Sandra Coppens MD, PhD, Nicolas Deconinck MD, PhD, Patricia Sullivan BAdvSci(Hons), PhD, Andrei Smolnikov BAdvSci(Hons), BA, MA(Res), Joshua S. Clayton PhD, Kaitlyn R. Griffin BSc, MNurs, Kristi J. Jones MBBS, FRACP, PhD, Catheline N. Vilain MD, PhD, Hazim Kadhim MD, PhD, DCH, MB-ChB, Board (Neuropathology), Samantha J. Bryen BSc(Hons), PhD, Fathimath Faiz PhD, Leigh B. Waddell BMedSc, PhD, Frances J. Evesson PhD, Madhura Bakshi MBBS, MD, DCh, FRACP, Jason R. Pinner BA, MA, MBBS, FRACP, Amanda Charlton MBChB, BMedSc, FRCPA, Susan Brammah BSc, MApplSc, Nicole S. Graf MBBS, FRCPA, Michael Krivanek MBBS, FRCPA, Chee Geap Tay MBBS, MPaeds, Nicola C. Foulds BSc, MA, PhD, MBChB, FRCP, Marjorie A. Illingworth MB BCH BAO(Hons), MRCPCH, Neil H. Thomas MA, MB BChir, FRCP, FRCPCH, DCH, Sian Ellard PhD, FRCPath, Ingrid Mazanti MD, Soo-Mi Park BSc, MBBS, PhD, FRCP, Courtney E. French PhD, Jennifer Brewster MB ChB, MRCOG, Gusztav Belteki MD, PhD, FRCPCH, Shazia Hoodbhoy BM BS, MRCPCH, Kieren Allinson BSc (Hons), MBChB, FRCPath, Deepa Krishnakumar MBBS, MRCPCH, DCH, Gareth Baynam MBBS, PhD, Bradley M. Wood MBBS, FRANZCR, Michelle Ward BSc, PGDip, Kayal Vijayakumar MBBS, MRCPCH, Amber Syed BSc, MBBCh, MRCPCH, Archana Murugan MB BS, Anirban Majumdar BMBS, FRCPCH, Ingrid J. Scurr BSc, MBBS, MRCPCH, Miranda P. Splitt MBBS, MD, FRCP, Corina Moldovan MD, MPH, FRCPath, Deepthi C. de Silva MBChB, MRCP, Kumudu Senanayake MBBS, MD (Histopath), Thatjana Gardeitchik MD, PhD, Yvonne Arens MD, PhD, Sandra T. Cooper PhD, Nigel G. Laing PhD, F. Lucy Raymond MD, DPhil, FRCP, FRCPath, Heinz Jungbluth MD, PhD, Erik-Jan Kamsteeg PhD, Adnan Manzur MB BS, FRCPCH, Susan M. Corley LLB, LLM, BSc(Hons), PhD, Gianina Ravenscroft PhD, Marc R. Wilkins BSc(Hons), PhD, DSc, Mark J. Cowley BSc(Bioinf), PhD, Mark Pinese BSc(Hons), PhD, Titin Research Consortium, Rahul Phadke MD, FRCPath, Mark R. Davis PhD, Francesco Muntoni MD, Emily C. Oates BMedSc(Hons), MBBS(Hons), FRACP, PhD
{"title":"Congenital Titinopathy: Comprehensive Characterization of the Most Severe End of the Disease Spectrum","authors":"Sandra Coppens MD, PhD, Nicolas Deconinck MD, PhD, Patricia Sullivan BAdvSci(Hons), PhD, Andrei Smolnikov BAdvSci(Hons), BA, MA(Res), Joshua S. Clayton PhD, Kaitlyn R. Griffin BSc, MNurs, Kristi J. Jones MBBS, FRACP, PhD, Catheline N. Vilain MD, PhD, Hazim Kadhim MD, PhD, DCH, MB-ChB, Board (Neuropathology), Samantha J. Bryen BSc(Hons), PhD, Fathimath Faiz PhD, Leigh B. Waddell BMedSc, PhD, Frances J. Evesson PhD, Madhura Bakshi MBBS, MD, DCh, FRACP, Jason R. Pinner BA, MA, MBBS, FRACP, Amanda Charlton MBChB, BMedSc, FRCPA, Susan Brammah BSc, MApplSc, Nicole S. Graf MBBS, FRCPA, Michael Krivanek MBBS, FRCPA, Chee Geap Tay MBBS, MPaeds, Nicola C. Foulds BSc, MA, PhD, MBChB, FRCP, Marjorie A. Illingworth MB BCH BAO(Hons), MRCPCH, Neil H. Thomas MA, MB BChir, FRCP, FRCPCH, DCH, Sian Ellard PhD, FRCPath, Ingrid Mazanti MD, Soo-Mi Park BSc, MBBS, PhD, FRCP, Courtney E. French PhD, Jennifer Brewster MB ChB, MRCOG, Gusztav Belteki MD, PhD, FRCPCH, Shazia Hoodbhoy BM BS, MRCPCH, Kieren Allinson BSc (Hons), MBChB, FRCPath, Deepa Krishnakumar MBBS, MRCPCH, DCH, Gareth Baynam MBBS, PhD, Bradley M. Wood MBBS, FRANZCR, Michelle Ward BSc, PGDip, Kayal Vijayakumar MBBS, MRCPCH, Amber Syed BSc, MBBCh, MRCPCH, Archana Murugan MB BS, Anirban Majumdar BMBS, FRCPCH, Ingrid J. Scurr BSc, MBBS, MRCPCH, Miranda P. Splitt MBBS, MD, FRCP, Corina Moldovan MD, MPH, FRCPath, Deepthi C. de Silva MBChB, MRCP, Kumudu Senanayake MBBS, MD (Histopath), Thatjana Gardeitchik MD, PhD, Yvonne Arens MD, PhD, Sandra T. Cooper PhD, Nigel G. Laing PhD, F. Lucy Raymond MD, DPhil, FRCP, FRCPath, Heinz Jungbluth MD, PhD, Erik-Jan Kamsteeg PhD, Adnan Manzur MB BS, FRCPCH, Susan M. Corley LLB, LLM, BSc(Hons), PhD, Gianina Ravenscroft PhD, Marc R. Wilkins BSc(Hons), PhD, DSc, Mark J. Cowley BSc(Bioinf), PhD, Mark Pinese BSc(Hons), PhD, Titin Research Consortium, Rahul Phadke MD, FRCPath, Mark R. Davis PhD, Francesco Muntoni MD, Emily C. Oates BMedSc(Hons), MBBS(Hons), FRACP, PhD","doi":"10.1002/ana.27087","DOIUrl":null,"url":null,"abstract":"<div>\n \n <section>\n \n <p>Congenital titinopathy has recently emerged as one of the most common congenital muscle disorders.</p>\n </section>\n \n <section>\n \n <h3> Objective</h3>\n \n <p>To better understand the presentation and clinical needs of the under-characterized extreme end of the congenital titinopathy severity spectrum.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>We comprehensively analyzed the clinical, imaging, pathology, autopsy, and genetic findings in 15 severely affected individuals from 11 families.