Cylindrical spirals in a patient with fascioscapulohumeral muscular dystrophy

To the Editor, Cylindrical spirals (CSs) are a rare structural finding in muscle biopsies characterized by the accumulation of concentrically wrapped lamellae in skeletal muscle fibers; they were first described by Carpenter et al.1 CSs are associated with several neurological diseases.2 Here, we first identified a patient with fascioscapulohumeral muscular dystrophy (FSHD) with CSs in his muscle biopsy. The patient was an 18-year-old man who could only lift his left upper limb to a position of 45°. There was muscle atrophy in the left supraspinatus after the fracture of the left clavicle when he was 16 years old. His creatine kinase (CK) level was found to be elevated to 700 IU/L in early 2023; it then fluctuated from several hundred to 1300 IU/L thereafter. He presented with difficulty in lifting his right upper limb since May 2023. He had a small palpebral fissure of the left eye since middle school. He was born to non-consanguineous parents, and his developmental milestones were normal. No family history was reported. On examination, he had small left palpebral fissure and bilateral weakness when bulging his cheeks. The superior manubrium fossa was slightly concave. There was atrophy of bilateral scapular-girdle muscles (Figure 1A). Both upper limbs could only lift to a position of 45°. Muscle strength was grade 5- in bilateral shoulder abduction and wrist extension, and grade 5 in other muscle groups. The Beevor sign was negative. The CK level was 472 IU/L on admission. Muscle MRI of upper limbs showed diminished muscle volume. Electromyography showed myopathic changes in bilateral supraspinatus, right pectoralis major and T10 paraspinal muscle. Nerve conduction velocity was normal. A left deltoid biopsy was performed. Hematoxylin and eosin (H&E) staining showed scattered small angular atrophic muscle fibers and weakly basophilic inclusions in many subsarcolemmal and cytoplasmic regions (Figure 1C). They were stained reddish with modified Gomori trichrome (mGT) and intensely stained for nicotinamide adenine dinucleotide tetrazolium reductase (NADH-TR) and non-specific esterase (Figure 1D, E) but were negative in periodic acid-Schiff and cytochrome oxidase stains. No pathological changes of inflammatory myopathies, metabolic myopathies, or neurogenic disorders were observed. By electron microscopy, clusters of CSs were observed in the subsarcolemmal regions (Figure 1F, G), and with glycogen in the center of the spirals (Figure 1H). Whole-exome sequencing was performed and did not detect pathogenic mutations associated with this patient. Optical genome mapping was performed later and found that the repeat copy numbers of D4Z4 on chromosome 4q35 were 3 (4qA) and 25 (4qA) (Figure 1B). Clinical phenotype and pathological features of the patient. (A) The patient presented with shoulder-girdle weakness; he could only lift both upper limbs to a position of 45°. (B) Optical genome mapping showed repeat copy numbers of D4Z4 on chromosome 4q35. (C) H&E stain of the muscle biopsy showed scattered small angular atrophic muscle fibers distributed in groups, and slightly basophilic inclusions in many subsarcolemmal and cytoplasmic regions. (D, E) The inclusions stained reddish with mGT (D) and were intensely stained for NADH-TR (E). (F, G) Electron microscopy showed clusters of cylindrical spirals (CSs) in the subsarcolemmal regions in the transverse plane (F). The CSs appeared as needle-like structures in the longitudinal plane (G). (H) Enlarged image shows the accumulation of glycogen in the center of the spirals. Scale bars: A = 50 um; D, E = 20 um, F, G = 500 nm; H = 200 nm. Clusters of CSs were present in variable lengths and measuring 1- to 5-μm in diameter. The spirals were composed of up to 20 concentric lamellae with a rounded central core continuous at its ends with sarcoplasm containing small vesicles and/or glycogen granules.3 CSs are thought to originate from a sarcoplasmic reticulum (SR) component. A previous study found that CSs were highly immunoreactive for the longitudinal SR protein SERCA1 but were not immunoreactive to the junctional SR proteins RYR1 and CASQ, indicating that they arise from longitudinal SR.4 Thirty-one cases (13 male) with CSs have been reported in 16 studies to date.1,2,4–12 The age of onset ranged from infant to adulthood. The patients presented with a variety of clinical phenotypes, suggesting clinical heterogeneity and that CSs may not be disease-specific features. Among the reported patients, 10 were sporadic and 21 were familial cases. EBF3 variant, TTN gene variant, trinucleotide repeat expansion of huntingtin gene, MT-TL1 m.3243A > G mutation, ALS2 variant, PMP22 gene deletion, MYPN along with GAA mutations, PMPCB gene, KIF21A gene were reported in cases with CSs thereby expanding the genetic spectrum.2,11 Although a common pattern of inheritance is difficult establish, the formation of CSs has been speculated to be an acquired genetic defect in calcium handling. FSHD, which is characterized as facial and shoulder-girdle weakness, is one of the most common muscular dystrophies The majority of cases are FSHD type1 (FSHD1) caused by a deletion of copies of a 3.3 kb DNA repeat fragment in the subtelomeric region of chromosome 4q (D4Z4). The fragment size varies with 11-100 or more D4Z4 repeats in normal individuals but only 1-10 repeats in FSHD1.13 The loss of D4Z4 repeats in association with a permissive 4qA haplotype allows re-expression of DUX4 protein, a transcription factor that initiates a large gene deregulation cascade leading to muscle atrophy, inflammation, differentiation defects, and oxidative stress.14 Our patient fulfilled the diagnosis of FSHD1. This is the first report of a large amount of CSs in FSHD. The exact relationship between FSHD and CSs is unclear. We hypothesize that the toxicity of the expression of DUX4 protein may cause dysregulation of calcium homeostasis indirectly, such as by aberrant oxidative stress and endoplasmic reticulum stress,14,15 and that this further induces the formation of CSs. Our case expands the clinical and genetic spectrums associated with CSs. As the immunohistochemical features of CSs are similar to those of tubular aggregates, CSs may have been previously under-reported. Several genes are known to be associated with tubular aggregates,16 but no gene has been reported to be associated with CSs. We emphasize the importance of electron microscopy to distinguish CSs from tubular aggregates. Further studies will be required to explore the underlying genetic deficits to CSs. The authors wish to thank the patient and his family for participating in this study. This work was supported by the National Natural Science Foundation of China (81801243 to Q.G.). None declared. Written consent from the patient’s family was obtained.