Cylindrical spirals in two families: Clinical and genetic investigations
Introduction
Cylindrical spirals are an ultra-rare ultrastructural abnormality found in skeletal myofibres, with fewer than 20 published cases [1] since the first description in 1979 [2]. These whorled structures are characterised by accumulations of spiral lamellae, typically found under the sarcolemma in type II myofibres [1,2]. Cylindrical spirals are considered nonspecific due to the breadth of associated clinical features, ranging from muscle cramps exacerbated by exercise to severe congenital encephalomyopathy [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. Although cylindrical spirals appear to be heritable in some cases [1], no genes have been associated with this feature. The pathomechanism leading to the formation of cylindrical spirals in skeletal muscle remains uncertain.
Cylindrical spirals have been seen to co-occur or be continuous with tubular aggregates, another rare ultrastructural abnormality comprised of membranous tubules in the sarcoplasm [12]. Tubular aggregates have been shown to arise from the whole sarcoplasmic reticulum (SR), therefore containing all components required for Ca2+ uptake, storage, and release [13]. In contrast, cylindrical spirals appear to arise from the longitudinal SR [1]. The genetic forms of tubular aggregate myopathy are caused by heterozygous mutations in STIM1 and ORAI1, which produce constitutive activation of store operated Ca2+ entry [14]. The tubular aggregates may act a protective Ca2+ sink against the excessive cytosolic Ca2+ influx [12]. Given the co-occurrence and similar histological staining of tubular aggregates and cylindrical spirals [1,12], they may have a similar etiology (i.e. Ca2+ dysregulation). Previous studies showed that addition of Ca2+ to sonicated preparation of phosphatidylserine in aqueous NaCl buffer produces spiral shaped lipid cylinders that develop into flattened sheets, which then form coiled elongated multilamellar cylinders [5].
Here we describe two families (one from Australia, one from Spain) with cylindrical spirals as the hallmark feature on muscle biopsy. In the Australian family, a mother and son were both affected by an unclassified myopathy. In the Spanish family, the proband was diagnosed with congenital myopathy. Through familial exome sequencing, we reached a genetic diagnosis for both families, implicating EBF3 and TTN, respectively. Thus, we have identified for the first time, as far as we are aware, genetic mutations that are associated with cylindrical spirals.
Section snippets
Patients and methods
This study was approved by the UWA Human Research Ethics Committee, and all patients gave informed consent.
Family AUS1
As a child, AUS1 I:2 was grossly hypotonic with developmental delay and delayed motor milestones, walking at 2.5 years of age. She required ten years of speech therapy as a child. She had surgery for scoliosis at age 17 years. Examination in her mid-thirties revealed mild facial weakness with bilateral eyelid ptosis. She had a pointed chin, marked pes planus, very short thumbs bilaterally and a short great-toe on the right. She did not have scapular winging. Her muscle strength was globally
Discussion
The rarity of ultrastructural myopathies has limited investigation into their genetic and mechanistic origins. We present two families with EBF3 and TTN variants harbouring cylindrical spirals in their muscle biopsy. Inclusions within muscle from both families were detected by H&E, modified Gomori trichrome, NADH staining and electron microscopy consistent with the histochemical and ultrastructural signatures identified by other authors [3,6,12].
EBF3 is a highly conserved transcription factor
Acknowledgments
We extend our sincere thanks to the families involved in this study. SJB is funded by The Fred Liuzzi Foundation (TFLF) (Melbourne, Australia). NGL (APP1117510) and GR (APP1122952) are supported by the Australian National Health and Medical Research Council (NHMRC). GR is also supported by a Western Australian Department of Health Future Health's WA Merit Award. This work is funded by TFLF and NHMRC (APP1080587). M.O. is supported by a grant from ISCIII PI14/00738, and FEDER funds “a way to
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