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)

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

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

1. (jones2024clustereddenovo pages 1-3): 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.

2. (jones2024clustereddenovo pages 11-12): 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.

3. (jones2024clustereddenovo pages 3-4): 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.

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

• Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

All extracted references resolved successfully.