{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:14:18Z","timestamp":1785406458554,"version":"3.56.0"},"reference-count":19,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004320","name":"Shiraz University of Medical Sciences","doi-asserted-by":"crossref","award":["33168"],"award-info":[{"award-number":["33168"]}],"id":[{"id":"10.13039\/501100004320","id-type":"DOI","asserted-by":"crossref"}]},{"award":["33168"],"award-info":[{"award-number":["33168"]}],"id":[{"id":"https:\/\/ror.org\/01n3s4692","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: L-2-hydroxyglutaric aciduria (L2HGA) is a rare autosomal recessive neurometabolic disorder marked by developmental delay, intellectual disability, and progressive movement abnormalities. Variants in RYR1 can cause congenital myopathies, but data on the co-occurrence of variants in populations are limited. The aim of this study was to characterize the clinical and genetic basis of the neurometabolic and neuromuscular abnormalities and to investigate the potential interaction between the identified variants. Methods: Patients with complex, previously undiagnosed clinical presentations underwent neurological evaluation, including brain magnetic resonance imaging, electromyography, biochemical testing, and whole-exome sequencing (WES). Identified variants were analyzed in silico and confirmed by Sanger sequencing in the patient and her parents. Three cases were reviewed, and one of these patients exhibited developmental delay, hypotonia, intellectual disability, and progressive motor dysfunction. Biochemical tests revealed markedly elevated urinary 2-hydroxyglutaric acid levels, consistent with L2HGA. Results: WES identified a homozygous likely pathogenic variant in L2HGDH (c.589_590insGGC, p.Q197insG), confirming the molecular diagnosis of L2HGA. In addition, a heterozygous missense variant in RYR1 (c.7268T&gt;A, p.M2423K), classified as a variant of uncertain significance, was detected and was inherited from her mildly affected father. The L2HGDH variant explains the neurometabolic phenotype of the patient, whereas the RYR1 variant remains of uncertain significance, and its clinical contribution cannot be clearly established. Conclusions: To our knowledge, this case illustrates the co-occurrence of a likely pathogenic L2HGDH variant and a heterozygous RYR1 variant of uncertain significance. The findings expand the mutational spectrum of L2HGA and underscore the value of comprehensive genomic testing in complex neurometabolic and neuromuscular disorders.<\/jats:p>","DOI":"10.3390\/genes17070735","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T08:43:57Z","timestamp":1782463437000},"page":"735","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical and Genetic Analysis of L-2-Hydroxyglutaric Aciduria Caused by a Novel L2HGDH Mutation with a Concurrent RYR1 Variant"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8987-2555","authenticated-orcid":false,"given":"Zahra","family":"Beyzaei","sequence":"first","affiliation":[{"name":"Shiraz Transplant Research Center (STRC), Shiraz University of Medical Sciences, Shiraz 7193711351, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seyed Mohsen","family":"Dehghani","sequence":"additional","affiliation":[{"name":"Gastroenterology and Hepatology Research Center, Shiraz University of Medical Sciences, Shiraz 7193711351, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bita","family":"Geramizadeh","sequence":"additional","affiliation":[{"name":"Shiraz Transplant Research Center (STRC), Shiraz University of Medical Sciences, Shiraz 7193711351, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3888-0931","authenticated-orcid":false,"given":"Ralf","family":"Weiskirchen","sequence":"additional","affiliation":[{"name":"Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC) RWTH University Hospital Aachen, D-52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/BF02312543","article-title":"L-2-Hydroxyglutaric aciduria: An inborn error of metabolism?","volume":"3","author":"Duran","year":"1980","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1002\/humu.21197","article-title":"An overview of L-2-hydroxyglutarate dehydrogenase gene (L2HGDH) variants: A genotype-phenotype study","volume":"31","author":"Steenweg","year":"2010","journal-title":"Hum. Mutat."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1055\/s-2008-1081217","article-title":"L-2-hydroxyglutaric aciduria and brain tumors in children with mutations in the L2HGDH gene: Neuroimaging findings","volume":"39","author":"Haliloglu","year":"2008","journal-title":"Neuropediatrics"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1186\/1750-1172-8-117","article-title":"Genotype-phenotype correlations in recessive RYR1-related myopathies","volume":"8","author":"Amburgey","year":"2013","journal-title":"Orphanet. J. Rare Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2024","DOI":"10.1093\/brain\/awm096","article-title":"Molecular mechanisms and phenotypic variation in RYR1-related congenital myopathies","volume":"130","author":"Zhou","year":"2007","journal-title":"Brain"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1002\/(SICI)1098-1004(200001)15:1<7::AID-HUMU4>3.0.CO;2-N","article-title":"Mutation nomenclature extensions and suggestions to describe complex mutations: A discussion","volume":"15","author":"Antonarakis","year":"2000","journal-title":"Hum. Mut."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.nmd.2009.12.005","article-title":"Multi-minicore disease and atypical periodic paralysis associated with novel mutations in the skeletal muscle ryanodine receptor (RYR1) gene","volume":"20","author":"Zhou","year":"2010","journal-title":"Neuromuscul. Disord."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1212\/01.wnl.0000188870.37076.f2","article-title":"Minicore myopathy with ophthalmoplegia caused by mutations in the ryanodine receptor type 1 gene","volume":"65","author":"Jungbluth","year":"2005","journal-title":"Neurology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1002\/humu.22056","article-title":"Clinical and genetic findings in a large cohort of patients with ryanodine receptor 1 gene-associated myopathies","volume":"33","author":"Klein","year":"2012","journal-title":"Hum. Mutat."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2599","DOI":"10.1093\/hmg\/9.18.2599","article-title":"An autosomal dominant congenital myopathy with cores and rods is associated with a neomutation in the RYR1 gene encoding the skeletal muscle ryanodine receptor","volume":"9","author":"Monnier","year":"2000","journal-title":"Hum. Mol. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1111\/j.1365-2990.2010.01149.x","article-title":"Recessive RYR1 mutations cause unusual congenital myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization","volume":"37","author":"Bevilacqua","year":"2011","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_14","first-page":"100979","article-title":"Glutaric aciduria and L-2-hydroxyglutaric aciduria: Clinical and molecular findings of 35 patients from Turkey","volume":"36","author":"Bozaci","year":"2023","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1002\/humu.9373","article-title":"Novel L2HGDH mutations in 21 patients with L-2-hydroxyglutaric aciduria of Portuguese origin","volume":"26","author":"Vilarinho","year":"2005","journal-title":"Hum. Mutat."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"39","DOI":"10.4274\/jpr.59454","article-title":"Clinical, Neuroimaging, and Genetic Features of the Patients with L-2-Hydroxyglutaric Aciduria","volume":"5","author":"Canda","year":"2018","journal-title":"J. Pediatr. Res."},{"key":"ref_17","first-page":"101135","article-title":"The broad spectrum of clinical manifestations observed in three patients with L2 hydroxyglutaric aciduria spans from febrile seizures to complex dystonia","volume":"41","author":"Alsayed","year":"2024","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1056\/NEJMoa1516767","article-title":"Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation","volume":"376","author":"Posey","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2496","DOI":"10.1038\/s41436-019-0531-0","article-title":"Targeted gene sequencing in 6994 individuals with neurodevelopmental disorder with epilepsy","volume":"21","author":"Heyne","year":"2019","journal-title":"Genet. Med."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/7\/735\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T04:12:45Z","timestamp":1782619965000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/7\/735"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,26]]},"references-count":19,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["genes17070735"],"URL":"https:\/\/doi.org\/10.3390\/genes17070735","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,26]]}}}