Ryanodine Myopathies Without Central Cores—Clinical, Histopathologic, and Genetic Description of Three Cases

Abstract

BACKGROUND: Mutations in ryanodine receptor 1 gene (RYR1) are frequent causes of myopathies. They classically present with central core disease; however, clinical variability and histopathologic overlap are being increasingly recognized. PATIENTS: Patient 1 is a 15-year-old girl with mild proximal, four-limb weakness from age 5, presenting with a progressive scoliosis starting at age 10. Patient 2 is an 18-year-old girl with progressively worsening muscle hypotrophy and mild proximal, four-limb weakness. She developed a rapidly progressive scoliosis from age 11 and needed surgical treatment at age 14 years. Patient 3 is an 11-year-old boy with moderate proximal limb weakness and progressive neck flexor weakness, first noticed at age 2. Muscle biopsies revealed type 1 fiber predominance (Patients 1 and 2) or abnormal type 1 fiber uniformity (Patient 3). Different RYR1 variants were identified in all patients. In Patients 1 and 3, these changes were validated as being pathogenic. CONCLUSIONS: These patients illustrate early-onset, progressive myopathies with predominant axial involvement. Histopathologic findings were abnormal but not specific for a diagnosis, particularly central core myopathy. Genetic testing helped broaden the range of phenotypes included in the RYR1-related myopathies. Our patients reinforce the need to recognize the broad histopathologic variability of RYR1-related myopathies and sometimes lack of pathognomonic findings that may reduce the diagnostic threshold of this disease. We suggest that the predominance of type 1 fibers and involvement of axial muscles may be an important element to consider the RYR1 gene as candidate.

Targeted massively parallel sequencing and histological assessment of skeletal muscles for the molecular diagnosis of inherited muscle disorders

“…We also identified several rare variants in RYR1 in patients with CFTD or CMP with type 1 fibre predominance. Mutations in RYR1 are associated with these phenotypes;33 34 however, it is unclear whether these mutations are pathogenic because there is no suitable in vitro or in vivo analytical method to prove their pathogenicity. Interestingly, patients 6 and 7 shared the same phenotype and the same rare variant in NEB ; moreover, patients 12 and 13 shared the same rare variant in RYR1 .…”

A Rare Case of Severe Congenital RYR1-Associated Myopathy

“…The ryanodine receptor 1 gene maps to chromosome 19q13.2 and encodes the skeletal muscle isoform of a calcium-release channel in the sarcoplasmic reticulum (RyR1) [ 6 , 10 ]. It has been involved in both dominant and recessive congenital myopathies and it plays a central role in excitation-contraction coupling, causing altered excitability and/or changes in calcium homeostasis in muscle cells [ 11 – 14 ].…”

“…The most known CCD is the autosomal dominant inherited form caused by mutations localized in three hot spots in the ryanodine receptor 1 gene (RYR1), associated with malignant hyperthermia susceptibility (MHS) and clinically characterized by minor hypotonia and nonprogressive weakness. Recessive mutations are located throughout the entire RYR1 gene and characterized by a more severe and progressive clinical presentation with neonatal-onset and significant generalized muscle weakness [ 6 – 8 ] .…”

Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature

“…A number of earlier cases were described prior to RYR1 gene identification and association with disease and, thus, may have been classified differently today. However, these histopathologic features are not unique to RYR1-RM, can be dynamic over time, may vary based on biopsy site, and may be absent when biopsy is performed at an early age [25,26] or reflect a consequence of the gene dose (heterozygous = MH susceptibility versus homozygous = clinical myopathy) [27]. There are also several clinical and histopathologic similarities between the main RYR1-RM diagnostic categories of central core disease (CCD; MIM # 117000), multi-mini core disease (MmD; MIM #255320), core-rod myopathy (CRM), centronuclear myopathy (CNM), and congenital fiber-type disproportion (CFTD) [28,29].…”