| Item type | Specific data | Evidence note with cited source short name + year |
|---|---|---|
| Identifier | **MONDO:** MONDO_0010327 (HSD10 mitochondrial disease) | OpenTargets disease mapping (pqac-00000000) |
| Identifier | **Orphanet:** Orphanet_391417 (HSD10 disease) | OpenTargets disease mapping (pqac-00000000) |
| Identifier | **Orphanet subtype:** Orphanet_85295 (HSD10 disease, atypical type) | OpenTargets disease mapping (pqac-00000000) |
| Synonym | HSD10 disease | Standard disease name in clinical review and recent case literature (pqac-00000001, pqac-00000004) |
| Synonym | HSD10 mitochondrial disease; HSD10MD | Used in modern clinical genetics literature (pqac-00000035, pqac-00000044) |
| Synonym | 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency; MHBD deficiency; 2-methyl-3-hydroxybutyric aciduria | Historical/biochemical names; older nomenclature emphasized isoleucine pathway defect (pqac-00000002, pqac-00000043) |
| Gene-Protein | **Gene:** HSD17B10 (Xp11.2, X-linked); **protein aliases:** 17β-HSD10, SDR5C1, MRPP2; multifunctional mitochondrial matrix protein and mtRNase P component | Zschocke 2012 and mechanistic studies (pqac-00000002, pqac-00000011, pqac-00000054) |
| Inheritance | **X-linked**; affected males usually hemizygous and more severe; heterozygous females show variable expressivity due to X-inactivation/skewing, ranging from asymptomatic to developmental delay/intellectual disability | Clinical review and female case reports (pqac-00000034, pqac-00000008, pqac-00000043) |
| Key phenotypes | Core spectrum: infantile neurodegeneration, developmental delay/regression, intellectual disability, epilepsy/refractory seizures, choreoathetosis or movement disorder, microcephaly, retinopathy/vision loss, hearing impairment, cardiomyopathy | Summarized across review and 2023–2024 sources (pqac-00000002, pqac-00000044, pqac-00000045) |
| Key phenotypes | Distinct forms reported: **neonatal** severe encephalopathic/cardiomyopathic form; **classical infantile** form with normal early development then regression at 6–18 months; **juvenile/late** and **atypical/nonprogressive** forms | Natural history synthesis from Zschocke 2012 and recent reports (pqac-00000002, pqac-00000007, pqac-00000038) |
| Key biomarkers-Dx | Urine organic acids: elevated **3-hydroxy-2-methylbutyrate / 2-methyl-3-hydroxybutyrate** and **tiglylglycine**; often no elevation of 2-methylacetoacetate | Hallmark biochemical screen (pqac-00000017, pqac-00000018, pqac-00000023) |
| Key biomarkers-Dx | Supportive markers/tests: lactic acidosis or elevated plasma/CSF lactate; occasional elevated urinary C5:1/tiglylcarnitine; MHBD/HSD10 enzyme assay in fibroblasts or leukocytes; confirm by **HSD17B10 sequencing/WES** | Biochemical and molecular diagnostic approach (pqac-00000017, pqac-00000022, pqac-00000021) |
| Key biomarkers-Dx | Imaging can be normal in some patients, but reported abnormalities include mild cerebral atrophy, ventricular dilatation, thin corpus callosum, globus pallidus T2 hyperintensity; MRS may show cerebral lactate | Imaging variability across cases (pqac-00000018, pqac-00000021, pqac-00000017) |
| Key mechanisms | Disease mechanism is **not explained solely by MHBD enzymatic deficiency**; HSD10 is a moonlighting protein whose non-enzymatic functions are central to pathogenesis | Clinical-pathophysiologic reinterpretation in reviews and functional studies (pqac-00000001, pqac-00000050, pqac-00000053) |
| Key mechanisms | HSD10/MRPP2 is an essential subunit of **mitochondrial RNase P** and required for mt-tRNA 5′ processing and m1R9 methylation; pathogenic variants impair mtRNA processing | Mechanistic core from Chatfield 2015, Vilardo 2015, Rauschenberger work (pqac-00000011, pqac-00000015, pqac-00000055) |
| Key mechanisms | Downstream cascade: defective mtDNA transcript processing → impaired mitochondrial translation/respiratory-chain assembly (complexes I, III, IV, V) → reduced ATP/mitochondrial energy failure → neurodegeneration and cardiomyopathy | Human tissue studies and mechanistic synthesis (pqac-00000011, pqac-00000056) |
| Variants-GenotypePhenotype | **p.Arg130Cys (c.388C>T)** is the recurrent major allele, present in ~half of reported families/cases and strongly associated with the classical infantile phenotype; often **de novo** | Recurrent hotspot summarized in reviews (pqac-00000034, pqac-00000036, pqac-00000042) |
| Variants-GenotypePhenotype | Reported genotype-phenotype groupings: **infantile** p.L122V, p.R130C, p.P210S; **neonatal** p.D86G, p.R226Q, p.N247S; **juvenile** p.E249Q; atypical presentations with p.Q165H and c.574C>A splicing-efficiency variant | Variant spectrum and clinical form associations (pqac-00000038) |
| Variants-GenotypePhenotype | **p.Leu122Val (c.364C>G)**: mild/attenuated nonprogressive phenotype, including an asymptomatic hemizygote; identified in 4 unrelated French-Canadian Quebec families with **founder effect**; gnomAD allele frequency **1/183,336**; currently treated cautiously as VUS in that report | Waters et al. 2019 founder-effect study (pqac-00000035) |
| Treatments & evidence gaps | No proven disease-modifying therapy. **Isoleucine restriction** and **mitochondrial cocktail** (CoQ10, lipoic acid, vitamins C/E, magnesium, selenium) have been tried, but published evidence shows **no measurable benefit** or only anecdotal use without outcome data | Zschocke 2012 and recent case reports (pqac-00000025, pqac-00000026, pqac-00000027) |
| Treatments & evidence gaps | Current practical management is supportive: balanced diet, avoid catabolic stress, rapid treatment during illness, symptomatic neurologic/cardiac care; avoid mitochondrial-toxic drugs such as **valproate/valproic acid** when possible | Supportive-care recommendations from review/case literature (pqac-00000026, pqac-00000028) |
| Epidemiology | Ultra-rare disorder. Earlier review reported mutations in **19 families**; recent 2024 report states **fewer than 40 index cases** reported overall, with female index cases especially rare | Case-count statistics from review and 2024 case report (pqac-00000034, pqac-00000043) |
| Epidemiology | Robust population **prevalence/incidence not available** in gathered evidence; disease knowledge is based mainly on case reports/series and aggregated disease resources rather than EHR-scale datasets | Evidence-gap statement from available literature base (pqac-00000002, pqac-00000043) |


*Table: This table condenses the main identifiers, nomenclature, genetics, phenotype spectrum, diagnostics, mechanisms, variant correlations, treatment evidence gaps, and epidemiology for HSD10 mitochondrial disease. It is designed as a compact knowledge-base summary anchored to the cited evidence contexts.*