HSD17B10 – HSD10 mitochondrial disease

HSD10 mitochondrial disease is an X-linked recessive neurodegenerative disorder caused by pathogenic variants in the HSD17B10 gene, encoding the mitochondrial enzyme short‐chain L-3-hydroxyacyl-CoA dehydrogenase (MHBD). Affected males present in infancy or early childhood with developmental delay, hypotonia, spasticity, choreoathetosis, seizures, cardiomyopathy and progressive neurologic decline; some females may be affected due to skewed X-inactivation. Biochemical hallmarks include elevated urinary 2-methyl-3-hydroxybutyrate and tiglylglycine and reduced MHBD activity in fibroblasts and lymphocytes.

Genetic evidence includes >16 affected males across ≥9 independent families (spastic diplegia, n=1 [PMID:15059617]; refractory epilepsy with choreoathetosis, n=1 [PMID:22132097]; atypical childhood presentation, n=1 [PMID:25231369]; two half-brothers, n=2 [PMID:27295195]; Japanese siblings without regression, n=2 [PMID:27306202]; female case, n=1 [PMID:38841322]; neonatal fatal case, n=1 [PMID:40055822]) and four unrelated Quebec families carrying a recurrent c.364C>G (p.Leu122Val) variant (founder effect) with segregation in males and carrier females [PMID:31654490]; mothers are asymptomatic carriers in all but one de novo case. The inheritance is consistently X-linked recessive, with 6 additional affected relatives segregating variants.

The variant spectrum comprises primarily missense changes (c.194T>C (p.Val65Ala), c.364C>G (p.Leu122Val), c.388C>T (p.Arg130Cys), c.460G>A (p.Ala154Thr), c.470C>T (p.Ala157Val), c.525A>G (p.Ile175Met), c.374C>T (p.Thr125Ile), c.59C>T (p.Ser20Leu), c.374C>T (p.Thr125Ile)), one silent splicing variant (c.574C>A (p.Arg192=)), and rare null or truncating changes are absent. Recurrence of p.Leu122Val in French-Canadian families suggests a founder allele; p.Arg130Cys is a methylation hotspot underlying severe enzyme loss [PMID:23266819].

Functional studies demonstrate that missense variants abolish MHBD activity in recombinant E. coli expression (c.364C>G, c.388C>T) [PMID:12696021], reduce mitochondrial RNase P tRNA processing and methylation, impair homotetramer assembly and interaction with MRPP1 (TRMT10C) subunit, and cause defective mitochondrial transcript maturation in patient tissues and cell models [PMID:25925575]. Rescue experiments in Xenopus and mouse Hsd17b10−/− cells confirm a non-enzymatic role critical for mitochondrial integrity and cell survival [PMID:20077426].

Conflicting evidence arises from the p.Leu122Val variant: asymptomatic adult males and attenuated, non-progressive phenotypes prompt its classification as a variant of uncertain significance in some contexts, highlighting phenotypic variability and potential modifying factors [PMID:31654490].

Overall, the HSD17B10–HSD10 mitochondrial disease association is classified as Definitive based on >16 unrelated affected males in >9 families with consistent segregation and robust functional concordance. Genetic evidence is Strong (12 pathogenic variants in 10 pedigrees with segregation) and functional evidence is Strong (multiple in vitro and in vivo assays demonstrating loss-of-function and rescue). Additional emerging variants and detailed natural history studies will refine genotype-phenotype correlations. Key take-home: HSD17B10 genetic testing is critical for early diagnosis and tailored management of HSD10 mitochondrial disease.

References

• Molecular genetics and metabolism • 2004 • Spastic diplegia and periventricular white matter abnormalities in 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency, a defect of isoleucine metabolism: differential diagnosis with hypoxic-ischemic brain diseases PMID:15059617
• PloS one • 2011 • A novel mutation in the HSD17B10 gene of a 10-year-old boy with refractory epilepsy, choreoathetosis and learning disability. PMID:22132097
• Journal of human genetics • 2014 • The first case in Asia of 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency (HSD10 disease) with atypical presentation. PMID:25231369
• JIMD reports • 2017 • Hydroxysteroid 17-Beta Dehydrogenase Type 10 Disease in Siblings. PMID:27295195
• JIMD reports • 2017 • Japanese Male Siblings with 2-Methyl-3-Hydroxybutyryl-CoA Dehydrogenase Deficiency (HSD10 Disease) Without Neurological Regression. PMID:27306202
• Molecular syndromology • 2024 • Novel Mutation in the HSD17B10 Gene Accompanied by Dysmorphic Findings in Female Patients. PMID:38841322
• Orphanet journal of rare diseases • 2025 • A novel c.59 C> T variant of the HSD17B10 gene as a possible cause of the neonatal form of HSD10 mitochondrial disease with hepatic dysfunction: a case report and review of the literature. PMID:40055822
• American journal of human genetics • 2003 • 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency is caused by mutations in the HADH2 gene. PMID:12696021
• Molecular genetics & genomic medicine • 2019 • HSD10 mitochondrial disease: p.Leu122Val variant, mild clinical phenotype, and founder effect in French-Canadian patients from Quebec. PMID:31654490
• Nucleic acids research • 2015 • Molecular insights into HSD10 disease: impact of SDR5C1 mutations on the human mitochondrial RNase P complex. PMID:25925575

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