Central core disease ; Malignant hyperthermia ; Multiminicores ; Ryanodine receptor type 1
Abstract
Background and PurposeᄏAt least 100 Ryanodine receptor type 1 (RYR1) mutations associated
with malignant hyperthermia (MH) and central core disease (CCD) have been identified,
but 2 RYR1 mutations accompanying multiminicore myopathy in an MH and/or CCD family
have been reported only rarely.
MethodsᄏFifty-three members of a large MH family were investigated with clinical, histopathologic,
RYR1 mutation, and haplotyping studies. Blood creatine kinase (CK) and myoglobin
levels were also measured where possible.
ResultsᄏSequencing of the entire RYR1 coding region identified a double RYR1 mutation
(R2435H and A4295V) in MH/CCD regions 2 and 3. Haplotyping analysis revealed that the
two missense heterozygous mutations (c.7304G>A and c.12891C>T) were always present on a
common haplotype allele, and were closely cosegregated with histological multiminicores and
elevated serum CK. All the subjects with the double mutation showed elevated serum CK and
myoglobin, and the obtained muscle biopsy samples showed multiminicore lesions, but only
two family members presented a late-onset, slowly progressive myopathy.
ConclusionsᄏWe found multiminicore myopathy with clinical and histological variability in
a large MH family with an unusual double RYR1 mutation, including a typical CCD-causing
known mutant. These results suggest that multiminicore lesions are associated with the presence
of more than two mutations in the RYR1 gene.