{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T17:08:31Z","timestamp":1792084111349,"version":"4.4.0"},"reference-count":49,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,3,18]],"date-time":"2021-03-18T00:00:00Z","timestamp":1616025600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000156","name":"Fonds de Recherche du Qu\u00e9bec - Sant\u00e9","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000156","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2021,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    <jats:italic>GCH1<\/jats:italic>\n                    mutations have been associated with dopa\u2010responsive dystonia (DRD), Parkinson's disease (PD) and tetrahydrobiopterin (BH\n                    <jats:sub>4<\/jats:sub>\n                    )\u2010deficient hyperphenylalaninemia B. Recently,\n                    <jats:italic>GCH1<\/jats:italic>\n                    mutations have been reported in five patients with hereditary spastic paraplegia (HSP). Here, we analyzed a total of 400 HSP patients (291 families) from different centers across Canada by whole exome sequencing (WES). Three patients with heterozygous\n                    <jats:italic>GCH1<\/jats:italic>\n                    variants were identified: monozygotic twins with a p.(Ser77_Leu82del) variant, and a patient with a p.(Val205Glu) variant. The former variant is predicted to be likely pathogenic and the latter is pathogenic. The three patients presented with childhood\u2010onset lower limb spasticity, hyperreflexia and abnormal plantar responses. One of the patients had diurnal fluctuations, and none had parkinsonism or dystonia. Phenotypic differences between the monozygotic twins were observed, who responded well to levodopa treatment. Pathway enrichment analysis suggested that GCH1 shares processes and pathways with other HSP\u2010associated genes, and structural analysis of the variants indicated a disruptive effect. In conclusion,\n                    <jats:italic>GCH1<\/jats:italic>\n                    mutations may cause HSP; therefore, we suggest a levodopa trial in HSP patients and including\n                    <jats:italic>GCH1<\/jats:italic>\n                    in the screening panels of HSP genes. Clinical differences between monozygotic twins suggest that environmental factors, epigenetics, and stochasticity could play a role in the clinical presentation.\n                  <\/jats:p>","DOI":"10.1111\/cge.13955","type":"journal-article","created":{"date-parts":[[2021,3,13]],"date-time":"2021-03-13T11:37:20Z","timestamp":1615635440000},"page":"51-58","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["<scp>\n                      <i>GCH1<\/i>\n                    <\/scp>\n                    mutations in hereditary spastic paraplegia"],"prefix":"10.1111","volume":"100","author":[{"given":"Parizad","family":"Varghaei","sequence":"first","affiliation":[{"name":"Division of Experimental Medicine, Department of Medicine McGill University  Montreal Quebec Canada"},{"name":"Montreal Neurological Institute and Hospital McGill University  Montreal Quebec 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