simplified gyral pattern HP:0009879 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Simplified gyral pattern (HP:0009879). HP:0009879 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30575854 SUPPORT Human Clinical
"simplified gyral structures, diffuse volume loss of the brain, and cerebral edema"
Documents the simplified gyral pattern.
Increased CSF glutamine concentration HP:0500197 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased CSF glutamine concentration (HP:0500197). HP:0500197 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41865506 SUPPORT Human Clinical
"Metabolic investigations demonstrated elevated glutamine concentrations in cerebrospinal fluid"
Documents elevated CSF glutamine.
Increased CSF glycine concentration HP:0500230 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased CSF glycine concentration (HP:0500230). HP:0500230 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39559284 SUPPORT Human Clinical
"elevated levels of glutamine and glycine in the cerebrospinal fluid"
Documents elevated CSF glycine alongside CSF glutamine in a reported case.
Hyperalaninemia HP:0003348 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperalaninemia (HP:0003348). HP:0003348 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41865506 SUPPORT Human Clinical
"increased serum alanine and glutamine levels, biochemical features characteristic of urea cycle disorders"
Documents increased serum alanine.
Vegetative state HP:0031358 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vegetative state (HP:0031358). HP:0031358 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41865506 SUPPORT Human Clinical
"progressing to either a persistent vegetative state or early death"
Documents progression to a persistent vegetative state as one of the two reported outcomes.
🧬

Genetic Associations

1
GLS
Gene: GLS hgnc:4331 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GLS (hgnc:4331). hgnc:4331 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:30575854 SUPPORT Human Clinical
"We identified a homozygous frameshift variant p.(Asp232Glufs*2) in GLS in the first family, as well as compound heterozygous variants p.(Gln81*) and p.(Arg272Lys) in GLS in the second family."
Identifies the causal biallelic GLS lesions in the two original families.
PMID:41865506 SUPPORT Human Clinical
"p.Gly392Arg) in both siblings from family 1, and a novel homozygous missense variant"
Identifies two further causal homozygous GLS missense alleles.
PMID:31603991 SUPPORT Human Clinical
"GLS; GLS; EC 3.5.1.2 n = 9 bi‐allelic, AR"
Classifies GLS glutaminase deficiency as a bi-allelic, autosomal recessive inborn error of glutamate metabolism.
💊

Medical Actions

2
Supportive and Symptomatic Care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Management is supportive and symptomatic; no disease-modifying therapy is established. Care comprises intensive-care support with mechanical ventilation for respiratory insufficiency and antiseizure medication, which is characteristically ineffective — the seizures are therapy-refractory.
Show evidence (1 reference)
PMID:30575854 SUPPORT Human Clinical
"4 children who each had lethal, therapy-refractory early neonatal seizures with status epilepticus and suppression bursts, respiratory insufficiency"
Documents that the seizures do not respond to antiseizure therapy and that the course was lethal despite intensive support, which is why management remains supportive rather than disease-modifying.
Genetic Counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Genetic counseling for this autosomal recessive disorder, including recurrence-risk counseling and discussion of options for future pregnancies. Molecular diagnosis by exome sequencing enables this even when the outcome for the index child is fatal.
Show evidence (1 reference)
PMID:39559284 SUPPORT Human Clinical
"it was possible to offer genetic counseling and recommendations for future pregnancies following exome sequencing"
Documents genetic counseling as the actionable outcome of molecular diagnosis in a fatal case.
🔬

Biochemical Markers

4
Plasma glutamine (INCREASED)
Context: Elevated circulating glutamine is the diagnostic biochemical marker, reflecting the blocked hydrolysis of glutamine to glutamate. Reported z scores in the original series were 3.2 and 11.7.
Show evidence (1 reference)
PMID:30575854 SUPPORT Human Clinical
"glutamine was increased in affected children (available z scores, 3.2 and 11.7)"
Quantifies the elevation of glutamine in affected infants.
CSF glutamine (INCREASED)
Context: Cerebrospinal-fluid glutamine is elevated. Because the proposed neurotoxic species is glutamine itself, the CSF measurement is mechanistically more informative than the plasma value.
Show evidence (1 reference)
PMID:41865506 SUPPORT Human Clinical
"elevated glutamine concentrations in cerebrospinal fluid"
Documents the elevated CSF glutamine.
Serum alanine (INCREASED)
Context: Serum alanine is increased, contributing to a biochemical picture characteristic of urea cycle disorders.
Show evidence (1 reference)
PMID:41865506 SUPPORT Human Clinical
"increased serum alanine and glutamine levels"
Documents the increase in serum alanine.
Blood ammonia (NORMAL)
Context: Ammonia is characteristically normal. This is the key discriminator from the urea cycle disorders that the rest of the biochemical profile (high glutamine, high alanine) and the cystic brain MRI lesions otherwise mimic — a normal ammonia does not exclude this diagnosis.
Show evidence (1 reference)
PMID:41865506 SUPPORT Human Clinical
"biochemical features characteristic of urea cycle disorders, while ammonia levels remained within the normal range"
Documents normal ammonia despite the otherwise urea-cycle-like profile.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Ultra-rare. Fewer than ten affected individuals are reported: four infants from two unrelated families in the original 2019 series, three infants from two further unrelated families in the 2026 series, and additional single case reports.
Show evidence (2 references)
PMID:30575854 SUPPORT Human Clinical
"A total of 4 infants from 2 unrelated families"
Documents the size of the original reported cohort.
PMID:41865506 SUPPORT Human Clinical
"We describe three infants from two unrelated families"
Documents the size of the second reported cohort.
{ }

