Central core disease is due to RYR1 mutations in more than 90% of patients

Abstract

Ryanodine receptor 1 (RYR1) gene mutations are associated with central core disease (CCD), multiminicore disease (MmD) and malignant hyperthermia (MH), and have been reported to be responsible for 47-67% of patients with CCD and rare cases with MmD. However, to date, the true frequency and distribution of the mutations along the RYR1 gene have not been determined yet, since mutation screening has been limited to three 'hot spots', with particular attention to the C-terminal region. In this study, 27 unrelated Japanese CCD patients were included. Clinical histories and muscle biopsies were carefully reviewed. We sequenced all the 106 exons encoding RYR1 with their flanking exon-intron boundaries, and identified 20 novel and 3 previously reported heterozygous missense mutations in 25 of the 27 CCD patients (93%), which is a much higher mutation detection rate than that perceived previously. Among them, six were located outside the known 'hot spots'. Sixteen of 27 (59%) CCD patients had mutations in the C-terminal 'hot spot'. Three CCD patients had a probable autosomal recessive disease with two heterozygous mutations. Patients with C-terminal mutations had earlier onset and rather consistent muscle pathology characterized by the presence of distinct cores in almost all type 1 fibres, interstitial fibrosis and type 2 fibre deficiency. In contrast, patients with mutations outside the C-terminal region had milder clinical phenotype and harbour more atypical cores in their muscle fibres. We also sequenced two genes encoding RYR1-associated proteins as candidate causative genes for CCD: the 12 kD FK506-binding protein (FKBP12) and the alpha1 subunit of L-type voltage-dependent calcium channel or dihydropyridine receptor (CACNA1S). However, no mutation was found, suggesting that these genes may not, or only rarely, be responsible for CCD. Our results indicate that CCD may be caused by RYR1 mutations in the majority of patients.

Dominant and recessive RYR1 mutations in adults with core lesions and mild muscle symptoms

“…25 It has been suggested that mutations located in the C-terminal region are associated with specific clinical findings, such as infantile hypotonia, delayed motor development, and limb muscle weakness. 29 In contrast, the majority of CCD patients with at least one mutation located outside this region present milder musculoskeletal abnormalities, such as joint contractures and scoliosis. 29 Our work corroborates these observations, considering the mutation spectrum in this particular cohort with mild clinical presentation and late onset.…”

“…29 In contrast, the majority of CCD patients with at least one mutation located outside this region present milder musculoskeletal abnormalities, such as joint contractures and scoliosis. 29 Our work corroborates these observations, considering the mutation spectrum in this particular cohort with mild clinical presentation and late onset. The second mutation detected in patient 1 (p.His2204Gln) is located in hotspot 2, more precisely between amino acids 1924 and 2446, a region found to be critical for excitationcontraction (E-C) coupling.…”

Round Table on Malignant Hyperthermia in Physically Active Populations: Meeting Proceedings

“…The muscle weakness in these myopathies is caused by reductions in calcium release and muscle activation. 16 The pathophysiology of MH is linked to the impairment of myoplasmic calcium homeostasis, which leads to increased muscle tension and metabolism. Malignant hyperthermia manifests as increased production of carbon dioxide and heart rate and is often accompanied by accentuated muscle rigidity, hyperkalemia, increased acid content in the blood, release of myoglobin into the urine, and release of the muscle enzyme creatine kinase.…”

Clinical utility gene card for: Central core disease

“…More specifically, clinical sensitivity for RYR1 mutation screening also depends on the method used for mutation screening, as for example rarely larger copy number variations or genomic rearrangements may be missed on routine sequencing, and, more importantly, the stringent application of clinical and histopathological selection criteria as outlined in Paragraph 1.6. Although a recent study in the Japanese population involving larger patient numbers indicates that RYR1 is the causative gene in more than 90% of patients with CCD, 9 there is also evidence for genetic heterogeneity accounting for the imperfect clinical sensitivity of RYR1 screening in CCD:…”