{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,12]],"date-time":"2025-05-12T23:10:06Z","timestamp":1747091406770,"version":"3.40.5"},"reference-count":30,"publisher":"Georg Thieme Verlag KG","issue":"03","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Neuropediatrics"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>\n          Background\u2003Non-selective sodium leak channel (NALCN) protein encoded by the NALCN gene is of key importance for neuronal cell excitability. Previous reports showed that biallelic NALCN pathogenic variants cause infantile hypotonia with psychomotor retardation and characteristic facies 1 (IHPRF1) while monoallelic variants lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD). In our work, we aimed to expand the heterozygous NALCN-related clinical spectrum, presenting two affected individuals and a literature review.<\/jats:p><jats:p>\n          Methods\u2003We describe two new unrelated subjects harboring monoallelic NALCN pathogenic variants identified through clinical exome sequencing and review the current literature of other heterozygous NALCN patients.<\/jats:p><jats:p>\n          Results\u2003The c.3542G\u2009&gt;\u2009A (p.Arg1181Gln) and the novel c.3423C\u2009&gt;\u2009A (p.Phe1141Leu) heterozygous missense variants were disclosed in two subjects manifesting a similar phenotype characterized by congenital ataxia with progressive cerebellar atrophy, camptodactyly, and hypertrichosis of the arms (CAPCACH). Other NALCN subjects with overlapping features have already been reported. A combination of these clinical and neuroimaging findings suggests the definition of the new CAPCACH phenotype.<\/jats:p><jats:p>\n          Conclusion\u2003We expand the heterozygous NALCN-related clinical spectrum from the more severe CLIFFAHDD to the milder CAPCACH phenotype. These conditions should be considered in the differential diagnosis of syndromic congenital ataxias, and the presence of camptodactyly and\/or hypertrichosis may represent peculiar diagnostic clues.<\/jats:p>","DOI":"10.1055\/a-2524-9091","type":"journal-article","created":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T00:12:26Z","timestamp":1738887146000},"page":"185-193","source":"Crossref","is-referenced-by-count":0,"title":["Congenital Ataxia with Progressive Cerebellar Atrophy, Camptodactyly, and Hypertrichosis: A Novel Recognizable Phenotype for NALCN Heterozygous Variants"],"prefix":"10.1055","volume":"56","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2367-6371","authenticated-orcid":false,"given":"Jacopo","family":"Sartorelli","sequence":"additional","affiliation":[{"name":"Unit of Muscular and Neurodegenerative Diseases, Bambino Ges\u00f9 Children's Hospital, IRCCS, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorena","family":"Travaglini","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Ges\u00f9 Children's Hospital, IRCCS, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giacomo","family":"Garone","sequence":"additional","affiliation":[{"name":"Neurology, Epilepsy and Movement Disorders Unit, Bambino Ges\u00f9 Children's Hospital, IRCCS, Full Member of European Reference Network on Rare and Complex Epilepsies, EpiCARE, Rome, Italy"},{"name":"Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), Faculty of Medicine and Psychology, Sapienza University of Rome, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria L.","family":"Dentici","sequence":"additional","affiliation":[{"name":"Rare Diseases and Medical Genetics Unit, Bambino Ges\u00f9 Children's Hospital, IRCCS, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorenzo","family":"Sinibaldi","sequence":"additional","affiliation":[{"name":"Rare Diseases and Medical Genetics Unit, Bambino Ges\u00f9 Children's Hospital, IRCCS, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria C.","family":"Digilio","sequence":"additional","affiliation":[{"name":"Rare Diseases and Medical Genetics Unit, Bambino Ges\u00f9 Children's Hospital, IRCCS, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Novelli","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Ges\u00f9 Children's Hospital, IRCCS, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emanuele","family":"Agolini","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Ges\u00f9 Children's Hospital, IRCCS, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adele","family":"D'Amico","sequence":"additional","affiliation":[{"name":"Unit of Muscular and Neurodegenerative Diseases, Bambino Ges\u00f9 Children's Hospital, IRCCS, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enrico","family":"Bertini","sequence":"additional","affiliation":[{"name":"Unit of Muscular and Neurodegenerative Diseases, Bambino