Source YAML

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name: Neonatal Epileptic Encephalopathy Due to Glutaminase Deficiency
creation_date: "2026-08-07T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: neonatal epileptic encephalopathy due to glutaminase deficiency
  term:
    id: MONDO:0032678
    label: developmental and epileptic encephalopathy, 71
parents:
- hereditary disease
- inborn error of metabolism
- Epileptic Encephalopathy
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  icimd_category:
  - classification_value: glu_gln_and_asp_asn
    notes: >-
      ICIMD (Ferreira et al. 2021, PMID:33340416): group "Disorders of
      glutamate/glutamine and aspartate/asparagine metabolism" under category
      "Disorders of amino acid metabolism". GLS glutaminase deficiency is a
      disorder of glutamine catabolism.
description: >
  The severe, neonatal-onset end of the GLS glutaminase-deficiency spectrum: an
  autosomal recessive inborn error of amino acid metabolism caused by biallelic
  loss-of-function variants in GLS, the gene encoding phosphate-activated
  glutaminase. Because glutaminase hydrolyzes glutamine to glutamate, complete
  enzyme deficiency both blocks glutamine catabolism — so glutamine accumulates
  in blood and cerebrospinal fluid — and removes the neuronal route to glutamate,
  the principal excitatory neurotransmitter of the central nervous system.
  Affected neonates present in the first days of life with therapy-refractory
  seizures and status epilepticus on a burst-suppression EEG, respiratory
  insufficiency requiring ventilation, and structural brain abnormalities
  (simplified gyral pattern, diffuse volume loss, cerebral edema, and cystic
  lesions resembling those of urea cycle defects). Outcome is usually death in
  the neonatal period or progression to a persistent vegetative state, though at
  least one reported patient survived to age six.

  Named "developmental and epileptic encephalopathy, 71" (DEE71) in OMIM/MONDO
  and "neonatal epileptic encephalopathy due to glutaminase deficiency" in
  Orphanet, this entity sits under the MONDO grouping class glutaminase
  deficiency (MONDO:0600001) alongside spastic ataxia-dysarthria due to
  glutaminase deficiency (MONDO:0034146). It is allelic to, but clinically and
  mechanistically distinct from, the milder repeat-expansion form Global
  Developmental Delay, Progressive Ataxia, and Elevated Glutamine
  (MONDO:0032733 / OMIM 618412), and from the mechanistically opposite de novo
  gain-of-function (hypermorphic) GLS disorder characterized by glutamate excess
  (MONDO:0032685 / OMIM 618339).
references:
- reference: PMID:30575854
  title: "Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy."
- reference: PMID:41865506
  title: "Glutaminase deficiency provides insight to the role of glutamine accumulation and neurotoxicity."
- reference: PMID:31603991
  title: "Inborn errors of enzymes in glutamate metabolism."

pathophysiology:
- name: Biallelic GLS Loss-of-Function Variants
  biological_scale: MOLECULAR
  description: >
    The primary genomic lesion is a biallelic (homozygous or compound
    heterozygous) coding loss-of-function lesion in GLS. Reported alleles include
    the frameshift p.(Asp232Glufs*2), the nonsense p.(Gln81*), the missense
    p.(Arg272Lys), and the homozygous missense variants p.(Gly392Arg) and
    p.(Leu344Pro). Unlike the noncoding 5' untranslated region GCA-repeat
    expansion that causes the milder repeat-expansion form, these coding lesions
    are detectable by exome sequencing.
  evidence:
  - reference: PMID:30575854
    reference_title: "Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a homozygous frameshift variant p.(Asp232Glufs*2) in GLS in the first family, as well as compound heterozygous variants p.(Gln81*) and p.(Arg272Lys) in GLS in the second family."
    explanation: >
      Documents the causal biallelic coding GLS lesions in the two originally
      reported families.
  - reference: PMID:41865506
    reference_title: "Glutaminase deficiency provides insight to the role of glutamine accumulation and neurotoxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing identified a homozygous, unreported missense variant in GLS"
    explanation: >
      Documents two further homozygous missense GLS lesions in a second cohort
      of neonatal-onset patients.
  downstream:
  - target: Complete Phosphate-Activated Glutaminase Deficiency
    description: Biallelic loss-of-function alleles abolish glutaminase activity.
    causal_link_type: DIRECT

