Developmental and Epileptic Encephalopathy 116

Mendelian MONDO:0970945 Pathograph 12 Show in embeddings browser Genetic Developmental and Epileptic Encephalopathy

Developmental and epileptic encephalopathy 116 is caused by heterozygous de novo variants in GLUL, which encodes glutamine synthetase. It is the dominant, gain-of-function counterpart of a disease that had been known for twenty years in its recessive, loss-of-function form, and the two are mechanistically opposite. Biallelic loss of glutamine synthetase causes congenital glutamine deficiency, with brain malformation, multiorgan failure and death in infancy. This entity instead makes the enzyme too stable. The lesion is in the regulation of protein turnover, not in the enzyme's chemistry. Glutamine synthetase carries an N-terminal degron that triggers its own ubiquitin-mediated degradation when glutamine is abundant, so the enzyme destroys itself in proportion to how much product it has made. The disease variants remove the start codon, either by changing it directly or by disrupting splicing of the 5' untranslated region so that the initiation codon is skipped. Translation then restarts at an in-frame methionine seventeen residues downstream, past the degron. The resulting protein is shorter, fully enzymatically competent, and deaf to its own feedback signal. The authors of the founding study named the mechanism gain of stabilization. What follows clinically is a severe early-onset epileptic encephalopathy: seizures usually starting in the first months of life and often refractory, global developmental delay with little or no milestone progress, and a characteristic imaging picture. Markedly enlarged perivascular spaces are the most distinctive radiological feature and have been proposed as a diagnostic clue; thinning of the corpus callosum, white matter signal abnormality with hypomyelination, cerebral atrophy and deep grey matter T2 hyperintensity are variably present. Unlike the recessive disease, patients survive: the nine individuals in the founding cohort were all alive between 16 months and 16 years of age. A third feature is odd enough to be worth flagging: every one of the nine patients in the founding cohort was female. The first male was reported the following year with the same phenotype, so males are affected, but with ten patients described in total the imbalance is unexplained. Two further things about this entity are unresolved and are curated here as open questions rather than as mechanism. First, the biochemistry does not do what the mechanism predicts. A stabilized, feedback-insensitive glutamine synthetase should raise glutamine and lower ammonia; instead plasma and cerebrospinal fluid glutamine are usually normal and sometimes low, and some patients are hyperammonaemic, so the metabolic consequence of the stabilized enzyme in the brain is not captured by the peripheral measurements available. Second, the mutational spectrum is widening beyond the start codon: a heterozygous missense variant in the catalytic domain and an in-frame duplication have both been reported in patients with the same phenotype, the latter with a demonstrated regulatory rather than a stability defect, so removal of the degron may be one route to the disease rather than the definition of it.

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Mappings
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Inheritance
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Pathophys.
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Phenotypes
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Gaps
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Pathograph
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Genes
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Medical Actions
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Differentials
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Models
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References
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Deep Research
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Classifications

Harrison's Part
NEUROLOGIC GENETICS ENVIRONMENT DISEASE ENDOCRINOLOGY METABOLISM
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Mappings

MONDO
MONDO:0970945 developmental and epileptic encephalopathy 116
skos:exactMatch MONDO
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Inheritance

1
Autosomal dominant inheritance HP:0000006
Every reported patient carries a heterozygous variant that arose de novo, confirmed by trio sequencing of the proband and both parents. No familial transmission has been described, which is consistent with the severity of the phenotype. This is the point of contrast with the other GLUL disease: congenital glutamine deficiency requires biallelic loss-of-function variants and is recessive.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:41083803 SUPPORT Human Clinical
"Biallelic loss-of-function variants cause congenital glutamine deficiency, leading to developmental and epileptic encephalopathy (DEE) in an autosomal recessive manner. In contrast, certain variants of GLUL that lead to the loss of the N-terminal degron exert a gain-of-function effect, causing..."
States both the dominant transmission of this entity and its contrast with the recessive GLUL disease.
PMID:38579670 SUPPORT Human Clinical
"We ascertained nine individuals with severe developmental delay, seizures, and white matter abnormalities but normal plasma and cerebrospinal fluid biochemistry with de novo variants in GLUL."
Establishes the de novo origin of the variants in the founding cohort.
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Discussions and Knowledge Gaps

3
Why does a stabilized, feedback-insensitive glutamine synthetase not produce the biochemical profile it predicts, and what is actually happening to glutamine and ammonia in the brains of these patients?
KNOWLEDGE GAP OPEN dee116_biochemistry_contradicts_mechanism
Attached to
pathophysiology#Disrupted Glutamate-Glutamine Homeostasis in the Developing Brain pathophysiology#Unregulated Glutamine Synthetase Activity in Astrocytes and Glial Progenitors
The mechanism makes a clear prediction. An enzyme that converts glutamate and ammonia into glutamine, and that can no longer be degraded when glutamine is high, should raise glutamine and lower ammonia. The recessive disease behaves as the mirror of this: loss of the enzyme gives low glutamine and high ammonia, and that is what is usually measured. The dominant disease does not. The founding cohort of nine had normal plasma and cerebrospinal fluid biochemistry. A later series found heterogeneous profiles, with plasma glutamine low in one patient and normal in two, cerebrospinal fluid glutamine ranging from low to high across reported patients, and elevated ammonia in two of three. The reporting authors state plainly that the biochemistry did not agree with the gain-of-function mechanism. Several explanations are available and none has been tested. Peripheral blood may simply not report on astrocytic glutamine handling, in which case the measurement is wrong rather than the mechanism. The stabilized enzyme may be limited by substrate rather than by its own abundance, so more enzyme does not mean more product. The hyperammonaemia may be iatrogenic, since valproic acid raises ammonia and is among the drugs these patients receive, which is the explanation the reporting authors themselves offer. Or the pathogenic consequence may be something other than net flux through the enzyme, for instance the loss of a regulatory signal that the degron itself carries. This matters practically as well as mechanistically, because it is why biochemical testing cannot be used to screen for or confirm this diagnosis.
Proposed experiments
Magnetic resonance spectroscopy of glutamine and glutamate in patient brain
dee116_brain_glutamine_mrs
Measure glutamine and glutamate directly in the brains of patients with confirmed dominant GLUL variants, rather than inferring brain metabolism from plasma. This distinguishes the two leading explanations: if brain glutamine is raised while plasma is normal, the mechanism is right and the peripheral measurement is uninformative; if brain glutamine is also normal, the mechanism needs revisiting.
Metabolic flux measurement in patient-derived astrocytes
dee116_astrocyte_flux_assay
Differentiate astrocytes from patient induced pluripotent stem cells and measure labelled glutamate to glutamine conversion under varying glutamine and ammonia loads. Directly tests whether the stabilized enzyme increases flux, or whether flux is substrate-limited so that the extra enzyme has no metabolic consequence.
Ammonia measurement stratified by valproic acid exposure
dee116_ammonia_valproate_stratification
Compare ammonia levels in patients on and off valproic acid, or before and after starting it. This is the cheapest of the three and settles whether the hyperammonaemia is a disease feature or a drug effect, which currently confounds every biochemical description of the disorder.
Show evidence (3 references)
PMID:38579670 SUPPORT Human Clinical
"We ascertained nine individuals with severe developmental delay, seizures, and white matter abnormalities but normal plasma and cerebrospinal fluid biochemistry with de novo variants in GLUL."
Establishes that biochemistry was normal in the founding cohort despite the demonstrated stabilization of the enzyme.
PMID:41083803 SUPPORT Human Clinical
"In contrast, the analysis of patients with AD type of the disease did not yield consistent results with the gain-of-function mechanism."
The explicit statement that the observed biochemistry contradicts the mechanism.
PMID:41083803 SUPPORT Human Clinical
"Some showed low glutamine levels in the plasma or CSF and elevation of ammonia, although the high ammonia level might have been caused by the use of valproic acid"
Records both the contradictory finding and the drug-effect explanation the authors offer for part of it.
Why were all nine individuals in the founding cohort female, and is the apparent female predominance real or an artefact of ascertainment?
KNOWLEDGE GAP OPEN dee116_female_predominance
Attached to
pathophysiology#GLUL Start-Loss and 5' UTR Splice Variants pathophysiology#Unregulated Glutamine Synthetase Activity in Astrocytes and Glial Progenitors
A de novo autosomal dominant disorder has no reason to affect one sex. This one appeared to: every one of the nine probands in the founding cohort was female, and the reporting authors noted that the phenotype was uncharacterized in males. The hypothesis they offered was a reported difference in glutamine metabolism between the sexes, which would place the modifier downstream of the variant rather than in transmission. The first male proband was reported the following year, and his phenotype matched the female cases: refractory seizures, global developmental delay, hypotonia. That settles the strong version of the question, which was whether males are affected at all. It does not settle the weaker one. With ten patients in total, nine of one sex, the imbalance could be chance, could be ascertainment, or could be real with males either less severely affected or affected differently enough to be diagnosed as something else. Distinguishing these needs more patients rather than a new experiment, but the metabolic hypothesis is separately testable and would be worth testing even at the current cohort size, because a sex difference in glutamine handling would bear on the biochemistry gap recorded in the other discussion here.
Proposed experiments
Sex ratio in a prospectively accrued GLUL cohort
dee116_sex_ratio_cohort_accrual
Accrue patients through GeneMatcher and diagnostic laboratories without selecting on phenotype, and report the sex ratio. Ten patients cannot distinguish a real 9-to-1 imbalance from chance; a few dozen can.
Sex-stratified measurement of glutamine synthetase turnover
dee116_sex_stratified_gs_turnover
Measure glutamine synthetase abundance and glutamine-induced degradation in male and female control cells, and in patient cells of both sexes. This tests the specific hypothesis the founding authors offered, that sex differences in glutamine metabolism modify the consequence of losing the degron.
Show evidence (2 references)
PMID:39985170 SUPPORT Human Clinical
"The original study highlighted that all reported individuals were female and that the phenotype remains uncharacterized in males. The overrepresentation of females was hypothesized to be due to the reported difference in glutamine metabolism between sexes."
States the observation and the hypothesis offered for it.
PMID:39985170 SUPPORT Human Clinical
"This indicates that this genetic condition clinically affects both male and female individuals. The reason for female predominance among reported individuals remains an open question."
Settles that males are affected, and states explicitly that the imbalance itself is unexplained.
A patient with a start-loss GLUL variant had periventricular nodular heterotopia, but overexpressing stabilized glutamine synthetase in mouse cortex produced no migration defect. Does the human neuronal migration phenotype belong to this disease, and if so why does the mouse experiment not reproduce it?
HUMAN MODEL MISMATCH OPEN dee116_heterotopia_mouse_mismatch
Attached to
pathophysiology#Unregulated Glutamine Synthetase Activity in Astrocytes and Glial Progenitors pathophysiology#Disrupted Glutamate-Glutamine Homeostasis in the Developing Brain
The founding study reported one individual with periventricular nodular heterotopia, a disorder of neuronal migration, and then tested the obvious hypothesis directly: it overexpressed the stabilized enzyme in the developing mouse cortex by in utero electroporation and looked for migration defects. There were none. The authors report the negative result rather than omitting it, which is why it is curated here as a mismatch rather than as an absence of evidence. Three readings are open. The heterotopia may be coincidental in a single patient, in which case it is not a feature of the disease at all. The mouse experiment may not model the human condition adequately, since electroporation overexpresses the protein in a subset of cells for a limited window whereas patients carry the variant in every cell from conception, and since GLUL is expressed in progenitors whose human biology the mouse cortex represents imperfectly. Or the migration phenotype may depend on the astrocytic and progenitor context rather than on the enzyme being present in the migrating neuron, in which case overexpressing it in the electroporated cells tests the wrong cell type. Whether the heterotopia belongs to the disease is not resolvable from one patient, and no subsequent series has reported a second case; the more recent cohorts describe atrophy, callosal thinning and perivascular space enlargement instead.
Proposed experiments
Germline knock-in mouse carrying the human start-loss allele
dee116_knockin_mouse_migration
Replace the electroporation overexpression model with a knock-in that carries the human variant in every cell from conception, and assess cortical lamination and neuronal migration. This tests the leading explanation for the negative result, that the model system rather than the hypothesis was inadequate.
Systematic re-review of brain imaging across all reported patients
dee116_imaging_review_for_heterotopia
Have a neuroradiologist blinded to genotype look specifically for heterotopia in the imaging of every reported patient. Periventricular nodular heterotopia is easy to miss when it is not being sought, and a second case would change the interpretation from coincidence to phenotype.
Show evidence (1 reference)
PMID:38579670 SUPPORT Model Organism
"One individual with a start-loss GLUL variant demonstrated periventricular nodular heterotopia, a neuronal migration disorder, yet overexpression of stabilized GS in mice using in utero electroporation demonstrated no migratory deficits."
Reports both halves of the mismatch: the human finding and the negative mouse result that failed to reproduce it.
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Pathophysiology

7
GLUL Start-Loss and 5' UTR Splice Variants
The disease alleles cluster on one target: the initiation codon of GLUL. They reach it two ways. Seven of the nine founding patients had variants in the start codon itself, and two had variants at the canonical splice site of the 5' untranslated region that exclude the initiation codon from the mature transcript. Later reports add further alleles at the same splice acceptor. All are heterozygous and all arose de novo. The spectrum has since begun to widen past the start codon. A de novo heterozygous missense variant in the catalytic domain and an in-frame duplication have each been reported in a patient with the same phenotype. The duplication was shown to disrupt regulation of enzyme activity without changing protein expression, which is a different route to the same endpoint; the missense variant is not functionally characterised. Both are single observations and are curated here as spectrum expansion rather than as an established second mechanism.
GLUL hgnc:4341 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GLUL (hgnc:4341). hgnc:4341 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: DE_NOVO zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION
Heterozygous de novo variants abolishing use of the canonical GLUL start codon, either by altering it directly or by excluding it through a 5' untranslated region splice defect.
Downstream
Translation Reinitiation at Methionine 18 With the canonical initiation codon unavailable, the ribosome starts at the next in-frame methionine.
Show evidence (2 references)
PMID:38579670 SUPPORT Human Clinical
"Seven out of nine were start-loss variants and two out of nine disrupted 5' UTR splicing resulting in splice exclusion of the initiation codon."
Defines the two allele classes that converge on loss of the canonical start codon.
PMID:42311234 SUPPORT Human Clinical
"All reported dominant mutations are within the start codon or the 5 ' UTR. Here, we report a DEE patient with a de novo variant, c.522_536dup, in the catalytic domain of GLUL."
Records the first reported dominant allele outside the start codon region, which extends the allelic spectrum beyond the founding description.
Translation Reinitiation at Methionine 18
The alternative start codon lies seventeen residues into the protein, in frame with the rest of it. Reinitiation there produces a glutamine synthetase that is complete except for its N-terminal seventeen amino acids. That short missing segment is the entire pathogenic consequence: it contains the degron, and nothing else about the protein is altered. This is why the variants are not loss-of-function despite abolishing the normal start codon.
translational initiation GO:0006413 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal translational initiation (GO:0006413). GO:0006413 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Experimental models
Transfection-based expression system for GLUL start-loss variants CELL LINE Mass spectrometry of the expressed protein identifies the actual translation start site, which is the observation the whole mechanism rests on and which no clinical measurement could supply.
Downstream
Escape from Glutamine-Induced Degradation of Glutamine Synthetase The truncated protein no longer carries the degron that would target it for ubiquitin-mediated degradation when glutamine is high.
Show evidence (1 reference)
PMID:39985170 SUPPORT Human Clinical
"In both scenarios, a truncated protein is produced by reinitiation of the translation at an alternative start codon 17 amino acids downstream (Met18), removing a 5′ degron sequence critical to the regulation of glutamine synthetase degradation."
States precisely what reinitiation at methionine 18 removes and why it matters.
Escape from Glutamine-Induced Degradation of Glutamine Synthetase
Glutamine synthetase is normally held in check by its own product. When glutamine is abundant, lysine residues in the N-terminal region are acetylated, which triggers ubiquitin-mediated degradation of the enzyme. That degron is a negative feedback loop implemented as protein turnover rather than as allosteric inhibition, and it is what the disease removes. The truncated enzyme is not degraded under high glutamine, so its abundance is no longer set by how much product it has made. The founding study named this gain of stabilization, and it is the rate-limiting step of the disorder: everything upstream converges on it, and everything downstream follows from it.
proteasome-mediated ubiquitin-dependent protein catabolic process GO:0043161 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161). GO:0043161 is a biological process from the Gene Ontology. ↓ DECREASED protein stabilization GO:0050821 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased protein stabilization (GO:0050821). GO:0050821 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Unregulated Glutamine Synthetase Activity in Astrocytes and Glial Progenitors An enzyme that cannot be removed in proportion to its product keeps working when it should be switched off.
Show evidence (3 references)
PMID:38579670 SUPPORT Human Clinical
"GS levels are regulated post-translationally by an N-terminal degron that enables the ubiquitin-mediated degradation of GS in a glutamine-induced manner."
Describes the normal feedback mechanism whose removal defines the disease.
PMID:39985170 SUPPORT In Vitro
"The truncated glutamine synthetase retains its enzymatic activity yet fails to undergo degradation in conditions of high glutamine"
States the defining property of the stabilized enzyme, and that catalysis is unaffected.
PMID:41083803 SUPPORT Human Clinical
"Normally, the lysine residues located in the N-terminal region of GS are acetylated at high glutamine concentrations, triggering ubiquitin-mediated protein degradation and serving as a negative feedback mechanism"
Gives the molecular detail of the feedback loop, the acetylation step that reads glutamine concentration.
Unregulated Glutamine Synthetase Activity in Astrocytes and Glial Progenitors
The cell type matters, and it is not the neuron. Single-cell transcriptomic analysis of human tissue shows GLUL expressed in neural and glial progenitor cells and in mature astrocytes, and not in post-mitotic neurons. The astrocyte is where glutamate taken up from the synaptic cleft is converted to glutamine for return to the neuron, so an astrocytic enzyme running outside its feedback control acts directly on the supply side of the glutamate-glutamine cycle. Expression in progenitors adds a developmental dimension: the same dysregulation is present while the brain is being built, not only once it is working.
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. Neural progenitor cell CL:0011020 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Neural progenitor cell (CL:0011020). CL:0011020 is a cell type from the Cell Ontology.
glutamine synthetase activity GO:0004356 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves glutamine synthetase activity (GO:0004356), qualified as gain of function. GO:0004356 is a molecular function from the Gene Ontology. ⇑ GAIN OF FUNCTION
Animal models
Mouse in utero electroporation overexpressing stabilized glutamine synthetase Mouse fails to recapitulate Overexpression of the stabilized enzyme in the developing mouse cortex produced no migratory deficit, so this model does not reproduce the periventricular nodular heterotopia seen in one patient and provides no support for a migration-defect route from the enzyme to the human brain phenotype.
Downstream
Disrupted Glutamate-Glutamine Homeostasis in the Developing Brain Loss of feedback control over the enzyme that sets the glutamine supply perturbs the tightly regulated balance between glutamate and glutamine.
Show evidence (2 references)
PMID:38579670 SUPPORT Computational
"Analysis of human single-cell transcriptomes demonstrated that GLUL is widely expressed in neuro- and glial-progenitor cells and mature astrocytes but not in post-mitotic neurons."
Establishes which cells carry the dysregulated enzyme, and excludes the neuron.
PMID:42311234 SUPPORT Human Clinical
"Glutamate is excreted by neurons into the synaptic cleft as a neurotransmitter and absorbed by astrocytes, where it is converted into glutamine by GS."
Places the enzyme at the astrocytic step of the glutamate-glutamine cycle, which is why an astrocytic defect changes neurotransmitter handling.
Disrupted Glutamate-Glutamine Homeostasis in the Developing Brain
Glutamine synthetase sits at the junction of three things the brain cannot afford to get wrong: it makes the precursor from which both glutamate and GABA are regenerated, and it is the principal route by which ammonia is detoxified in the brain. Losing regulatory control of it during neurodevelopment is the proposed proximate cause of both the epilepsy and the developmental arrest. The confidence here is PROVISIONAL rather than ESTABLISHED, and deliberately so. The step is asserted on the basis of what the enzyme does rather than on a measurement of glutamate or glutamine in an affected brain, and the peripheral biochemistry that is available does not behave as the mechanism predicts. That mismatch is recorded as an open knowledge gap rather than resolved here.
L-glutamine metabolic process GO:0006541 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated L-glutamine metabolic process (GO:0006541). GO:0006541 is a biological process from the Gene Ontology. ↕ DYSREGULATED glutamate metabolic process GO:0006536 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated glutamate metabolic process (GO:0006536). GO:0006536 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Developmental and Epileptic Encephalopathy Perturbed excitatory and inhibitory neurotransmitter supply during development produces the seizure and developmental phenotype.
White Matter and Perivascular Space Abnormality The same metabolic dysregulation is associated with a distinctive structural brain phenotype, most consistently enlarged perivascular spaces and a thin corpus callosum. The link is a clinical association; no study has shown how glutamine synthetase dysregulation produces these changes, hence INDIRECT.
Show evidence (2 references)
PMID:38579670 SUPPORT Human Clinical
"GS is pivotal for the generation of the neurotransmitters glutamate and gamma-aminobutyric acid and is the primary mechanism of ammonia detoxification in the brain."
Establishes the three brain functions that depend on this enzyme and are therefore exposed by its dysregulation.
PMID:38579670 SUPPORT Human Clinical
"These findings underline the importance of tight regulation of glutamine metabolism during neurodevelopment in humans."
The founding study's own conclusion, framed at the level of regulation during development rather than of enzyme quantity.
Developmental and Epileptic Encephalopathy
The clinical endpoint. Seizures typically begin in the first months of life, are often refractory to multiple antiseizure medications, and take varied forms across patients: generalized tonic-clonic, myoclonic, tonic, clonic, focal, and infantile spasms have all been reported. Global developmental delay is universal and severe, with several patients achieving head control and little beyond it. Unlike the recessive GLUL disease, which kills in infancy, this one is survivable.
Show evidence (2 references)
PMID:39985170 SUPPORT Human Clinical
"Distinct from the recessive form of disease, the dominant form is associated with intractable seizures, global developmental delay, and hypotonia."
Summarises the clinical endpoint and contrasts it with the recessive disease.
PMID:39985170 SUPPORT Human Clinical
"Moreover, all nine individuals are alive at current ages of 16 months to 16 years."
Establishes survival into childhood and adolescence, the sharpest clinical difference from congenital glutamine deficiency.
White Matter and Perivascular Space Abnormality
A structural imaging phenotype consistent enough to be proposed as a diagnostic clue. Markedly enlarged perivascular spaces are the most distinctive finding and were present in most reported patients with the dominant disease; thinning of the corpus callosum accompanies them. Hypomyelination or demyelination was described in seven of ten earlier patients but absent in a later series of three, while that later series found cerebral atrophy in all three and deep grey matter T2 hyperintensity in two. The mechanism connecting glutamine synthetase dysregulation to these changes is not known, and the reporting authors say so.
Show evidence (3 references)
PMID:42311234 SUPPORT Human Clinical
"Her brain MRI demonstrated involvement of the white matter signal-intensity alterations and markedly enlarged perivascular spaces."
Documents both components of this node in a patient with a confirmed de novo GLUL variant.
PMID:41083803 SUPPORT Human Clinical
"These findings are frequently associated with systemic metabolic abnormality and mitochondrial diseases"
The only mechanistic framing the literature offers for these imaging findings is an analogy to other metabolic disorders, which is why this node is PROVISIONAL.
PMID:39985170 SUPPORT Human Clinical
"His brain magnetic resonance imaging (MRI) at ages 1 and 3 years was normal."
A genetically confirmed patient with entirely normal imaging at two time points in early childhood. Structural change is therefore not obligatory, and a normal MRI does not argue against the diagnosis.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Developmental and Epileptic Encephalopathy 116 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

