Abstract
Several morphological phenotypes have been associated to RYR1-recessive myopathies. We recharacterized the RYR1-recessive morphological spectrum by a large monocentric study performed on 54 muscle biopsies from a large cohort of 48 genetically confirmed patients, using histoenzymology, immunohistochemistry, and ultrastructural studies. We also analysed the level of RyR1 expression in patients’ muscle biopsies. We defined “dusty cores” the irregular areas of myofibrillar disorganisation characterised by a reddish-purple granular material deposition with uneven oxidative stain and devoid of ATPase activity, which represent the characteristic lesion in muscle biopsy in 54% of patients. We named Dusty Core Disease (DuCD) the corresponding entity of congenital myopathy. Dusty cores had peculiar histological and ultrastructural characteristics compared to the other core diseases. DuCD muscle biopsies also showed nuclear centralization and type1 fibre predominance. Dusty cores were not observed in other core myopathies and centronuclear myopathies. The other morphological groups in our cohort of patients were: Central Core (CCD: 21%), Core-Rod (C&R:15%) and Type1 predominance “plus” (T1P+:10%). DuCD group was associated to an earlier disease onset, a more severe clinical phenotype and a lowest level of RyR1 expression in muscle, compared to the other groups. Variants located in the bridge solenoid and the pore domains were more frequent in DuCD patients. In conclusion, DuCD is the most frequent histopathological presentation of RYR1-recessive myopathies. Dusty cores represent the unifying morphological lesion among the DuCD pathology spectrum and are the morphological hallmark for the recessive form of disease.
Highlights
The RYR1 gene encodes the ryanodine receptor channel 1 (RyR1), a sarcoplasmic reticulum (SR) calcium channel involved in excitation-contraction coupling through interaction with the dihydropyridine receptor (DHPR) in the T-tubule
We report an extensive monocentric analysis of 54 muscle biopsies from a large cohort of 48 RYR1-recessive patients to have a homogenous interpretation of morphological findings with the aim to find a closer correlation between morphology, clinical phenotype and genetic background
No dusty cores were observed among 154 muscle biopsies of dominant RYR1- and 10 of MYH7-related myopathies examined in our lab [30, 32]
Summary
The RYR1 gene encodes the ryanodine receptor channel 1 (RyR1), a sarcoplasmic reticulum (SR) calcium channel involved in excitation-contraction coupling through interaction with the dihydropyridine receptor (DHPR) in the T-tubule. Even if RYR1-recessive patients could present a clinical picture similar to the dominant one, including an early onset, non-progressive, proximal muscle weakness, other peculiar clinical phenotypes of recessive forms are characterized by a more diffuse muscle weakness, ocular involvement with ptosis and/or ophthalmoplegia, and a severe bulbar and respiratory muscle weakness [19, 20, 35]. Concerning morphology, the phenotypic variability of histopathological findings in recessive forms increases even more, including CCD [10, 16, 31, 41], Multiminicore Disease (MmD) [11, 18, 25], Congenital Fibre Type Disproportion (CFTD) [7] and Centronuclear Myopathy (CNM) [1, 17, 37]. In the largest review of 106 RYR1-recessive cases, up to 40% of patients did not fill these categories and were classified as Atypical Core Myopathy or different nonspecific histopathological groups [2]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
