| 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**. (pqac-00000010, pqac-00000016) | 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 (pqac-00000016) |
| 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. (pqac-00000001, pqac-00000009, pqac-00000012) | 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. (pqac-00000001, pqac-00000004, pqac-00000008) | 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. (pqac-00000004, pqac-00000008) | 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. (pqac-00000000, pqac-00000008) | 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. (pqac-00000005, pqac-00000008) | 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**. (pqac-00000000, pqac-00000004, pqac-00000010) | 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**. (pqac-00000000, pqac-00000003, pqac-00000009, pqac-00000010) | 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”). (pqac-00000001, pqac-00000005, pqac-00000012, pqac-00000014, pqac-00000015) | 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**). (pqac-00000006, pqac-00000014, pqac-00000015) | 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. (pqac-00000005, pqac-00000011) | 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. (pqac-00000005, pqac-00000011, pqac-00000015) | 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. (pqac-00000000) | 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. (pqac-00000003, pqac-00000007, pqac-00000010) | 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.*