10
Musculoskeletal 2
Hypertonia HP:0001276 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertonia (HP:0001276). HP:0001276 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:41083803 SUPPORT Human Clinical
"However, our patients exhibited additional phenotypes, such as hypertonia, cerebral atrophy, and T2 hyperintensity in deep grey matter, which have not been described in patients with autosomal dominant GLUL-related DEE."
Records hypertonia and its status as newly described in the dominant disease.
PMID:41083803 SUPPORT Human Clinical
"At 1 year of age, neurological examination revealed microcephaly and generalized spasticity with hyperreflexia."
A specific patient description of the hypertonic phenotype.
PMID:41083803 SUPPORT Human Clinical
"Although all patients carrying AD variants in the previous studies exhibited hypotonia, the neurological examinations of our patients revealed rigidity and spasticity."
States the contrast directly: increased tone in this series against hypotonia in every previously reported dominant patient.
Hypotonia VERY_FREQUENT Generalized hypotonia HP:0001290 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Generalized hypotonia (HP:0001290). HP:0001290 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39985170 SUPPORT Human Clinical
"Distinct from the recessive form of disease, the dominant form is associated with intractable seizures, global developmental delay, and hypotonia."
Lists hypotonia among the defining features of the dominant disease.
PMID:41083803 SUPPORT Human Clinical
"Although all patients carrying AD variants in the previous studies exhibited hypotonia, the neurological examinations of our patients revealed rigidity and spasticity."
Supplies the denominator behind the VERY_FREQUENT band, all previously reported dominant patients, and simultaneously records the three-patient series in which tone was increased instead.
Nervous System 5
Seizures VERY_FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:41083803 SUPPORT Human Clinical
"A comparison of our patients with previously reported cases revealed common symptoms, including epilepsy and global developmental delay."
Establishes epilepsy as a feature shared across every reported patient with this entity, supporting the VERY_FREQUENT band.
PMID:41083803 SUPPORT Human Clinical
"The seizure patterns and responses to antiseizure medications varied among patients, reflecting their diverse phenotypic spectrum."
Records the heterogeneity of semiology and drug response.
PMID:39985170 SUPPORT Human Clinical
"Here, we report the first male with a pathogenic de novo variant in the same critical region of GLUL, with a phenotype of refractory focal and generalized seizures, as well as developmental delays."
Documents refractory focal and generalized seizures in a genetically confirmed patient.
+ 1 more reference
Global Developmental Delay VERY_FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41083803 SUPPORT Human Clinical
"A comparison of our patients with previously reported cases revealed common symptoms, including epilepsy and global developmental delay."
Establishes global developmental delay as common to every reported patient, supporting the VERY_FREQUENT band.
PMID:38579670 SUPPORT Human Clinical
"We ascertained nine individuals with severe developmental delay, seizures, and white matter abnormalities but normal plasma and cerebrospinal fluid biochemistry with de novo variants in GLUL."
Records severe developmental delay across the founding cohort of nine.
Abnormal Cerebral White Matter FREQUENT Abnormal cerebral white matter morphology HP:0002500 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal cerebral white matter morphology (HP:0002500). HP:0002500 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38579670 SUPPORT Human Clinical
"We ascertained nine individuals with severe developmental delay, seizures, and white matter abnormalities but normal plasma and cerebrospinal fluid biochemistry with de novo variants in GLUL."
Records white matter abnormality as a defining feature of the founding cohort of nine.
PMID:41083803 SUPPORT Human Clinical
"Although hypomyelination or demyelination was also commonly observed in previously reported cases (7 out of 10 in AD cases), our patients did not have these features."
Gives the count behind the FREQUENT band, 7 of 10, and simultaneously shows the feature is absent in some patients.
Cerebral Hypomyelination FREQUENT HP:0006808 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral hypomyelination (HP:0006808). HP:0006808 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41083803 SUPPORT Human Clinical
"Although hypomyelination or demyelination was also commonly observed in previously reported cases (7 out of 10 in AD cases), our patients did not have these features."
Gives the count behind the FREQUENT band, 7 of 10, and records that the feature was absent in a later three-patient series.
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.
Frequency omitted. Cerebral atrophy was reported in three of three patients in one series and explicitly described as not previously reported in this disease, so a frequency band over all patients cannot be justified from either number.
Show evidence (1 reference)
PMID:41083803 SUPPORT Human Clinical
"Conversely, all our patients showed cerebral atrophy, and two of them (Patients 1 and 2) had T2 hyperintensity in the basal ganglia or the thalamus."
Documents cerebral atrophy in all three patients of the series that first described it in this entity.
Other 3
Dilation of Perivascular Spaces FREQUENT Dilation of Virchow-Robin spaces HP:0012520 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dilation of Virchow-Robin spaces (HP:0012520). HP:0012520 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41083803 SUPPORT Human Clinical
"Prominent perivascular spaces, which is a finding associated with small vessel disease and various neuroinflammatory and neurodegenerative conditions, were identified in most patients with AD type of the disease"
States that the finding was present in most patients with the dominant disease, which supports the FREQUENT band, and records that it is not specific to this disorder.
PMID:42311234 SUPPORT Human Clinical
"highlights enlarged perivascular spaces as a diagnostic clue in GLUL-related disorders"
Proposes the finding as a diagnostic pointer toward GLUL in an undiagnosed encephalopathy.
Thin Corpus Callosum HP:0033725 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin corpus callosum (HP:0033725). HP:0033725 is a phenotype from the Human Phenotype Ontology.
Frequency omitted. The source says "consistently revealed" without giving a count or proportion, and the phrase is a qualitative summary across two cohorts rather than a frequency statement about a defined denominator.
Show evidence (1 reference)
PMID:41083803 SUPPORT Human Clinical
"The brain MRI findings consistently revealed prominent perivascular spaces and thinning of the corpus callosum in patients with AD type of the disease."
Records callosal thinning as a consistent finding in the dominant disease.
Deep Grey Matter T2 Hyperintensity Abnormal basal ganglia MRI signal intensity HP:0012751 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal basal ganglia MRI signal intensity (HP:0012751). HP:0012751 is a phenotype from the Human Phenotype Ontology.
Bound to HP:0012751 Abnormal basal ganglia MRI signal intensity, the closest available term. HPO has no single term covering signal change across the deep grey matter as a whole, and the thalamic component is therefore not captured by this binding. Searched with runoak against sqlite:obo:hp for "basal ganglia" and reviewed all fifteen matches.
Show evidence (1 reference)
PMID:41083803 SUPPORT Human Clinical
"However, our patients exhibited additional phenotypes, such as hypertonia, cerebral atrophy, and T2 hyperintensity in deep grey matter, which have not been described in patients with autosomal dominant GLUL-related DEE."
Records the finding and its status as newly described in this entity.
🧬

Genetic Associations

1
GLUL
Gene: GLUL hgnc:4341 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GLUL (hgnc:4341). hgnc:4341 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: DE_NOVO
Show evidence (3 references)
PMID:41083803 SUPPORT Human Clinical
"Both loss-of-function and gain-of-function variants of GLUL are known to cause genetic disorders in humans."
States the bidirectional genotype-phenotype relationship of the gene.
PMID:41083803 SUPPORT Human Clinical
"Only six autosomal recessive cases and ten autosomal dominant cases have been reported to date, and knowledge about GLUL-related DEE remains limited."
Quantifies how few patients define this entity, which bounds every frequency and genotype-phenotype statement in this entry.
PMID:41083803 SUPPORT Human Clinical
"Another novel variant, c.604T > C (p.Trp202Arg), was heterozygous without any additional pathogenic or likely pathogenic variant in GLUL, unlike all other previously reported missense variants which exhibited a biallelic status."
Records the first heterozygous missense allele, which does not fit the start-loss mechanism and is uncharacterised functionally.
💊

Medical Actions

1
Antiseizure Medication
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
There is no treatment directed at the mechanism. Seizure control is attempted with conventional antiseizure medications and, in some patients, a ketogenic diet, and the results are poor and inconsistent: several patients remained refractory through multiple agents, while others achieved partial control with valproic acid or perampanel added late. Agents reported in use include vigabatrin, prednisolone, topiramate, valproic acid, lacosamide, perampanel, lamotrigine and levetiracetam. No agent has been shown to work better than another in this disorder, and no genotype-directed choice is possible on current evidence. One practical caution follows from the biochemistry. Some patients are hyperammonaemic, and the authors of the series reporting that raise valproic acid as a possible cause rather than a disease feature. Since valproic acid is among the drugs used here, a rising ammonia in a treated patient should not be assumed to reflect the underlying enzyme defect.
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (5 references)
PMID:41083803 SUPPORT Human Clinical
"The seizure patterns and responses to antiseizure medications varied among patients, reflecting their diverse phenotypic spectrum."
Supports the use of antiseizure medication while establishing that response is inconsistent, which is why the support is PARTIAL.
PMID:41083803 SUPPORT Human Clinical
"Seizures persisted despite trials of multiple antiseizure medications and a ketogenic diet, but at 3 years of age, the seizures were controlled with the addition of valproic acid."
A specific illustration of refractoriness followed by partial response, in a single patient.
PMID:39985170 SUPPORT Human Clinical
"Overall, zonisamide and brivaracetam have proven most effective in reducing the frequency of the myoclonic and GTC seizures, respectively."
The only drug-specific efficacy statement in the literature for this disorder. It is one patient followed over two decades, so it is a starting point for drug choice rather than evidence of superiority.
+ 2 more references
🔬

Biochemical Markers

2
Plasma and Cerebrospinal Fluid Glutamine (VARIABLE)
Context: The measurement the mechanism predicts should be abnormal, and usually is not. A stabilized, feedback-insensitive glutamine synthetase should raise glutamine; in the founding cohort of nine, plasma and cerebrospinal fluid biochemistry was normal. A later three-patient series found plasma glutamine low in one and normal in two. Across all reported dominant patients, cerebrospinal fluid glutamine has ranged from low to high. This is the observation the entry's principal knowledge gap is about.
Show evidence (2 references)
PMID:38579670 SUPPORT Human Clinical
"We ascertained nine individuals with severe developmental delay, seizures, and white matter abnormalities but normal plasma and cerebrospinal fluid biochemistry with de novo variants in GLUL."
Establishes that biochemistry was normal across the founding cohort.
PMID:41083803 SUPPORT Human Clinical
"Although some patients with the AD type of the disease showed reduced plasma glutamine levels, most patients exhibited normal plasma glutamine. The CSF glutamine levels were also inconsistent among patients, ranging from low to high."
Records the range across reported patients, including values in the direction opposite to the one the mechanism predicts.
Plasma Ammonia (VARIABLE)
Context: Raised in two of the three patients in the most recent series, at 227 and 184 micrograms per decilitre. That direction also contradicts the mechanism, since more glutamine synthetase should consume more ammonia, not less. The reporting authors raise valproic acid, which these patients receive and which is known to raise ammonia, as a possible explanation.
Show evidence (2 references)
PMID:41083803 SUPPORT Human Clinical
"Furthermore, Patients 1 and 3 in our cohort showed elevated ammonia levels."
Records the hyperammonaemia in the dominant disease.
PMID:41083803 SUPPORT Human Clinical
"Some showed low glutamine levels in the plasma or CSF and elevation of ammonia, although the high ammonia level might have been caused by the use of valproic acid"
The drug-effect confound, which is why the raised ammonia cannot be read as a disease feature without stratifying by valproic acid exposure.
🔬

Diagnosis

2
Trio Exome or Genome Sequencing
Molecular diagnosis is the only reliable route, and it must be trio-based: the variants are de novo, so demonstrating that neither parent carries the change is what establishes causality for a variant class that is easy to overlook. Two features make these variants easy to miss on a standard pipeline. Variants in the 5' untranslated region fall outside the coding sequence that many analyses prioritise, and start-loss variants are not always flagged as high-impact. RNA sequencing was used in one patient to confirm that a splice acceptor variant does produce the predicted degron-removing transcript.
Show evidence (2 references)
PMID:41083803 SUPPORT Human Clinical
"An alternative splicing event causing loss of the N-terminal degron of GS was confirmed by RNA sequencing in a patient carrying c.-13-1G > C variant."
Shows RNA sequencing confirming the functional consequence of a non-coding variant, which sequence analysis alone would leave uncertain.
PMID:39985170 SUPPORT Human Clinical
"More than half of individuals with a suspected Mendelian disease remain undiagnosed after analysis of the exome or genome."
Context for why this patient was diagnosed only on reanalysis after the gene-disease association was published, which is the practical diagnostic point for a newly described entity.
Plasma and Cerebrospinal Fluid Amino Acid Analysis
Worth understanding mainly for what it does not do. Biochemical testing is diagnostically useful in the recessive GLUL disease, where low glutamine with raised ammonia is the expected and usually observed pattern. In this dominant entity it is not: the founding cohort had normal plasma and cerebrospinal fluid biochemistry, and a later series found heterogeneous profiles including low glutamine and elevated ammonia, which is the opposite of what a stabilized enzyme predicts. A normal amino acid panel therefore does not exclude the diagnosis, and an abnormal one does not confirm it.
Show evidence (2 references)
PMID:38579670 SUPPORT Human Clinical
"We ascertained nine individuals with severe developmental delay, seizures, and white matter abnormalities but normal plasma and cerebrospinal fluid biochemistry with de novo variants in GLUL."
Establishes that biochemistry was normal across the founding cohort, so a normal result cannot exclude the diagnosis.
PMID:41083803 SUPPORT Human Clinical
"These observations suggest that biochemical testing might have some value in confirming the AR type of the disease, but its value in the diagnosis of the AD type of the disease remains unclear."
The authors' own conclusion about the diagnostic utility of biochemistry in this entity.
📈

Progression

3
Presentation and seizure onset
Age: First two years of life, most often the first months
Presentation is with seizures, developmental delay, or both. Seizure onset across the founding cohort spanned 10 weeks to 22 months; in a later series of three, two began at 3 months and one at 4 weeks. The one adult reported so far began at 24 months, the latest onset described.
Show evidence (1 reference)
PMID:39985170 SUPPORT Human Clinical
"Seizures were first reported between ages 1 and 2 years."
Records the later end of the onset range, in the one adult proband.
Developmental arrest
Milestones are not merely delayed but stop. In the most recent series one patient could sit with support at six years and gained nothing further, which the reporting authors describe as developmental arrest; another gained head control and rolling but no further milestones by seven years, even across periods when seizures were controlled. That dissociation matters clinically, because it means seizure control cannot be expected to restore developmental progress.
Show evidence (2 references)
PMID:41083803 SUPPORT Human Clinical
"At the last follow-up at 6 years of age, he was only able to sit with support, with no further developmental progress observed, suggesting developmental arrest."
The explicit statement of developmental arrest in one patient.
PMID:41083803 SUPPORT Human Clinical
"Although neurological examination revealed increased rigidity, the patient gained the ability to control his head and roll over. Nevertheless, no further developmental milestones were achieved even by 7 years of age."
A second patient in whom milestones stopped despite periods of seizure control.
Long-term course
Age: Reported to 25 years
Survival into adulthood is documented. Every patient in the founding cohort was alive at ages between 16 months and 16 years, and the one adult reported was 25 at the time of writing, still with myoclonic and generalized tonic-clonic seizures, non-verbal and requiring total care. This is the sharpest contrast with the recessive GLUL disease, which is lethal in infancy.
Show evidence (2 references)
PMID:39985170 SUPPORT Human Clinical
"Moreover, all nine individuals are alive at current ages of 16 months to 16 years."
Establishes survival across the founding cohort.
PMID:39985170 SUPPORT Human Clinical
"Now age 25, while taking zonisamide, brivaracetam, and cannabidiol, his seizures continue and are predominantly myoclonic (occurring less than 10 times per week) and GTC (occurring, on average, every 4-5 days), with occasional tonic seizures."
Documents the adult course, with seizures continuing on treatment at 25 years.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Developmental and Epileptic Encephalopathy 116:

