J Clin Neurol.  2008 Sep;4(3):123-130. 10.3988/jcn.2008.4.3.123.

A Double Mutation of the Ryanodine Receptor Type 1 Gene in a Malignant Hyperthermia Family with Multiminicore Myopathy

• Jeong SK
• Kim DC
• Cho YG
• Sunwo IN
• Kim DS

• KMID: 2287676
• DOI: http://doi.org/10.3988/jcn.2008.4.3.123

Abstract

BACKGROUND AND PURPOSE: At 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.
METHODS
Fifty-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.
RESULTS
Sequencing 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.
CONCLUSIONS
We 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.

Keyword

Malignant hyperthermia; Central core disease; Multiminicores; Ryanodine receptor type 1

MeSH Terms

Alleles
Biopsy
Clinical Coding
Creatine Kinase
Haplotypes
Humans
Malignant Hyperthermia
Muscles
Muscular Diseases
Myoglobin
Myopathies, Structural, Congenital
Myopathy, Central Core
Ophthalmoplegia
Ryanodine
Ryanodine Receptor Calcium Release Channel
Creatine Kinase
Myoglobin
Myopathies, Structural, Congenital
Ophthalmoplegia
Ryanodine
Ryanodine Receptor Calcium Release Channel

Figure

• 

  Fig. 1 Pedigree and haplotyping analysis of the present family. Arrows denote probands who experienced malignant hyperthermia episodes or individuals showing overt clinical myopathies. Black shapes indicate individuals with histological multiminicore lesions. Empty shapes and a question mark denote individuals in whom muscle biopsies and genetic tests were not performed, respectively. Genotypes: +/-, heterozygous carrier of R2435H and A4295V mutations; -/-, no mutation. The results of marker typing and identification of the mutation are shown in the following order: D19S191-D19S220-RYR1 mutations-D19S422-D19S190-D19S223.

• 

  Fig. 2 DNA sequencing of the regions of the ryanodine receptor type 1 (RYR1) gene in which the 7304CGC>CAC (Arg 2435His) missense mutation in exon 45 and 12891GCG>GTG (Ala4295Val) missense mutation in exon 91 were detected. Individual III-3 without the two mutations showed a single peak, but individual III-17 (a proband with an MH episode) showed two superimposed peaks (arrows) in both exons 45 and 91, indicating heterozygous missense mutations. F and R, forward and reverse sequencing, respectively.

• 

  Fig. 3 Muscle biopsy sections stained for NADH-TR with a scattered motheaten appearance and unstained multiminicores in the father (II-1, A) and subtle moth-eaten changes in his son (III-7, B).

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  Fig. 4 Electron micrographs showing streaming and disruption of irregular Z-lines, and the amorphous cores from individuals III-17 (A) and III-1 (B).

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  Fig. 5 Amino acid sequence alignments in the region of RYR1 isoforms flanking the A4295V mutation in human, pig and rabbit. *Denotes the conserved segment in A4295V.

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