{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:07:38Z","timestamp":1791220058164,"version":"4.1.0"},"reference-count":35,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2012,5,8]],"date-time":"2012-05-08T00:00:00Z","timestamp":1336435200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","award":["GUP09004"],"award-info":[{"award-number":["GUP09004"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002426","name":"Fondazione Telethon","doi-asserted-by":"publisher","award":["GGP09207"],"award-info":[{"award-number":["GGP09207"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003500","name":"Universit\u00e0 degli Studi di Padova","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003500","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2013,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Recessive mutations in the mitochondrial arginyl\u2010transfer RNA synthetase (<jats:italic>RARS2<\/jats:italic>) gene have been associated with early onset encephalopathy with signs of oxidative phosphorylation defects classified as pontocerebellar hypoplasia 6. We describe clinical, neuroimaging and molecular features on five patients from three unrelated families who displayed mutations in <jats:italic>RARS2<\/jats:italic>. All patients rapidly developed a neonatal or early\u2010infantile epileptic encephalopathy with intractable seizures. The long\u2010term follow\u2010up revealed a virtual absence of psychomotor development, progressive microcephaly, and feeding difficulties. Mitochondrial respiratory chain enzymes in muscle and fibroblasts were normal in two. Blood and CSF lactate was abnormally elevated in all five patients at early stages while appearing only occasionally abnormal with the progression of the disease. Cerebellar vermis hypoplasia with normal aspect of the cerebral and cerebellar hemispheres appeared within the first months of life at brain MRI. In three patients follow\u2010up neuroimaging revealed a progressive pontocerebellar and cerebral cortical atrophy. Molecular investigations of <jats:italic>RARS2<\/jats:italic> disclosed the c.25A&gt;G\/p.I9V and the c.1586+3A&gt;T in family A, the c.734G&gt;A\/p.R245Q and the c.1406G&gt;A\/p.R469H in family B, and the c.721T&gt;A\/p.W241R and c.35A&gt;G\/p.Q12R in family C. Functional complementation studies in <jats:italic>Saccharomyces cerevisiae<\/jats:italic> showed that mutation MSR1\u2010R531H (equivalent to human p.R469H) abolished respiration whereas the MSR1\u2010R306Q strain (corresponding to p.R245Q) displayed a reduced growth on non\u2010fermentable YPG medium. Although mutations functionally disrupted yeast we found a relatively well preserved arginine aminoacylation of mitochondrial tRNA. Clinical and neuroimaging findings are important clues to raise suspicion and to reach diagnostic accuracy for <jats:italic>RARS2<\/jats:italic> mutations considering that biochemical abnormalities may be absent in muscle biopsy.<\/jats:p>","DOI":"10.1007\/s10545-012-9487-9","type":"journal-article","created":{"date-parts":[[2012,5,7]],"date-time":"2012-05-07T14:47:15Z","timestamp":1336402035000},"page":"43-53","source":"Crossref","is-referenced-by-count":78,"title":["Pontocerebellar hypoplasia type 6 caused by mutations in <i>RARS2<\/i>: definition of the clinical spectrum and molecular findings in five patients"],"prefix":"10.1002","volume":"36","author":[{"given":"Denise","family":"Cassandrini","sequence":"first","affiliation":[{"name":"IRCCS Fondazione Stella Maris Pisa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Roberta","family":"Cilio","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Disorders Bambino Ges\u00f9 Children's Research Hospital P.za S. Onofrio, 4 Rome 00165 Italy"},{"name":"Department of Neurology University of California San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marzia","family":"Bianchi","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Disorders Bambino Ges\u00f9 Children's Research Hospital P.za S. Onofrio, 4 Rome 00165 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mara","family":"Doimo","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Unit of Clinical Genetics Padova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Balestri","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Disorders Bambino Ges\u00f9 Children's Research Hospital P.za S. Onofrio, 4 Rome 00165 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Tessa","sequence":"additional","affiliation":[{"name":"IRCCS Fondazione Stella Maris Pisa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Rizza","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Disorders Bambino Ges\u00f9 Children's Research Hospital P.za S. Onofrio, 4 Rome 00165 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geppo","family":"Sartori","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of Padua Padua Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Chiara","family":"Meschini","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Disorders Bambino Ges\u00f9 Children's Research Hospital P.za S. Onofrio, 4 Rome 00165 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Nesti","sequence":"additional","affiliation":[{"name":"IRCCS Fondazione Stella Maris Pisa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Tozzi","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Disorders Bambino Ges\u00f9 Children's Research Hospital P.za S. Onofrio, 4 Rome 00165 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vittoria","family":"Petruzzella","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Medical Biology University of Bari Bari Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiorella","family":"Piemonte","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Disorders Bambino Ges\u00f9 Children's Research Hospital P.za S. Onofrio, 4 Rome 00165 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Bisceglia","sequence":"additional","affiliation":[{"name":"Medical Genetics, IRCCS Casa Sollievo della Sofferenza Foggia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Bruno","sequence":"additional","affiliation":[{"name":"Neuromuscular Unit, IRCCS G. Gaslini Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Dionisi\u2010Vici","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Bambino Ges\u00f9 Hospital Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adele","family":"D'Amico","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Disorders Bambino Ges\u00f9 Children's Research Hospital P.za S. Onofrio, 4 Rome 00165 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabiana","family":"Fattori","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Disorders Bambino Ges\u00f9 Children's Research Hospital P.za S. 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