| Evidence unit / publication | Genotype | Patient count | Core phenotype and onset | Key biochemical / pathology evidence | Outcome / treatment | Evidence type and limitations |
|---|---|---:|---|---|---|---|
| Menezes et al., *Human Molecular Genetics* (published January 2, 2015); PMID: 25556185; DOI: [10.1093/hmg/ddu747](https://doi.org/10.1093/hmg/ddu747) | Homozygous **MRPS7** c.550A>G, p.(Met184Val), rs115047866; affected sisters homozygous, parents and unaffected sister heterozygous | 2 affected sisters | Both had profound congenital bilateral sensorineural deafness and childhood lactic acidemia. P1 developed recurrent emesis and failure to thrive in infancy, hypoglycemia <0.5 mmol/L and lactate 4.1 mmol/L at 13 months, then progressive hepatic and renal failure. P2 had intermittent childhood hyperlactatemia/hypoglycemia, mild learning difficulties, failed puberty, primary hypogonadism at 16 years, mildly elevated TSH (6.75 mIU/L), and primary adrenal failure. | Liver respiratory-chain activities were deficient in complexes I, III, and IV: P1/P2 complex I 7/6 (reference 10–21), complex III 7.4/4.5 (9–14), and complex IV 0.2/1.1 (1.1–1.6) nmol/min/mg or /min/mg as reported. P1 muscle complex III was 11.6 (14–67); other muscle activities were largely preserved. P2 renal biopsy at 13 years showed tubular atrophy/dilatation and giant mitochondria up to 5.5 μm versus normal 0.5–1.0 μm, with increased matrix and reduced cristae. P1 fibroblasts showed near-absent MRPS7, reduced 12S rRNA, impaired mitochondrial translation, reduced OXPHOS proteins, complexes I/IV dysfunction, mitochondrial-network fragmentation, and significantly reduced ATP production (P<0.003). Wild-type—but not mutant—MRPS7 restored 12S rRNA and respiratory-chain activity. | P1 received resuscitation, antibiotics, nutritional support, ventilation, and hemofiltration; a left parieto-occipital infarct precluded transplantation, and she died at 14 years 5 months after intensive support was withdrawn. P2 received cochlear implantation, estrogen replacement, and low-dose hydrocortisone; later follow-up reported combined liver–renal transplantation at 25 years with a positive outcome. | Human familial case series plus patient-fibroblast rescue experiments; strongest direct causal evidence. Only one family, no controlled treatment data, ancestry not specified, and marked intrafamilial variability limit frequency and prognostic inference. Historical allele estimates were heterozygosity 0.002 in dbSNP and 0.67% in an in-house CAG dataset, not current gnomAD frequencies. (pqac-00000016, pqac-00000017, pqac-00000018, pqac-00000019) |
| Kline et al., *Genes* (published November 14, 2022); DOI: [10.3390/genes13112113](https://doi.org/10.3390/genes13112113) — proband | Compound heterozygous **MRPS7** c.373A>T, p.(Lys125*) and c.536G>A, p.(Arg179His), demonstrated in trans; both classified likely pathogenic by the authors | 1 molecularly characterized proband | Sensorineural hearing loss diagnosed at 9 years; normal puberty followed by secondary amenorrhea and premature ovarian insufficiency diagnosed at 25 years; Hashimoto disease. FSH 102 IU/L, LH 34 IU/L, estradiol 29 pg/mL, AMH 0.15 ng/mL, TSH 12.89 mIU/L, and anti-TPO 102 IU/mL. | Ultrasound at 25 years showed small ovaries: right 18×4.5 mm with two microfollicles and left 14×6 mm without visible follicles. Karyotype/microarray showed 46,XX; FMR1-premutation and ovarian-autoantibody testing were negative. p.(Lys125*) was predicted to undergo nonsense-mediated decay; structural modeling predicted p.(Arg179His) would disrupt interactions with Glu153 and Asp176. No patient-cell functional assay was reported. | Hashimoto disease was described as well managed. Bone mineral density was not osteoporotic. No disease-modifying therapy or treatment-response data were reported; the authors highlighted potential benefits of early hormone replacement or oocyte collection for mitochondrial-disease-associated POI generally. | Human single-case report with WES, Sanger validation, phasing, clinical endocrine testing, and computational modeling. Independent allelic replication supports causality, but lack of functional validation, parental DNA, longitudinal outcome, and disease-specific treatment evidence limits interpretation. (pqac-00000007, pqac-00000009, pqac-00000010, pqac-00000012) |
| Kline et al. (2022) — clinically affected sister of the new proband | Presumed familial MRPS7-related disease; sister’s genotype was not reported | 1 clinically affected sister | Congenital hearing loss and POI diagnosed at 21 years | No biochemical, imaging, histopathologic, or functional data reported | Treatment and outcome not reported | Human phenotype-only familial evidence; cannot independently confirm genotype, mechanism, or biochemical COXPD34. (pqac-00000007, pqac-00000009) |
| Combined published human evidence through 2022 | Three reported disease-associated alleles: c.550A>G p.(Met184Val), c.373A>T p.(Lys125*), and c.536G>A p.(Arg179His) | 4 clinically affected females across 2 unrelated families; 3 molecularly documented in the cited reports | Sensorineural hearing loss occurred in all 4 reported individuals; ovarian insufficiency/hypogonadism was documented in the 3 who survived to an assessable reproductive age. Severe progressive hepatorenal disease was documented in the original sisters; biochemical combined OXPHOS deficiency was demonstrated only in that family. | Direct functional evidence is confined to p.(Met184Val) patient fibroblasts. The nearby p.(Arg179His) and p.(Met184Val) residues lie within the predicted ribosomal-protein S7 domain (codons 82–234), which interacts with 12S rRNA. | No curative or genotype-specific therapy and no controlled treatment response have been reported. Organ transplantation and endocrine, adrenal, auditory, nutritional, renal, and intensive supportive interventions were used in individual patients. | Ultra-small, ascertainment-biased literature; percentages are descriptive rather than population estimates. Penetrance, prevalence, incidence, carrier frequency, sex ratio, survival rates, and robust genotype–phenotype correlations remain unknown. (pqac-00000006, pqac-00000011, pqac-00000027) |


*Table: Disease-specific clinical, genetic, biochemical, and functional evidence for MRPS7-related combined oxidative phosphorylation deficiency 34. The table highlights the very small evidence base, exact reported measurements, outcomes, and major limitations.*