Congenital glutamine deficiency
Overlapping Features The other GLUL disease, and the one a clinician is more likely to have heard of. It is caused by biallelic loss-of-function variants, is autosomal recessive, and presents in the neonatal period with severe brain malformation, multiorgan failure and death in infancy. Its biochemistry is the mirror image of what this entity was predicted to show: markedly reduced plasma and cerebrospinal fluid glutamine with hyperammonaemia.
Distinguishing Features
  • Inheritance separates them cleanly: biallelic inherited variants in the recessive disease versus a single de novo variant in this one.
  • Outcome separates them. Congenital glutamine deficiency kills in infancy; every reported patient with the dominant disease was alive between 16 months and 16 years of age.
  • Biochemistry separates them in principle but not in practice. Low glutamine with raised ammonia is expected and usually observed in the recessive disease. In the dominant one glutamine is usually normal and ammonia is sometimes raised, so the panel neither confirms nor excludes it.
  • Imaging differs: brain malformation and ventriculomegaly in the recessive disease, against enlarged perivascular spaces and a thin corpus callosum in this one.
Show evidence (2 references)
PMID:42311234 SUPPORT Human Clinical
"Recessive forms are associated with congenital glutamine deficiency, manifesting with severe brain malformation, multiorgan failure, and early death."
Characterises the recessive disease that must be distinguished from this one.
PMID:41083803 SUPPORT Human Clinical
"In AR cases, low plasma or CSF glutamine and elevated ammonia levels were common findings, although two patients (Patients 18 and 19) showed normal plasma glutamine levels."
Gives the biochemical profile of the recessive disease, and notes that even there it is not universal.
🧫

Experimental Models

1
Transfection-based expression system for GLUL start-loss variants CELL_LINE
The system in which the mechanism was established. Wild-type and variant GLUL constructs were expressed and the resulting protein analysed by mass spectrometry, which is what showed that the variants shift the initiation site to methionine 18 rather than simply abolishing expression. The same system supported the stability and feedback-response experiments behind the gain-of-stabilization claim.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Transfected cell line expressing wild-type or variant GLUL constructs
Publication
PMID:38579670
Pathograph links
Translation Reinitiation at Methionine 18 measures fidelity: moderate Mass spectrometry of the expressed protein identifies the actual translation start site, which is the observation the whole mechanism rests on and which no clinical measurement could supply.
Limitations: Constructs are expressed from a plasmid rather than from the endogenous locus, so transcript abundance and the 5' untranslated region context are not those of the patient allele. The system therefore establishes that reinitiation at methionine 18 occurs and that the product is stable, but not the relative abundance of the truncated and full-length proteins in patient tissue.
Readouts
Translation initiation site of the expressed protein
Direction: ALTERED
Interpretation: Mass spectrometry places the start of the variant protein at methionine 18 rather than methionine 1.
Show evidence (1 reference)
PMID:38579670 SUPPORT In Vitro
"Using transfection-based expression systems and mass spectrometry, these variants were shown to lead to translation initiation of GS from methionine 18, downstream of the N-terminal degron motif"
Reports the measurement and its result.
Show evidence (1 reference)
PMID:38579670 SUPPORT In Vitro
"resulting in a protein that is stable and enzymatically competent but insensitive to negative feedback by glutamine"
The three properties of the variant protein that this system established, all of which are claims about the molecule rather than about a tissue.
Deliberately minimal. The cached record for PMID:38579670 is the PubMed abstract only, which names the transfection-based expression system and mass spectrometry but does not describe the cell lines, the cycloheximide chase, or the enzyme activity assay in enough detail to curate them as separate models with quotable readouts. Anything more would be curated from a secondary summary rather than from the source.
🐁

Animal Models

1
Mouse in utero electroporation overexpressing stabilized glutamine synthetase
Not a genetic model of the disease but a targeted test of one hypothesis. One patient with a start-loss GLUL variant had periventricular nodular heterotopia, a disorder of neuronal migration. The founding study electroporated the stabilized enzyme into embryonic mouse neocortex to ask whether stabilized glutamine synthetase disturbs migration. It did not, and the authors reported the negative result rather than omitting it.
Species
Mouse
Genotype
Wild type, transiently overexpressing degron-truncated glutamine synthetase in embryonic neocortex
Publication
PMID:38579670
Pathograph links
Unregulated Glutamine Synthetase Activity in Astrocytes and Glial Progenitors fails to recapitulate fidelity: low Overexpression of the stabilized enzyme in the developing mouse cortex produced no migratory deficit, so this model does not reproduce the periventricular nodular heterotopia seen in one patient and provides no support for a migration-defect route from the enzyme to the human brain phenotype.
Limitations: Three limitations bear directly on how far the negative result can be taken. Electroporation overexpresses the protein transiently, in a subset of cells, within a narrow developmental window, whereas patients carry the variant in every cell from conception. It adds stabilized protein on top of the endogenous wild-type enzyme rather than replacing it, so it models a gain of dose rather than the patient genotype. And GLUL is expressed in astrocytes and neural and glial progenitors rather than in post-mitotic neurons, so delivering it to electroporated cortical cells may not test the cell type in which the relevant activity resides. The result therefore weakens the migration hypothesis without excluding it.
Readouts
Neuronal migration in the developing neocortex
Direction: UNCHANGED
Interpretation: No migratory deficit was detected relative to control. This is a real negative result rather than an unperformed measurement.
Show evidence (1 reference)
PMID:38579670 SUPPORT Model Organism
"One individual with a start-loss GLUL variant demonstrated periventricular nodular heterotopia, a neuronal migration disorder, yet overexpression of stabilized GS in mice using in utero electroporation demonstrated no migratory deficits."
Reports the measurement and the absence of an effect.
Show evidence (1 reference)
PMID:38579670 REFUTE Model Organism
"One individual with a start-loss GLUL variant demonstrated periventricular nodular heterotopia, a neuronal migration disorder, yet overexpression of stabilized GS in mice using in utero electroporation demonstrated no migratory deficits."
The model fails to reproduce the human finding it was built to test. Whether that means the heterotopia is coincidental in one patient or that the model is inadequate is unresolved, and is curated as the dee116_heterotopia_mouse_mismatch discussion.
Cross-reference: the interpretation of this negative result is curated as the HUMAN_MODEL_MISMATCH discussion dee116_heterotopia_mouse_mismatch, which sets out the three competing readings and the experiments that would distinguish them.
{ }

Source YAML

click to show 
name: Developmental and Epileptic Encephalopathy 116
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
description: >-
  Developmental and epileptic encephalopathy 116 is caused by heterozygous de
  novo variants in GLUL, which encodes glutamine synthetase. It is the
  dominant, gain-of-function counterpart of a disease that had been known for
  twenty years in its recessive, loss-of-function form, and the two are
  mechanistically opposite. Biallelic loss of glutamine synthetase causes
  congenital glutamine deficiency, with brain malformation, multiorgan failure
  and death in infancy. This entity instead makes the enzyme too stable.

  The lesion is in the regulation of protein turnover, not in the enzyme's
  chemistry. Glutamine synthetase carries an N-terminal degron that triggers
  its own ubiquitin-mediated degradation when glutamine is abundant, so the
  enzyme destroys itself in proportion to how much product it has made. The
  disease variants remove the start codon, either by changing it directly or by
  disrupting splicing of the 5' untranslated region so that the initiation
  codon is skipped. Translation then restarts at an in-frame methionine
  seventeen residues downstream, past the degron. The resulting protein is
  shorter, fully enzymatically competent, and deaf to its own feedback signal.
  The authors of the founding study named the mechanism gain of stabilization.

  What follows clinically is a severe early-onset epileptic encephalopathy:
  seizures usually starting in the first months of life and often refractory,
  global developmental delay with little or no milestone progress, and a
  characteristic imaging picture. Markedly enlarged perivascular spaces are the
  most distinctive radiological feature and have been proposed as a diagnostic
  clue; thinning of the corpus callosum, white matter signal abnormality with
  hypomyelination, cerebral atrophy and deep grey matter T2 hyperintensity are
  variably present. Unlike the recessive disease, patients survive: the nine
  individuals in the founding cohort were all alive between 16 months and 16
  years of age.

  A third feature is odd enough to be worth flagging: every one of the nine
  patients in the founding cohort was female. The first male was reported the
  following year with the same phenotype, so males are affected, but with ten
  patients described in total the imbalance is unexplained.

  Two further things about this entity are unresolved and are curated here as
  open questions rather than as mechanism. First, the biochemistry does not do what
  the mechanism predicts. A stabilized, feedback-insensitive glutamine
  synthetase should raise glutamine and lower ammonia; instead plasma and
  cerebrospinal fluid glutamine are usually normal and sometimes low, and some
  patients are hyperammonaemic, so the metabolic consequence of the stabilized
  enzyme in the brain is not captured by the peripheral measurements available.
  Second, the mutational spectrum is widening beyond the start codon: a
  heterozygous missense variant in the catalytic domain and an in-frame
  duplication have both been reported in patients with the same phenotype, the
  latter with a demonstrated regulatory rather than a stability defect, so
  removal of the degron may be one route to the disease rather than the
  definition of it.
parents:
- Genetic Developmental and Epileptic Encephalopathy
synonyms:
- DEE116
- DEE 116
- GLUL-related developmental and epileptic encephalopathy
- autosomal dominant GLUL-related developmental and epileptic encephalopathy
- epileptic encephalopathy, early infantile, 116
disease_term:
  preferred_term: developmental and epileptic encephalopathy 116
  term:
    id: MONDO:0970945
    label: developmental and epileptic encephalopathy 116
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0970945
      label: developmental and epileptic encephalopathy 116
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:38579670
      reference_title: "Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We ascertained nine individuals with severe developmental delay,
        seizures, and white matter abnormalities but normal plasma and
        cerebrospinal fluid biochemistry with de novo variants in GLUL.
      explanation: >-
        Establishes the disorder as a seizure and neurodevelopmental disease of
        the central nervous system.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:41083803
      reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In contrast, certain variants of GLUL that lead to the loss of the
        N-terminal degron exert a gain-of-function effect, causing an autosomal
        dominant DEE.
      explanation: >-
        Establishes the single-gene, dominant, gain-of-function genetic basis
        that defines the entity.
  - classification_value: ENDOCRINOLOGY_METABOLISM
    evidence:
    - reference: PMID:38579670
      reference_title: "Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        GS is pivotal for the generation of the neurotransmitters glutamate and
        gamma-aminobutyric acid and is the primary mechanism of ammonia
        detoxification in the brain.
      explanation: >-
        Places the affected protein in amino acid and ammonia metabolism, the
        inherited metabolic disease domain.
references:
- reference: PMID:38579670
  title: "Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase."
- reference: PMID:41083803
  title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
- reference: PMID:39985170
  title: "Male proband with intractable seizures and a de novo start-codon-disrupting variant in GLUL."
- reference: PMID:42311234
  title: "A Novel Gain-of-Function GLUL Variant Is Associated With Developmental and Epileptic Encephalopathy With Enlarged Perivascular Spaces."

inheritance:
- name: Autosomal dominant inheritance
  description: >-
    Every reported patient carries a heterozygous variant that arose de novo,
    confirmed by trio sequencing of the proband and both parents. No familial
    transmission has been described, which is consistent with the severity of
    the phenotype. This is the point of contrast with the other GLUL disease:
    congenital glutamine deficiency requires biallelic loss-of-function
    variants and is recessive.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biallelic loss-of-function variants cause congenital glutamine
      deficiency, leading to developmental and epileptic encephalopathy (DEE)
      in an autosomal recessive manner. In contrast, certain variants of GLUL
      that lead to the loss of the N-terminal degron exert a gain-of-function
      effect, causing an autosomal dominant DEE.
    explanation: >-
      States both the dominant transmission of this entity and its contrast
      with the recessive GLUL disease.
  - reference: PMID:38579670
    reference_title: "Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We ascertained nine individuals with severe developmental delay,
      seizures, and white matter abnormalities but normal plasma and
      cerebrospinal fluid biochemistry with de novo variants in GLUL.
    explanation: >-
      Establishes the de novo origin of the variants in the founding cohort.

pathophysiology:
- name: GLUL Start-Loss and 5' UTR Splice Variants
  biological_scale: MOLECULAR
  role: trigger
  mechanism_confidence: ESTABLISHED
  description: >-
    The disease alleles cluster on one target: the initiation codon of GLUL.
    They reach it two ways. Seven of the nine founding patients had variants in
    the start codon itself, and two had variants at the canonical splice site of
    the 5' untranslated region that exclude the initiation codon from the
    mature transcript. Later reports add further alleles at the same splice
    acceptor. All are heterozygous and all arose de novo.

    The spectrum has since begun to widen past the start codon. A de novo
    heterozygous missense variant in the catalytic domain and an in-frame
    duplication have each been reported in a patient with the same phenotype.
    The duplication was shown to disrupt regulation of enzyme activity without
    changing protein expression, which is a different route to the same
    endpoint; the missense variant is not functionally characterised. Both are
    single observations and are curated here as spectrum expansion rather than
    as an established second mechanism.
  genes:
  - preferred_term: GLUL
    term:
      id: hgnc:4341
      label: GLUL
  genetic_context:
    functional_impact_category: GAIN_OF_FUNCTION
    variant_origin: DE_NOVO
    zygosity: HETEROZYGOUS
    description: >-
      Heterozygous de novo variants abolishing use of the canonical GLUL start
      codon, either by altering it directly or by excluding it through a 5'
      untranslated region splice defect.
  evidence:
  - reference: PMID:38579670
    reference_title: "Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seven out of nine were start-loss variants and two out of nine disrupted
      5' UTR splicing resulting in splice exclusion of the initiation codon.
    explanation: >-
      Defines the two allele classes that converge on loss of the canonical
      start codon.
  - reference: PMID:42311234
    reference_title: "A Novel Gain-of-Function GLUL Variant Is Associated With Developmental and Epileptic Encephalopathy With Enlarged Perivascular Spaces."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All reported dominant mutations are within the start codon or the 5 '
      UTR. Here, we report a DEE patient with a de novo variant, c.522_536dup,
      in the catalytic domain of GLUL.
    explanation: >-
      Records the first reported dominant allele outside the start codon
      region, which extends the allelic spectrum beyond the founding
      description.
  downstream:
  - target: Translation Reinitiation at Methionine 18
    causal_link_type: DIRECT
    description: >-
      With the canonical initiation codon unavailable, the ribosome starts at
      the next in-frame methionine.
    evidence:
    - reference: PMID:38579670
      reference_title: "Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Using transfection-based expression systems and mass spectrometry,
        these variants were shown to lead to translation initiation of GS from
        methionine 18, downstream of the N-terminal degron motif
      explanation: >-
        Directly demonstrates, by mass spectrometry, that the variants shift
        the initiation site to methionine 18.

- name: Translation Reinitiation at Methionine 18
  biological_scale: MOLECULAR
  role: intermediate
  mechanism_confidence: ESTABLISHED
  description: >-
    The alternative start codon lies seventeen residues into the protein, in
    frame with the rest of it. Reinitiation there produces a glutamine
    synthetase that is complete except for its N-terminal seventeen amino
    acids. That short missing segment is the entire pathogenic consequence: it
    contains the degron, and nothing else about the protein is altered. This is
    why the variants are not loss-of-function despite abolishing the normal
    start codon.
  biological_processes:
  - preferred_term: translational initiation
    modifier: ABNORMAL
    term:
      id: GO:0006413
      label: translational initiation
  evidence:
  - reference: PMID:39985170
    reference_title: "Male proband with intractable seizures and a de novo start-codon-disrupting variant in GLUL."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In both scenarios, a truncated protein is produced by reinitiation of the
      translation at an alternative start codon 17 amino acids downstream
      (Met18), removing a 5′ degron sequence critical to the regulation of
      glutamine synthetase degradation.
    explanation: >-
      States precisely what reinitiation at methionine 18 removes and why it
      matters.
  downstream:
  - target: Escape from Glutamine-Induced Degradation of Glutamine Synthetase
    causal_link_type: DIRECT
    description: >-
      The truncated protein no longer carries the degron that would target it
      for ubiquitin-mediated degradation when glutamine is high.
    evidence:
    - reference: PMID:38579670
      reference_title: "Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        resulting in a protein that is stable and enzymatically competent but
        insensitive to negative feedback by glutamine
      explanation: >-
        The direct statement of the consequence: stability retained, catalysis
        retained, feedback lost.

- name: Escape from Glutamine-Induced Degradation of Glutamine Synthetase
  biological_scale: MOLECULAR
  role: central_effector
  mechanism_confidence: ESTABLISHED
  description: >-
    Glutamine synthetase is normally held in check by its own product. When
    glutamine is abundant, lysine residues in the N-terminal region are
    acetylated, which triggers ubiquitin-mediated degradation of the enzyme.
    That degron is a negative feedback loop implemented as protein turnover
    rather than as allosteric inhibition, and it is what the disease removes.
    The truncated enzyme is not degraded under high glutamine, so its abundance
    is no longer set by how much product it has made. The founding study named
    this gain of stabilization, and it is the rate-limiting step of the
    disorder: everything upstream converges on it, and everything downstream
    follows from it.
  biological_processes:
  - preferred_term: proteasome-mediated ubiquitin-dependent protein catabolic process
    modifier: DECREASED
    term:
      id: GO:0043161
      label: proteasome-mediated ubiquitin-dependent protein catabolic process
  - preferred_term: protein stabilization
    modifier: INCREASED
    term:
      id: GO:0050821
      label: protein stabilization
  evidence:
  - reference: PMID:38579670
    reference_title: "Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      GS levels are regulated post-translationally by an N-terminal degron that
      enables the ubiquitin-mediated degradation of GS in a glutamine-induced
      manner.
    explanation: >-
      Describes the normal feedback mechanism whose removal defines the
      disease.
  - reference: PMID:39985170
    reference_title: "Male proband with intractable seizures and a de novo start-codon-disrupting variant in GLUL."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The truncated glutamine synthetase retains its enzymatic activity yet
      fails to undergo degradation in conditions of high glutamine
    explanation: >-
      States the defining property of the stabilized enzyme, and that catalysis
      is unaffected.
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Normally, the lysine residues located in the N-terminal region of GS are
      acetylated at high glutamine concentrations, triggering ubiquitin-mediated
      protein degradation and serving as a negative feedback mechanism
    explanation: >-
      Gives the molecular detail of the feedback loop, the acetylation step
      that reads glutamine concentration.
  downstream:
  - target: Unregulated Glutamine Synthetase Activity in Astrocytes and Glial Progenitors
    causal_link_type: DIRECT
    description: >-
      An enzyme that cannot be removed in proportion to its product keeps
      working when it should be switched off.
    evidence:
    - reference: PMID:42311234
      reference_title: "A Novel Gain-of-Function GLUL Variant Is Associated With Developmental and Epileptic Encephalopathy With Enlarged Perivascular Spaces."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        However, under either low or high glutamine concentrations, the mutant
        exhibited significantly higher enzyme activity than the wild-type,
        indicating disrupted regulation of glutamine synthetase activity.
      explanation: >-
        Measures the functional endpoint directly: activity that fails to track
        glutamine concentration in either direction.

