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

Abstract

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 Ca2+ ATPase type 1 (SERCA1), 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 SERCA1, but SERCA2 upregulation in slow and fast myofibers, suggesting a compensatory mechanism that partially restores the diminished Ca2+ transport in Brody myopathy. This compensatory adaptation to the lack of SERCA1 Ca2+ 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 SERCA1 due to disease-associated mutations. Although there are obvious differences in clinical expression and molecular mechanisms between MH and Brody myopathy, a feature common to both conditions is elevated myoplasmic Ca2+ content. Prolonged intracellular Ca2+ elevation is likely to have led to MHS diagnosis in vitro and postoperative MH-like symptoms in Brody patient.

Brody myopathy demonstrates a pseudo‐increment on repetitive nerve stimulation

“…Electrodiagnostic examination was carried out in 10 patients using standard techniques and standardized provocative tests . Briefly, CMAPs were evoked by supramaximal nerve stimulation and recorded using skin electrodes.…”

“…Relaxation is then triggered by the pumping of calcium from the cytoplasm back to the sarcoplasmic reticulum, through the sarco/endoplasmic calcium adenosine triphosphatase (SERCA) pumps. There are two main SERCA isoforms in mammalian cells, the major one being SERCA1, or ATP2A1, expressed in fast‐twitch (type 2) skeletal muscle fibers . Recessive mutations in the ATP2A1 gene may be responsible for Brody myopathy (BM), a disease characterized by exercise‐induced impaired muscle relaxation and stiffness .…”

Excitation-Contraction Coupling Alterations in Myopathies

“…Mutations in the ATP2A1 gene are responsible for the absence of SERCA1 protein (non-sense or missense mutations that destabilize the protein) or affect calcium reuptake by SERCA1 into SR after contraction, altering muscle relaxation and, therefore, impacting subsequent muscle contractions. In the presence of two null alleles, it has been shown that upregulation of the SERCA2 isoform could explain the mild phenotype with regard to the central role of calcium reuptake in SR during the excitation-contraction coupling [51]. In addition, an increase in cytosolic calcium has been detected in the muscles of the patient, which could explain positive testing for malignant hyperthermia [51].…”

“…In the presence of two null alleles, it has been shown that upregulation of the SERCA2 isoform could explain the mild phenotype with regard to the central role of calcium reuptake in SR during the excitation-contraction coupling [51]. In addition, an increase in cytosolic calcium has been detected in the muscles of the patient, which could explain positive testing for malignant hyperthermia [51]. …”

Malignant Hyperthermia

“…Muscular conditions other than abnormalities of excitation-contraction coupling may be responsible for the adverse reaction to anesthetics experienced by the proband [13,14]. There is continued discussion regarding the MH risk in patients with myopathy or other diseases such as one of the myotonias (see http://www.mhaus.org/healthcare-professionals/be-prepared/associatedconditions).…”