- name: Complete Phosphate-Activated Glutaminase Deficiency
  biological_scale: MOLECULAR
  description: >
    Biallelic loss-of-function alleles produce a complete deficiency of
    phosphate-activated glutaminase, the mitochondrial enzyme (EC 3.5.1.2) that
    hydrolyzes glutamine to glutamate and ammonia. This is the primary enzymatic
    defect. The completeness of the enzymatic block distinguishes this entity
    from the partial/relative deficiency of the repeat-expansion form and is the
    proximate reason for the far more severe, neonatal-onset phenotype.
  molecular_functions:
  - preferred_term: glutaminase activity
    term:
      id: GO:0004359
      label: glutaminase activity
    modifier: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:30575854
    reference_title: "Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 3 variants probably lead to a loss of function and thus glutaminase deficiency."
    explanation: >
      Establishes loss of glutaminase function as the enzymatic consequence of
      the identified GLS variants.
  - reference: PMID:41865506
    reference_title: "Glutaminase deficiency provides insight to the role of glutamine accumulation and neurotoxicity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional studies of patient fibroblasts and recombinantly expressed mutant glutaminase protein, demonstrated a complete glutaminase deficiency."
    explanation: >
      Confirms by direct functional assay in patient fibroblasts and recombinant
      protein that the enzymatic deficiency is complete, not partial.
  downstream:
  - target: Impaired Glutamine Catabolism and Glutamine Accumulation
    description: Loss of glutaminase activity blocks hydrolysis of glutamine to glutamate.
    causal_link_type: DIRECT
  - target: Organelle Stress and Mitochondrial Bioenergetic Failure
    description: >-
      Loss of the glutaminase-supplied anaplerotic route into the TCA cycle is
      associated with organelle stress and impaired mitochondrial respiration in
      patient fibroblasts.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES

- name: Impaired Glutamine Catabolism and Glutamine Accumulation
  biological_scale: MOLECULAR
  description: >
    With glutaminase activity abolished, hydrolysis of glutamine to glutamate
    fails, so glutamine accumulates in blood and cerebrospinal fluid while the
    glutaminase-dependent route to glutamate is lost. The biochemical profile —
    elevated glutamine and alanine with normal ammonia — mimics that of a urea
    cycle disorder and is the diagnostic clue.
  biological_processes:
  - preferred_term: L-glutamine catabolic process
    term:
      id: GO:0006543
      label: L-glutamine catabolic process
    modifier: DECREASED
  - preferred_term: L-glutamate biosynthetic process
    term:
      id: GO:0097054
      label: L-glutamate biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:30575854
    reference_title: "Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Indeed, glutamine was increased in affected children"
    explanation: >
      Documents glutamine accumulation as the direct biochemical consequence of
      the glutaminase block.
  - reference: PMID:41865506
    reference_title: "Glutaminase deficiency provides insight to the role of glutamine accumulation and neurotoxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "elevated glutamine concentrations in cerebrospinal fluid and increased serum alanine and glutamine levels, biochemical features characteristic of urea cycle disorders, while ammonia levels remained within the normal range"
    explanation: >
      Documents the urea-cycle-like biochemical signature (high glutamine and
      alanine, normal ammonia) produced by the glutaminase block.
  downstream:
  - target: Glutamine Neurotoxicity
    description: Accumulated glutamine exerts a direct neurotoxic effect.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - glutamine_neurotoxicity
  - target: Impaired Glutamatergic Neurotransmission
    description: Loss of neuronal glutamate synthesis impairs glutamatergic signaling.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - glutamate_deficiency

- name: Glutamine Neurotoxicity
  biological_scale: CELLULAR
  description: >
    Accumulated glutamine is held to be directly neurotoxic, by the same route
    that operates in hepatic encephalopathy and urea cycle defects, where
    glutamine taken up by astrocytes acts as an osmolyte and drives astrocytic
    swelling and cerebral edema. In glutaminase deficiency this model is
    supported by elevated cerebrospinal-fluid glutamine together with brain MRI
    cystic lesions that resemble those of urea cycle defects — and it explains
    the cerebral edema, which a pure glutamate-deficiency model does not.
  cell_types:
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:41865506
    reference_title: "Glutaminase deficiency provides insight to the role of glutamine accumulation and neurotoxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "support a key role for elevated glutamine in the neuropathogenesis of both glutaminase-deficient patients and individuals with hepatic encephalopathy and/or urea cycle defects"
    explanation: >
      Directly supports glutamine accumulation as a driver of the
      neuropathology, linking it to the established glutamine-mediated injury of
      hepatic encephalopathy and urea cycle defects.
  - reference: PMID:41865506
    reference_title: "Glutaminase deficiency provides insight to the role of glutamine accumulation and neurotoxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "brain magnetic resonance imaging revealed cystic lesions resembling the neuroimaging findings typically observed in patients with urea cycle defects"
    explanation: >
      The urea-cycle-defect-like neuroimaging phenotype is the structural
      correlate predicted by a glutamine-osmolyte mechanism.
  downstream:
  - target: Structural Brain Injury
    description: Glutamine-driven osmotic stress contributes to cerebral edema and volume loss.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - glutamine_neurotoxicity

- name: Impaired Glutamatergic Neurotransmission
  biological_scale: CELLULAR
  description: >
    Neuronal glutaminase supplies glutamate — the principal excitatory
    neurotransmitter of the central nervous system and the precursor of GABA —
    from astrocyte-derived glutamine via the glutamate-glutamine cycle. Complete
    glutaminase deficiency is proposed to deprive neurons of this route,
    disturbing excitatory and downstream inhibitory neurotransmission and
    contributing to the refractory seizures and to the failure of central
    respiratory regulation.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  biological_processes:
  - preferred_term: glutamate secretion, neurotransmission
    term:
      id: GO:0061535
      label: glutamate secretion, neurotransmission
    modifier: DECREASED
  evidence:
  - reference: PMID:30575854
    reference_title: "Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The GLS gene encodes glutaminase (Enzyme Commission 3.5.1.2), which plays a major role in the conversion of glutamine into glutamate, the main excitatory neurotransmitter of the central nervous system."
    explanation: >
      Establishes the enzymatic role of GLS in supplying glutamate, the
      neurotransmitter whose loss underpins this arm of the model.
  - reference: PMID:30575854
    reference_title: "Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We theorize that the potential reduction of glutamate and the excess of glutamine were a probable cause of the described physiological and structural abnormalities of the central nervous system."
    explanation: >
      The authors advance reduced glutamate as a probable contributor, but
      explicitly frame it as a theory rather than a demonstrated mechanism —
      hence PARTIAL.
  downstream:
  - target: Neonatal Epileptic Encephalopathy
    description: Disturbed excitatory/inhibitory balance contributes to refractory seizures.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - glutamate_deficiency
  - target: Central Respiratory Failure
    description: >-
      Loss of glutamatergic signaling in brainstem respiratory networks is
      proposed to underlie the respiratory insufficiency.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - glutamate_deficiency