- name: Unregulated Glutamine Synthetase Activity in Astrocytes and Glial Progenitors
  biological_scale: CELLULAR
  role: intermediate
  mechanism_confidence: ESTABLISHED
  description: >-
    The cell type matters, and it is not the neuron. Single-cell transcriptomic
    analysis of human tissue shows GLUL expressed in neural and glial progenitor
    cells and in mature astrocytes, and not in post-mitotic neurons. The
    astrocyte is where glutamate taken up from the synaptic cleft is converted
    to glutamine for return to the neuron, so an astrocytic enzyme running
    outside its feedback control acts directly on the supply side of the
    glutamate-glutamine cycle. Expression in progenitors adds a developmental
    dimension: the same dysregulation is present while the brain is being
    built, not only once it is working.
  molecular_functions:
  - preferred_term: glutamine synthetase activity
    modifier: GAIN_OF_FUNCTION
    term:
      id: GO:0004356
      label: glutamine synthetase activity
  cell_types:
  - preferred_term: Astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  - preferred_term: Neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  evidence:
  - reference: PMID:38579670
    reference_title: "Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Analysis of human single-cell transcriptomes demonstrated that GLUL is
      widely expressed in neuro- and glial-progenitor cells and mature
      astrocytes but not in post-mitotic neurons.
    explanation: >-
      Establishes which cells carry the dysregulated enzyme, and excludes the
      neuron.
  - reference: PMID:42311234
    reference_title: "A Novel Gain-of-Function GLUL Variant Is Associated With Developmental and Epileptic Encephalopathy With Enlarged Perivascular Spaces."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Glutamate is excreted by neurons into the synaptic cleft as a
      neurotransmitter and absorbed by astrocytes, where it is converted into
      glutamine by GS.
    explanation: >-
      Places the enzyme at the astrocytic step of the glutamate-glutamine
      cycle, which is why an astrocytic defect changes neurotransmitter
      handling.
  downstream:
  - target: Disrupted Glutamate-Glutamine Homeostasis in the Developing Brain
    causal_link_type: DIRECT
    description: >-
      Loss of feedback control over the enzyme that sets the glutamine supply
      perturbs the tightly regulated balance between glutamate and glutamine.
    evidence:
    - reference: PMID:41083803
      reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Alterations in the functionality of the protein can disrupt
        glutamate–glutamine homeostasis, causing severe consequences in brain
        development and function.
      explanation: >-
        States the causal step from altered enzyme function to disrupted
        homeostasis and developmental consequence.

- name: Disrupted Glutamate-Glutamine Homeostasis in the Developing Brain
  biological_scale: TISSUE
  role: intermediate
  mechanism_confidence: PROVISIONAL
  description: >-
    Glutamine synthetase sits at the junction of three things the brain cannot
    afford to get wrong: it makes the precursor from which both glutamate and
    GABA are regenerated, and it is the principal route by which ammonia is
    detoxified in the brain. Losing regulatory control of it during
    neurodevelopment is the proposed proximate cause of both the epilepsy and
    the developmental arrest.

    The confidence here is PROVISIONAL rather than ESTABLISHED, and
    deliberately so. The step is asserted on the basis of what the enzyme does
    rather than on a measurement of glutamate or glutamine in an affected
    brain, and the peripheral biochemistry that is available does not behave as
    the mechanism predicts. That mismatch is recorded as an open knowledge gap
    rather than resolved here.
  biological_processes:
  - preferred_term: L-glutamine metabolic process
    modifier: DYSREGULATED
    term:
      id: GO:0006541
      label: L-glutamine metabolic process
  - preferred_term: glutamate metabolic process
    modifier: DYSREGULATED
    term:
      id: GO:0006536
      label: glutamate metabolic process
  evidence:
  - reference: PMID:38579670
    reference_title: "Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      GS is pivotal for the generation of the neurotransmitters glutamate and
      gamma-aminobutyric acid and is the primary mechanism of ammonia
      detoxification in the brain.
    explanation: >-
      Establishes the three brain functions that depend on this enzyme and are
      therefore exposed by its dysregulation.
  - reference: PMID:38579670
    reference_title: "Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings underline the importance of tight regulation of glutamine
      metabolism during neurodevelopment in humans.
    explanation: >-
      The founding study's own conclusion, framed at the level of regulation
      during development rather than of enzyme quantity.
  downstream:
  - target: Developmental and Epileptic Encephalopathy
    causal_link_type: DIRECT
    description: >-
      Perturbed excitatory and inhibitory neurotransmitter supply during
      development produces the seizure and developmental phenotype.
    evidence:
    - reference: PMID:41083803
      reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        However, the loss of this critical domain disturbs the regulatory
        process while preserving the enzyme activity, causing pathological
        symptoms including epilepsy and GDD
      explanation: >-
        States the causal step from loss of degron-mediated regulation to
        epilepsy and global developmental delay.
  - target: White Matter and Perivascular Space Abnormality
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The same metabolic dysregulation is associated with a distinctive
      structural brain phenotype, most consistently enlarged perivascular
      spaces and a thin corpus callosum. The link is a clinical association;
      no study has shown how glutamine synthetase dysregulation produces these
      changes, hence INDIRECT.
    evidence:
    - reference: PMID:41083803
      reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The brain MRI findings consistently revealed prominent perivascular
        spaces and thinning of the corpus callosum in patients with AD type of
        the disease.
      explanation: >-
        Establishes the structural phenotype as a consistent feature of the
        dominant GLUL disease.

- name: Developmental and Epileptic Encephalopathy
  biological_scale: ORGANISM
  role: consequence
  mechanism_confidence: ESTABLISHED
  description: >-
    The clinical endpoint. Seizures typically begin in the first months of
    life, are often refractory to multiple antiseizure medications, and take
    varied forms across patients: generalized tonic-clonic, myoclonic, tonic,
    clonic, focal, and infantile spasms have all been reported. Global
    developmental delay is universal and severe, with several patients
    achieving head control and little beyond it. Unlike the recessive GLUL
    disease, which kills in infancy, this one is survivable.
  evidence:
  - reference: PMID:39985170
    reference_title: "Male proband with intractable seizures and a de novo start-codon-disrupting variant in GLUL."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Distinct from the recessive form of disease, the dominant form is
      associated with intractable seizures, global developmental delay, and
      hypotonia.
    explanation: >-
      Summarises the clinical endpoint and contrasts it with the recessive
      disease.
  - reference: PMID:39985170
    reference_title: "Male proband with intractable seizures and a de novo start-codon-disrupting variant in GLUL."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Moreover, all nine individuals are alive at current ages of 16 months to
      16 years.
    explanation: >-
      Establishes survival into childhood and adolescence, the sharpest
      clinical difference from congenital glutamine deficiency.

- name: White Matter and Perivascular Space Abnormality
  biological_scale: TISSUE
  role: consequence
  mechanism_confidence: PROVISIONAL
  description: >-
    A structural imaging phenotype consistent enough to be proposed as a
    diagnostic clue. Markedly enlarged perivascular spaces are the most
    distinctive finding and were present in most reported patients with the
    dominant disease; thinning of the corpus callosum accompanies them.
    Hypomyelination or demyelination was described in seven of ten earlier
    patients but absent in a later series of three, while that later series
    found cerebral atrophy in all three and deep grey matter T2 hyperintensity
    in two. The mechanism connecting glutamine synthetase dysregulation to
    these changes is not known, and the reporting authors say so.
  evidence:
  - reference: PMID:42311234
    reference_title: "A Novel Gain-of-Function GLUL Variant Is Associated With Developmental and Epileptic Encephalopathy With Enlarged Perivascular Spaces."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Her brain MRI demonstrated involvement of the white matter
      signal-intensity alterations and markedly enlarged perivascular spaces.
    explanation: >-
      Documents both components of this node in a patient with a confirmed de
      novo GLUL variant.
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings are frequently associated with systemic metabolic
      abnormality and mitochondrial diseases
    explanation: >-
      The only mechanistic framing the literature offers for these imaging
      findings is an analogy to other metabolic disorders, which is why this
      node is PROVISIONAL.
  - reference: PMID:39985170
    reference_title: "Male proband with intractable seizures and a de novo start-codon-disrupting variant in GLUL."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His brain magnetic resonance imaging (MRI) at ages 1 and 3 years was
      normal.
    explanation: >-
      A genetically confirmed patient with entirely normal imaging at two time
      points in early childhood. Structural change is therefore not obligatory,
      and a normal MRI does not argue against the diagnosis.

phenotypes:
- category: Neurological
  name: Seizures
  description: >-
    Seizures are the presenting feature in most patients. Onset spans the first
    two years of life, most often within the first months, though the one adult
    reported so far began at 24 months. They are frequently refractory:
    multiple antiseizure medications and a ketogenic diet were tried without
    lasting control in several reported patients. The semiology is not uniform.
    Generalized tonic-clonic, myoclonic, tonic, clonic, focal, atonic and
    spasm-like seizures have all been reported, and the mix differs between
    patients; in the adult proband the combination of seizure types and the
    electroencephalographic findings amounted to a clinical diagnosis of
    Lennox-Gastaut syndrome.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A comparison of our patients with previously reported cases revealed
      common symptoms, including epilepsy and global developmental delay.
    explanation: >-
      Establishes epilepsy as a feature shared across every reported patient
      with this entity, supporting the VERY_FREQUENT band.
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The seizure patterns and responses to antiseizure medications varied
      among patients, reflecting their diverse phenotypic spectrum.
    explanation: >-
      Records the heterogeneity of semiology and drug response.
  - reference: PMID:39985170
    reference_title: "Male proband with intractable seizures and a de novo start-codon-disrupting variant in GLUL."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report the first male with a pathogenic de novo variant in the
      same critical region of GLUL, with a phenotype of refractory focal and
      generalized seizures, as well as developmental delays.
    explanation: >-
      Documents refractory focal and generalized seizures in a genetically
      confirmed patient.
  - reference: PMID:39985170
    reference_title: "Male proband with intractable seizures and a de novo start-codon-disrupting variant in GLUL."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Taken together, his multiple seizure types and EEG findings are
      consistent with a clinical diagnosis of Lennox Gastaut syndrome.
    explanation: >-
      Records that the seizure phenotype in the one adult reported so far met
      criteria for a recognised electroclinical syndrome.

- category: Neurological
  name: Global Developmental Delay
  description: >-
    Universal and severe. Reported patients typically achieve head control and
    little more; one series describes developmental arrest, with no further
    milestones gained between two and six years of age despite improving
    seizure control. Speech is generally absent.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A comparison of our patients with previously reported cases revealed
      common symptoms, including epilepsy and global developmental delay.
    explanation: >-
      Establishes global developmental delay as common to every reported
      patient, supporting the VERY_FREQUENT band.
  - reference: PMID:38579670
    reference_title: "Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We ascertained nine individuals with severe developmental delay,
      seizures, and white matter abnormalities but normal plasma and
      cerebrospinal fluid biochemistry with de novo variants in GLUL.
    explanation: >-
      Records severe developmental delay across the founding cohort of nine.

- category: Neuroimaging
  name: Dilation of Perivascular Spaces
  description: >-
    The most distinctive imaging finding, and the one proposed as a diagnostic
    clue for GLUL-related disease. Enlarged perivascular spaces were present in
    most reported patients with the dominant form and can be marked. They are
    otherwise associated with small vessel disease and with neuroinflammatory
    and neurodegenerative conditions, so the finding is not specific in
    isolation; it is their presence in an infant with a developmental and
    epileptic encephalopathy that is informative.
  phenotype_term:
    preferred_term: Dilation of Virchow-Robin spaces
    term:
      id: HP:0012520
      label: Dilation of Virchow-Robin spaces
  frequency: FREQUENT
  evidence:
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prominent perivascular spaces, which is a finding associated with small
      vessel disease and various neuroinflammatory and neurodegenerative
      conditions, were identified in most patients with AD type of the disease
    explanation: >-
      States that the finding was present in most patients with the dominant
      disease, which supports the FREQUENT band, and records that it is not
      specific to this disorder.
  - reference: PMID:42311234
    reference_title: "A Novel Gain-of-Function GLUL Variant Is Associated With Developmental and Epileptic Encephalopathy With Enlarged Perivascular Spaces."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      highlights enlarged perivascular spaces as a diagnostic clue in
      GLUL-related disorders
    explanation: >-
      Proposes the finding as a diagnostic pointer toward GLUL in an
      undiagnosed encephalopathy.

- category: Neuroimaging
  name: Thin Corpus Callosum
  description: >-
    Reported consistently alongside the enlarged perivascular spaces, and in
    one series the callosal thinning was most severe in the patient with the
    most severe cerebral atrophy.
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  evidence:
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The brain MRI findings consistently revealed prominent perivascular
      spaces and thinning of the corpus callosum in patients with AD type of
      the disease.
    explanation: >-
      Records callosal thinning as a consistent finding in the dominant
      disease.
  notes: >-
    Frequency omitted. The source says "consistently revealed" without giving a
    count or proportion, and the phrase is a qualitative summary across two
    cohorts rather than a frequency statement about a defined denominator.

- category: Neuroimaging
  name: Abnormal Cerebral White Matter
  description: >-
    White matter signal abnormality was described in the founding cohort, and
    hypomyelination or demyelination in seven of ten earlier patients. The
    finding is not universal: a later series of three patients had neither,
    which is one of the ways the imaging phenotype turns out to be more
    variable than the first description suggested.
  phenotype_term:
    preferred_term: Abnormal cerebral white matter morphology
    term:
      id: HP:0002500
      label: Abnormal cerebral white matter morphology
  frequency: FREQUENT
  evidence:
  - reference: PMID:38579670
    reference_title: "Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We ascertained nine individuals with severe developmental delay,
      seizures, and white matter abnormalities but normal plasma and
      cerebrospinal fluid biochemistry with de novo variants in GLUL.
    explanation: >-
      Records white matter abnormality as a defining feature of the founding
      cohort of nine.
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although hypomyelination or demyelination was also commonly observed in
      previously reported cases (7 out of 10 in AD cases), our patients did not
      have these features.
    explanation: >-
      Gives the count behind the FREQUENT band, 7 of 10, and simultaneously
      shows the feature is absent in some patients.

- category: Neuroimaging
  name: Cerebral Hypomyelination
  description: >-
    Hypomyelination or demyelination was reported in seven of the ten earlier
    patients with the dominant disease, and in none of the three in the most
    recent series. It is curated separately from the general white matter
    finding because the founding cohort described it specifically.
  phenotype_term:
    preferred_term: Cerebral hypomyelination
    term:
      id: HP:0006808
      label: Cerebral hypomyelination
  frequency: FREQUENT
  evidence:
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although hypomyelination or demyelination was also commonly observed in
      previously reported cases (7 out of 10 in AD cases), our patients did not
      have these features.
    explanation: >-
      Gives the count behind the FREQUENT band, 7 of 10, and records that the
      feature was absent in a later three-patient series.

- category: Neuroimaging
  name: Cerebral Atrophy
  description: >-
    Present in all three patients of the most recent series and explicitly
    listed by those authors as a feature not previously described in the
    dominant GLUL disease. It appears alongside ventriculomegaly and
    progressive white matter volume loss on follow-up imaging.
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  evidence:
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Conversely, all our patients showed cerebral atrophy, and two of them
      (Patients 1 and 2) had T2 hyperintensity in the basal ganglia or the
      thalamus.
    explanation: >-
      Documents cerebral atrophy in all three patients of the series that first
      described it in this entity.
  notes: >-
    Frequency omitted. Cerebral atrophy was reported in three of three patients
    in one series and explicitly described as not previously reported in this
    disease, so a frequency band over all patients cannot be justified from
    either number.

- category: Neuroimaging
  name: Deep Grey Matter T2 Hyperintensity
  description: >-
    Symmetric T2 signal change in the thalamus and basal ganglia, in one
    patient extending to the mammillary body and brainstem. Like cerebral
    atrophy, this was first described in the most recent series and had not
    been reported in earlier patients with the dominant disease.
  phenotype_term:
    preferred_term: Abnormal basal ganglia MRI signal intensity
    term:
      id: HP:0012751
      label: Abnormal basal ganglia MRI signal intensity
  evidence:
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, our patients exhibited additional phenotypes, such as
      hypertonia, cerebral atrophy, and T2 hyperintensity in deep grey matter,
      which have not been described in patients with autosomal dominant
      GLUL-related DEE.
    explanation: >-
      Records the finding and its status as newly described in this entity.
  notes: >-
    Bound to HP:0012751 Abnormal basal ganglia MRI signal intensity, the closest
    available term. HPO has no single term covering signal change across the
    deep grey matter as a whole, and the thalamic component is therefore not
    captured by this binding. Searched with runoak against sqlite:obo:hp for
    "basal ganglia" and reviewed all fifteen matches.

- category: Neurological
  name: Hypertonia
  description: >-
    Increased tone, rigidity and generalized spasticity with hyperreflexia have
    been described in the most recent series, and were listed by those authors
    as newly reported in this entity. The founding description instead
    emphasised hypotonia, so tone abnormality in either direction should be
    expected rather than one specific pattern.
  phenotype_term:
    preferred_term: Hypertonia
    term:
      id: HP:0001276
      label: Hypertonia
  evidence:
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, our patients exhibited additional phenotypes, such as
      hypertonia, cerebral atrophy, and T2 hyperintensity in deep grey matter,
      which have not been described in patients with autosomal dominant
      GLUL-related DEE.
    explanation: >-
      Records hypertonia and its status as newly described in the dominant
      disease.
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At 1 year of age, neurological examination revealed microcephaly and
      generalized spasticity with hyperreflexia.
    explanation: >-
      A specific patient description of the hypertonic phenotype.
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although all patients carrying AD variants in the previous studies
      exhibited hypotonia, the neurological examinations of our patients
      revealed rigidity and spasticity.
    explanation: >-
      States the contrast directly: increased tone in this series against
      hypotonia in every previously reported dominant patient.

