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Histology, In Vitro Contracture Tests, and Genetic Characterization

Sandrine Guis, MD, PhD; Dominique Figarella-Branger, MD, PhD; Nicole Monnier, PhD; David Bendahan, PhD; Geneviève Kozak-Ribbens, MD, PhD; Jean-Pierre Mattei, MD, PhD; Joël Lunardi, PhD; Patrick J. Cozzone, PhD; Jean-François Pellissier, MD

Arch Neurol. 2004;61:106-113.

Background  Histological anomalies associated with malignant hyperthermia (MH) have been scarcely reported. In some patients susceptible to MH (MHS), central cores have been identified and a genetic association has been proposed, but multiminicore lesions have not been systematically reported.

Objective  To analyze the association between multiminicores and MHS in a large family with MH with an approach combining histology, in vitro contracture tests, and genetic analysis.

Patients and Methods  Twenty-nine members of an MH family (147 members) were investigated.

Main Outcome Measures  Muscle biopsy specimens were analyzed histologically and with in vitro contracture tests. Genetic analyses were performed to determine the presence of mutations in the ryanodine receptor (RYR1) gene.

Results  According to the gold standard in vitro contracture tests, 17 patients were diagnosed as having MHS and 10 as not being susceptible. Multiminicores were found in 16 of the 17 MHS patients and in a single nonsusceptible participant. A linkage between the MH trait and the RYR1 locus in chromosome 19 was demonstrated, whereas no already known mutations were found. Two missense heterozygous mutations (R2676W and T2787S) were identified from sequencing of the entire coding complementary DNA. Overall, we found a significant association between MHS and the presence of multiminicores (² = 26.5, P<.001) on the one hand and the presence of new mutations in the RYR1 gene (² = 19.0, P<.001) on the other hand. This remarkably high occurrence of multiminicores in an MHS family is uncommon, and genetic analyses indicate that the association between multiminicores and MHS is linked to a novel R2656W and T2787S substitution present on the same allele of the RYR1 gene.

Conclusions  These results indicate that multiminicore lesions are observed in MHS patients with neither clinical signs related to multiminicore disease nor histological features of congenital myopathies. These multiminicore lesions may be secondary to mutations in the RYR1 gene. As a consequence, these patients must be distinguished from patients with multiminicore disease and from other MHS patients for whom multiminicores are not observed.

From the Centre de Résonance Magnétique Biologique et Médicale, Faculté de Médecine (Drs Guis, Bendahan, Kozak-Ribbens, Mattei, and Cozzone), and Service d'Anatomie-Pathologie et de Neuropathologie, Hôpital de la Timone (Drs Figarella-Branger and Pellissier), Marseille, France; and Laboratoire de Biochimie A, Hôpital de la Tronche, Grenoble, France (Drs Monnier and Lunardi). Drs Guis and Figarella-Branger should both be considered first authors because they contributed equally to this work.

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