{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,17]],"date-time":"2026-01-17T18:51:45Z","timestamp":1768675905018,"version":"3.49.0"},"reference-count":69,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,3,15]],"date-time":"2021-03-15T00:00:00Z","timestamp":1615766400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008061","name":"Fundaci\u00f3n Mutua Madrile\u00f1a","doi-asserted-by":"publisher","award":["Reference number AP163052016 (XIII Call on Research Grants 2016)"],"award-info":[{"award-number":["Reference number AP163052016 (XIII Call on Research Grants 2016)"]}],"id":[{"id":"10.13039\/100008061","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ataxia in children is a common clinical sign of numerous neurological disorders consisting of impaired coordination of voluntary muscle movement. Its most common form, cerebellar ataxia, describes a heterogeneous array of neurologic conditions with uncountable causes broadly divided as acquired or genetic. Numerous genetic disorders are associated with chronic progressive ataxia, which complicates clinical management, particularly on the diagnostic stage. Advances in omics technologies enable improvements in clinical practice and research, so we proposed a multi-omics approach to aid in the genetic diagnosis and molecular elucidation of an undiagnosed infantile condition of chronic progressive cerebellar ataxia. Using whole-exome sequencing, RNA-seq, and untargeted metabolomics, we identified three clinically relevant mutations (rs141471029, rs191582628 and rs398124292) and an altered metabolic profile in our patient. Two POLR1C diagnostic variants already classified as pathogenic were found, and a diagnosis of hypomyelinating leukodystrophy was achieved. A mutation on the MMACHC gene, known to be associated with methylmalonic aciduria and homocystinuria cblC type, was also found. Additionally, preliminary metabolome analysis revealed alterations in our patient\u2019s amino acid, fatty acid and carbohydrate metabolism. Our findings provided a definitive genetic diagnosis reinforcing the association between POLR1C mutations and hypomyelinating leukodystrophy and highlighted the relevance of multi-omics approaches to the disease.<\/jats:p>","DOI":"10.3390\/ijms22062990","type":"journal-article","created":{"date-parts":[[2021,3,15]],"date-time":"2021-03-15T22:16:54Z","timestamp":1615846614000},"page":"2990","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Combined Genome, Transcriptome and Metabolome Analysis in the Diagnosis of Childhood Cerebellar Ataxia"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8266-430X","authenticated-orcid":false,"given":"Ana","family":"Ching-L\u00f3pez","sequence":"first","affiliation":[{"name":"CIBER Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain"},{"name":"Andalusian School of Public Health (EASP), 18080 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2202-0662","authenticated-orcid":false,"given":"Luis Javier","family":"Martinez-Gonzalez","sequence":"additional","affiliation":[{"name":"GENYO, Centre for Genomics and Oncological Research, Pfizer, University of Granada, Andalusian Regional Government, PTS Granada, 18016 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luisa","family":"Arrabal","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Department, Hospital Virgen de las Nieves, 18014 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorge","family":"S\u00e1iz","sequence":"additional","affiliation":[{"name":"Centre for Metabolomics and Bioanalysis (CEMBIO), Chemistry and Biochemistry Department, Pharmacy Faculty, Universidad San Pablo-CEU, 28925 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00c1ngela","family":"Gavil\u00e1n","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine of Seville (IBIS), 41013 Seville, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4722-491X","authenticated-orcid":false,"given":"Coral","family":"Barbas","sequence":"additional","affiliation":[{"name":"Centre for Metabolomics and Bioanalysis (CEMBIO), Chemistry and Biochemistry Department, Pharmacy Faculty, Universidad San Pablo-CEU, 28925 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jose Antonio","family":"Lorente","sequence":"additional","affiliation":[{"name":"GENYO, Centre for Genomics and Oncological Research, Pfizer, University of Granada, Andalusian Regional Government, PTS Granada, 18016 Granada, Spain"},{"name":"Laboratory of Genetic Identification, Legal Medicine and Toxicology Department, Faculty of Medicine-PTS, University of Granada, 18016 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susana","family":"Rold\u00e1n","sequence":"additional","affiliation":[{"name":"Pediatric Neurology Department, Hospital Virgen de las Nieves, 18014 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4817-0757","authenticated-orcid":false,"given":"Maria Jos\u00e9","family":"S\u00e1nchez","sequence":"additional","affiliation":[{"name":"CIBER Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain"},{"name":"Andalusian School of Public Health (EASP), 18080 Granada, Spain"},{"name":"Instituto de Investigaci\u00f3n Biosanitaria ibs.GRANADA, 18012 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Purificacion","family":"Gutierrez-R\u00edos","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biosanitaria ibs.GRANADA, 18012 Granada, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1177\/0883073812448231","article-title":"Childhood cerebellar ataxia","volume":"27","author":"Fogel","year":"2012","journal-title":"J. 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