- category: Neurological
  name: Hypotonia
  description: >-
    Reported as a feature of the dominant disease in the founding description
    and in the first male proband. It sits in tension with the hypertonia
    reported in the most recent series; both are recorded here rather than one
    being preferred, because the two cohorts are small and the sources do not
    reconcile them.
  phenotype_term:
    preferred_term: Generalized hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:39985170
    reference_title: "Male proband with intractable seizures and a de novo start-codon-disrupting variant in GLUL."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Distinct from the recessive form of disease, the dominant form is
      associated with intractable seizures, global developmental delay, and
      hypotonia.
    explanation: >-
      Lists hypotonia among the defining features of the dominant disease.
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although all patients carrying AD variants in the previous studies
      exhibited hypotonia, the neurological examinations of our patients
      revealed rigidity and spasticity.
    explanation: >-
      Supplies the denominator behind the VERY_FREQUENT band, all previously
      reported dominant patients, and simultaneously records the three-patient
      series in which tone was increased instead.

biochemical:
- name: Plasma and Cerebrospinal Fluid Glutamine
  context: >-
    The measurement the mechanism predicts should be abnormal, and usually is
    not. A stabilized, feedback-insensitive glutamine synthetase should raise
    glutamine; in the founding cohort of nine, plasma and cerebrospinal fluid
    biochemistry was normal. A later three-patient series found plasma
    glutamine low in one and normal in two. Across all reported dominant
    patients, cerebrospinal fluid glutamine has ranged from low to high. This
    is the observation the entry's principal knowledge gap is about.
  presence: VARIABLE
  evidence:
  - reference: PMID:38579670
    reference_title: "Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We ascertained nine individuals with severe developmental delay,
      seizures, and white matter abnormalities but normal plasma and
      cerebrospinal fluid biochemistry with de novo variants in GLUL.
    explanation: >-
      Establishes that biochemistry was normal across the founding cohort.
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although some patients with the AD type of the disease showed reduced
      plasma glutamine levels, most patients exhibited normal plasma glutamine.
      The CSF glutamine levels were also inconsistent among patients, ranging
      from low to high.
    explanation: >-
      Records the range across reported patients, including values in the
      direction opposite to the one the mechanism predicts.
  notes: >-
    Not usable as a diagnostic marker. See the second diagnosis entry and the
    dee116_biochemistry_contradicts_mechanism discussion.
- name: Plasma Ammonia
  context: >-
    Raised in two of the three patients in the most recent series, at 227 and
    184 micrograms per decilitre. That direction also contradicts the
    mechanism, since more glutamine synthetase should consume more ammonia, not
    less. The reporting authors raise valproic acid, which these patients
    receive and which is known to raise ammonia, as a possible explanation.
  presence: VARIABLE
  evidence:
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Furthermore, Patients 1 and 3 in our cohort showed elevated ammonia
      levels.
    explanation: >-
      Records the hyperammonaemia in the dominant disease.
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some showed low glutamine levels in the plasma or CSF and elevation of
      ammonia, although the high ammonia level might have been caused by the
      use of valproic acid
    explanation: >-
      The drug-effect confound, which is why the raised ammonia cannot be read
      as a disease feature without stratifying by valproic acid exposure.

genetic:
- name: GLUL
  notes: >-
    GLUL encodes glutamine synthetase. It is the single causative gene, and it
    causes two different diseases by two opposite mechanisms. Biallelic
    loss-of-function missense variants abolish enzyme activity and cause
    congenital glutamine deficiency, an autosomal recessive disorder with brain
    malformation, multiorgan failure and infantile death. Heterozygous de novo
    variants that remove the N-terminal degron stabilize the enzyme and cause
    this entity. Reported dominant alleles include c.1A>C, c.1A>G, c.1A>T and
    c.3G>A affecting the initiation codon directly, c.-13-2A>G and c.-13-1G>A
    and c.-13-1G>C affecting the 5' untranslated region splice acceptor, and
    more recently c.604T>C p.(Trp202Arg) and c.522_536dup in the coding
    sequence. Both diseases are rare: roughly six recessive and thirteen
    dominant patients had been reported by late 2025.
  gene_term:
    preferred_term: GLUL
    term:
      id: hgnc:4341
      label: GLUL
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  evidence:
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both loss-of-function and gain-of-function variants of GLUL are known to
      cause genetic disorders in humans.
    explanation: >-
      States the bidirectional genotype-phenotype relationship of the gene.
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only six autosomal recessive cases and ten autosomal dominant cases have
      been reported to date, and knowledge about GLUL-related DEE remains
      limited.
    explanation: >-
      Quantifies how few patients define this entity, which bounds every
      frequency and genotype-phenotype statement in this entry.
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Another novel variant, c.604T > C (p.Trp202Arg), was heterozygous without
      any additional pathogenic or likely pathogenic variant in GLUL, unlike
      all other previously reported missense variants which exhibited a
      biallelic status.
    explanation: >-
      Records the first heterozygous missense allele, which does not fit the
      start-loss mechanism and is uncharacterised functionally.

differential_diagnoses:
- name: Congenital glutamine deficiency
  description: >-
    The other GLUL disease, and the one a clinician is more likely to have
    heard of. It is caused by biallelic loss-of-function variants, is
    autosomal recessive, and presents in the neonatal period with severe brain
    malformation, multiorgan failure and death in infancy. Its biochemistry is
    the mirror image of what this entity was predicted to show: markedly
    reduced plasma and cerebrospinal fluid glutamine with hyperammonaemia.
  distinguishing_features:
  - >-
    Inheritance separates them cleanly: biallelic inherited variants in the
    recessive disease versus a single de novo variant in this one.
  - >-
    Outcome separates them. Congenital glutamine deficiency kills in infancy;
    every reported patient with the dominant disease was alive between 16
    months and 16 years of age.
  - >-
    Biochemistry separates them in principle but not in practice. Low glutamine
    with raised ammonia is expected and usually observed in the recessive
    disease. In the dominant one glutamine is usually normal and ammonia is
    sometimes raised, so the panel neither confirms nor excludes it.
  - >-
    Imaging differs: brain malformation and ventriculomegaly in the recessive
    disease, against enlarged perivascular spaces and a thin corpus callosum in
    this one.
  evidence:
  - reference: PMID:42311234
    reference_title: "A Novel Gain-of-Function GLUL Variant Is Associated With Developmental and Epileptic Encephalopathy With Enlarged Perivascular Spaces."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recessive forms are associated with congenital glutamine deficiency,
      manifesting with severe brain malformation, multiorgan failure, and early
      death.
    explanation: >-
      Characterises the recessive disease that must be distinguished from this
      one.
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In AR cases, low plasma or CSF glutamine and elevated ammonia levels were
      common findings, although two patients (Patients 18 and 19) showed normal
      plasma glutamine levels.
    explanation: >-
      Gives the biochemical profile of the recessive disease, and notes that
      even there it is not universal.

progression:
- phase: Presentation and seizure onset
  age_range: First two years of life, most often the first months
  notes: >-
    Presentation is with seizures, developmental delay, or both. Seizure onset
    across the founding cohort spanned 10 weeks to 22 months; in a later series
    of three, two began at 3 months and one at 4 weeks. The one adult reported
    so far began at 24 months, the latest onset described.
  evidence:
  - reference: PMID:39985170
    reference_title: "Male proband with intractable seizures and a de novo start-codon-disrupting variant in GLUL."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seizures were first reported between ages 1 and 2 years.
    explanation: >-
      Records the later end of the onset range, in the one adult proband.
- phase: Developmental arrest
  notes: >-
    Milestones are not merely delayed but stop. In the most recent series one
    patient could sit with support at six years and gained nothing further,
    which the reporting authors describe as developmental arrest; another
    gained head control and rolling but no further milestones by seven years,
    even across periods when seizures were controlled. That dissociation
    matters clinically, because it means seizure control cannot be expected to
    restore developmental progress.
  evidence:
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At the last follow-up at 6 years of age, he was only able to sit with
      support, with no further developmental progress observed, suggesting
      developmental arrest.
    explanation: >-
      The explicit statement of developmental arrest in one patient.
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although neurological examination revealed increased rigidity, the patient
      gained the ability to control his head and roll over. Nevertheless, no
      further developmental milestones were achieved even by 7 years of age.
    explanation: >-
      A second patient in whom milestones stopped despite periods of seizure
      control.
- phase: Long-term course
  age_range: Reported to 25 years
  notes: >-
    Survival into adulthood is documented. Every patient in the founding cohort
    was alive at ages between 16 months and 16 years, and the one adult reported
    was 25 at the time of writing, still with myoclonic and generalized
    tonic-clonic seizures, non-verbal and requiring total care. This is the
    sharpest contrast with the recessive GLUL disease, which is lethal in
    infancy.
  evidence:
  - reference: PMID:39985170
    reference_title: "Male proband with intractable seizures and a de novo start-codon-disrupting variant in GLUL."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Moreover, all nine individuals are alive at current ages of 16 months to
      16 years.
    explanation: >-
      Establishes survival across the founding cohort.
  - reference: PMID:39985170
    reference_title: "Male proband with intractable seizures and a de novo start-codon-disrupting variant in GLUL."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Now age 25, while taking zonisamide, brivaracetam, and cannabidiol, his
      seizures continue and are predominantly myoclonic (occurring less than 10
      times per week) and GTC (occurring, on average, every 4-5 days), with
      occasional tonic seizures.
    explanation: >-
      Documents the adult course, with seizures continuing on treatment at 25
      years.

treatments:
- name: Antiseizure Medication
  description: >-
    There is no treatment directed at the mechanism. Seizure control is
    attempted with conventional antiseizure medications and, in some patients,
    a ketogenic diet, and the results are poor and inconsistent: several
    patients remained refractory through multiple agents, while others achieved
    partial control with valproic acid or perampanel added late. Agents
    reported in use include vigabatrin, prednisolone, topiramate, valproic
    acid, lacosamide, perampanel, lamotrigine and levetiracetam. No agent has
    been shown to work better than another in this disorder, and no
    genotype-directed choice is possible on current evidence.

    One practical caution follows from the biochemistry. Some patients are
    hyperammonaemic, and the authors of the series reporting that raise
    valproic acid as a possible cause rather than a disease feature. Since
    valproic acid is among the drugs used here, a rising ammonia in a treated
    patient should not be assumed to reflect the underlying enzyme defect.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The seizure patterns and responses to antiseizure medications varied
      among patients, reflecting their diverse phenotypic spectrum.
    explanation: >-
      Supports the use of antiseizure medication while establishing that
      response is inconsistent, which is why the support is PARTIAL.
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seizures persisted despite trials of multiple antiseizure medications and
      a ketogenic diet, but at 3 years of age, the seizures were controlled with
      the addition of valproic acid.
    explanation: >-
      A specific illustration of refractoriness followed by partial response,
      in a single patient.
  - reference: PMID:39985170
    reference_title: "Male proband with intractable seizures and a de novo start-codon-disrupting variant in GLUL."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall, zonisamide and brivaracetam have proven most effective in
      reducing the frequency of the myoclonic and GTC seizures, respectively.
    explanation: >-
      The only drug-specific efficacy statement in the literature for this
      disorder. It is one patient followed over two decades, so it is a
      starting point for drug choice rather than evidence of superiority.
  - reference: PMID:39985170
    reference_title: "Male proband with intractable seizures and a de novo start-codon-disrupting variant in GLUL."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Throughout the course of his adolescence, various interventions,
      including a ketogenic diet, medical cannabis, and cannabidiol, were
      introduced, with no clear benefit to seizure frequency or duration of
      post-ictal recovery.
    explanation: >-
      Refutes benefit from ketogenic diet, medical cannabis and cannabidiol in
      the one patient in whom all three were tried. A second patient likewise
      failed a ketogenic diet.
  - reference: PMID:39985170
    reference_title: "Male proband with intractable seizures and a de novo start-codon-disrupting variant in GLUL."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whether this reduction in GTC seizure frequency was in response to
      treatment interventions or merely the effect of having completed the
      pubertal transition is unclear.
    explanation: >-
      The reporting authors' own caveat on the one apparent drug response in
      the literature, which is why no antiseizure medication can be recommended
      on current evidence.
  notes: >-
    No therapeutic_agent is bound because no single drug is established for this
    disorder; the treatment entry describes a class of symptomatic management,
    and binding one CHEBI agent would misrepresent a list of agents tried
    empirically as a recommended therapy.

experimental_models:
- name: Transfection-based expression system for GLUL start-loss variants
  experimental_model_type: CELL_LINE
  cell_source: Transfected cell line expressing wild-type or variant GLUL constructs
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:38579670
  description: >-
    The system in which the mechanism was established. Wild-type and variant
    GLUL constructs were expressed and the resulting protein analysed by mass
    spectrometry, which is what showed that the variants shift the initiation
    site to methionine 18 rather than simply abolishing expression. The same
    system supported the stability and feedback-response experiments behind the
    gain-of-stabilization claim.
  modeled_mechanisms:
  - target: Translation Reinitiation at Methionine 18
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      Mass spectrometry of the expressed protein identifies the actual
      translation start site, which is the observation the whole mechanism rests
      on and which no clinical measurement could supply.
    limitations: >-
      Constructs are expressed from a plasmid rather than from the endogenous
      locus, so transcript abundance and the 5' untranslated region context are
      not those of the patient allele. The system therefore establishes that
      reinitiation at methionine 18 occurs and that the product is stable, but
      not the relative abundance of the truncated and full-length proteins in
      patient tissue.
    readouts:
    - name: Translation initiation site of the expressed protein
      target: Translation Reinitiation at Methionine 18
      direction: ALTERED
      interpretation: >-
        Mass spectrometry places the start of the variant protein at methionine
        18 rather than methionine 1.
      evidence:
      - reference: PMID:38579670
        reference_title: "Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Using transfection-based expression systems and mass spectrometry,
          these variants were shown to lead to translation initiation of GS from
          methionine 18, downstream of the N-terminal degron motif
        explanation: >-
          Reports the measurement and its result.
    evidence:
    - reference: PMID:38579670
      reference_title: "Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        resulting in a protein that is stable and enzymatically competent but
        insensitive to negative feedback by glutamine
      explanation: >-
        The three properties of the variant protein that this system
        established, all of which are claims about the molecule rather than
        about a tissue.
  notes: >-
    Deliberately minimal. The cached record for PMID:38579670 is the PubMed
    abstract only, which names the transfection-based expression system and mass
    spectrometry but does not describe the cell lines, the cycloheximide chase,
    or the enzyme activity assay in enough detail to curate them as separate
    models with quotable readouts. Anything more would be curated from a
    secondary summary rather than from the source.

animal_models:
- name: Mouse in utero electroporation overexpressing stabilized glutamine synthetase
  species: Mouse
  genotype: Wild type, transiently overexpressing degron-truncated glutamine synthetase in embryonic neocortex
  publication: PMID:38579670
  description: >-
    Not a genetic model of the disease but a targeted test of one hypothesis.
    One patient with a start-loss GLUL variant had periventricular nodular
    heterotopia, a disorder of neuronal migration. The founding study
    electroporated the stabilized enzyme into embryonic mouse neocortex to ask
    whether stabilized glutamine synthetase disturbs migration. It did not, and
    the authors reported the negative result rather than omitting it.
  modeled_mechanisms:
  - target: Unregulated Glutamine Synthetase Activity in Astrocytes and Glial Progenitors
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      Overexpression of the stabilized enzyme in the developing mouse cortex
      produced no migratory deficit, so this model does not reproduce the
      periventricular nodular heterotopia seen in one patient and provides no
      support for a migration-defect route from the enzyme to the human brain
      phenotype.
    limitations: >-
      Three limitations bear directly on how far the negative result can be
      taken. Electroporation overexpresses the protein transiently, in a subset
      of cells, within a narrow developmental window, whereas patients carry
      the variant in every cell from conception. It adds stabilized protein on
      top of the endogenous wild-type enzyme rather than replacing it, so it
      models a gain of dose rather than the patient genotype. And GLUL is
      expressed in astrocytes and neural and glial progenitors rather than in
      post-mitotic neurons, so delivering it to electroporated cortical cells
      may not test the cell type in which the relevant activity resides. The
      result therefore weakens the migration hypothesis without excluding it.
    readouts:
    - name: Neuronal migration in the developing neocortex
      target: Unregulated Glutamine Synthetase Activity in Astrocytes and Glial Progenitors
      direction: UNCHANGED
      interpretation: >-
        No migratory deficit was detected relative to control. This is a real
        negative result rather than an unperformed measurement.
      evidence:
      - reference: PMID:38579670
        reference_title: "Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          One individual with a start-loss GLUL variant demonstrated
          periventricular nodular heterotopia, a neuronal migration disorder,
          yet overexpression of stabilized GS in mice using in utero
          electroporation demonstrated no migratory deficits.
        explanation: >-
          Reports the measurement and the absence of an effect.
    evidence:
    - reference: PMID:38579670
      reference_title: "Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase."
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      snippet: >-
        One individual with a start-loss GLUL variant demonstrated
        periventricular nodular heterotopia, a neuronal migration disorder, yet
        overexpression of stabilized GS in mice using in utero electroporation
        demonstrated no migratory deficits.
      explanation: >-
        The model fails to reproduce the human finding it was built to test.
        Whether that means the heterotopia is coincidental in one patient or
        that the model is inadequate is unresolved, and is curated as the
        dee116_heterotopia_mouse_mismatch discussion.
  notes: >-
    Cross-reference: the interpretation of this negative result is curated as
    the HUMAN_MODEL_MISMATCH discussion dee116_heterotopia_mouse_mismatch, which
    sets out the three competing readings and the experiments that would
    distinguish them.

diagnosis:
- name: Trio Exome or Genome Sequencing
  description: >-
    Molecular diagnosis is the only reliable route, and it must be trio-based:
    the variants are de novo, so demonstrating that neither parent carries the
    change is what establishes causality for a variant class that is easy to
    overlook. Two features make these variants easy to miss on a standard
    pipeline. Variants in the 5' untranslated region fall outside the coding
    sequence that many analyses prioritise, and start-loss variants are not
    always flagged as high-impact. RNA sequencing was used in one patient to
    confirm that a splice acceptor variant does produce the predicted
    degron-removing transcript.
  evidence:
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An alternative splicing event causing loss of the N-terminal degron of GS
      was confirmed by RNA sequencing in a patient carrying c.-13-1G > C
      variant.
    explanation: >-
      Shows RNA sequencing confirming the functional consequence of a
      non-coding variant, which sequence analysis alone would leave uncertain.
  - reference: PMID:39985170
    reference_title: "Male proband with intractable seizures and a de novo start-codon-disrupting variant in GLUL."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      More than half of individuals with a suspected Mendelian disease remain
      undiagnosed after analysis of the exome or genome.
    explanation: >-
      Context for why this patient was diagnosed only on reanalysis after the
      gene-disease association was published, which is the practical diagnostic
      point for a newly described entity.

- name: Plasma and Cerebrospinal Fluid Amino Acid Analysis
  description: >-
    Worth understanding mainly for what it does not do. Biochemical testing is
    diagnostically useful in the recessive GLUL disease, where low glutamine
    with raised ammonia is the expected and usually observed pattern. In this
    dominant entity it is not: the founding cohort had normal plasma and
    cerebrospinal fluid biochemistry, and a later series found heterogeneous
    profiles including low glutamine and elevated ammonia, which is the
    opposite of what a stabilized enzyme predicts. A normal amino acid panel
    therefore does not exclude the diagnosis, and an abnormal one does not
    confirm it.
  evidence:
  - reference: PMID:38579670
    reference_title: "Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We ascertained nine individuals with severe developmental delay,
      seizures, and white matter abnormalities but normal plasma and
      cerebrospinal fluid biochemistry with de novo variants in GLUL.
    explanation: >-
      Establishes that biochemistry was normal across the founding cohort, so a
      normal result cannot exclude the diagnosis.
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These observations suggest that biochemical testing might have some value
      in confirming the AR type of the disease, but its value in the diagnosis
      of the AD type of the disease remains unclear.
    explanation: >-
      The authors' own conclusion about the diagnostic utility of biochemistry
      in this entity.

discussions:
- discussion_id: dee116_biochemistry_contradicts_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why does a stabilized, feedback-insensitive glutamine synthetase not
    produce the biochemical profile it predicts, and what is actually happening
    to glutamine and ammonia in the brains of these patients?
  attaches_to:
  - "pathophysiology#Disrupted Glutamate-Glutamine Homeostasis in the Developing Brain"
  - "pathophysiology#Unregulated Glutamine Synthetase Activity in Astrocytes and Glial Progenitors"
  rationale: >-
    The mechanism makes a clear prediction. An enzyme that converts glutamate
    and ammonia into glutamine, and that can no longer be degraded when
    glutamine is high, should raise glutamine and lower ammonia. The recessive
    disease behaves as the mirror of this: loss of the enzyme gives low
    glutamine and high ammonia, and that is what is usually measured.

    The dominant disease does not. The founding cohort of nine had normal
    plasma and cerebrospinal fluid biochemistry. A later series found
    heterogeneous profiles, with plasma glutamine low in one patient and normal
    in two, cerebrospinal fluid glutamine ranging from low to high across
    reported patients, and elevated ammonia in two of three. The reporting
    authors state plainly that the biochemistry did not agree with the
    gain-of-function mechanism.

    Several explanations are available and none has been tested. Peripheral
    blood may simply not report on astrocytic glutamine handling, in which case
    the measurement is wrong rather than the mechanism. The stabilized enzyme
    may be limited by substrate rather than by its own abundance, so more
    enzyme does not mean more product. The hyperammonaemia may be iatrogenic,
    since valproic acid raises ammonia and is among the drugs these patients
    receive, which is the explanation the reporting authors themselves offer.
    Or the pathogenic consequence may be something other than net flux through
    the enzyme, for instance the loss of a regulatory signal that the degron
    itself carries.