- name: Organelle Stress and Mitochondrial Bioenergetic Failure
  biological_scale: CELLULAR
  description: >
    Patient-derived fibroblasts show a broad cell-biological phenotype beyond the
    amino acid disturbance: nuclear dysmorphism, lysosomal dysfunction with
    glycogen accumulation, endoplasmic reticulum stress, Golgi disruption, and
    mitochondrial fragmentation, accompanied by impaired mitochondrial
    respiratory function. This is consistent with loss of the glutaminase-derived
    anaplerotic supply of glutamate to alpha-ketoglutarate and the TCA cycle, and
    adds a bioenergetic dimension to the neurotransmitter-centred models.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: response to endoplasmic reticulum stress
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
    modifier: INCREASED
  - preferred_term: mitochondrial fission
    term:
      id: GO:0000266
      label: mitochondrial fission
    modifier: INCREASED
  evidence:
  - reference: PMID:41865506
    reference_title: "Glutaminase deficiency provides insight to the role of glutamine accumulation and neurotoxicity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "patient-derived fibroblasts exhibited pronounced ultrastructural abnormalities, including nuclear dysmorphisms, lysosomal dysfunction with glycogen accumulation, ER stress, Golgi disruption, and mitochondrial fragmentation, along with altered cellular bioenergetics characterized by impaired mitochondrial respiratory function"
    explanation: >
      Documents the organelle-stress and bioenergetic phenotype in patient
      fibroblasts.
  downstream:
  - target: Structural Brain Injury
    description: >-
      Bioenergetic failure is proposed to compound the neuronal injury, though
      the fibroblast findings are not themselves a measurement in brain.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES

- name: Neonatal Epileptic Encephalopathy
  biological_scale: ORGANISM
  description: >
    Therapy-refractory seizures beginning in the first days of life, with status
    epilepticus and a burst-suppression EEG pattern — the defining clinical
    syndrome of this entity.
  evidence:
  - reference: PMID:30575854
    reference_title: "Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "lethal, therapy-refractory early neonatal seizures with status epilepticus and suppression bursts"
    explanation: >
      Documents the refractory neonatal seizure phenotype with status
      epilepticus and burst suppression.
  downstream:
  - target: Neonatal Death or Persistent Vegetative State
    description: The encephalopathy is usually lethal in the neonatal period.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES

- name: Central Respiratory Failure
  biological_scale: ORGANISM
  description: >
    Respiratory insufficiency requiring ventilatory support, with apnea, is a
    cardinal and often terminal feature. The original report singles out
    respiratory regulation as one of the physiological functions for which GLS
    is required.
  evidence:
  - reference: PMID:30575854
    reference_title: "Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This inborn error of metabolism underlines the importance of GLS for appropriate glutamine homeostasis and respiratory regulation, signal transduction, and survival."
    explanation: >
      Identifies respiratory regulation as a GLS-dependent physiological
      function that fails in this disorder.
  downstream:
  - target: Neonatal Death or Persistent Vegetative State
    description: Respiratory failure is a proximate cause of neonatal death.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES

- name: Structural Brain Injury
  biological_scale: TISSUE
  description: >
    Structural brain abnormalities comprise a simplified gyral pattern, diffuse
    volume loss, cerebral edema, and cystic lesions resembling those seen in urea
    cycle defects. The simplified gyral pattern implies a prenatal, developmental
    component to the injury, not purely postnatal seizure-related damage.
  evidence:
  - reference: PMID:30575854
    reference_title: "Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "simplified gyral structures, diffuse volume loss of the brain, and cerebral edema"
    explanation: >
      Documents the structural brain abnormalities of the disorder.
  downstream:
  - target: Neonatal Death or Persistent Vegetative State
    description: Severe structural brain injury underlies the poor neurological outcome.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES

- name: Neonatal Death or Persistent Vegetative State
  biological_scale: ORGANISM
  description: >
    Outcome is death within the neonatal period in the originally reported
    families, or progression to a persistent vegetative state; survival beyond
    infancy is exceptional but documented.
  evidence:
  - reference: PMID:30575854
    reference_title: "Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 4 infants from 2 unrelated families, each of whom died less than 40 days after birth, were included."
    explanation: >
      Documents the lethal neonatal outcome in all four originally reported
      infants.
  - reference: PMID:41865506
    reference_title: "Glutaminase deficiency provides insight to the role of glutamine accumulation and neurotoxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressing to either a persistent vegetative state or early death"
    explanation: >
      Documents the two outcome trajectories in a second cohort.

phenotypes:
- name: Neonatal seizures
  category: Neurologic
  description: >
    Therapy-refractory seizures with onset in the first days of life.
  phenotype_term:
    preferred_term: Neonatal seizure
    term:
      id: HP:0032807
      label: Neonatal seizure
    temporality: ACUTE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:30575854
    reference_title: "Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "4 children who each had lethal, therapy-refractory early neonatal seizures with status epilepticus and suppression bursts"
    explanation: >
      All four originally reported infants had refractory early neonatal
      seizures, supporting a VERY_FREQUENT frequency band (4/4).

