AbstractHeterozygous transmembrane protein 63A (TMEM63A) variants cause transient infantile hypomyelinating leukodystrophy-19, which features remarkable natural resolution of clinical and imaging findings during childhood. Previous reports have mainly described de novo variants lacking detailed familial cases.

摘要杂合跨膜蛋白63A（TMEM63A）变体引起短暂的婴儿低髓鞘性白细胞营养不良-19，其在儿童时期的临床和影像学表现具有显着的自然分辨率。先前的报道主要描述了缺乏详细家族病例的从头变异。

Herein, we describe the clinical course of familial cases with a TMEM63A variant. A 5-month-old girl presented with nystagmus, global hypotonia, and difficulty swallowing since birth. Brain magnetic resonance imaging at 1.5 and 5 months revealed diffuse hypomyelination. Her mother, maternal aunt, and grandfather had nystagmus and motor developmental delays in infancy, which resolved spontaneously during childhood.

在此，我们描述了具有TMEM63A变体的家族性病例的临床过程。一名5个月大的女孩出生后出现眼球震颤，全身肌张力低下和吞咽困难。1.5个月和5个月的脑磁共振成像显示弥漫性髓鞘减少。她的母亲，姨妈和祖父在婴儿期患有眼球震颤和运动发育迟缓，在儿童时期会自发消退。

Compared with these cases, the proband’s motor developmental delay was profound, and she was the only one with feeding difficulties, necessitating nasogastric tube feeding. Genetic testing revealed a heterozygous TMEM63A variant (NM_014698.3:c.1658G>A, p.(Gly553Asp)) in the proband and her family. This is the first three-generation familial report of a TMEM63A variant that provides insight into its history and heterogeneity..

与这些病例相比，先证者的运动发育迟缓很严重，她是唯一一个进食困难的人，需要鼻胃管喂养。基因测试显示先证者及其家庭中有一个杂合的TMEM63A变异体（NM014698.3:c.1658G a，p。（Gly553Asp））。这是TMEM63A变体的前三代家族报告，可深入了解其历史和异质性。。

Access through your institution

通过您的机构访问

Buy or subscribe

购买或订阅

This is a preview of subscription content, access via your institution

这是订阅内容的预览，可通过您的机构访问

Access options

访问选项

Access through your institution

通过您的机构访问

Access through your institution

通过您的机构访问

Change institution

变革机构

Buy or subscribe

购买或订阅

Subscribe to this journalReceive 12 print issues and online access251,40 € per yearonly 20,95 € per issueLearn moreBuy this articlePurchase on Springer LinkInstant access to full article PDFBuy nowPrices may be subject to local taxes which are calculated during checkout

订阅本期刊每年可收到12期印刷版和在线访问251,40欧元每期仅20,95欧元了解更多购买本文在Springer Link上购买即时访问全文PDFBuy NOW价格可能需要缴纳结帐时计算的当地税费

Additional access options:

其他访问选项：

Log in

登录

Learn about institutional subscriptions

了解机构订阅

Read our FAQs

阅读我们的常见问题

Contact customer support

联系客户支持

Fig. 1Fig. 2

图1图。2

Data availability

数据可用性

The nucleotide sequence date reported are available in the ClinVar database under the accession number SCV004812254.

报告的核苷酸序列日期可在ClinVar数据库中获得，登录号为SCV004812254。

ReferencesWolf NI, Ffrench-Constant C, van der Knaap MS. Hypomyelinating leukodystrophies - unravelling myelin biology. Nat Rev Neurol. 2021;17:88–103.Article

参考文献Wolf NI，Ffrench Constant C，van der Knaap MS.低髓鞘性脑白质营养不良-解开髓鞘生物学。。2021年；17： 88-103.文章

CAS

中科院

Google Scholar

谷歌学者

Torii T, Yamauchi J. Molecular Pathogenic Mechanisms of Hypomyelinating Leukodystrophies (HLDs). Neurol Int. 2023;15:1155–73.Article

