| Category | Finding (with numbers where available) | Evidence type (cohort/case report/model) | Publication (year, journal) + URL | Supporting citation IDs |
|---|---|---|---|---|
| Phenotype / cohort overview | Single-center pediatric hepatic MDDS cohort: **n=24 total**, including **10 MPV17** cases; **median age at presentation 3 months** overall; liver involvement in MPV17 developed at **median 2.5 months**. | Human cohort | Vara et al., 2023, *Journal of Inherited Metabolic Disease* — https://doi.org/10.1002/jimd.12633 | (pqac-00000009, pqac-00000011) |
| Natural history / mortality | In the same cohort, **17/24 died** at **median age 8 months**; among MPV17 patients, **5/10 died** at **median 8 months**. Authors conclude MPV17 often causes **early-onset/neonatal acute liver failure or rapidly progressive cholestasis** with death before 12 months in many cases. | Human cohort | Vara et al., 2023, *Journal of Inherited Metabolic Disease* — https://doi.org/10.1002/jimd.12633 | (pqac-00000009) |
| Liver transplantation outcomes | **3 MPV17 patients** underwent liver transplantation at **median age 24 months** (range **5–132 months**) and were alive at **19, 18, and 3 years** post-transplant, supporting that a subset may benefit from LT. | Human cohort | Vara et al., 2023, *Journal of Inherited Metabolic Disease* — https://doi.org/10.1002/jimd.12633 | (pqac-00000009, pqac-00000011, pqac-00000013) |
| Core presenting features | In a 17-patient MPV17 cohort, **all patients had liver disease**; common features were **poor feeding, hypoglycaemia, raised serum lactate, hypotonia, and faltering growth**. | Human cohort | Uusimaa et al., 2014, *European Journal of Human Genetics* — https://doi.org/10.1038/ejhg.2013.112 | (pqac-00000002, pqac-00000016) |
| Biochemical findings | Initial/plasma lactate ranged **3–21.4 mmol/L**; CSF lactate up to **5.1 mmol/L**; notably **five patients** had at least one **normal blood or CSF lactate**, so normal lactate does not exclude disease. | Human cohort | Uusimaa et al., 2014, *European Journal of Human Genetics* — https://doi.org/10.1038/ejhg.2013.112 | (pqac-00000004, pqac-00000018) |
| Tissue mtDNA depletion / severity correlation | **mtDNA depletion in liver was demonstrated in all 7/7 cases** with liver tissue available; severe liver mtDNA depletion (**<~20% of age-matched controls**) correlated with **earlier onset and more severe course/death**. Mosaic mtDNA depletion was also seen in fibroblasts. | Human cohort / cellular | Uusimaa et al., 2014, *European Journal of Human Genetics* — https://doi.org/10.1038/ejhg.2013.112 | (pqac-00000002, pqac-00000005, pqac-00000012, pqac-00000022) |
| Histology / organ involvement | Liver histology showed variable **necrosis, steatosis, cholestasis, fibrosis**, with abnormal respiratory-chain enzymology in a subset. | Human cohort | Vara et al., 2023, *Journal of Inherited Metabolic Disease* — https://doi.org/10.1002/jimd.12633 | (pqac-00000009) |
| Neonatal fulminant presentation | 2023 neonatal case: presented with **hypoglycemia, jaundice, hypotonia, rotatory nystagmus**, severe coagulopathy, hyperlactatemia, aminoaciduria; homozygous pathogenic MPV17 missense variant found; infant **died at 2 weeks** with refractory ascites. | Human case report | Abduljalil et al., 2023, *Case Reports in Hepatology* — https://doi.org/10.1155/2023/4514552 | (pqac-00000007, pqac-00000021) |
| Supportive management / transplant experience | Review of available therapy noted **frequent feeding using slow-release carbohydrates/cornstarch** to prevent fatal hypoglycemia; among **10 transplanted** MPV17 patients reported in literature, **5 died early** after LT from multiorgan failure or sepsis. | Human literature summary / translational | Bottani et al., 2014, *Molecular Therapy* — https://doi.org/10.1038/mt.2013.230 | (pqac-00000003) |
| Inheritance | Disease is **autosomal recessive**; cases arise in **homozygous or compound heterozygous** states, often in consanguineous families. | Human cohort / case report | Uusimaa et al., 2014, *European Journal of Human Genetics* — https://doi.org/10.1038/ejhg.2013.112; Abduljalil et al., 2023, *Case Reports in Hepatology* — https://doi.org/10.1155/2023/4514552 | (pqac-00000016, pqac-00000021) |
| Key pathogenic variants | Uusimaa 2014 identified **12 MPV17 mutations** (11 novel) in 17 patients, including **p.Arg50Gln (p.R50Q)**, **p.Arg41Trp**, **p.Pro64Arg**, **p.Gly94Arg**, and **p.Pro98Leu**; mutation classes included **missense and truncating** alleles. | Human cohort | Uusimaa et al., 2014, *European Journal of Human Genetics* — https://doi.org/10.1038/ejhg.2013.112 | (pqac-00000015, pqac-00000018) |
| Genotype-phenotype note | **p.R50Q** is the classic Navajo neurohepatopathy-associated allele. Uusimaa 2014 suggested some **missense genotypes** (e.g., **p.Arg41Trp, p.Pro64Arg, p.Pro98Leu, p.R50Q**) may retain residual function and show relatively milder survival than severe truncating/other alleles, although genotype-phenotype correlation was described as **loose**. | Human cohort | Uusimaa et al., 2014, *European Journal of Human Genetics* — https://doi.org/10.1038/ejhg.2013.112 | (pqac-00000015, pqac-00000022) |
| Mechanistic function of MPV17 | MPV17 encodes an **inner mitochondrial membrane protein** that forms a **regulated non-selective channel** (~**1.8 nm** pore) and modulates **mitochondrial membrane potential** and **ROS**, linking loss of function to mtDNA instability. | In vitro / mouse model | Antonenkov et al., 2015, *Journal of Biological Chemistry* — https://doi.org/10.1074/jbc.m114.608083 | (pqac-00000019) |
| Mechanistic insight into depletion | Drosophila and prior mouse work support that MPV17 loss perturbs **mitochondrial nucleotide homeostasis** (including reduced **dGTP/dTTP**), increases aberrant **riboGTP incorporation**, and contributes to **mtDNA replication arrest/depletion**; Drosophila Mpv17 also formed a channel and affected energy metabolism. | Model organism / mechanistic | Corrà et al., 2023, *iScience* — https://doi.org/10.1016/j.isci.2023.107955 | (pqac-00000010) |


*Table: This table summarizes clinically important phenotype, natural history, outcomes, pathogenic variants, and mechanistic findings for MPV17-related mitochondrial DNA depletion syndrome. It is designed to support disease knowledge base curation with specific numbers and citation-backed genotype-phenotype notes.*