- name: Status epilepticus
  category: Neurologic
  description: >
    Status epilepticus accompanied the refractory neonatal seizures.
  phenotype_term:
    preferred_term: Status epilepticus
    term:
      id: HP:0002133
      label: Status epilepticus
  evidence:
  - reference: PMID:30575854
    reference_title: "Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "early neonatal seizures with status epilepticus and suppression bursts"
    explanation: >
      Documents status epilepticus in the reported infants.

- name: EEG with burst suppression
  category: Neurologic
  description: >
    A burst-suppression EEG pattern accompanies the neonatal seizures and is
    reported in both independent case series.
  phenotype_term:
    preferred_term: EEG with burst suppression
    term:
      id: HP:0010851
      label: EEG with burst suppression
  evidence:
  - reference: PMID:41865506
    reference_title: "Glutaminase deficiency provides insight to the role of glutamine accumulation and neurotoxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neonatal onset refractory burst-suppression epileptic encephalopathy and respiratory failure"
    explanation: >
      Documents the burst-suppression EEG pattern in the second reported cohort.

- name: Respiratory failure
  category: Respiratory
  description: >
    Respiratory insufficiency requiring ventilatory support, a cardinal and often
    terminal feature.
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  evidence:
  - reference: PMID:41865506
    reference_title: "Glutaminase deficiency provides insight to the role of glutamine accumulation and neurotoxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neonatal onset refractory burst-suppression epileptic encephalopathy and respiratory failure"
    explanation: >
      Documents respiratory failure as a presenting feature.

- name: Apnea
  category: Respiratory
  description: >
    Significant apnea was a presenting feature in an independently reported
    neonate.
  phenotype_term:
    preferred_term: Apnea
    term:
      id: HP:0002104
      label: Apnea
  evidence:
  - reference: PMID:39559284
    reference_title: "Neonatal Encephalopathy due to Glutaminase Deficiency in a Neonate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neonatal encephalopathy characterized by refractory seizures and significant apnea resulting from glutaminase deficiency"
    explanation: >
      Documents significant apnea in a further reported neonate.

- name: Simplified gyral pattern
  category: Neurologic
  description: >
    Simplified gyral structures on neuroimaging, implying a prenatal
    developmental component to the brain injury.
  phenotype_term:
    preferred_term: Simplified gyral pattern
    term:
      id: HP:0009879
      label: Simplified gyral pattern
  evidence:
  - reference: PMID:30575854
    reference_title: "Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "simplified gyral structures, diffuse volume loss of the brain, and cerebral edema"
    explanation: >
      Documents the simplified gyral pattern.

- name: Cerebral atrophy
  category: Neurologic
  description: >
    Diffuse volume loss of the brain on neuroimaging.
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  evidence:
  - reference: PMID:30575854
    reference_title: "Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "simplified gyral structures, diffuse volume loss of the brain, and cerebral edema"
    explanation: >
      Documents diffuse cerebral volume loss.

- name: Cerebral edema
  category: Neurologic
  description: >
    Cerebral edema, the structural finding most consistent with a
    glutamine-osmolyte mechanism.
  phenotype_term:
    preferred_term: Cerebral edema
    term:
      id: HP:0002181
      label: Cerebral edema
  evidence:
  - reference: PMID:30575854
    reference_title: "Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "simplified gyral structures, diffuse volume loss of the brain, and cerebral edema"
    explanation: >
      Documents cerebral edema.

- name: Hyperglutaminemia
  category: Metabolic
  description: >
    Elevated circulating glutamine, the biochemical hallmark of glutaminase
    deficiency.
  phenotype_term:
    preferred_term: Hyperglutaminemia
    term:
      id: HP:0003217
      label: Hyperglutaminemia
  evidence:
  - reference: PMID:30575854
    reference_title: "Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Indeed, glutamine was increased in affected children"
    explanation: >
      Documents elevated glutamine in affected infants.

- name: Increased CSF glutamine concentration
  category: Metabolic
  description: >
    Elevated cerebrospinal-fluid glutamine, mirroring the pattern of urea cycle
    disorders and central to the glutamine-neurotoxicity model.
  phenotype_term:
    preferred_term: Increased CSF glutamine concentration
    term:
      id: HP:0500197
      label: Increased CSF glutamine concentration
  evidence:
  - reference: PMID:41865506
    reference_title: "Glutaminase deficiency provides insight to the role of glutamine accumulation and neurotoxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Metabolic investigations demonstrated elevated glutamine concentrations in cerebrospinal fluid"
    explanation: >
      Documents elevated CSF glutamine.

- name: Increased CSF glycine concentration
  category: Metabolic
  description: >
    Elevated cerebrospinal-fluid glycine accompanied the elevated CSF glutamine
    in an independently reported neonate.
  phenotype_term:
    preferred_term: Increased CSF glycine concentration
    term:
      id: HP:0500230
      label: Increased CSF glycine concentration
  evidence:
  - reference: PMID:39559284
    reference_title: "Neonatal Encephalopathy due to Glutaminase Deficiency in a Neonate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "elevated levels of glutamine and glycine in the cerebrospinal fluid"
    explanation: >
      Documents elevated CSF glycine alongside CSF glutamine in a reported case.