Torii T，Yamauchi J.低髓鞘性脑白质营养不良（HLD）的分子致病机制。神经病学国际2023；15： 1155-73.条

CAS

中科院

Google Scholar

谷歌学者

Yan H, Helman G, Murthy SE, Ji H, Crawford J, Kubisiak T, et al. Heterozygous Variants in the Mechanosensitive Ion Channel TMEM63A Result in Transient Hypomyelination during Infancy. Am J Hum Genet. 2019;105:996–1004.Article

Yan H，Helman G，Murthy SE，Ji H，Crawford J，Kubisiak T等人。机械敏感离子通道TMEM63A中的杂合变体导致婴儿期短暂的髓鞘减少。我是J Hum Genet。2019年；105:996–1004.文章

CAS

中科院

Google Scholar

谷歌学者

Murthy SE, Dubin AE, Whitwam T, Jojoa-Cruz S, Cahalan SM, Mousavi SAR, et al. OSCA/TMEM63 are an Evolutionarily Conserved Family of Mechanically Activated Ion Channels. Elife 2018;7:e41844.Article

Murthy SE，Dubin AE，Whitwam T，Jojoa Cruz S，Cahalan SM，Mousavi SAR等。OSCA/TMEM63是机械激活离子通道的进化保守家族。；7： e41844条款

Google Scholar

谷歌学者

Fukumura S, Hiraide T, Yamamoto A, Tsuchida K, Aoto K, Nakashima M, et al. A novel de novo TMEM63A variant in a patient with severe hypomyelination and global developmental delay. Brain Dev. 2022;44:178–83.Article

。大脑发展2022；44:178–83.文章

CAS

中科院

Google Scholar

谷歌学者

Omasits U, Ahrens CH, Müller S, Wollscheid B. Protter: interactive protein feature visualization and integration with experimental proteomic data. Bioinformatics. 2014;30:884–6.Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Omasits U，Ahrens CH，Müller S，Wollscheid B.Protter：交互式蛋白质特征可视化和与实验蛋白质组学数据的整合。生物信息学。2014年；30:884–6.Richards S，Aziz N，Bale S，Bick D，Das S，Gastier Foster J等人。序列变异解释的标准和指南：美国医学遗传学和基因组学学院与分子病理学协会的联合共识建议。

Genet Med. 2015;17:405–24.Article .

Genet Med.2015；17:405–24文章。

Google Scholar

谷歌学者

Biesecker LG, Byrne AB, Harrison SM, Pesaran T, Schäffer AA, Shirts BH, et al. ClinGen guidance for use of the PP1/BS4 co-segregation and PP4 phenotype specificity criteria for sequence variant pathogenicity classification. Am J Hum Genet. 2024;111:24–38.Article

Biesecker LG，Byrne AB，Harrison SM，Pesaran T，Schäffer AA，Shirts BH等。ClinGen指南，用于序列变异致病性分类的PP1/BS4共分离和PP4表型特异性标准的使用。我是J Hum Genet。；111:24–38.文章

CAS

中科院

Google Scholar

谷歌学者

Yan H, Ji H, Kubisiak T, Wu Y, Xiao J, Gu Q, et al. Genetic analysis of 20 patients with hypomyelinating leukodystrophy by trio-based whole-exome sequencing. J Hum Genet. 2021;66:761–8.Article

Yan H，Ji H，Kubisiak T，Wu Y，Xiao J，Gu Q，等。基于三重全外显子组测序的20例低髓鞘性脑白质营养不良患者的遗传分析。J哼哼Genet。2021年；66:761–8.文章

CAS

中科院

Google Scholar

谷歌学者

Tonduti D, Mura E, Masnada S, Bertini E, Aiello C, Zini D, et al. Spinal cord involvement and paroxysmal events in “Infantile Onset Transient Hypomyelination” due to TMEM63A mutation. J Hum Genet. 2021;66:1035–7.Article

