{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T08:54:45Z","timestamp":1791190485304,"version":"4.1.0"},"reference-count":37,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2015,8,21]],"date-time":"2015-08-21T00:00:00Z","timestamp":1440115200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001826","name":"Netherlands Organisation for Health Research and Development","doi-asserted-by":"publisher","award":["91211005"],"award-info":[{"award-number":["91211005"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Optimix Foundation for Scientific Research","award":["-"],"award-info":[{"award-number":["-"]}]},{"name":"RVO-VFN","award":["64165\/2012"],"award-info":[{"award-number":["64165\/2012"]}]},{"name":"Tide BC","award":["-"],"award-info":[{"award-number":["-"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2015,10]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To identify the etiology of a novel, heritable encephalopathy in a small group of patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Magnetic resonance imaging (MRI) pattern analysis was used to select patients with the same pattern. Homozygosity mapping and whole exome sequencing (WES) were performed to find the causal gene mutations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Seven patients from 4 families (2 consanguineous) were identified with a similar MRI pattern characterized by T\n                      <jats:sub>2<\/jats:sub>\n                      signal abnormalities and diffusion restriction in the posterior limb of the internal capsule, often also optic radiation, brainstem tracts, and cerebellar white matter, in combination with delayed myelination and progressive brain atrophy. Patients presented with early infantile onset encephalopathy characterized by progressive microcephaly, seizures, variable cardiac defects, and early death. Metabolic testing was unrevealing. Single nucleotide polymorphism array revealed 1 overlapping homozygous region on chromosome 20 in the consanguineous families. In all patients, WES subsequently revealed recessive predicted loss of function mutations in\n                      <jats:italic>ITPA<\/jats:italic>\n                      , encoding inosine triphosphate pyrophosphatase (ITPase). ITPase activity in patients' erythrocytes and fibroblasts was severely reduced.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      Until now\n                      <jats:italic>ITPA<\/jats:italic>\n                      variants have only been associated with adverse reactions to specific drugs. This is the first report associating\n                      <jats:italic>ITPA<\/jats:italic>\n                      mutations with a human disorder. ITPase is important in purine metabolism because it removes noncanonical nucleotides from the cellular nucleotide pool. Toxicity of accumulated noncanonical nucleotides, leading to neuronal apoptosis and interference with proteins normally using adenosine triphosphate\/guanosine triphosphate, probably explains the disease. This study confirms that combining MRI pattern recognition to define small, homogeneous patient groups with WES is a powerful approach for providing a fast diagnosis in patients with an unclassified genetic encephalopathy. Ann Neurol 2015;78:649\u2013658\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.24496","type":"journal-article","created":{"date-parts":[[2015,7,29]],"date-time":"2015-07-29T21:04:09Z","timestamp":1438203849000},"page":"649-658","source":"Crossref","is-referenced-by-count":60,"title":["Recessive\n                    <scp>\n                      <i>ITPA<\/i>\n                    <\/scp>\n                    mutations cause an early infantile encephalopathy"],"prefix":"10.1002","volume":"78","author":[{"given":"Sietske H.","family":"Kevelam","sequence":"first","affiliation":[{"name":"Department of Child Neurology VU University Medical Center  Amsterdam the Netherlands"},{"name":"Neuroscience Campus Amsterdam VU University  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rgen","family":"Bierau","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Maastricht University Medical Center Maastricht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramona","family":"Salvarinova","sequence":"additional","affiliation":[{"name":"Division of Biochemical Diseases Department of Pediatrics University of British Columbia, British Columbia Children's Hospital Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shakti","family":"Agrawal","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology Birmingham Children's Hospital Birmingham United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomas","family":"Honzik","sequence":"additional","affiliation":[{"name":"Department of Pediatrics First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague  Prague Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"Visser","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Maastricht University Medical Center Maastricht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjan M.","family":"Weiss","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics VU University Medical Center  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gajja S.","family":"Salomons","sequence":"additional","affiliation":[{"name":"Neuroscience Campus Amsterdam VU University  Amsterdam the Netherlands"},{"name":"Department of Clinical Chemistry Metabolic Unit, VU University Medical Center  Amsterdam the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Truus E. 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