- name: Hyperalaninemia
  category: Metabolic
  description: >
    Increased serum alanine, part of the urea-cycle-like biochemical signature.
  phenotype_term:
    preferred_term: Hyperalaninemia
    term:
      id: HP:0003348
      label: Hyperalaninemia
  evidence:
  - reference: PMID:41865506
    reference_title: "Glutaminase deficiency provides insight to the role of glutamine accumulation and neurotoxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "increased serum alanine and glutamine levels, biochemical features characteristic of urea cycle disorders"
    explanation: >
      Documents increased serum alanine.

- name: Vegetative state
  category: Neurologic
  description: >
    Survivors of the acute neonatal presentation may progress to a persistent
    vegetative state rather than dying in the neonatal period.
  phenotype_term:
    preferred_term: Vegetative state
    term:
      id: HP:0031358
      label: Vegetative state
  evidence:
  - reference: PMID:41865506
    reference_title: "Glutaminase deficiency provides insight to the role of glutamine accumulation and neurotoxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressing to either a persistent vegetative state or early death"
    explanation: >
      Documents progression to a persistent vegetative state as one of the two
      reported outcomes.

biochemical:
- name: Plasma glutamine
  presence: INCREASED
  context: >
    Elevated circulating glutamine is the diagnostic biochemical marker,
    reflecting the blocked hydrolysis of glutamine to glutamate. Reported z
    scores in the original series were 3.2 and 11.7.
  biomarker_term:
    preferred_term: L-glutamine
    term:
      id: CHEBI:28300
      label: glutamine
  evidence:
  - reference: PMID:30575854
    reference_title: "Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "glutamine was increased in affected children (available z scores, 3.2 and 11.7)"
    explanation: >
      Quantifies the elevation of glutamine in affected infants.

- name: CSF glutamine
  presence: INCREASED
  context: >
    Cerebrospinal-fluid glutamine is elevated. Because the proposed neurotoxic
    species is glutamine itself, the CSF measurement is mechanistically more
    informative than the plasma value.
  biomarker_term:
    preferred_term: L-glutamine
    term:
      id: CHEBI:28300
      label: glutamine
  evidence:
  - reference: PMID:41865506
    reference_title: "Glutaminase deficiency provides insight to the role of glutamine accumulation and neurotoxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "elevated glutamine concentrations in cerebrospinal fluid"
    explanation: >
      Documents the elevated CSF glutamine.

- name: Serum alanine
  presence: INCREASED
  context: >
    Serum alanine is increased, contributing to a biochemical picture
    characteristic of urea cycle disorders.
  biomarker_term:
    preferred_term: L-alanine
    term:
      id: CHEBI:16977
      label: L-alanine
  evidence:
  - reference: PMID:41865506
    reference_title: "Glutaminase deficiency provides insight to the role of glutamine accumulation and neurotoxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "increased serum alanine and glutamine levels"
    explanation: >
      Documents the increase in serum alanine.

- name: Blood ammonia
  presence: NORMAL
  context: >
    Ammonia is characteristically normal. This is the key discriminator from the
    urea cycle disorders that the rest of the biochemical profile (high
    glutamine, high alanine) and the cystic brain MRI lesions otherwise mimic —
    a normal ammonia does not exclude this diagnosis.
  evidence:
  - reference: PMID:41865506
    reference_title: "Glutaminase deficiency provides insight to the role of glutamine accumulation and neurotoxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biochemical features characteristic of urea cycle disorders, while ammonia levels remained within the normal range"
    explanation: >
      Documents normal ammonia despite the otherwise urea-cycle-like profile.

definitions:
- name: Biochemical-plus-genetic diagnosis of neonatal glutaminase deficiency
  definition_type: DIAGNOSTIC_CRITERIA
  description: >-
    Suspect this entity in a neonate with therapy-refractory seizures on a
    burst-suppression EEG and respiratory insufficiency whose plasma and
    cerebrospinal-fluid amino acids show elevated glutamine (with increased
    serum alanine) but a normal ammonia — a urea-cycle-like profile without
    hyperammonemia — particularly when brain MRI shows cystic lesions or a
    simplified gyral pattern. Confirmation is by demonstrating biallelic
    loss-of-function GLS variants. Unlike the repeat-expansion form, the coding
    lesions of this entity are detectable by exome sequencing.
  scope: GLS glutaminase deficiency (biallelic coding loss-of-function form)
  evidence:
  - reference: PMID:41865506
    reference_title: "Glutaminase deficiency provides insight to the role of glutamine accumulation and neurotoxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biochemical features characteristic of urea cycle disorders, while ammonia levels remained within the normal range"
    explanation: >
      Establishes the discriminating biochemical signature — urea-cycle-like
      amino acids with normal ammonia — on which the diagnostic suspicion rests.
  - reference: PMID:39559284
    reference_title: "Neonatal Encephalopathy due to Glutaminase Deficiency in a Neonate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "access to exome sequencing is a significant advantage in developing countries"
    explanation: >
      Confirms that exome sequencing is the diagnostic modality for this coding
      form, in contrast to the repeat-expansion form that exome misses.

