Coppens Sandra, Deconinck Nicolas, Sullivan Patricia, Smolnikov Andrei, Clayton Joshua S, Griffin Kaitlyn R, Jones Kristi J, Vilain Catheline N, Kadhim Hazim, Bryen Samantha J, Faiz Fathimath, Waddell Leigh B, Evesson Frances J, Bakshi Madhura, Pinner Jason R, Charlton Amanda, Brammah Susan, Graf Nicole S, Krivanek Michael, Tay Chee Geap, Foulds Nicola C, Illingworth Marjorie A, Thomas Neil H, Ellard Sian, Mazanti Ingrid, Park Soo-Mi, French Courtney E, Brewster Jennifer, Belteki Gusztav, Hoodbhoy Shazia, Allinson Kieren, Krishnakumar Deepa, Baynam Gareth, Wood Bradley M, Ward Michelle, Vijayakumar Kayal, Syed Amber, Murugan Archana, Majumdar Anirban, Scurr Ingrid J, Splitt Miranda P, Moldovan Corina, de Silva Deepthi C, Senanayake Kumudu, Gardeitchik Thatjana, Arens Yvonne, Cooper Sandra T, Laing Nigel G, Raymond F Lucy, Jungbluth Heinz, Kamsteeg Erik-Jan, Manzur Adnan, Corley Susan M, Ravenscroft Gianina, Wilkins Marc R, Cowley Mark J, Pinese Mark, Phadke Rahul, Davis Mark R, Muntoni Francesco, Oates Emily C
Hopital Erasme, ULB Center of Human Genetics, Université Libre de Bruxelles, Brussels, Belgium.
Department of Paediatric Neurology, Neuromuscular Reference Center, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Brussels, Belgium.
Ann Neurol. 2025 Apr;97(4):611-628. doi: 10.1002/ana.27087. Epub 2025 Jan 24.
Congenital titinopathy has recently emerged as one of the most common congenital muscle disorders.
To better understand the presentation and clinical needs of the under-characterized extreme end of the congenital titinopathy severity spectrum.
We comprehensively analyzed the clinical, imaging, pathology, autopsy, and genetic findings in 15 severely affected individuals from 11 families.
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.
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.
先天性肌联蛋白病最近已成为最常见的先天性肌肉疾病之一。
为了更好地了解先天性肌联蛋白病严重程度谱中特征描述不足的极端情况的表现和临床需求。
我们全面分析了来自11个家庭的15名严重受累个体的临床、影像学、病理学、尸检和基因检测结果。
产前特征包括运动减少或运动不能以及生长受限。6例妊娠终止。9名婴儿足月或接近足月出生，伴有严重至极重度肌无力，需要复苏。7例在撤除生命支持后死亡。2名存活儿童需要持续呼吸支持。大多数队列成员至少有1个预测会导致一些接近正常长度的肌联蛋白表达的致病变异。来自2个无关家庭的例外情况是，有纯合截短变异，预计会导致完全的无义介导衰变。然而，随后的分析表明，每个家庭中的致病变异对剪接有额外的先前未被认识到的影响，可能导致一些接近正常长度的肌联蛋白表达。1个变异通过小基因检测证实了这种影响。
本研究证实了先天性肌联蛋白病的临床变异性。严重受累个体在产前/婴儿期死亡，而其他个体存活至成年。这种变异性可能是由于所表达的肌联蛋白的数量和/或长度不同。如果得到证实，对肌联蛋白表达的分析可能有助于临床预测，增加表达可能是一种有效的治疗策略。我们的研究结果也进一步支持了这样的假设，即一些接近正常长度的肌联蛋白表达对产前早期存活至关重要。有时正常/接近正常长度的肌联蛋白表达是由于致病变异对剪接有额外影响。《神经病学纪事》2025年；97:611 - 628。
