What causes central core disease (CCD)?

Updated: Mar 11, 2019
  • Author: Matthew Harmelink, MD; Chief Editor: Amy Kao, MD  more...
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Answer

Central core disease (CCD) is due to either autosomal dominant or recessive mutations in the ryanodine receptor (RYR1) gene.

The typical presentation of this congenital myopathy is in an autosomal dominant fashion with onset at birth or early childhood. Typically, patients present with nonprogressive limb weakness, mild facial weakness, and hypotonia. As with other congenital myopathy, hypotonia, arthrogryposis, and a history of decreased fetal movements can be common.

However, more severe forms can present with neonatal akinesia syndromes and severe respiratory distress and feeding difficulties after birth. On the other end of the spectrum, a late-onset, slowly progressive limb-girdle-type disease, or even malignant hyperthermia in an otherwise asymptomatic patient, have been known presentations.

CCD is usually transmitted in an autosomal dominant fashion with variable expression and incomplete penetrance (rare autosomal recessive and sporadic cases) and is almost always due to a mutation in the ryanodine receptor 1 (RYR1). CCD has been reported in a few families with familial hypertrophic cardiomyopathy due to a mutation in the cardiac myosin b-heavy chain.

Mutations (most often missense) in RYR1 can cause CCD, as described above, malignant hyperthermia susceptibility, or both. Mutations in RYR1 can also cause core-rod myopathy, multiminicore myopathy, and rare cases of centronuclear myopathy.

RYR1 is the calcium channel on the sarcoplasmic reticulum (SR) that releases calcium into the muscle cytoplasm during excitation-contraction coupling, thereby allowing calcium to interact with muscle contractile proteins. It exists as a tetrameric structure and associates with several other proteins including the dihydropteridine receptor, calmodulin, and calsequestrin. Ordered two-dimensional arrays are formed at the junctional terminal cisternae, in which each of the 4 subunits in every other RYR1 tetramer is physically coupled to a dihydropteridine receptor, and each RYR1 tetramer is physically coupled to 4 other tetramers.

One hypothesis proposed to explain malignant hyperthermia suggests that it results from abnormal repetitive Ca2+ cycling, characterized by spontaneous Ca2+ release and reuptake triggered by volatile anesthetics, stress, or elevated temperature. [28]

  • The basis for this hypothesis is that  RyR1 mutations cause a lowered threshold for store overload-induced Ca 2+ release (SOICR). SOICR is the process by which there is a rapid release of Ca 2+ store when the size of the Ca 2+ store reaches a certain threshold triggered by luminal Ca 2+ concentration. (This sensor mechanism is in addition to a cytosolic Ca 2+ sensor).
  • Halothane further lowers the mutation-lowered SOICR threshold causing RYR1 to be triggered to open when the free luminal Ca 2+ level overshoots its lowered SOICR threshold. Elevated cytosolic Ca 2+ then triggers muscle contraction and hypermetabolism.

Other proposed mechanisms for malignant hyperthermia include inter-domain unzipping of RYR subunits, changes in RYR redox status, increased rate of Ca2+ entry into the sarcoplasmic reticulum lumen following adrenergic stimulus, changes in RyR phosphorylation status and elevated enzymatic Ryr function.

A hypothesis to explain phenotypic variability, variable penetrance and core formation is based on nonuniformity of the Ca2+ release unit48 The Ca2+ release unit refers to the two-dimensional array of RyR1 molecules described above.

Because CCD is typically associated with heterozygous missense mutations, both wild type and mutant subunits are expressed. Random combination of subunits into RyR1 tetramers would produce 16 possible arrangements with 6 variants (homotetrameric wild type channels [1], homotetrameric mutant channels [1] and heterotetrameric channels in arrangements 3:1 [4]; 1:3 [4], 2:2 (side by side-[4]); 2:2 (diagonal-[2]).

The random association of different subunits within each tetramer followed by the random association of the 16 different types of tetramers within each Ca2+ release unit would set the stage for nonuniformity of Ca2+ release. This could also lead to nonuniformity of contraction among sarcomeric domains and subsequently to nonuniformity within myofibrils, myofibers, and muscle fasciculi ultimately, resulting in variable degrees of weakness that characterize RyR1-related myopathies.

Cores could be formed due to discordant contraction between adjacent myofibers. This would cause physical stress that could lead to tearing and shearing between myofibrils as well as displacement of mitochondria and the sarcotubular system. Eventually, small foci of damage would coalesce and manifest as cores.


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