genetic:
- name: GLS
  gene_term:
    preferred_term: GLS
    term:
      id: hgnc:4331
      label: GLS
  relationship_type: CAUSATIVE
  notes: >
    Biallelic coding loss-of-function lesions in GLS cause this entity. Reported
    alleles are the homozygous frameshift p.(Asp232Glufs*2); compound
    heterozygous p.(Gln81*) and p.(Arg272Lys); and the homozygous missense
    variants p.(Gly392Arg) (NM_014905.5:c.1174G>A) and p.(Leu344Pro)
    (NM_014905.5:c.1031T>C). GLS encodes phosphate-activated (kidney-type)
    glutaminase, EC 3.5.1.2. Contrast the milder allelic entity Global
    Developmental Delay, Progressive Ataxia, and Elevated Glutamine, caused by a
    noncoding 5' untranslated region GCA-repeat expansion producing only a
    partial deficiency.
  evidence:
  - reference: PMID:30575854
    reference_title: "Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a homozygous frameshift variant p.(Asp232Glufs*2) in GLS in the first family, as well as compound heterozygous variants p.(Gln81*) and p.(Arg272Lys) in GLS in the second family."
    explanation: >
      Identifies the causal biallelic GLS lesions in the two original families.
  - reference: PMID:41865506
    reference_title: "Glutaminase deficiency provides insight to the role of glutamine accumulation and neurotoxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "p.Gly392Arg) in both siblings from family 1, and a novel homozygous missense variant"
    explanation: >
      Identifies two further causal homozygous GLS missense alleles.
  - reference: PMID:31603991
    reference_title: "Inborn errors of enzymes in glutamate metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GLS; GLS; EC 3.5.1.2 n = 9 bi‐allelic, AR"
    explanation: >
      Classifies GLS glutaminase deficiency as a bi-allelic, autosomal recessive
      inborn error of glutamate metabolism.

inheritance:
- name: Autosomal recessive inheritance
  description: >
    Autosomal recessive; affected infants carry biallelic loss-of-function GLS
    variants, either homozygous (consanguineous or founder families) or compound
    heterozygous.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:30575854
    reference_title: "Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a novel autosomal recessive neurometabolic disorder of loss of function of glutaminase that leads to lethal early neonatal encephalopathy."
    explanation: >
      States the autosomal recessive inheritance of the disorder.

prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >
    Ultra-rare. Fewer than ten affected individuals are reported: four infants
    from two unrelated families in the original 2019 series, three infants from
    two further unrelated families in the 2026 series, and additional single case
    reports.
  evidence:
  - reference: PMID:30575854
    reference_title: "Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 4 infants from 2 unrelated families"
    explanation: >
      Documents the size of the original reported cohort.
  - reference: PMID:41865506
    reference_title: "Glutaminase deficiency provides insight to the role of glutamine accumulation and neurotoxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe three infants from two unrelated families"
    explanation: >
      Documents the size of the second reported cohort.

treatments:
- name: Supportive and Symptomatic Care
  description: >
    Management is supportive and symptomatic; no disease-modifying therapy is
    established. Care comprises intensive-care support with mechanical
    ventilation for respiratory insufficiency and antiseizure medication, which
    is characteristically ineffective — the seizures are therapy-refractory.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:30575854
    reference_title: "Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "4 children who each had lethal, therapy-refractory early neonatal seizures with status epilepticus and suppression bursts, respiratory insufficiency"
    explanation: >
      Documents that the seizures do not respond to antiseizure therapy and that
      the course was lethal despite intensive support, which is why management
      remains supportive rather than disease-modifying.

- name: Genetic Counseling
  description: >
    Genetic counseling for this autosomal recessive disorder, including
    recurrence-risk counseling and discussion of options for future pregnancies.
    Molecular diagnosis by exome sequencing enables this even when the outcome
    for the index child is fatal.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:39559284
    reference_title: "Neonatal Encephalopathy due to Glutaminase Deficiency in a Neonate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "it was possible to offer genetic counseling and recommendations for future pregnancies following exome sequencing"
    explanation: >
      Documents genetic counseling as the actionable outcome of molecular
      diagnosis in a fatal case.

mechanistic_hypotheses:
- hypothesis_group_id: glutamate_deficiency
  hypothesis_label: Glutamate Deficiency (Loss-of-Function) Model
  status: ALTERNATIVE
  description: >
    Because glutaminase produces glutamate — the principal excitatory
    neurotransmitter and the precursor of GABA — from astrocyte-derived
    glutamine, complete glutaminase deficiency is proposed to deprive neurons of
    glutamate and so disturb excitatory and inhibitory neurotransmission,
    producing the refractory seizures and the failure of central respiratory
    regulation. This was the framing of the original report. Its weakness is that
    it does not readily account for the cerebral edema and the cystic brain
    lesions.
  evidence:
  - reference: PMID:30575854
    reference_title: "Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We theorize that the potential reduction of glutamate and the excess of glutamine were a probable cause of the described physiological and structural abnormalities of the central nervous system."
    explanation: >
      The original authors advance reduced glutamate as a probable cause, but
      explicitly as a theory and jointly with glutamine excess — so it supports
      the model only partially.
- hypothesis_group_id: glutamine_neurotoxicity
  hypothesis_label: Glutamine Accumulation Neurotoxicity Model
  status: EMERGING
  description: >
    The alternative model holds that accumulated glutamine is itself the
    neurotoxic species, by the astrocytic-osmolyte route established in hepatic
    encephalopathy and urea cycle defects. In this entity it is supported by
    elevated cerebrospinal-fluid glutamine, a urea-cycle-like amino acid profile
    with normal ammonia, and brain MRI cystic lesions resembling those of urea
    cycle defects. It accounts for the cerebral edema that the
    glutamate-deficiency model does not. The two models are not mutually
    exclusive, and the original report invoked both.
  evidence:
  - reference: PMID:41865506
    reference_title: "Glutaminase deficiency provides insight to the role of glutamine accumulation and neurotoxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The biochemical and clinical findings in our patients support a key role for elevated glutamine in the neuropathogenesis"
    explanation: >
      Directly supports elevated glutamine as a key driver of the
      neuropathogenesis.

