GeneticdiseasesthatcausedisturbancesinCa++ homeostasisinskeletalmuscleincludemalignant hyperthermia, central core disease, andBrody’s disease. Malignanthyperthermiaisanautosomaldominanttraitthathaslife-threateningconsequencesincertainsurgicalinstances.AnestheticssuchashalothaneoretherandthemusclerelaxantsuccinylcholinecanproduceuncontrolledreleaseofCa++ fromtheSR,therebyresultinginskeletalmusclerigidity,tachycardia,hyperventilation,andhyperthermia.Thisconditionislethalifnottreatedimmediately.Therearecurrentlyaseriesoftests(involvingcontractileresponsesofmusclebiopsyspecimens)toassesswhetherapatienthasmalignanthyperthermia.Theincidenceofthisconditionisapproximately1per15,000childrenand1per50,000adultstreatedwithanesthetics.MalignanthyperthermiaistheresultofadefectintheSRCa++ releasechannel(RYR),whichbecomesactivatedinthepresenceoftheaforementionedanesthetics,causesthereleaseofCa++ intothemyoplasm,andhenceprolongsmusclecontraction(rigidity).ThedefectintheRYRisnotrestrictedtoasinglelocus.Insomecases,malignanthyperthermiahasbeenlinkedtoadefectintheDHPRoftheTtubule.
Centralcorediseaseisarareautosomaldominanttraitthatresultsinmuscleweakness,lossofmitochondriainthecoreofskeletalmusclefibers,andsomedisintegrationofcontractilefilaments.Itisoftencloselyassociatedwithmalignanthyperthermia,andsopatientswithcentralcorediseasearetreatedasthoughtheyaresusceptibletomalignanthyperthermiainsurgicalsituations.ItishypothesizedthatcentralcoresdevoidofmitochondriarepresentareasofelevatedintracellularCa++ secondarytoamutationintheRYR.ThelossofmitochondriaisthoughttooccurwhentheytakeuptheelevatedCa++ ,whichleadstomitochondrialCa++ overload.
Brody’sdiseaseischaracterizedbypainlessmusclecrampingandimpairedmusclerelaxationduringexercise.Whileanaffectedpersonrunsupstairs,forexample,musclesmaystiffenandtemporarilycannotbeused.Thisrelaxation myosin head to bind to the underlying actin (state b). Myosin next undergoes a conformational change termed “ratchet action” that pulls the actin filament toward the center of the sarcomere (state c). Myosin releases adenosine diphosphate (ADP) and inorganic phosphate during the transition to state c. Binding of ATP to myosin decreases the affinity of myosin for actin, thereby resulting in the release of myosin from the actin filament (state d). Myosin then partially hydrolyzes the ATP, and part of the energy in the ATP is used to recock the head and return to the resting state.