    This matters practically as well as mechanistically, because it is why
    biochemical testing cannot be used to screen for or confirm this diagnosis.
  proposed_experiments:
  - experiment_id: dee116_brain_glutamine_mrs
    name: Magnetic resonance spectroscopy of glutamine and glutamate in patient brain
    description: >-
      Measure glutamine and glutamate directly in the brains of patients with
      confirmed dominant GLUL variants, rather than inferring brain metabolism
      from plasma. This distinguishes the two leading explanations: if brain
      glutamine is raised while plasma is normal, the mechanism is right and
      the peripheral measurement is uninformative; if brain glutamine is also
      normal, the mechanism needs revisiting.
  - experiment_id: dee116_astrocyte_flux_assay
    name: Metabolic flux measurement in patient-derived astrocytes
    description: >-
      Differentiate astrocytes from patient induced pluripotent stem cells and
      measure labelled glutamate to glutamine conversion under varying
      glutamine and ammonia loads. Directly tests whether the stabilized enzyme
      increases flux, or whether flux is substrate-limited so that the extra
      enzyme has no metabolic consequence.
  - experiment_id: dee116_ammonia_valproate_stratification
    name: Ammonia measurement stratified by valproic acid exposure
    description: >-
      Compare ammonia levels in patients on and off valproic acid, or before
      and after starting it. This is the cheapest of the three and settles
      whether the hyperammonaemia is a disease feature or a drug effect, which
      currently confounds every biochemical description of the disorder.
  evidence:
  - reference: PMID:38579670
    reference_title: "Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We ascertained nine individuals with severe developmental delay,
      seizures, and white matter abnormalities but normal plasma and
      cerebrospinal fluid biochemistry with de novo variants in GLUL.
    explanation: >-
      Establishes that biochemistry was normal in the founding cohort despite
      the demonstrated stabilization of the enzyme.
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast, the analysis of patients with AD type of the disease did not
      yield consistent results with the gain-of-function mechanism.
    explanation: >-
      The explicit statement that the observed biochemistry contradicts the
      mechanism.
  - reference: PMID:41083803
    reference_title: "Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some showed low glutamine levels in the plasma or CSF and elevation of
      ammonia, although the high ammonia level might have been caused by the
      use of valproic acid
    explanation: >-
      Records both the contradictory finding and the drug-effect explanation
      the authors offer for part of it.

- discussion_id: dee116_female_predominance
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why were all nine individuals in the founding cohort female, and is the
    apparent female predominance real or an artefact of ascertainment?
  attaches_to:
  - "pathophysiology#GLUL Start-Loss and 5' UTR Splice Variants"
  - "pathophysiology#Unregulated Glutamine Synthetase Activity in Astrocytes and Glial Progenitors"
  rationale: >-
    A de novo autosomal dominant disorder has no reason to affect one sex. This
    one appeared to: every one of the nine probands in the founding cohort was
    female, and the reporting authors noted that the phenotype was
    uncharacterized in males. The hypothesis they offered was a reported
    difference in glutamine metabolism between the sexes, which would place the
    modifier downstream of the variant rather than in transmission.

    The first male proband was reported the following year, and his phenotype
    matched the female cases: refractory seizures, global developmental delay,
    hypotonia. That settles the strong version of the question, which was
    whether males are affected at all. It does not settle the weaker one. With
    ten patients in total, nine of one sex, the imbalance could be chance,
    could be ascertainment, or could be real with males either less severely
    affected or affected differently enough to be diagnosed as something else.

    Distinguishing these needs more patients rather than a new experiment, but
    the metabolic hypothesis is separately testable and would be worth testing
    even at the current cohort size, because a sex difference in glutamine
    handling would bear on the biochemistry gap recorded in the other
    discussion here.
  proposed_experiments:
  - experiment_id: dee116_sex_ratio_cohort_accrual
    name: Sex ratio in a prospectively accrued GLUL cohort
    description: >-
      Accrue patients through GeneMatcher and diagnostic laboratories without
      selecting on phenotype, and report the sex ratio. Ten patients cannot
      distinguish a real 9-to-1 imbalance from chance; a few dozen can.
  - experiment_id: dee116_sex_stratified_gs_turnover
    name: Sex-stratified measurement of glutamine synthetase turnover
    description: >-
      Measure glutamine synthetase abundance and glutamine-induced degradation
      in male and female control cells, and in patient cells of both sexes.
      This tests the specific hypothesis the founding authors offered, that
      sex differences in glutamine metabolism modify the consequence of losing
      the degron.
  evidence:
  - reference: PMID:39985170
    reference_title: "Male proband with intractable seizures and a de novo start-codon-disrupting variant in GLUL."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The original study highlighted that all reported individuals were female
      and that the phenotype remains uncharacterized in males. The
      overrepresentation of females was hypothesized to be due to the reported
      difference in glutamine metabolism between sexes.
    explanation: >-
      States the observation and the hypothesis offered for it.
  - reference: PMID:39985170
    reference_title: "Male proband with intractable seizures and a de novo start-codon-disrupting variant in GLUL."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This indicates that this genetic condition clinically affects both male
      and female individuals. The reason for female predominance among reported
      individuals remains an open question.
    explanation: >-
      Settles that males are affected, and states explicitly that the imbalance
      itself is unexplained.

- discussion_id: dee116_heterotopia_mouse_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    A patient with a start-loss GLUL variant had periventricular nodular
    heterotopia, but overexpressing stabilized glutamine synthetase in mouse
    cortex produced no migration defect. Does the human neuronal migration
    phenotype belong to this disease, and if so why does the mouse experiment
    not reproduce it?
  attaches_to:
  - "pathophysiology#Unregulated Glutamine Synthetase Activity in Astrocytes and Glial Progenitors"
  - "pathophysiology#Disrupted Glutamate-Glutamine Homeostasis in the Developing Brain"
  rationale: >-
    The founding study reported one individual with periventricular nodular
    heterotopia, a disorder of neuronal migration, and then tested the obvious
    hypothesis directly: it overexpressed the stabilized enzyme in the
    developing mouse cortex by in utero electroporation and looked for
    migration defects. There were none. The authors report the negative result
    rather than omitting it, which is why it is curated here as a mismatch
    rather than as an absence of evidence.

    Three readings are open. The heterotopia may be coincidental in a single
    patient, in which case it is not a feature of the disease at all. The mouse
    experiment may not model the human condition adequately, since
    electroporation overexpresses the protein in a subset of cells for a
    limited window whereas patients carry the variant in every cell from
    conception, and since GLUL is expressed in progenitors whose human biology
    the mouse cortex represents imperfectly. Or the migration phenotype may
    depend on the astrocytic and progenitor context rather than on the enzyme
    being present in the migrating neuron, in which case overexpressing it in
    the electroporated cells tests the wrong cell type.

    Whether the heterotopia belongs to the disease is not resolvable from one
    patient, and no subsequent series has reported a second case; the more
    recent cohorts describe atrophy, callosal thinning and perivascular space
    enlargement instead.
  proposed_experiments:
  - experiment_id: dee116_knockin_mouse_migration
    name: Germline knock-in mouse carrying the human start-loss allele
    description: >-
      Replace the electroporation overexpression model with a knock-in that
      carries the human variant in every cell from conception, and assess
      cortical lamination and neuronal migration. This tests the leading
      explanation for the negative result, that the model system rather than
      the hypothesis was inadequate.
  - experiment_id: dee116_imaging_review_for_heterotopia
    name: Systematic re-review of brain imaging across all reported patients
    description: >-
      Have a neuroradiologist blinded to genotype look specifically for
      heterotopia in the imaging of every reported patient. Periventricular
      nodular heterotopia is easy to miss when it is not being sought, and a
      second case would change the interpretation from coincidence to
      phenotype.
  evidence:
  - reference: PMID:38579670
    reference_title: "Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      One individual with a start-loss GLUL variant demonstrated
      periventricular nodular heterotopia, a neuronal migration disorder, yet
      overexpression of stabilized GS in mice using in utero electroporation
      demonstrated no migratory deficits.
    explanation: >-
      Reports both halves of the mismatch: the human finding and the negative
      mouse result that failed to reproduce it.

notes: >-
  One gene, two opposite diseases. GLUL causes congenital glutamine deficiency
  through biallelic loss of function and this entity through heterozygous gain
  of stabilization, and the two differ in inheritance, biochemistry, imaging
  and survival. They are modelled here as separate entities with a
  differential_diagnoses link rather than as subtypes of one disease, because
  the mechanisms run in opposite directions. Congenital glutamine deficiency
  does not currently have a dismech entry.

  Not curated here, and why. No prevalence record: the disorder was described in
  2024 and roughly thirteen dominant patients had been reported by late 2025, so
  no population estimate exists and none can be derived from a case series.
  No environmental section: no exposure has been examined in relation to this
  disorder. No experimental_models or animal_models section: the only model
  reported is the in utero electroporation overexpression experiment, which is
  a single negative result rather than a characterised model, and it is curated
  in the HUMAN_MODEL_MISMATCH discussion where its negative finding carries the
  meaning. No datasets: the entity is too new for a disease-specific omics
  dataset, and the neighbouring GABRB3 entry records that dataset search on the
  phrase "developmental epileptic encephalopathy" returns GLUL-labelled
  accessions by text match, so the reverse error is a live risk here too.

  Targeted therapy is proposed but does not exist, and is deliberately not
  curated as a treatment. Two approaches have been floated in the literature.
  Antisense oligonucleotides could in principle block the aberrant splice event
  or knock down the mis-spliced transcript allele-specifically, which is
  attractive because the recurrent c.-13-2A>G allele produces a defined
  aberrant transcript. Methionine sulfoximine, an irreversible glutamine
  synthetase inhibitor trialled in rats for hyperammonaemic encephalopathy, has
  also been mentioned. Neither has been tested in this disorder, the authors
  proposing the antisense route say extensive experimental validation is needed
  first, and inhibiting an enzyme whose deficiency causes a lethal disease is
  not a manoeuvre to record as a therapy on the strength of a suggestion. No
  conformance to the antisense_oligonucleotide_therapy module is declared for
  the same reason: there is no drug, no trial, and no demonstrated splice
  redirection.

  The mechanistic name "glutamine synthetase stabilization disorder" appears in
  secondary sources attributed to the founding study. The cached record for that
  study is the PubMed abstract only, which does not contain the phrase, so it is
  not curated as a synonym here.

  GeneReviews has no chapter for this entity, and a PubMed search for one
  returned nothing. Given that the disorder was first described in 2024, that is
  expected rather than an omission.

  Frequency bands. Every frequency in this entry rests on a denominator of ten
  to thirteen patients, and two phenotypes reported only in the most recent
  three-patient series (cerebral atrophy, deep grey matter T2 hyperintensity)
  carry no frequency at all, because a feature found in three of three patients
  in one series and in none of the earlier ten cannot be banded honestly.
📚

References & Deep Research

References

4
PMID:38579670
Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase.
No top-level findings curated for this source.
PMID:41083803
Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy.
No top-level findings curated for this source.
PMID:39985170
Male proband with intractable seizures and a de novo start-codon-disrupting variant in GLUL.
No top-level findings curated for this source.
PMID:42311234
A Novel Gain-of-Function GLUL Variant Is Associated With Developmental and Epileptic Encephalopathy With Enlarged Perivascular Spaces.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Developmental and Epileptic Encephalopathy 116 (DEE116): Disease-Characteristics Report
Edison Scientific Literature 20 citations 2026-08-27T02:58:53.739862

Developmental and Epileptic Encephalopathy 116 (DEE116): Disease-Characteristics Report

Executive summary and evidence limits

Developmental and epileptic encephalopathy 116 (DEE116) is a newly delineated, ultra-rare, autosomal-dominant neurodevelopmental disorder caused by heterozygous variants that abolish the canonical translation start of GLUL, the gene encoding glutamine synthetase (GS; glutamate-ammonia ligase). The authors of the foundational 2024 report proposed the mechanistic name glutamine synthetase stabilization disorder (GSSD). Unlike recessive glutamine-synthetase deficiency, DEE116 is a gain-of-stabilization disorder: translation reinitiates at Met18, removing an N-terminal degradation signal while retaining catalytic function. The resulting GS protein evades glutamine-induced proteasomal degradation. (jones2024clustereddenovo pages 1-3, jones2024clustereddenovo pages 11-12, jones2024clustereddenovo pages 3-4)

The evidence base remains extremely small: nine females reported in the foundational 2024 cohort and one 25-year-old male reported in 2025. Consequently, phenotype percentages below are descriptive case-series frequencies—not population estimates—and penetrance, survival, genotype-response relationships, and treatment response rates cannot yet be estimated reliably. (carbonell2025maleprobandwith pages 1-2, jones2024clustereddenovo pages 5-6, carbonell2025maleprobandwith pages 3-5)

Topic Summary Evidence type Key source(s)
Identity / identifier Developmental and epileptic encephalopathy 116 (DEE116); MONDO:0970945; also proposed as “glutamine synthetase stabilization disorder (GSSD)”. Disease-target association links DEE116 to GLUL. (jones2024clustereddenovo pages 11-12, OpenTargets Search: Developmental and epileptic encephalopathy 116-GLUL) Human cohort; database Jones et al., Am J Hum Genet 2024, PMID: 38579670, DOI: https://doi.org/10.1016/j.ajhg.2024.03.005; OpenTargets disease-target association (OpenTargets Search: Developmental and epileptic encephalopathy 116-GLUL)
Causal gene / inheritance Caused by heterozygous GLUL start-codon-disrupting variants or 5′UTR splice variants causing start loss; de novo in all evaluated families; mechanism is autosomal dominant by protein stabilization rather than deficiency. GLUL OMIM: 138290; DEE116 gene listed as GLUL MIM: 620806 in follow-up case report. (carbonell2025maleprobandwith pages 1-2, jones2024clustereddenovo pages 4-5, jones2024clustereddenovo pages 3-4) Human cohort; case report Jones et al. 2024 PMID: 38579670; Carbonell et al. 2025 PMID: 39985170, DOI: https://doi.org/10.1016/j.xhgg.2025.100419
Reported cohort size / sex / ages Foundational cohort: 9 probands, all female, ages 16 months–16 years; follow-up report adds 1 adult male, age 25 years, making 10 reported individuals total in current literature. (carbonell2025maleprobandwith pages 1-2, jones2024clustereddenovo pages 5-6, carbonell2025maleprobandwith pages 3-5) Human cohort; case report Jones et al. 2024 PMID: 38579670; Carbonell et al. 2025 PMID: 39985170
Core phenotype frequencies In Jones cohort: seizures 8/8, global developmental delay 9/9, hypotonia 9/9; severe/profound developmental impairment was typical. Male case: non-verbal, cortical visual impairment, limb contractures, scoliosis, feeding difficulties, growth delay, total-care dependent. (jones2024clustereddenovo pages 5-6, carbonell2025maleprobandwith pages 3-5) Human cohort; case report Jones et al. 2024 PMID: 38579670; Carbonell et al. 2025 PMID: 39985170
Seizure onset / types Jones cohort seizure onset 10 weeks–22 months; generalized onset 7/8, focal onset 4/8; tonic-clonic 6/8, tonic 2/8, clonic 2/8, myoclonic 4/8, atonic 1/8, absence 1/8, epileptic spasms 1/8; seizure frequency ranged sporadic to daily; treatment refractory 6/7. Male case onset at 24 months, weekly focal and generalized seizures, including myoclonic and generalized tonic-clonic seizures, compatible with Lennox-Gastaut syndrome. (carbonell2025maleprobandwith pages 2-3, carbonell2025maleprobandwith pages 3-5) Human cohort; case report Jones et al. 2024 PMID: 38579670; Carbonell et al. 2025 PMID: 39985170
MRI findings Jones cohort MRI abnormal in 7/7; enlarged perivascular spaces 5/7, thinning corpus callosum 7/7, hypomyelination 7/7; one patient had periventricular nodular heterotopia. Male case had normal brain MRI at ages 1 and 3 years. (jones2024clustereddenovo pages 1-3, carbonell2025maleprobandwith pages 3-5) Human cohort; case report Jones et al. 2024 PMID: 38579670; Carbonell et al. 2025 PMID: 39985170
Biochemistry Despite GLUL involvement, Jones cohort showed normal plasma glutamine in 6/8, normal CSF glutamine in 5/7 (abstract says normal CSF biochemistry; evidence summary notes normal CSF glutamine n=4 in available excerpt), and normal serum ammonia in 3 tested; male case had no plasma/CSF glutamine or ammonia measured. (carbonell2025maleprobandwith pages 2-3, jones2024clustereddenovo pages 5-6, jones2024clustereddenovo pages 11-12) Human cohort; case report Jones et al. 2024 PMID: 38579670; Carbonell et al. 2025 PMID: 39985170
Variant spectrum Seven/9 original probands had start-loss variants in the initiation codon: c.3G>A, c.1A>T, c.1A>C, c.1A>G (recurrent c.1A>G in 4 individuals). Two had 5′UTR splice-disrupting variants upstream of exon 2: c.-13-1G>A and c.-13-2A>G (format normalized from article excerpt). Male case carried recurrent c.-13-2A>G; variant absent from gnomAD v4 in that report and diagnostic submission was ClinVar SCV005619927. Jones ClinVar series: SCV004177219–SCV004177224. (carbonell2025maleprobandwith pages 2-3, carbonell2025maleprobandwith pages 5-6, jones2024clustereddenovo pages 4-5, jones2024clustereddenovo pages 11-12) Human cohort; case report; database-linked Jones et al. 2024 PMID: 38579670; Carbonell et al. 2025 PMID: 39985170
Molecular mechanism Variants abolish canonical start codon usage; translation reinitiates at Met18, removing the N-terminal degron. Resulting GS is stable and enzymatically competent but insensitive to glutamine-mediated degradation/negative feedback (“gain-of-stabilization”). (carbonell2025maleprobandwith pages 1-2, jones2024clustereddenovo pages 1-3, jones2024clustereddenovo pages 3-4, jones2024clustereddenovo pages 7-8, jones2024clustereddenovo pages 8-10) Human cohort; in vitro Jones et al. 2024 PMID: 38579670; Carbonell et al. 2025 PMID: 39985170
Functional evidence Patient fibroblasts and HEK293 GLUL-KO transfection studies showed a smaller GS band; mass spectrometry aligned mutant protein with Met18 initiation; cycloheximide/high-glutamine assays showed truncated GS resists degradation; enzyme assay showed GS_met18 activity ~0.99 of full-length, while known recessive deficiency controls had reduced activity (0.64–0.65). (jones2024clustereddenovo pages 6-7, jones2024clustereddenovo pages 7-8, jones2024clustereddenovo pages 8-10) In vitro Jones et al. 2024 PMID: 38579670
Cell-type localization Single-cell / single-nucleus transcriptomics of human cortex showed GLUL expression in neuro- and glial-progenitor populations and mature glial cells, especially astrocytes, but not post-mitotic neurons. (jones2024clustereddenovo pages 1-3, jones2024clustereddenovo pages 10-11) Computational single-cell Jones et al. 2024 PMID: 38579670
Mouse evidence In utero electroporation in embryonic mouse neocortex overexpressing stabilized GS did not show significant effects on neural progenitor abundance, gliogenic progenitors, or neuronal migration, arguing against a simple migration-defect explanation for the single heterotopia case. (jones2024clustereddenovo pages 1-3, jones2024clustereddenovo pages 10-11, jones2024clustereddenovo pages 8-10) Mouse Jones et al. 2024 PMID: 38579670
Current treatment evidence No disease-specific standard therapy established. Human evidence is limited to symptomatic antiseizure management. In the adult male case, zonisamide and brivaracetam were reported as most effective for seizure reduction after long-standing refractory epilepsy. (carbonell2025maleprobandwith pages 2-3) Case report Carbonell et al. 2025 PMID: 39985170
Experimental therapy status No DEE116-specific interventional trial identified. Proposed but unproven approaches include methionine sulfoximine (MSO), an irreversible GS inhibitor extrapolated from hyperammonemic animal models, and antisense oligonucleotides (ASOs) for splice correction or allele-specific silencing; both remain speculative and require major safety/validation work. (carbonell2025maleprobandwith pages 5-6, jones2024clustereddenovo pages 11-12) In vitro / translational hypothesis; no disease-specific trial Jones et al. 2024 PMID: 38579670; Carbonell et al. 2025 PMID: 39985170; no relevant ClinicalTrials.gov hit found in prior search

Table: This table condenses the currently available disease-specific evidence for GLUL-related DEE116 across human, experimental, and database sources. It is useful as a quick reference for identifiers, phenotype frequencies, mechanism, and the present absence of validated targeted therapy.

