Cylindrical spirals in two families: Clinical and genetic investigations

• Published in: Neuromuscular disorders : NMD 2020-02, Vol.30 (2), p.151-158
• Main Authors: Beecroft, Sarah J, Olive, Montse, Quereda, Lidia Gonzalez, Gallano, Pia, Ojanguren, Isabel, McLean, Catriona, McCombe, Pamela, Laing, Nigel G, Ravenscroft, Gianina
• Format: Article
• Language: English
• Subjects: Adult; Child, Preschool; Connectin - genetics; Cylindrical spiral myopathy; EBF3; Female; High-Throughput Nucleotide Sequencing; Humans; Male; Muscle, Skeletal - ultrastructure; Myopathies, Structural, Congenital - genetics; Myopathies, Structural, Congenital - pathology; Myopathies, Structural, Congenital - physiopathology; Next-generation sequencing; Pedigree; Transcription Factors - genetics; TTN; Tubular aggregates
• ISSN: 0960-8966; 1873-2364
• DOI: 10.1016/j.nmd.2019.12.006

•Two families with cylindrical spirals on muscle biopsy and suspected genetic cause.•Association of the EBF3 neurodevelopmental syndrome with cylindrical spirals.•Clinical investigation of patients with rare ultra-structural muscle features. 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.