discussions:
- discussion_id: neonatal-vs-gdpag-lump-split
  kind: INTERPRETATION
  status: RESOLVED
  prompt: >-
    Should the neonatal-onset lethal form of GLS glutaminase deficiency be a
    separate Disease entry from the milder repeat-expansion form (Global
    Developmental Delay, Progressive Ataxia, and Elevated Glutamine)?
  rationale: >-
    Recent literature frames GLS glutaminase deficiency as a single disorder with
    a broad phenotypic spectrum, from early-onset global developmental delay to
    lethal early neonatal encephalopathy. Against that, the two ends carry
    distinct OMIM and MONDO identities (618328 / MONDO:0032678 versus 618412 /
    MONDO:0032733) and mechanistically distinct lesions: biallelic coding
    loss-of-function producing complete enzymatic deficiency (this entry) versus
    a noncoding 5' untranslated region GCA-repeat expansion producing only a
    partial deficiency.
  resolution_note: >-
    Curator decision: keep split, mirroring the decision already recorded on the
    repeat-expansion entry (raised by ai4c-reviewer on PR #7138). This entry is
    scoped to the biallelic coding loss-of-function form. The shared upstream
    mechanism is captured by both entries citing the same enzymatic chain, and
    the MONDO grouping class glutaminase deficiency (MONDO:0600001) is the
    natural anchor for a future dismech Grouping over the GLS entities.
  posed_by: curator
  resolved_date: "2026-08-07T00:00:00Z"
  evidence:
  - reference: PMID:41865506
    reference_title: "Glutaminase deficiency provides insight to the role of glutamine accumulation and neurotoxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Glutaminase deficiency has recently been identified as a novel inherited metabolic disorder with a broad phenotypic spectrum ranging from early-onset global developmental delay to lethal early neonatal encephalopathy"
    explanation: >-
      Documents the spectrum framing that motivates the lump/split question; the
      curator resolution keeps the neonatal form as a distinct entry aligned to
      its own OMIM/MONDO identity.

- discussion_id: mondo-dee71-label-vs-mechanism
  kind: INTERPRETATION
  status: OPEN
  prompt: >-
    Is "developmental and epileptic encephalopathy, 71" an appropriate primary
    label for this entity, given that the disorder is a metabolic glutaminase
    deficiency rather than a primary channelopathy-style DEE?
  rationale: >-
    MONDO:0032678 carries the OMIM DEE-series label, which places the entity in a
    numbered epilepsy series and makes the metabolic mechanism invisible in the
    name. Orphanet:557064 instead calls it "neonatal epileptic encephalopathy due
    to glutaminase deficiency", which is mechanistically transparent; MONDO
    retains that as an exact synonym and classifies the term under both
    MONDO:0100062 (genetic developmental and epileptic encephalopathy) and
    MONDO:0600001 (glutaminase deficiency). This dismech entry uses the Orphanet
    phrasing as its name and preferred_term while binding term.label to the
    canonical MONDO label, per the repository convention that preferred_term may
    be more informative than the ontology label.
  posed_by: curator

notes: >
  Terminology: this entity appears in the literature and in ontologies under
  several names — "developmental and epileptic encephalopathy, 71" (DEE71,
  EIEE71; OMIM 618328, MONDO:0032678), "neonatal epileptic encephalopathy due to
  glutaminase deficiency" (Orphanet:557064), and descriptively as the severe or
  lethal neonatal end of the glutaminase-deficiency spectrum. It is one of three
  distinct GLS disease entities in MONDO, alongside MONDO:0032733 (the
  repeat-expansion form) and MONDO:0032685 (the gain-of-function form).

  Ontology observation: MONDO places this entity and MONDO:0034146 (spastic
  ataxia-dysarthria due to glutaminase deficiency) under the grouping class
  MONDO:0600001 (glutaminase deficiency), but does not place MONDO:0032733 there,
  even though the repeat-expansion form is also mechanistically a glutaminase
  deficiency. That looks like an incompleteness in the MONDO hierarchy rather
  than a deliberate exclusion, and is worth reporting upstream. The
  gain-of-function entity MONDO:0032685 is correctly outside the grouping, being
  the opposite direction of effect.
📚

References & Deep Research

References

3
PMID:30575854
Identification of a Loss-of-Function Mutation in the Context of Glutaminase Deficiency and Neonatal Epileptic Encephalopathy.
No top-level findings curated for this source.
PMID:41865506
Glutaminase deficiency provides insight to the role of glutamine accumulation and neurotoxicity.
No top-level findings curated for this source.
PMID:31603991
Inborn errors of enzymes in glutamate metabolism.
No top-level findings curated for this source.