1. Disease information

Definition

DEE116 is a severe, usually infantile-onset developmental and epileptic encephalopathy characterized by global developmental impairment, hypotonia, multiple seizure types that are commonly drug resistant, and frequent cerebral white-matter abnormalities. The causal metabolic disturbance is believed to arise principally in neurodevelopmental progenitors and astroglial cells rather than post-mitotic neurons. (jones2024clustereddenovo pages 5-6, jones2024clustereddenovo pages 1-3, jones2024clustereddenovo pages 10-11)

Identifiers and synonyms

  • MONDO: MONDO:0970945.
  • Disease OMIM/MIM: 620806, as cited in the 2025 follow-up report.
  • Causal gene: GLUL; gene OMIM 138290; Ensembl ENSG00000135821.
  • Preferred name: developmental and epileptic encephalopathy 116.
  • Synonyms: DEE116; developmental and epileptic encephalopathy-116; glutamine synthetase stabilization disorder (GSSD); GLUL-related developmental and epileptic encephalopathy.
  • Distinct allelic disorder: autosomal-recessive glutamine synthetase deficiency, OMIM 610015, caused by biallelic hypomorphic variants and associated with low glutamine. It should not be merged with dominant DEE116. (jones2024clustereddenovo pages 11-12, jones2024clustereddenovo pages 3-4, OpenTargets Search: Developmental and epileptic encephalopathy 116-GLUL)
  • Orphanet, MeSH, ICD-10/ICD-11: no disease-specific entries or dedicated codes were established in the retrieved evidence. Operational coding would therefore use broader developmental/epileptic encephalopathy or genetic epilepsy categories.

OpenTargets associates MONDO:0970945 specifically with GLUL and reports five underlying evidence records. (OpenTargets Search: Developmental and epileptic encephalopathy 116-GLUL)

Evidence provenance

The disease definition is aggregated from a research cohort assembled through GeneMatcher, functional laboratory studies, and a subsequent single-patient case report—not from an EHR-derived population dataset. The male case incorporated longitudinal clinical records, genome sequencing, annual reanalysis, RNA sequencing, and ClinVar deposition. (jones2024clustereddenovo pages 5-6, carbonell2025maleprobandwith pages 5-6, carbonell2025maleprobandwith pages 3-5, jones2024clustereddenovo pages 3-4)

Key primary sources

  1. Jones AG et al. “Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase.” American Journal of Human Genetics. Published April 4, 2024; 111:729–741. PMID: 38579670. DOI: https://doi.org/10.1016/j.ajhg.2024.03.005. (jones2024clustereddenovo pages 5-6, jones2024clustereddenovo pages 12-13)
  2. Carbonell E et al. “Male proband with intractable seizures and a de novo start-codon-disrupting variant in GLUL.” Human Genetics and Genomics Advances. Published April 10, 2025; 6:100419. PMID: 39985170. DOI: https://doi.org/10.1016/j.xhgg.2025.100419. (carbonell2025maleprobandwith pages 2-3, carbonell2025maleprobandwith pages 5-6)

Exact abstract statement from the foundational study: “We ascertained nine individuals with severe developmental delay, seizures, and white matter abnormalities but normal plasma and cerebrospinal fluid biochemistry with de novo variants in GLUL.” (jones2024clustereddenovo pages 1-3)

2. Etiology, risk, and protective factors

Causal factors

The established cause is a heterozygous, usually demonstrably de novo, germline GLUL variant that directly disrupts the start codon or alters 5′-UTR splicing so that the canonical initiation codon is excluded. Parental testing was completed in eight foundational families, and the variant was de novo in all eight; de novo status was unavailable for the ninth. The later male case was also de novo. (carbonell2025maleprobandwith pages 2-3, jones2024clustereddenovo pages 4-5)

Genetic risk factors

The known pathogenic region is unusually constrained mechanistically:

  • Start-loss variants: NM_001033044.4:c.3G>A, c.1A>T, c.1A>C, and c.1A>G, all annotated p.Met1?.
  • The recurrent c.1A>G occurred in four of nine foundational cases.
  • 5′-UTR splice variants: c.-13-1G>A and c.-13-2A>G; the latter recurred in the adult male.
  • All foundational variants were absent from gnomAD v3.1.2; the male’s c.-13-2A>G variant was also absent from gnomAD v4. (carbonell2025maleprobandwith pages 2-3, jones2024clustereddenovo pages 5-6, jones2024clustereddenovo pages 4-5)

The c.-13-2A>G variant was classified as likely pathogenic, using PS2_Moderate, PM1, PS3_Supporting, and PM2_Supporting. Relevant submissions include ClinVar SCV004177219–SCV004177224 for the foundational series and SCV005619927 for the male case. (carbonell2025maleprobandwith pages 2-3, carbonell2025maleprobandwith pages 5-6, jones2024clustereddenovo pages 11-12)

Environmental, lifestyle, infectious, and demographic risk

No toxin, infection, diet, occupation, parental age, lifestyle exposure, or other environmental cause has been established. No susceptibility loci or validated modifier genes are known. An initial all-female cohort prompted speculation about sex-dependent glutamine metabolism, but the affected male establishes that disease is not female limited; the apparent sex imbalance may reflect ascertainment in a cohort of only ten people. (carbonell2025maleprobandwith pages 3-5, jones2024clustereddenovo pages 10-11)

Protective factors and gene–environment interaction

No genetic or environmental protective factor has been demonstrated. Glutamine concentration regulates degradation of normal GS in vitro, but there is no clinical evidence that dietary glutamine manipulation is beneficial or safe. This biochemical substrate-response relationship must not be interpreted as an established dietary gene–environment interaction. (jones2024clustereddenovo pages 7-8, jones2024clustereddenovo pages 8-10)

3. Phenotypes

Neurologic and developmental phenotype

Phenotype Frequency/current evidence Onset/course and impact Suggested HPO term
Seizures 8/8 with data in the original cohort; present in male 10 weeks–22 months in cohort; 24 months in male; sporadic-to-daily or weekly; often chronic and refractory Seizure, HP:0001250
Drug-resistant epilepsy 6/7 evaluable foundational cases; male also refractory Persistent despite multiple antiseizure medicines; major care burden Drug-resistant epilepsy, HP:0100543
Generalized seizure onset 7/8; male also had generalized seizures Infantile/early childhood; episodic Generalized-onset seizure, HP:0002197
Focal seizure onset 4/8; male also affected Episodic; evolved to multifocal/generalized EEG abnormalities in male Focal-onset seizure, HP:0007359
Tonic-clonic seizures 6/8; male affected Variable frequency and severity HP:0002069
Myoclonic seizures 4/8; male affected Episodic HP:0032794
Tonic seizures 2/8 Episodic HP:0032792
Clonic seizures 2/8 Episodic HP:0020221
Atonic/absence/spasms Each 1/8 Rare in current series HP:0010819, HP:0011147, HP:0011097
Global developmental delay 9/9; male affected Severe-to-profound; chronic, with adult dependence HP:0001263
Hypotonia 9/9; male affected Early and persistent HP:0001252
Absent speech/non-verbal Documented in male; incompletely reported in cohort Lifelong communication limitation HP:0001344
Cortical visual impairment Documented in male, recognized at 5 months Chronic visual disability HP:0100704
Feeding difficulty/G-tube dependence Documented in male Chronic; affected nutrition and growth HP:0011968; gastrostomy status may be separately encoded
Contractures, hip dysplasia, neuromuscular scoliosis Documented in adult male Progressive secondary motor complications HP:0003121, HP:0001385, HP:0002650
Growth delay/short stature Documented in male: 40.8 kg, 152 cm at 25 years Chronic HP:0001510, HP:0004322

Frequencies and HPO mappings are derived from the published comparison table; denominators vary because not all variables were recorded in every patient. (carbonell2025maleprobandwith pages 3-5)

The adult male was non-verbal, unable to ambulate independently, G-tube dependent, and required total care in a group home. Nonetheless, caregivers reported enjoyment of social contact, music, outdoor activity, adaptive skiing/swimming, and vestibular activities. This is the only disease-specific qualitative quality-of-life information; no EQ-5D, SF-36, PROMIS, or validated caregiver-burden study has been reported. (carbonell2025maleprobandwith pages 3-5)

Neuroimaging and electrophysiology

MRI was abnormal in 7/7 evaluable foundational cases: hypomyelination 7/7, thin corpus callosum 7/7, and enlarged perivascular spaces 5/7. One individual had periventricular nodular heterotopia. In contrast, the adult male had normal MRIs at ages 1 and 3 years, demonstrating that normal early MRI does not exclude DEE116. Suggested HPO terms are HP:0006808, HP:0033725, HP:0012520, and HP:0007165. (jones2024clustereddenovo pages 1-3, carbonell2025maleprobandwith pages 3-5)

The male’s serial EEGs from infancy to age 24 evolved from central-parietal spike-wave discharges to multifocal and generalized abnormalities. His combined seizure phenotype was considered consistent with Lennox–Gastaut syndrome. Detailed aggregate EEG frequencies were not available for the nine-person cohort. (carbonell2025maleprobandwith pages 2-3)

Laboratory phenotype

Routine biochemical markers can be normal: plasma glutamine was normal in 6/8 and CSF glutamine in 5/7 in the later published comparison; serum ammonia was normal in the three reported as tested. The adult male had not undergone plasma/CSF glutamine or ammonia measurement. Thus, normal glutamine or ammonia does not exclude the diagnosis. (carbonell2025maleprobandwith pages 2-3, jones2024clustereddenovo pages 5-6, carbonell2025maleprobandwith pages 3-5, jones2024clustereddenovo pages 11-12)

4. Genetic and molecular information

Gene and protein

  • Gene: GLUL; approved protein name glutamate-ammonia ligase/glutamine synthetase.
  • Ensembl: ENSG00000135821.
  • Gene OMIM: 138290.
  • Protein: cytoplasmic GS; approximately 42 kDa per subunit; active protein is a cylindrical decamer.
  • Reaction: glutamate + ammonia + ATP → glutamine; relevant chemical annotations include CHEBI:29985 (L-glutamate), CHEBI:58359 (L-glutamine zwitterion), CHEBI:16134 (ammonia), and CHEBI:30616 (ATP), subject to local ontology-version verification. (jones2024clustereddenovo pages 3-4, OpenTargets Search: Developmental and epileptic encephalopathy 116-GLUL)

Variant class and functional consequence

All currently established dominant DEE116 variants are germline SNVs producing start loss either directly or through abnormal 5′-UTR splicing. No causal frameshift, nonsense, copy-number, chromosomal, repeat-expansion, mitochondrial, or somatic variant class has been established for DEE116. The c.-13-2A>G allele generated an aberrant splice junction in 44% of blood RNA reads, deleting 26 bases including the canonical start. (carbonell2025maleprobandwith pages 5-6)

Translation reinitiates at Met18, deleting the first 17 residues, including degron lysines 11 and 14. The mutant protein is catalytically competent but insensitive to glutamine-triggered negative feedback. Incorporation of truncated subunits may stabilize the entire heteromeric GS decamer, including full-length subunits. This is neither conventional haploinsufficiency nor dominant-negative loss of activity. (jones2024clustereddenovo pages 7-8, jones2024clustereddenovo pages 8-10)

Allele frequencies, modifiers, epigenetics, and chromosomal findings

All reported variants were absent from the cited gnomAD versions. Carrier frequency cannot be estimated and is expected to be extremely low because known cases are predominantly de novo. No modifier gene, founder allele, disease-specific methylation signature, histone abnormality, chromatin signature, or recurrent chromosomal abnormality has been reported. (carbonell2025maleprobandwith pages 2-3, jones2024clustereddenovo pages 5-6)

5. Environmental information

DEE116 is a Mendelian disorder without an established environmental, infectious, toxic, radiation, pollution, occupational, smoking, alcohol, exercise, or dietary etiology. Environmental exposures could still influence seizure threshold—as in epilepsy generally—but no DEE116-specific interaction has been studied. There is no zoonotic or transmissible component.

6. Mechanism and pathophysiology

Supported upstream causal chain

  1. A de novo heterozygous GLUL start-loss or 5′-UTR splice variant removes the canonical translation initiation site.
  2. Translation reinitiates at Met18.
  3. The first 17 amino acids—including the glutamine-sensitive N-terminal degron—are lost.
  4. Mutant GS retains approximately full catalytic activity but becomes resistant to glutamine-induced ubiquitin/proteasome degradation.
  5. GS abundance/activity is therefore inadequately downregulated, producing a gain-of-stabilization metabolic disorder during brain development.
  6. Dysregulated glutamate–glutamine, ammonia/nitrogen, and ATP homeostasis plausibly disrupts neural progenitor and astrocyte support of neuronal networks, contributing to developmental impairment, hypomyelination, and epilepsy. Steps 1–5 are experimentally supported; the precise links in step 6 remain mechanistic hypotheses. (jones2024clustereddenovo pages 1-3, jones2024clustereddenovo pages 6-7, jones2024clustereddenovo pages 11-12, jones2024clustereddenovo pages 7-8, jones2024clustereddenovo pages 8-10)

Exact abstract statement: the variants produce “a protein that is stable and enzymatically competent but insensitive to negative feedback by glutamine.” (jones2024clustereddenovo pages 1-3)

Human-cell and in-vitro evidence

Patient fibroblasts showed both full-length and smaller GS isoforms. Mass spectrometry aligned the start-loss product with Met18 initiation. In GLUL-knockout HEK293 cells, full-length GS underwent significantly more degradation in high than low glutamine, whereas Met18 GS did not. Met18 enzyme activity was 0.99 relative to full-length, while recessive-deficiency controls p.Arg324Cys and p.Arg341Cys were approximately 0.64–0.65 in the study assay. (jones2024clustereddenovo pages 6-7, jones2024clustereddenovo pages 7-8, jones2024clustereddenovo pages 8-10)

Suggested GO annotations include:

  • glutamine biosynthetic process, GO:0006542;
  • glutamate metabolic process, GO:0006536;
  • cellular nitrogen-compound metabolic process, GO:0034641;
  • protein ubiquitination, GO:0016567;
  • proteasomal protein catabolic process, GO:0010498;
  • regulation of neurotransmitter levels, GO:0001505;
  • gliogenesis, GO:0042063;
  • central nervous system myelination, GO:0022010.

Cell types and downstream hypotheses

Human single-cell/single-nucleus datasets showed GLUL expression in neuro- and glial-progenitor cells and, later, principally mature astrocytes; expression was low/absent in post-mitotic neurons. Suggested Cell Ontology terms are astrocyte (CL:0000127), neural progenitor cell (CL:0011020), radial glial cell (CL:0000681), oligodendrocyte precursor cell (CL:0002453), and neuron (CL:0000540) as a downstream affected rather than primary GLUL-expressing population. (jones2024clustereddenovo pages 1-3, jones2024clustereddenovo pages 10-11, jones2024clustereddenovo pages 8-10)

Proposed downstream mechanisms include:

  • excessive conversion of glutamate/ammonia to glutamine and disturbed neurotransmitter precursor homeostasis;
  • altered nitrogen flux and pH;
  • astrocytic osmotic stress/swelling;
  • suppression of glutaminolysis and altered neural-progenitor energetics;
  • excessive ATP consumption by stabilized GS;
  • reduced astrocytic ATP release, potentially weakening inhibition and myelination;
  • possible non-canonical effects through RHOJ, angiogenesis, and cytoskeletal remodeling.

These mechanisms are biologically plausible but have not been demonstrated directly in DEE116 brains. Systemic glutamine and ammonia may remain normal because liver and other tissues possess compensatory pathways. (jones2024clustereddenovo pages 11-12, jones2024clustereddenovo pages 12-13)

No disease-specific immune, inflammatory, oxidative-stress, apoptosis, autophagy, lipidomic, proteomic-biomarker, metabolomic-signature, spatial-transcriptomic, or integrated multi-omic dataset has been reported.

