{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T21:09:54Z","timestamp":1778533794764,"version":"3.51.4"},"reference-count":29,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2022,9,18]],"date-time":"2022-09-18T00:00:00Z","timestamp":1663459200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Cerebral palsy (CP) causes neurological disability in early childhood. Hypoxic\u2010ischaemic injury plays a major role in its aetiology, nevertheless, genetic and epigenetic factors may contribute to the clinical presentation. Mutations in\n                    <jats:italic>ADD3<\/jats:italic>\n                    (encoding \u03b3\u2010adducin) gene have been described in a monogenic form of spastic quadriplegic cerebral palsy (OMIM 601568). We studied a 16\u2010year\u2010old male with spastic diplegia. Several investigations including neurometabolic testing, brain and spine magnetic resonance imaging (MRI) and CGH\u2010Array were normal. Further, clinical genetics assessment and whole exome sequencing (WES) gave the diagnosis. We generated an animal model using\n                    <jats:italic>Drosophila<\/jats:italic>\n                    to study the effects of \u03b3\u2010adducin loss and gain of function. WES revealed a biallelic variant in the\n                    <jats:italic>ADD3<\/jats:italic>\n                    gene, NM_016824.5(ADD3): c.1100G\u2009&gt;\u2009A, p.(Gly367Asp). Mutations in this gene have been described as an ultra\u2010rare autosomal recessive, which is a known form of inherited cerebral palsy. Molecular modelling suggests that this mutation leads to a loss of structural integrity of \u03b3\u2010adducin and is therefore expected to result in a decreased level of functional protein. Pan\u2010neuronal over\u2010expression or knock\u2010down of the\n                    <jats:italic>Drosophila<\/jats:italic>\n                    ortholog of\n                    <jats:italic>ADD3<\/jats:italic>\n                    called\n                    <jats:italic>hts<\/jats:italic>\n                    caused a reduction of life span and impaired locomotion thereby phenocopying aspects of the human disease. Our animal experiments present a starting point to understand the biological processes underpinning the clinical phenotype and pathogenic mechanisms, to gain insights into potential future methods for treating or preventing\n                    <jats:italic>ADD3<\/jats:italic>\n                    related spastic quadriplegic cerebral palsy.\n                  <\/jats:p>","DOI":"10.1111\/cge.14220","type":"journal-article","created":{"date-parts":[[2022,9,1]],"date-time":"2022-09-01T02:48:50Z","timestamp":1662000530000},"page":"494-502","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Hereditary spastic paraparesis presenting as cerebral palsy due to\n                    <scp>\n                      <i>ADD3<\/i>\n                    <\/scp>\n                    variant with mechanistic insight provided by a\n                    <i>Drosophila<\/i>\n                    \u03b3\u2010adducin model"],"prefix":"10.1111","volume":"102","author":[{"given":"Silvia Beatriz","family":"Sanchez Marco","sequence":"first","affiliation":[{"name":"Department of Paediatric Neurology Bristol Children's Hospital  Bristol UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edgar","family":"Buhl","sequence":"additional","affiliation":[{"name":"School of Physiology, Pharmacology and Neuroscience University of Bristol  Bristol UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rose","family":"Firth","sequence":"additional","affiliation":[{"name":"School of Physiology, Pharmacology and Neuroscience University of Bristol  Bristol UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bangfu","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Physiology, Pharmacology and Neuroscience University of Bristol  Bristol UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mary","family":"Gainsborough","sequence":"additional","affiliation":[{"name":"Department of Community Paediatrics Sirona Care and Health  Bristol UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana","family":"Beleza\u2010Meireles","sequence":"additional","affiliation":[{"name":"Bristol Regional Genetics Service St Michael's Hospital  Bristol UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra","family":"Moore","sequence":"additional","affiliation":[{"name":"Exeter Genomics Laboratory Royal Devon and Exeter NHS Foundation Trust  Exeter UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0713-4602","authenticated-orcid":false,"given":"Richard","family":"Caswell","sequence":"additional","affiliation":[{"name":"Exeter Genomics Laboratory Royal Devon and Exeter NHS Foundation Trust  Exeter UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karen","family":"Stals","sequence":"additional","affiliation":[{"name":"Exeter Genomics Laboratory Royal Devon and Exeter NHS Foundation Trust  Exeter UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sian","family":"Ellard","sequence":"additional","affiliation":[{"name":"Exeter Genomics Laboratory Royal Devon and Exeter NHS Foundation Trust  Exeter UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cameron","family":"Kennedy","sequence":"additional","affiliation":[{"name":"Department of Paediatric Dermatology Bristol Children's Hospital  Bristol UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James J. L.","family":"Hodge","sequence":"additional","affiliation":[{"name":"School of Physiology, Pharmacology and Neuroscience University of Bristol  Bristol UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anirban","family":"Majumdar","sequence":"additional","affiliation":[{"name":"Department of Paediatric Neurology Bristol Children's Hospital  Bristol UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,9,18]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamapediatrics.2017.1689"},{"key":"e_1_2_11_3_1","first-page":"8","article-title":"A report:The definition and classification of cerebral palsy","volume":"109","author":"Rosenbaum P","year":"2007","journal-title":"Dev Med Child Neurol Suppl"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.siny.2005.10.010"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0012162201002675"},{"issue":"2","key":"e_1_2_11_6_1","first-page":"110","article-title":"Definition and classification of cerebral palsy: a problem that has already been solved?","volume":"45","author":"Robaina\u2010Castellanos GR","year":"2007","journal-title":"Rev Neurol"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.spen.2004.01.002"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/dmcn.13363"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.23971"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_11_11_1","unstructured":"EllardS BapleEL BerryI ForresterN TurnbullC OwensM et al.ACGS Best Practice Guidelines for Variant Classification 2019.2019. 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