Elsevier

Neuromuscular Disorders

Volume 30, Issue 2, February 2020, Pages 151-158
Neuromuscular Disorders

Cylindrical spirals in two families: Clinical and genetic investigations

https://doi.org/10.1016/j.nmd.2019.12.006Get rights and content

Highlights

  • 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.

Abstract

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.

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

References (45)

  • C.A.C. Ottenheijm et al.

    Altered contractility of skeletal muscle in mice deficient in titin's M-Band region

    J Mol Biol

    (2009)
  • J.W. Xu et al.

    Cylindrical spirals in skeletal muscles originate from the longitudinal sarcoplasmic reticulum

    J Neuropathol Exp Neurol

    (2016)
  • S. Carpenter et al.

    Cylindrical spirals in human skeletal muscle

    Muscle Nerve

    (1979)
  • K.E. Bove et al.

    Cylindrical spirals in a familial neuromuscular disorder

    Ann Neurol

    (1980)
  • J. Mcdougall et al.

    Spiral membrane cylinders in the skeletal muscle of a patient with melorheostosis

    Neuropathol Appl Neurobiol

    (1980)
  • E. Gibbels et al.

    Cylindrical spirals in skeletal muscle: a further observation with clinical, morphological, and biochemical analysis

    Muscle Nerve

    (1983)
  • M.J. Danon et al.

    Muscle pain associated with tubular aggregates and structures resembling cylindrical spirals

    Muscle Nerve

    (1989)
  • G. Sadalage et al.

    Tubular aggregates and cylindrical spirals in autoimmune limb-girdle myasthenia

    J Neurol Neurosurg Psychiatry

    (2016)
  • E. Malfatti et al.

    Cylindrical spirals associated with severe congenital muscle weakness and epileptic encephalopathy

    Muscle Nerve

    (2015)
  • H. Yamamoto et al.

    [A case of a mitochondrial myopathy with cylindrical spirals (author's transl)]

    Rinsho Shinkeigaku

    (1982)
  • S. Brady et al.

    Tubular aggregates and cylindrical spirals have distinct immunohistochemical signatures

    J Neuropathol Exp Neurol

    (2016)
  • F. Chevessier et al.

    The origin of tubular aggregates in human myopathies

    J Pathol

    (2005)
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