Tonduti D，Mura E，Masnada S，Bertini E，Aiello C，Zini D等。由于TMEM63A突变导致的“婴儿发作性短暂性髓鞘过少”中的脊髓受累和阵发性事件。J哼哼Genet。2021年；66:1035–7.文章

CAS

中科院

Google Scholar

谷歌学者

Gerik-Celebi HB, Aydin H, Bolat H, Unsel-Bolat G. Clinical and Genetic Characteristics of Patients with Unexplained Intellectual Disability/Developmental Delay without Epilepsy. Mol Syndromol. 2023;14:208–18.Article

Gerik Celebi HB，Aydin H，Bolat H，Unsel Bolat G.无癫痫的不明原因智力障碍/发育迟缓患者的临床和遗传特征。摩尔综合征。2023年；14：

CAS

中科院

Google Scholar

谷歌学者

Garg D, Agarwal A, Garg A, Srivastava AK. Adult-onset Leukodystrophy due to TMEM63A Variant Presenting with Rapidly Progressive Dementia with Parkinsonism. Ann Indian Acad Neurol. 2024;27:105–7.Article

Garg D，Agarwal A，Garg A，Srivastava AK。由TMEM63A变异引起的成人发作性脑白质营养不良，表现为帕金森病的快速进行性痴呆。Ann Indian Acad Neurol。；27:105–7.文章

Google Scholar

谷歌学者

Zheng W, Rawson S, Shen Z, Tamilselvan E, Smith HE, Halford J, et al. TMEM63 proteins function as monomeric high-threshold mechanosensitive ion channels. Neuron. 2023;111:3195–210.e7.Article

Zheng W，Rawson S，Shen Z，Tamilselvan E，Smith HE，Halford J等。TMEM63蛋白起单体高阈值机械敏感离子通道的作用。神经元。2023年；111:3195–210.e7.文章

CAS

中科院

Google Scholar

谷歌学者

Download referencesAcknowledgementsThe authors thank the patient and her family for their cooperation and consent for the publication of this report. We would like to thank Editage (www.editage.jp) for English language editing.FundingThis study was funded in part by grants from the Japan Agency for Medical Research and Development (AMED) under grant number JP23ek0109637 to KI and HS, the Ministry of Health, Labour and Welfare under grant number JPMH21FC1015 to KI and HS, and the Intramural Research Grant (3-6 and 6-6) for Neurological and Psychiatric Disorders of the National Center of Neurology and Psychiatry to YSM.

下载参考文献致谢作者感谢患者及其家人的合作和同意发表本报告。我们要感谢Editage（www.Editage.jp）的英语编辑。资助本研究的部分资金来自日本医学研究与发展署（AMED），授予KI和HS的资助号为JP23ek0109637，授予KI和HS的资助号为JPMH21FC1015的厚生劳动省，以及YSM国家神经病学和精神病学中心神经和精神疾病的壁内研究资助（3-6和6-6）。

The funding organizations had no role in the design or conduct of the study. The funding organization had no role in the collection, management, analysis, interpretation of data, preparation, review, or approval of the manuscript.Author informationAuthors and AffiliationsDepartment of Child Neurology, National Center of Neurology and Psychiatry, Tokyo, JapanShota Yoneno, Kaoru Yamamoto, Yuko Shimizu-Motohashi & Hirofumi KomakiDepartment of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, JapanKenshiro Tabata & Ken InoueDepartment of Neonatology, Toho University Omori Medical Center, Tokyo, JapanAyaka TomitaDepartment of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, JapanTaiju Hayashi & Hirotomo SaitsuDepartment of Radiology, National Center of Neurology and Psychiatry, Tokyo, JapanHiroyuki Maki & Noriko SatoTranslational Medical Center, National Center of Neurology and Psychiatry, Tokyo, JapanHirofumi KomakiAuthorsShota YonenoView author publicationsYou can also search for this author in.