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>Prenatal features included hypokinesia or akinesia and growth restriction. Six pregnancies were terminated. Nine infants were born at or near term with severe-to-profound weakness and required resuscitation. Seven died following withdrawal of life support. Two surviving children require ongoing respiratory support. Most cohort members had at least 1 disease-causing variant predicted to result in some near-normal-length titin expression. The exceptions, from 2 unrelated families, had homozygous truncating variants predicted to induce complete nonsense mediated decay. However, subsequent analyses suggested that the causative variant in each family had an additional previously unrecognized impact on splicing likely to result in some near-normal-length titin expression. This impact was confirmed by minigene assay for 1 variant.</p>\n </section>\n \n <section>\n \n <h3> Interpretation</h3>\n \n <p>This study confirms the clinical variability of congenital titinopathy. Severely affected individuals succumb prenatally/during infancy, whereas others survive into adulthood. It is likely that this variability is because of differences in the amount and/or length of expressed titin. If confirmed, analysis of titin expression could facilitate clinical prediction and increasing expression might be an effective treatment strategy. Our findings also further-support the hypothesis that some near-normal-length titin expression is essential to early prenatal survival. Sometimes expression of normal/near-normal-length titin is due to disease-causing variants having an additional impact on splicing. ANN NEUROL 2025;97:611–628</p>\n </section>\n </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"97 4","pages":"611-628"},"PeriodicalIF":7.7000,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27087","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annals of Neurology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ana.27087","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Congenital titinopathy has recently emerged as one of the most common congenital muscle disorders.
Objective
To better understand the presentation and clinical needs of the under-characterized extreme end of the congenital titinopathy severity spectrum.
Methods
We comprehensively analyzed the clinical, imaging, pathology, autopsy, and genetic findings in 15 severely affected individuals from 11 families.
Results
Prenatal features included hypokinesia or akinesia and growth restriction. Six pregnancies were terminated. Nine infants were born at or near term with severe-to-profound weakness and required resuscitation. Seven died following withdrawal of life support. Two surviving children require ongoing respiratory support. Most cohort members had at least 1 disease-causing variant predicted to result in some near-normal-length titin expression. The exceptions, from 2 unrelated families, had homozygous truncating variants predicted to induce complete nonsense mediated decay. However, subsequent analyses suggested that the causative variant in each family had an additional previously unrecognized impact on splicing likely to result in some near-normal-length titin expression. This impact was confirmed by minigene assay for 1 variant.
Interpretation
This study confirms the clinical variability of congenital titinopathy. Severely affected individuals succumb prenatally/during infancy, whereas others survive into adulthood. It is likely that this variability is because of differences in the amount and/or length of expressed titin. If confirmed, analysis of titin expression could facilitate clinical prediction and increasing expression might be an effective treatment strategy. Our findings also further-support the hypothesis that some near-normal-length titin expression is essential to early prenatal survival. Sometimes expression of normal/near-normal-length titin is due to disease-causing variants having an additional impact on splicing. ANN NEUROL 2025;97:611–628
期刊介绍：
Annals of Neurology publishes original articles with potential for high impact in understanding the pathogenesis, clinical and laboratory features, diagnosis, treatment, outcomes and science underlying diseases of the human nervous system. Articles should ideally be of broad interest to the academic neurological community rather than solely to subspecialists in a particular field. Studies involving experimental model system, including those in cell and organ cultures and animals, of direct translational relevance to the understanding of neurological disease are also encouraged.
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