| domain | established finding | evidence type/sample | confidence or limitation |
|---|---|---|---|
| Disease identity | Global developmental delay, progressive ataxia, and elevated glutamine corresponds to GDPAG; OMIM 618412 is explicitly linked in retrieved literature, and Open Targets maps the disease to EFO_0010257 with GLS as the associated target (pqac-00000003, pqac-00000000) | Disease database / review context | High for OMIM and EFO mapping; MONDO and other identifiers were not established from retrieved evidence |
| Gene and inheritance | Causal gene is **GLS** (glutaminase); the disorder is autosomal recessive, with biallelic pathogenic alleles including coding variants and/or 5′UTR GCA repeat expansions (pqac-00000003, pqac-00000008) | Human genetic evidence from 3 unrelated probands/families | High for GLS and AR inheritance |
| Case count | Three unrelated affected index cases/families were reported for the GLS 5′UTR GCA-repeat form of GDPAG (pqac-00000002, pqac-00000008) | Human case series | Moderate; retrieved text summarizes the study but does not provide full demographic detail |
| Genotype: Family 1 | Compound heterozygous: paternally inherited **c.938C>T (p.Pro313Leu)** plus maternally inherited 5′UTR **GCA repeat expansion**; expansion estimated as >90 by ExpansionHunter, rising to 246 with off-target reads; repeat PCR showed a major expansion product of ~680 repeats (pqac-00000010, pqac-00000008) | Human molecular genetics in 1 proband/family | Moderate; different assays yielded different size estimates, reflecting technical uncertainty for large repeats |
| Genotype: Family 2 | Homozygous 5′UTR **GCA repeat expansion** alleles inherited from both parents; repeat PCR showed a major expansion product of ~900 repeats (pqac-00000010, pqac-00000008) | Human molecular genetics in 1 proband/family | Moderate; exact allele-by-allele repeat lengths were not fully resolved |
| Genotype: Family 3 | Compound heterozygous: maternally inherited **c.923dupA (p.Tyr308\*)** plus paternally inherited 5′UTR **GCA repeat expansion**; repeat PCR showed a major expansion product of ~1500 repeats (pqac-00000010, pqac-00000008) | Human molecular genetics in 1 proband/family | Moderate; expansion size is approximate |
| Population repeat data | In 8,295 genomes, the GLS GCA repeat had median size **14 repeats**, bimodal peaks at **8** and **16**; 1 person was heterozygous for an allele with >90 repeats, implying allele frequency **6.03×10^-5** for such large expanded alleles (pqac-00000010) | Population genome screening | Moderate; based on short-read genome analysis at a difficult repeat locus |
| Core phenotype | The GLS repeat-expansion phenotype was reported as **early-onset/global developmental delay**, **progressive ataxia**, and **elevated plasma glutamine**; plasma glutamate was unaltered (pqac-00000002, pqac-00000008) | Human clinical/biochemical evidence | High for these core features; many additional phenotype details were not available in retrieved text |
| Biochemical marker | Elevated **plasma glutamine** with **normal plasma glutamate** is the main reported disease biomarker; biochemical and flux assays supported glutaminase deficiency in patient cells (pqac-00000002, pqac-00000010) | Human plasma biochemistry plus fibroblast/PBM functional assays | High for qualitative direction; quantitative metabolite values were not available |
| Enzyme deficiency | Patient fibroblasts and peripheral-blood mononuclear cells showed **reduced GLS activity** and decreased GLS protein/expression; residual activity was present, which was proposed to explain a milder phenotype than complete ablation (pqac-00000010, pqac-00000009) | Human patient-derived cells | High for reduced activity/expression; exact activity values not extracted |
| Molecular mechanism | The 5′UTR GCA repeat expansion did **not** show increased DNA methylation, but was associated with reduced **H3 acetylation** and **H3K4me3** and increased **H3K9me3**, consistent with repressive chromatin and decreased GLS transcription (pqac-00000009) | Patient fibroblast chromatin studies | High for chromatin-silencing mechanism in tested cells |
| Diagnostic methods | Detection required methods beyond exome sequencing: **singleton WGS/manual inspection**, **ExpansionHunter**, **triplet repeat–primed PCR**, **repeat-flanking PCR/agarose sizing**, **Sanger sequencing** for coding variants/non-expanded alleles, plus **qPCR/cDNA allelic expression** and **enzyme assays** (pqac-00000010, pqac-00000003) | Human diagnostic workflow evidence | High that standard ES can miss this lesion; exact clinical sensitivity/specificity not available |
| Distinction from other GLS disorders | Retrieved literature distinguishes GDPAG from a **de novo hypermorphic GLS** disorder and from other severe **GLS loss-of-function** epileptic/neonatal phenotypes; GDPAG specifically refers here to the AR GLS deficiency with developmental delay, progressive ataxia, and elevated glutamine (pqac-00000002, pqac-00000004) | Review synthesis across GLS-associated phenotypes | Moderate; distinction is clear, but retrieved sources did not fully harmonize modern nosology |
| Model organisms | **Zebrafish** knockdown of GLS orthologues (**glsa, glsl**) caused **smaller body size, curved body, and cardiac edema**; prior **mouse** data cited in the retrieved text indicate GLS ablation impairs glutamatergic synaptic transmission and causes early death from respiratory problems, with heterozygotes showing hippocampal hypoactivity (pqac-00000010, pqac-00000009) | Animal models | Moderate; model findings support biology but do not fully recapitulate the human GDPAG phenotype |
| Treatment | No disease-specific pharmacologic, gene, RNA, or dietary therapy for GDPAG was established in the retrieved evidence (pqac-00000002, pqac-00000010) | Evidence-gap assessment | Low therapeutic certainty because of absence of direct interventional studies |
| Clinical trials | No relevant interventional trials for GDPAG/glutaminase deficiency were identified; retrieved GLS trials were oncology **GLS inhibitor** studies and are not applicable to an enzyme-deficiency disorder (pqac-00000000) | Clinical-trial search context | High as a current evidence gap |
| Epidemiology | No prevalence or incidence estimate for GDPAG was identified in retrieved disease-specific evidence; currently evidence is limited to a very small number of families/cases (pqac-00000002, pqac-00000008) | Evidence-gap assessment from case literature | High as a gap; rarity is evident but not quantifiable from retrieved sources |


*Table: This table condenses the strongest retrieved evidence for GLS-associated GDPAG, emphasizing what is established versus what remains uncertain. It is useful for a knowledge-base entry because it separates core disease facts from important evidence gaps.*