Congenital Ataxia with Progressive Cerebellar Atrophy, Camptodactyly, and Hypertrichosis: A Novel Recognizable Phenotype for NALCN Heterozygous Variants.
Jacopo Sartorelli, Lorena Travaglini, Giacomo Garone, Maria L Dentici, Lorenzo Sinibaldi, Maria C Digilio, Antonio Novelli, Emanuele Agolini, Adele D'Amico, Enrico Bertini, Francesco Nicita
{"title":"Congenital Ataxia with Progressive Cerebellar Atrophy, Camptodactyly, and Hypertrichosis: A Novel Recognizable Phenotype for NALCN Heterozygous Variants.","authors":"Jacopo Sartorelli, Lorena Travaglini, Giacomo Garone, Maria L Dentici, Lorenzo Sinibaldi, Maria C Digilio, Antonio Novelli, Emanuele Agolini, Adele D'Amico, Enrico Bertini, Francesco Nicita","doi":"10.1055/a-2524-9091","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong> Non-selective sodium leak channel (NALCN) protein encoded by the <i>NALCN</i> gene is of key importance for neuronal cell excitability. Previous reports showed that biallelic <i>NALCN</i> 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 <i>NALCN</i>-related clinical spectrum, presenting two affected individuals and a literature review.</p><p><strong>Methods: </strong> We describe two new unrelated subjects harboring monoallelic <i>NALCN</i> pathogenic variants identified through clinical exome sequencing and review the current literature of other heterozygous <i>NALCN</i> patients.</p><p><strong>Results: </strong> The c.3542G > A (p.Arg1181Gln) and the novel c.3423C > A (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 <i>NALCN</i> subjects with overlapping features have already been reported. A combination of these clinical and neuroimaging findings suggests the definition of the new CAPCACH phenotype.</p><p><strong>Conclusion: </strong> We expand the heterozygous <i>NALCN</i>-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.</p>","PeriodicalId":19421,"journal":{"name":"Neuropediatrics","volume":" ","pages":""},"PeriodicalIF":1.1000,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neuropediatrics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1055/a-2524-9091","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Non-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.
Methods: We 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.
Results: The c.3542G > A (p.Arg1181Gln) and the novel c.3423C > A (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.
Conclusion: We 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.
期刊介绍:
For key insights into today''s practice of pediatric neurology, Neuropediatrics is the worldwide journal of choice. Original articles, case reports and panel discussions are the distinctive features of a journal that always keeps abreast of current developments and trends - the reason it has developed into an internationally recognized forum for specialists throughout the world.
Pediatricians, neurologists, neurosurgeons, and neurobiologists will find it essential reading.