Cylindrical spirals are a rare ultrastructural finding on muscle biopsy, with fewer than 20 reported cases since its first description in 1979. These structures are sometimes observed with tubular aggregates and are thought to comprise longitudinal sarcoplasmic reticulum. While mutations in genes encoding key components of Ca2+ handling (ORAI1 and STIM1) underlie tubular aggregate myopathy, no causative genes have been associated with cylindrical spirals. Here we describe two families with cylindrical spirals on muscle biopsy with a suspected genetic cause. In one family we identified a known truncating variant in EBF3, previously associated with a neurodevelopmental disorder. The affected individuals in this family present with clinical features overlapping with those described for EBF3 disease. An isolated proband in the second family harbours bi-allelic truncating variants in TTN and her clinical course and other features on biopsy are highly concordant for titinopathy. From experimental studies, EBF3 is known to be involved in Ca2+ regulation in muscle, thus EBF3 dysregulation may represent a novel mechanism of impaired Ca2+ handling leading to cylindrical spirals. Additional cases of EBF3 disease or titinopathy with cylindrical spirals need to be identified to support the involvement of these genes in the pathogenesis of cylindrical spirals.

中文翻译：

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两个家族的圆柱螺旋：临床和遗传研究

圆柱螺旋是肌肉活检中罕见的超微结构发现，自 1979 年首次描述以来报告的病例不到 20。这些结构有时观察到管状聚集体，并被认为包含纵向肌浆网。虽然编码 Ca2+ 处理关键成分（ORAI1 和 STIM1）的基因突变是管状聚集肌病的基础，但没有致病基因与圆柱螺旋相关。在这里，我们描述了两个在肌肉活检中呈圆柱形螺旋状且疑似遗传原因的家族。在一个家族中，我们在 EBF3 中发现了一种已知的截断变异，以前与神经发育障碍有关。该家族中受影响的个体表现出与 EBF3 疾病描述的临床特征重叠的临床特征。第二个家族中的一个孤立先证者在 TTN 中具有双等位基因截短变异，她的临床病程和活检的其他特征与肌动蛋白病高度一致。从实验研究中，已知 EBF3 参与肌肉中的 Ca2+ 调节，因此 EBF3 失调可能代表了 Ca2+ 处理受损导致圆柱形螺旋的新机制。需要确定具有圆柱螺旋的 EBF3 疾病或钛病的其他病例，以支持这些基因参与圆柱螺旋的发病机制。因此 EBF3 失调可能代表了一种新的 Ca2+ 处理受损导致圆柱形螺旋的机制。需要确定具有圆柱螺旋的 EBF3 疾病或钛病的其他病例，以支持这些基因参与圆柱螺旋的发病机制。因此 EBF3 失调可能代表了一种新的 Ca2+ 处理受损导致圆柱形螺旋的机制。需要确定具有圆柱螺旋的 EBF3 疾病或钛病的其他病例，以支持这些基因参与圆柱螺旋的发病机制。