7. Anatomical structures affected

Organ and tissue levels

The primary organ is the central nervous system, particularly the developing cerebral cortex and cerebral white matter. Suggested UBERON terms include brain (UBERON:0000955), cerebral cortex (UBERON:0000956), prefrontal cortex (UBERON:0000451), cerebral white matter (UBERON:0002437), and corpus callosum (UBERON:0002336), with local identifier validation recommended. Imaging suggests bilateral/diffuse rather than consistently lateralized disease. (jones2024clustereddenovo pages 5-6, jones2024clustereddenovo pages 1-3, jones2024clustereddenovo pages 10-11)

Secondary musculoskeletal involvement—contractures, hip dysplasia, and neuromuscular scoliosis—was documented in the adult male and is probably downstream of severe chronic motor impairment. Feeding/growth complications may require gastrointestinal nutritional support. (carbonell2025maleprobandwith pages 3-5)

Subcellular level

GS is a cytosolic enzyme, making cytosol (GO:0005829) and cytoplasm (GO:0005737) appropriate primary compartments. The dysregulated control process involves ubiquitin-mediated proteasomal degradation; proteasome complex (GO:0000502) is mechanistically relevant but is not the principal steady-state localization of GS. (jones2024clustereddenovo pages 3-4, jones2024clustereddenovo pages 7-8)

8. Temporal development

DEE116 is pediatric-onset and likely neurodevelopmental from prenatal brain development onward, although seizures began postnatally between 10 weeks and 24 months in known patients. Developmental impairment and hypotonia are chronic. Epilepsy is episodic but usually persistent and frequently drug resistant. (jones2024clustereddenovo pages 5-6, carbonell2025maleprobandwith pages 3-5)

No validated staging system exists. The adult male showed progressive motor complications and required total care, but whether neurodegeneration is intrinsic to DEE116 or these changes are secondary to severe static encephalopathy, epilepsy, immobility, and orthopedic complications remains uncertain. No spontaneous remission pattern or critical therapeutic window has been established. Because the causal disturbance acts during neurodevelopment, early molecular diagnosis is a rational—but not yet proven—intervention priority. (carbonell2025maleprobandwith pages 3-5)

9. Inheritance and population

Inheritance

The inheritance model is autosomal dominant, currently almost always de novo. Penetrance appears high among identified variant carriers, but unbiased penetrance cannot be calculated. Expressivity is variable, as illustrated by abnormal versus normal early MRI and variable seizure types. There is no evidence of anticipation, a founder effect, or a role for consanguinity. Parental germline mosaicism has not been documented but cannot be excluded after an apparently de novo result. (carbonell2025maleprobandwith pages 2-3, jones2024clustereddenovo pages 5-6, carbonell2025maleprobandwith pages 3-5)

Epidemiology

Only ten affected individuals were documented in the retrieved disease-specific literature: nine females aged approximately 16 months–16 years in 2024 and one 25-year-old male in 2025. Prevalence, incidence, carrier frequency, ethnic differences, geographic gradients, and a reliable sex ratio are unavailable. Cases in the original international cohort came from New Zealand, North America, Europe, and South Africa, providing no evidence for geographic restriction. (carbonell2025maleprobandwith pages 1-2, jones2024clustereddenovo pages 5-6)

10. Diagnostics

Clinical recognition

Consider DEE116 in an infant or child with severe developmental delay, hypotonia, early multiple seizure types or drug-resistant epilepsy, and hypomyelination/thin corpus callosum—especially when standard metabolic tests are normal. A normal early MRI does not exclude it. No society-endorsed disease-specific diagnostic criteria currently exist. (jones2024clustereddenovo pages 5-6, carbonell2025maleprobandwith pages 3-5)

Recommended investigations

  1. EEG: baseline and longitudinal video-EEG to classify focal/generalized seizures, epileptic spasms, and encephalopathic patterns.
  2. MRI brain: include high-quality myelin-sensitive sequences; assess corpus callosum, perivascular spaces, migration abnormalities, and longitudinal change.
  3. Biochemistry: plasma amino acids including glutamine, ammonia, blood gas/pH, metabolic panel; consider CSF amino acids where clinically justified. Normal results do not rule out DEE116.
  4. MR spectroscopy: investigationally useful for in-vivo cerebral glutamine because plasma and CSF may not represent brain interstitial metabolism; it is not a validated diagnostic biomarker. (carbonell2025maleprobandwith pages 3-5, jones2024clustereddenovo pages 10-11)

Genetic-testing strategy

  • First line: trio WES or WGS, or a comprehensive DEE/epilepsy panel that includes GLUL and covers non-coding exon/5′-UTR splice boundaries.
  • Variant interpretation: prioritize de novo variants affecting c.1–c.3 and 5′-UTR splice acceptors; do not restrict interpretation to recessive GLUL deficiency.
  • RNA sequencing: highly valuable for suspected 5′-UTR splice variants; blood RNA confirmed the 26-bp deletion and 44% aberrant junction in the male.
  • Reanalysis: essential when prior testing was negative. The male’s earlier 13- and 40-gene panels were negative, genome sequencing was initially inconclusive because GLUL was then associated only with recessive disease, and annual reanalysis ultimately enabled diagnosis.
  • CMA/karyotype/FISH: useful for broader developmental-delay workup but not targeted tests for the known SNV mechanism.
  • Mitochondrial or repeat-expansion testing: phenotype-driven only; neither is a known DEE116 mechanism. (carbonell2025maleprobandwith pages 5-6, carbonell2025maleprobandwith pages 3-5)

Differential diagnosis

Key differentials include recessive glutamine-synthetase deficiency, other monogenic DEEs, hypomyelinating leukodystrophies, neuronal-migration disorders, Lennox–Gastaut syndrome of another cause, structural epilepsies, and treatable metabolic epileptic encephalopathies. Recessive GS deficiency is distinguished by biallelic active-site variants, enzyme deficiency, and characteristically low plasma/CSF glutamine rather than dominant degron-loss stabilization. (carbonell2025maleprobandwith pages 3-5, jones2024clustereddenovo pages 3-4)

There is no population newborn screen, validated biochemical screen, or routine carrier-screening program. Cascade testing should confirm parental status and can inform reproductive counseling.

11. Outcome and prognosis

All nine foundational patients were reported alive at ages up to 16 years; the additional male was alive at 25 years. These observations demonstrate survival into adulthood but do not support survival-rate or life-expectancy estimates. No disease-specific mortality rate or sudden-unexpected-death-in-epilepsy estimate is available. (carbonell2025maleprobandwith pages 1-2, carbonell2025maleprobandwith pages 3-5)

Long-term morbidity is substantial: severe/profound developmental disability, persistent epilepsy, impaired communication and mobility, feeding dependence, and secondary orthopedic complications. Complete developmental recovery has not been reported. Prognostic biomarkers are unknown. Potential factors requiring future study include seizure burden, degree of white-matter abnormality, cerebral glutamine measured by MR spectroscopy, and residual ratio of normal to aberrant transcript. None is currently validated. (carbonell2025maleprobandwith pages 3-5, jones2024clustereddenovo pages 10-11)

12. Treatment

Current clinical implementation

There is no approved disease-modifying or DEE116-specific therapy. Management is individualized and symptomatic:

  • antiseizure pharmacotherapy selected by seizure type and EEG syndrome;
  • rescue plans for prolonged seizures/status epilepticus;
  • physical, occupational, speech/augmentative-communication, and visual therapy;
  • nutritional assessment, swallowing evaluation, and gastrostomy when necessary;
  • orthopedic surveillance for hip displacement, contractures, and scoliosis;
  • sleep, respiratory, bone-health, and caregiver-support assessment.

The adult male experienced the best reported seizure reduction with zonisamide plus brivaracetam, but this is a single uncontrolled observation and cannot establish comparative efficacy. Suggested NCIt concepts include Anticonvulsant Agent (NCIT:C264), Physical Therapy (NCIT:C15303), Occupational Therapy, Speech Therapy, and Gastrostomy, with exact local NCIt identifiers verified before ingestion. (carbonell2025maleprobandwith pages 2-3, carbonell2025maleprobandwith pages 3-5)

No DEE116 pharmacogenomic association or genotype-specific antiseizure algorithm has been reported.

Experimental precision approaches

  1. Methionine sulfoximine (MSO): an irreversible GS inhibitor proposed because the mutant enzyme remains active and over-stable. MSO attenuated some pathology in hyperammonemic rat models at subconvulsant doses, but toxicity, off-target effects, interspecies potency differences, and its own seizure-inducing potential are major barriers. It has not been tested as DEE116 therapy in humans. (jones2024clustereddenovo pages 11-12)
  2. Antisense oligonucleotides: the recurrent c.-13-2A>G splice defect creates a theoretical opportunity for splice correction or allele-specific knockdown. This proposal has no disease-model efficacy, dosing, biodistribution, or safety validation. (carbonell2025maleprobandwith pages 5-6)
  3. Gene replacement/editing: not currently supported. Unregulated replacement could worsen a gain-of-stabilization disorder, and an allele-selective approach would be required.

No disease-specific interventional trial or NCT identifier was identified in the ClinicalTrials.gov search. Treatment-response percentages and disease-specific adverse-event rates are unavailable.

13. Prevention

No vaccine, lifestyle modification, environmental intervention, diet, or prophylactic drug can prevent a de novo GLUL variant. Primary prevention is therefore limited to informed reproductive options after molecular diagnosis:

  • genetic counseling;
  • parental testing, with explanation of residual recurrence risk from possible germline mosaicism;
  • prenatal diagnosis or preimplantation genetic testing for a known familial variant;
  • donor-gamete or other reproductive options according to patient preferences.

Secondary/tertiary prevention consists of early genomic diagnosis, prompt seizure treatment, developmental intervention, aspiration/nutrition management, orthopedic surveillance, and injury/SUDEP risk counseling. Population newborn or carrier screening is not currently justified by prevalence data or an established presymptomatic intervention.

14. Other species and natural disease

No naturally occurring veterinary equivalent, breed predisposition, or zoonotic transmission has been reported. GLUL is evolutionarily conserved and its essential biology is illustrated by embryonic lethality of complete Glul knockout in mice at approximately embryonic day 3.5, but that loss-of-function state is not homologous to human dominant gain-of-stabilization DEE116. (jones2024clustereddenovo pages 3-4)

Relevant taxonomy suggestions are Homo sapiens, NCBI Taxon:9606 and Mus musculus, NCBI Taxon:10090. No VBO breed annotation applies.

15. Model organisms and experimental models

Available models

  • Patient dermal fibroblasts: reproduce full-length plus truncated GS isoforms and abnormal glutamine-dependent stability.
  • HEK293 GLUL-knockout complementation system: supports controlled expression, mass-spectrometric identification of Met18 initiation, stability assays, and catalytic assays.
  • Embryonic mouse in-utero electroporation: overexpression of full-length or start-loss GS in C57BL/6JRj neocortex at E13.5/E16.5.
  • Human single-cell computational models: reanalysis of fetal-to-adult cortical datasets localized GLUL expression to progenitors and astroglia. (jones2024clustereddenovo pages 4-5, jones2024clustereddenovo pages 7-8, jones2024clustereddenovo pages 8-10)

Recapitulation and limitations

The cell systems robustly reproduce the proximal molecular defect but do not model seizures, network development, or white-matter disease. Mouse electroporation found no significant change in Pax6-positive progenitors, Tbr2-positive lineage commitment, Olig2-positive gliogenic progenitors, or neuronal migration. It therefore did not reproduce the human heterotopia observation or broader DEE phenotype. Species differences may be particularly important because human fetal cortical progenitors have distinctive glutaminolysis biology. (jones2024clustereddenovo pages 1-3, jones2024clustereddenovo pages 10-11, jones2024clustereddenovo pages 8-10)

A rigorous future model would require heterozygous knock-in of a human-equivalent start-loss or splice variant, assessment across neural progenitors and astrocytes, EEG/seizure monitoring, myelination, metabolite flux, and rescue with allele-selective suppression. Patient-derived iPSC astrocytes, neuron–astrocyte co-cultures, and cerebral organoids would be valuable but were not reported in the retrieved literature.

Knowledge-base conclusions

DEE116 should be represented as a GLUL gain-of-stabilization disorder, not as generic GLUL deficiency. The most defensible disease graph is: de novo start-codon disruption → Met18 reinitiation → N-terminal degron loss → failure of glutamine-induced GS degradation → dysregulated astroglial/progenitor glutamine and energy homeostasis → altered neuronal-network development, myelination, and seizure susceptibility. The first five nodes are experimentally supported; downstream cellular and clinical links remain provisional. Current care is symptomatic, and neither MSO nor ASO therapy is ready for clinical implementation. (jones2024clustereddenovo pages 1-3, jones2024clustereddenovo pages 11-12, jones2024clustereddenovo pages 7-8, jones2024clustereddenovo pages 8-10)

References

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  4. (carbonell2025maleprobandwith pages 1-2): Elizabeth Carbonell, Sarah L. Stenton, Vijay S. Ganesh, Jialan Ma, Grace E. VanNoy, Lynn Pais, John N. Gaitanis, Melanie C. O’Leary, Heidi L. Rehm, and Anne O’Donnell-Luria. Male proband with intractable seizures and a de novo start-codon-disrupting variant in glul. Apr 2025. URL: https://doi.org/10.1016/j.xhgg.2025.100419, doi:10.1016/j.xhgg.2025.100419. This article has 3 citations and is from a peer-reviewed journal.

  5. (jones2024clustereddenovo pages 5-6): Amy G. Jones, Matilde Aquilino, Rory J. Tinker, Laura Duncan, Zandra Jenkins, Gemma L. Carvill, Stephanie J. DeWard, Dorothy K. Grange, MJ Hajianpour, Benjamin J. Halliday, Muriel Holder-Espinasse, Judit Horvath, Silvia Maitz, Vincenzo Nigro, Manuela Morleo, Victoria Paul, Careni Spencer, Alina I. Esterhuizen, Tilman Polster, Alice Spano, Inés Gómez-Lozano, Abhishek Kumar, Gemma Poke, John A. Phillips, Hunter R. Underhill, Gregory Gimenez, Takashi Namba, and Stephen P. Robertson. Clustered de novo start-loss variants in glul result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase. American journal of human genetics, 111 4:729-741, Apr 2024. URL: https://doi.org/10.1016/j.ajhg.2024.03.005, doi:10.1016/j.ajhg.2024.03.005. This article has 19 citations and is from a highest quality peer-reviewed journal.

  6. (carbonell2025maleprobandwith pages 3-5): Elizabeth Carbonell, Sarah L. Stenton, Vijay S. Ganesh, Jialan Ma, Grace E. VanNoy, Lynn Pais, John N. Gaitanis, Melanie C. O’Leary, Heidi L. Rehm, and Anne O’Donnell-Luria. Male proband with intractable seizures and a de novo start-codon-disrupting variant in glul. Apr 2025. URL: https://doi.org/10.1016/j.xhgg.2025.100419, doi:10.1016/j.xhgg.2025.100419. This article has 3 citations and is from a peer-reviewed journal.

  7. (OpenTargets Search: Developmental and epileptic encephalopathy 116-GLUL): Open Targets Query (Developmental and epileptic encephalopathy 116-GLUL, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  8. (jones2024clustereddenovo pages 4-5): Amy G. Jones, Matilde Aquilino, Rory J. Tinker, Laura Duncan, Zandra Jenkins, Gemma L. Carvill, Stephanie J. DeWard, Dorothy K. Grange, MJ Hajianpour, Benjamin J. Halliday, Muriel Holder-Espinasse, Judit Horvath, Silvia Maitz, Vincenzo Nigro, Manuela Morleo, Victoria Paul, Careni Spencer, Alina I. Esterhuizen, Tilman Polster, Alice Spano, Inés Gómez-Lozano, Abhishek Kumar, Gemma Poke, John A. Phillips, Hunter R. Underhill, Gregory Gimenez, Takashi Namba, and Stephen P. Robertson. Clustered de novo start-loss variants in glul result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase. American journal of human genetics, 111 4:729-741, Apr 2024. URL: https://doi.org/10.1016/j.ajhg.2024.03.005, doi:10.1016/j.ajhg.2024.03.005. This article has 19 citations and is from a highest quality peer-reviewed journal.

  9. (carbonell2025maleprobandwith pages 2-3): Elizabeth Carbonell, Sarah L. Stenton, Vijay S. Ganesh, Jialan Ma, Grace E. VanNoy, Lynn Pais, John N. Gaitanis, Melanie C. O’Leary, Heidi L. Rehm, and Anne O’Donnell-Luria. Male proband with intractable seizures and a de novo start-codon-disrupting variant in glul. Apr 2025. URL: https://doi.org/10.1016/j.xhgg.2025.100419, doi:10.1016/j.xhgg.2025.100419. This article has 3 citations and is from a peer-reviewed journal.

  10. (carbonell2025maleprobandwith pages 5-6): Elizabeth Carbonell, Sarah L. Stenton, Vijay S. Ganesh, Jialan Ma, Grace E. VanNoy, Lynn Pais, John N. Gaitanis, Melanie C. O’Leary, Heidi L. Rehm, and Anne O’Donnell-Luria. Male proband with intractable seizures and a de novo start-codon-disrupting variant in glul. Apr 2025. URL: https://doi.org/10.1016/j.xhgg.2025.100419, doi:10.1016/j.xhgg.2025.100419. This article has 3 citations and is from a peer-reviewed journal.

  11. (jones2024clustereddenovo pages 7-8): Amy G. Jones, Matilde Aquilino, Rory J. Tinker, Laura Duncan, Zandra Jenkins, Gemma L. Carvill, Stephanie J. DeWard, Dorothy K. Grange, MJ Hajianpour, Benjamin J. Halliday, Muriel Holder-Espinasse, Judit Horvath, Silvia Maitz, Vincenzo Nigro, Manuela Morleo, Victoria Paul, Careni Spencer, Alina I. Esterhuizen, Tilman Polster, Alice Spano, Inés Gómez-Lozano, Abhishek Kumar, Gemma Poke, John A. Phillips, Hunter R. Underhill, Gregory Gimenez, Takashi Namba, and Stephen P. Robertson. Clustered de novo start-loss variants in glul result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase. American journal of human genetics, 111 4:729-741, Apr 2024. URL: https://doi.org/10.1016/j.ajhg.2024.03.005, doi:10.1016/j.ajhg.2024.03.005. This article has 19 citations and is from a highest quality peer-reviewed journal.

  12. (jones2024clustereddenovo pages 8-10): Amy G. Jones, Matilde Aquilino, Rory J. Tinker, Laura Duncan, Zandra Jenkins, Gemma L. Carvill, Stephanie J. DeWard, Dorothy K. Grange, MJ Hajianpour, Benjamin J. Halliday, Muriel Holder-Espinasse, Judit Horvath, Silvia Maitz, Vincenzo Nigro, Manuela Morleo, Victoria Paul, Careni Spencer, Alina I. Esterhuizen, Tilman Polster, Alice Spano, Inés Gómez-Lozano, Abhishek Kumar, Gemma Poke, John A. Phillips, Hunter R. Underhill, Gregory Gimenez, Takashi Namba, and Stephen P. Robertson. Clustered de novo start-loss variants in glul result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase. American journal of human genetics, 111 4:729-741, Apr 2024. URL: https://doi.org/10.1016/j.ajhg.2024.03.005, doi:10.1016/j.ajhg.2024.03.005. This article has 19 citations and is from a highest quality peer-reviewed journal.

  13. (jones2024clustereddenovo pages 6-7): Amy G. Jones, Matilde Aquilino, Rory J. Tinker, Laura Duncan, Zandra Jenkins, Gemma L. Carvill, Stephanie J. DeWard, Dorothy K. Grange, MJ Hajianpour, Benjamin J. Halliday, Muriel Holder-Espinasse, Judit Horvath, Silvia Maitz, Vincenzo Nigro, Manuela Morleo, Victoria Paul, Careni Spencer, Alina I. Esterhuizen, Tilman Polster, Alice Spano, Inés Gómez-Lozano, Abhishek Kumar, Gemma Poke, John A. Phillips, Hunter R. Underhill, Gregory Gimenez, Takashi Namba, and Stephen P. Robertson. Clustered de novo start-loss variants in glul result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase. American journal of human genetics, 111 4:729-741, Apr 2024. URL: https://doi.org/10.1016/j.ajhg.2024.03.005, doi:10.1016/j.ajhg.2024.03.005. This article has 19 citations and is from a highest quality peer-reviewed journal.

  14. (jones2024clustereddenovo pages 10-11): Amy G. Jones, Matilde Aquilino, Rory J. Tinker, Laura Duncan, Zandra Jenkins, Gemma L. Carvill, Stephanie J. DeWard, Dorothy K. Grange, MJ Hajianpour, Benjamin J. Halliday, Muriel Holder-Espinasse, Judit Horvath, Silvia Maitz, Vincenzo Nigro, Manuela Morleo, Victoria Paul, Careni Spencer, Alina I. Esterhuizen, Tilman Polster, Alice Spano, Inés Gómez-Lozano, Abhishek Kumar, Gemma Poke, John A. Phillips, Hunter R. Underhill, Gregory Gimenez, Takashi Namba, and Stephen P. Robertson. Clustered de novo start-loss variants in glul result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase. American journal of human genetics, 111 4:729-741, Apr 2024. URL: https://doi.org/10.1016/j.ajhg.2024.03.005, doi:10.1016/j.ajhg.2024.03.005. This article has 19 citations and is from a highest quality peer-reviewed journal.

  15. (jones2024clustereddenovo pages 12-13): Amy G. Jones, Matilde Aquilino, Rory J. Tinker, Laura Duncan, Zandra Jenkins, Gemma L. Carvill, Stephanie J. DeWard, Dorothy K. Grange, MJ Hajianpour, Benjamin J. Halliday, Muriel Holder-Espinasse, Judit Horvath, Silvia Maitz, Vincenzo Nigro, Manuela Morleo, Victoria Paul, Careni Spencer, Alina I. Esterhuizen, Tilman Polster, Alice Spano, Inés Gómez-Lozano, Abhishek Kumar, Gemma Poke, John A. Phillips, Hunter R. Underhill, Gregory Gimenez, Takashi Namba, and Stephen P. Robertson. Clustered de novo start-loss variants in glul result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase. American journal of human genetics, 111 4:729-741, Apr 2024. URL: https://doi.org/10.1016/j.ajhg.2024.03.005, doi:10.1016/j.ajhg.2024.03.005. This article has 19 citations and is from a highest quality peer-reviewed journal.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 4
Resolved 4
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 4
On topic 3
Off topic 0

All extracted references resolved successfully.