{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T14:25:57Z","timestamp":1784125557819,"version":"3.55.0"},"reference-count":16,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2019,10,26]],"date-time":"2019-10-26T00:00:00Z","timestamp":1572048000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>HSD10 mitochondrial disease (HSD10MD), originally described as a deficiency of 2\u2010methyl\u20103\u2010hydroxybutyryl\u2010CoA dehydrogenase (MHBD), is a rare X\u2010linked disorder of a moonlighting protein encoded by the <jats:italic>HSD17B10<\/jats:italic>. The diagnosis is usually first suspected on finding elevated isoleucine degradation metabolites in urine, reflecting decreased MHBD activity. However, it is now known that clinical disease pathogenesis reflects other independent functions of the HSD10 protein; particularly its essential role in mitochondrial transcript processing and tRNA maturation. The classical phenotype of HSD10MD in affected males is an infantile\u2010onset progressive neurodegenerative disorder associated with severe mitochondrial dysfunction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Patients, Methods, and Results<\/jats:title><jats:p>In four unrelated families, we identified index patients with MHBD deficiency, which implied a diagnosis of HSD10MD. Each index patient was independently investigated because of neurological or developmental concerns. All had persistent elevations of urinary 2\u2010methyl\u20103\u2010hydroxybutyric acid and tiglylglycine. Analysis of <jats:italic>HSD17B10<\/jats:italic> identified a single missense variant, c.364C&gt;G, p.Leu122Val, in each case. This rare variant (1\/183336 alleles in gnomAD) was previously reported in one Dutch patient and was described as pathogenic. The geographic origins of our families and results of haplotype analysis together provide evidence of a founder effect for this variant in Quebec. Notably, we identified an asymptomatic hemizygous adult male in one family, while a second independent genetic disorder contributed substantially to the clinical phenotypes observed in probands from two other families.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The phenotype associated with p.Leu122Val in <jats:italic>HSD17B10<\/jats:italic> currently appears to be attenuated and nonprogressive. This report widens the spectrum of phenotypic severity of HSD10MD and contributes to genotype\u2013phenotype correlation. At present, we consider p.Leu122Val a \u201cvariant of uncertain significance.\u201d Nonetheless, careful follow\u2010up of our patients remains advisable, to assess long\u2010term clinical course and ensure appropriate management. It will also be important to identify other potential patients in our population and to characterize their phenotype.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.1000","type":"journal-article","created":{"date-parts":[[2019,10,26]],"date-time":"2019-10-26T08:38:58Z","timestamp":1572079138000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["HSD10 mitochondrial disease: p.Leu122Val variant, mild clinical phenotype, and founder effect in French\u2010Canadian patients from Quebec"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4898-1859","authenticated-orcid":false,"given":"Paula J.","family":"Waters","sequence":"first","affiliation":[{"name":"Medical Genetics Department of Pediatrics Universit\u00e9 de Sherbrooke\u2010CHUS Sherbrooke QC Canada"},{"name":"CRCHUS Sherbrooke QC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baiba","family":"Lace","sequence":"additional","affiliation":[{"name":"Medical Genetics Department of Pediatrics CHU de Qu\u00e9bec\u2010Universit\u00e9 Laval Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Buhas","sequence":"additional","affiliation":[{"name":"Medical Genetics Department of Specialized Medicine MUHC Montreal Canada"},{"name":"Department of Human Genetics McGill University Montreal Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serge","family":"Gravel","sequence":"additional","affiliation":[{"name":"Medical Genetics Department of Pediatrics Universit\u00e9 de Sherbrooke\u2010CHUS Sherbrooke QC Canada"},{"name":"CRCHUS Sherbrooke QC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis","family":"Cyr","sequence":"additional","affiliation":[{"name":"Medical Genetics Department of Pediatrics Universit\u00e9 de Sherbrooke\u2010CHUS Sherbrooke QC Canada"},{"name":"CRCHUS Sherbrooke QC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9e\u2010Myriam","family":"Boucher","sequence":"additional","affiliation":[{"name":"Neurology Department of Pediatrics CHU de Qu\u00e9bec\u2010Universit\u00e9 Laval Quebec QC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genevi\u00e8ve","family":"Bernard","sequence":"additional","affiliation":[{"name":"Medical Genetics Department of Specialized Medicine MUHC Montreal Canada"},{"name":"Department of Human Genetics McGill University Montreal Canada"},{"name":"Departments of Neurology\/Neurosurgery and Pediatrics McGill University Montreal Canada"},{"name":"RI\u2010MUHC Montreal Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9bastien","family":"L\u00e9vesque","sequence":"additional","affiliation":[{"name":"Medical Genetics Department of Pediatrics Universit\u00e9 de Sherbrooke\u2010CHUS Sherbrooke QC Canada"},{"name":"CRCHUS Sherbrooke QC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Maranda","sequence":"additional","affiliation":[{"name":"Medical Genetics Department of Pediatrics Universit\u00e9 de Sherbrooke\u2010CHUS Sherbrooke QC Canada"},{"name":"CRCHUS Sherbrooke QC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,10,26]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/8904_2016_570"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12987"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2014.12.005"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu072"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1080\/15476286.2016.1159381"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/jhg.2014.79"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1086\/375116"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1021251202287"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2003.11.013"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.200900055"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/8904_2016_547"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv658"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2011.06.011"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-011-9415-4"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-200012000-00025"}],"container-title":["Molecular Genetics &amp; 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