资助组织在研究的设计或实施中没有任何作用。资助组织在收集，管理，分析，解释数据，准备，审查或批准手稿方面没有任何作用。作者信息作者和附属机构日本东京国立神经病学和精神病学中心儿童神经病学系，日本东京，日本东京，日本东京，日本东京，日本东北大学大森医学中心新生儿科，日本东京，日本东京，日本东京，日本东京，日本东京，日本东京，日本东京，日本东京，日本东京，日本东京大学医学院，日本滨松大学医学院生物化学系日本神经病学和精神病学，东京，日本小崎惠一郎国立神经病学和精神病学中心，日本神经病学和精神病学研究中心，日本小崎惠一郎作者Shota YonenoView作者出版物您也可以在中搜索该作者。

PubMed Google ScholarKaoru YamamotoView author publicationsYou can also search for this author in

PubMed Google ScholarKaoru YamamotoView作者出版物您也可以在

PubMed Google ScholarKenshiro TabataView author publicationsYou can also search for this author in

PubMed Google ScholarKenshiro TabataView作者出版物您也可以在

PubMed Google ScholarYuko Shimizu-MotohashiView author publicationsYou can also search for this author in

PubMed Google ScholarYuko Shimizu MotohashiView作者出版物您也可以在

PubMed Google ScholarAyaka TomitaView author publicationsYou can also search for this author in

PubMed Google ScholarAyaka TomitaView作者出版物您也可以在

PubMed Google ScholarTaiju HayashiView author publicationsYou can also search for this author in

PubMed Google ScholarTaiju HayashiView作者出版物您也可以在

PubMed Google ScholarHiroyuki MakiView author publicationsYou can also search for this author in

PubMed谷歌学者Hiroyuki MakiView作者出版物您也可以在

PubMed Google ScholarNoriko SatoView author publicationsYou can also search for this author in

PubMed Google ScholarNoriko SatoView作者出版物您也可以在

PubMed Google ScholarKen InoueView author publicationsYou can also search for this author in

PubMed Google ScholarKen InoueView作者出版物您也可以在

PubMed Google ScholarHirotomo SaitsuView author publicationsYou can also search for this author in

PubMed Google ScholarHirotomo SaitsuView作者出版物您也可以在

PubMed Google ScholarHirofumi KomakiView author publicationsYou can also search for this author in

PubMed Google ScholarHirofumi KomakiView作者出版物您也可以在

PubMed Google ScholarContributionsSY, KY, YSM, and KI analyzed the data and wrote the manuscript. SY, KY, KT, AT, HM, and NS examined and evaluated the case. TH and HS performed multiple panel testing. KI and HK supervised the study.Corresponding authorCorrespondence to

PubMed Google ScholarContributionsSY，KY，YSM和KI分析了数据并撰写了手稿。。TH和HS进行了多面板测试。KI和HK监督了这项研究。对应作者对应

Kaoru Yamamoto.Ethics declarations

山本薰。道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

作者声明没有利益冲突。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary informationTable S1Rights and permissionsReprints and permissionsAbout this articleCite this articleYoneno, S., Yamamoto, K., Tabata, K.

Additional informationPublisher的注释Springer Nature在已发布的地图和机构隶属关系中的管辖权主张方面保持中立。补充信息表S1权利和许可打印和许可本文引用本文Yoneno，S.，Yamamoto，K.，Tabata，K。

et al. A novel heterozygous TMEM63A variant in a familial case with early onset nystagmus, severe hypomyelination, and a favorable adult prognosis..

等。家族性病例中的一种新型杂合TMEM63A变体，具有早发性眼球震颤，严重的髓鞘减少和良好的成人预后。。

J Hum Genet (2024). https://doi.org/10.1038/s10038-024-01268-zDownload citationReceived: 17 May 2024Revised: 18 June 2024Accepted: 20 June 2024Published: 01 July 2024DOI: https://doi.org/10.1038/s10038-024-01268-zShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

J Hum Genet（2024）。https://doi.org/10.1038/s10038-024-01268-zDownloadhttps://doi.org/10.1038/s10038-024-01268-zShare本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

Provided by the Springer Nature SharedIt content-sharing initiative

由Springer Nature SharedIt内容共享计划提供