Ges\u00f9 Children's Hospital, IRCCS, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5612-821X","authenticated-orcid":false,"given":"Francesco","family":"Nicita","sequence":"additional","affiliation":[{"name":"Unit of Muscular and Neurodegenerative Diseases, Bambino Ges\u00f9 Children's Hospital, IRCCS, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"194","published-online":{"date-parts":[[2025,2,6]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/s41586-020-2570-8","article-title":"Structure of the human sodium leak channel NALCN","volume":"587","author":"M Kschonsak","year":"2020","journal-title":"Nature"},{"issue":"21","key":"ref2","doi-asserted-by":"crossref","first-page":"7401","DOI":"10.1523\/JNEUROSCI.0143-10.2010","article-title":"Pacemaking in dopaminergic ventral tegmental area neurons: depolarizing drive from background and voltage-dependent sodium conductances","volume":"30","author":"Z M Khaliq","year":"2010","journal-title":"J Neurosci"},{"issue":"31","key":"ref3","doi-asserted-by":"crossref","first-page":"8174","DOI":"10.1523\/JNEUROSCI.1096-16.2016","article-title":"Nalcn is a \u201cleak\u201d sodium channel that regulates excitability of brainstem chemosensory neurons and breathing","volume":"36","author":"Y Shi","year":"2016","journal-title":"J Neurosci"},{"issue":"06","key":"ref4","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1016\/j.neuron.2013.01.018","article-title":"NLF-1 delivers a sodium leak channel to regulate neuronal excitability and modulate rhythmic locomotion","volume":"77","author":"L Xie","year":"2013","journal-title":"Neuron"},{"issue":"04","key":"ref5","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1016\/j.cell.2015.07.036","article-title":"A conserved bicycle model for circadian clock control of membrane excitability","volume":"162","author":"M Flourakis","year":"2015","journal-title":"Cell"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"e40984","DOI":"10.7554\/eLife.40984","article-title":"Gi\/o protein-coupled receptors in dopamine neurons inhibit the sodium leak channel NALCN","volume":"7","author":"F Philippart","year":"2018","journal-title":"eLife"},{"issue":"03","key":"ref7","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1016\/j.neuron.2010.09.014","article-title":"Extracellular calcium controls background current and neuronal excitability via an UNC79-UNC80-NALCN cation channel complex","volume":"68","author":"B Lu","year":"2010","journal-title":"Neuron"},{"issue":"01","key":"ref8","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/s41421-022-00392-4","article-title":"Architecture of the human NALCN channelosome","volume":"8","author":"L Zhou","year":"2022","journal-title":"Cell Discov"},{"issue":"01","key":"ref9","doi-asserted-by":"crossref","first-page":"2639","DOI":"10.1038\/s41467-022-30403-7","article-title":"Structure and mechanism of NALCN-FAM155A-UNC79-UNC80 channel complex","volume":"13","author":"Y Kang","year":"2022","journal-title":"Nat 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Gal","year":"2016","journal-title":"Eur J Med Genet"},{"issue":"02","key":"ref13","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1002\/ajmg.a.38543","article-title":"Biallelic mutations in NALCN: expanding the genotypic and phenotypic spectra of IHPRF1","volume":"176","author":"T Takenouchi","year":"2018","journal-title":"Am J Med Genet A"},{"issue":"03","key":"ref14","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1016\/j.ajhg.2015.01.003","article-title":"De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay","volume":"96","author":"J X Chong","year":"2015","journal-title":"Am J Hum Genet"},{"issue":"05","key":"ref15","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/jhg.2015.163","article-title":"De novo missense mutations in NALCN cause developmental and intellectual impairment with hypotonia","volume":"61","author":"R Fukai","year":"2016","journal-title":"J 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pyridostigmine","volume":"19","author":"A Winczewska-Wiktor","year":"2022","journal-title":"Int J Environ Res Public Health"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.parkreldis.2018.12.007","article-title":"SYNE1-ataxia: novel genotypic and phenotypic findings","volume":"62","author":"E Indelicato","year":"2019","journal-title":"Parkinsonism Relat Disord"},{"issue":"02","key":"ref30","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1038\/ejhg.2016.144","article-title":"Homozygous SYNE1 mutation causes congenital onset of muscular weakness with distal arthrogryposis: a genotype-phenotype correlation","volume":"25","author":"M Baumann","year":"2017","journal-title":"Eur J Hum 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