| Domain | Key finding/statistic | Evidence type | Source/year |
|---|---|---|---|
| Childhood clinical course | Retrospective monocentric cohort of **40 children** with childhood-onset POLG deficiency identified **3 clinical patterns**: neurologic, hepatic, and gastrointestinal; **24/40 (60%)** required urgent neurointensive care for seizures/status epilepticus; only **6/40 survived**; hepatic presentations had earliest onset and shortest survival; valproate was highlighted as an avoidable precipitant of hepatic failure/death (pqac-00000022) | Human clinical cohort | Rötig et al., 2024 |
| Status epilepticus burden | Multinational study of **195 genetically confirmed POLG patients**: **67% (130/194)** had epilepsy; **77% (97/126)** with epilepsy developed status epilepticus; median SE onset **7 years**; **97% (91/94)** convulsive SE; **67% (56/84)** epilepsia partialis continua; **66% (57/86)** refractory/super-refractory SE; median time from SE onset to death **5 months** (pqac-00000024) | Human multinational cohort | Hikmat et al., 2024 |
| Pediatric natural history | Early-onset POLG pediatric cohort of **27 patients**; for Alpers phenotype (**n=19**), **100%** had seizures and liver dysfunction; overall cohort mortality **85% (22/26)**; median age at death **15.8 months**; median survival from onset **4.9 months**; liver failure was main cause of death (**13/22**) (pqac-00000023, pqac-00000004) | Human clinical natural-history cohort | Hikmat et al., 2017 |
| Core syndrome definition | AHS is a severe pediatric POLG disorder characterized by the triad of **developmental regression, intractable seizures, and liver failure**; about **70%** of childhood POLG presentations are reported as AHS (pqac-00000001, pqac-00000006) | Human clinical review synthesizing cohorts | Rahman & Copeland, 2019 |
| EEG/MRI phenotype | POLG-related Alpers disease shows occipital-predominant epileptiform abnormalities; in one pediatric cohort, MRI lesions were present in **82% at onset** and **88% during disease course**; EEG often showed high-voltage polyspike-slow waves in occipitotemporal regions (pqac-00000010) | Human clinical cohort | Hikmat et al., 2017 |
| Neuropathology | Post-mortem study of **13 clinically/histologically defined Alpers patients** found severe respiratory-chain deficiency, especially **complex I**, in **inhibitory interneurons**, **pyramidal neurons** of occipital cortex, and **Purkinje cells**, with reduced neuronal densities supporting selective neuronal vulnerability underlying seizures/ataxia (pqac-00000007, pqac-00000009, pqac-00000011) | Human neuropathology | Hayhurst et al., 2019 |
| Common POLG variants | Frequently reported epilepsy-associated POLG variants include **p.Ala467Thr (A467T), p.Trp748Ser (W748S), and p.Gly848Ser (G848S)**; mtDNA depletion is a key downstream defect in severe disease (pqac-00000012, pqac-00000013) | Human genetic/clinical review | Anagnostou et al., 2016; Saneto et al., 2013 |
| Liver pathology/biomarkers | Characteristic liver pathology includes **microvesicular steatosis, bile duct proliferation, hepatocellular necrosis, bridging fibrosis/cirrhosis**; reported biomarkers include elevated **FGF21**, lactate, and plasma alanine in POLG disease (pqac-00000008) | Human pathology/review | Rahman & Copeland, 2019 |
| Experimental therapy: NAD+ precursor | Patient-derived iPSC cortical organoids from Alpers disease with **POLG A467T/P589L** recapitulated **neuronal loss, mtDNA depletion, and complex I defects**; **nicotinamide riboside** improved neuronal markers and normalized mitochondrial/synaptic transcriptomic pathways toward control profiles (pqac-00000020, pqac-00000021) | In vitro patient-derived organoid study | Hong et al., 2024 |


*Table: This compact table summarizes high-yield evidence for Alpers-Huttenlocher syndrome across natural history, neuropathology, genetics, and emerging experimental therapeutics. It emphasizes the most clinically actionable 2017-2024 findings with clear evidence-type labeling.*