Central Core Disease: Facial Weakness Differentiating Biallelic from Monoallelic Forms

Abstract

Central Core Disease (CCD) is a genetic neuromuscular disorder characterized by the presence of cores in muscle biopsy. The inheritance has been described as predominantly autosomal dominant (AD), and the disease may present as severe neonatal or mild adult forms. Here we report clinical and molecular data on a large cohort of Brazilian CCD patients, including a retrospective clinical analysis and molecular screening for RYR1 variants using Next-Generation Sequencing (NGS). We analyzed 27 patients from 19 unrelated families: four families (11 patients) with autosomal dominant inheritance (AD), two families (3 patients) with autosomal recessive (AR), and 13 sporadic cases. Biallelic RYR1 variants were found in six families (two AR and four sporadic cases) of the 14 molecularly analyzed families (~43%), suggesting a higher frequency of AR inheritance than expected. None of these cases presented a severe phenotype. Facial weakness was more common in biallelic than in monoallelic patients (p = 0.0043) and might be a marker for AR forms. NGS is highly effective for the identification of RYR1 variants in CCD patients, allowing the discovery of a higher proportion of AR cases with biallelic mutations. These data have important implications for the genetic counseling of the families.

Keywords: RYR1; central core disease; clinical heterogeneity; electromyography.

Figure 1

(A)—Distribution of the studied families, according to the pedigrees. (B)—Distribution of the 14 families with genetic studies, according to the presence of mono or biallelic variants in RYR1.

Figure 2

Imaging and muscle biopsy findings of patient 2.1 with the p.Gly4897Asp pathogenic variant in the RYR1 gene. (A)—Computed tomography demonstrated severe right vastus lateralis (vl) muscle fat replacement with relative rectus femoris (rf) preservation. Computed tomography of the pelvis, thighs, and legs. (B)—Muscle biopsy was performed in the rectus femoris demonstrating round core structures (*). SDH 100x. (C)—Core areas (*) were ultrastructurally characterized by myofibrillar disorganization with scarce mitochondria. Transmission electron microscopy 2500×. This figure was modified from Cotta et al., 2021 [6].

Figure 3

Diagram of the variants in the RYR1 gene in this cohort of patients. Novel variants identified in this work are depicted in red and previously described variants are represented in black. D1, D2, and D3 are the three hotspots for mutations in the RYR1 gene, and the majority of the variants identified in this cohort are located at D3. Figure created using IBS Illustrator for Biological Sequences [19].

Figure 4

Facial weakness in biallelic and monoallelic RYR1 families.