Exome analysis identifies B rody myopathy in a family diagnosed with malignant hyperthermia susceptibility

Whole exome sequencing ( WES ) was used to determine the primary cause of muscle disorder in a family diagnosed with a mild, undetermined myopathy and malignant hyperthermia ( MH ) susceptibility ( MHS ). WES revealed the compound heterozygous mutations, p.Ile235Asn and p.Glu982Lys, in ATP2A1 , encoding the sarco(endo)plasmic reticulum Ca 2+ ATPase type 1 ( SERCA 1), a calcium pump, expressed in fast‐twitch muscles. Recessive mutations in ATP2A1 are known to cause Brody myopathy, a rare muscle disorder characterized by exercise‐induced impairment of muscle relaxation and stiffness. Analyses of affected muscles showed the absence of SERCA 1, but SERCA 2 upregulation in slow and fast myofibers, suggesting a compensatory mechanism that partially restores the diminished Ca 2+ transport in Brody myopathy. This compensatory adaptation to the lack of SERCA 1 Ca 2+ pumping activity within the muscle explains, in part, the mild course of disease in our patient. Diagnosis of MHS in this family was secondary to a loss of SERCA 1 due to disease‐associated mutations. Although there are obvious differences in clinical expression and molecular mechanisms between MH and B rody myopathy, a feature common to both conditions is elevated myoplasmic Ca 2+ content. Prolonged intracellular Ca 2+ elevation is likely to have led to MHS diagnosis in vitro and postoperative MH‐like symptoms in Brody patient.