Résumé :
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Central core disease (CCD) is one of the most common congenital myopathies and characterized by predominantly central areas of reduced oxidative stain ("central cores") on muscle biopsy. CCD typically presents in infancy with hypotonia and motor developmental delay and features predominantly proximal weakness pronounced in the hip girdle; orthopaedic complications are common and malignant hyperthermia susceptibility (MHS) is a frequent complication. CCD and MHS are allelic conditions both due to mutations in the skeletal muscle ryanodine receptor (RYR1) gene, encoding the principal skeletal muscle sarcoplasmic reticulum calcium release channel (RyR1). Whilst dominant C-terminal RYR1 mutations, namely those concerning exons 100 - 102, are closely associated with features of typical CCD, recessive inheritance and dominant mutations affecting other domains of this large gene have been implicated in a much wider range of clinical and pathological phenotypes including subgroups of Multi-minicore Disease (MmD) and cases of centronuclear myopathy (CNM). Extraocular muscle involvement, not observed in typical CCD but prevalent in distinct subgroups of MmD, has been recently associated with marked RYR1 depletion due to either epigenetic allele silencing or RYR1 null mutations. The diagnosis of typical CCD is based on the presence of suggestive clinical findings and central cores on muscle biopsy, but a characteristic pattern of selective involvement on muscle MRI may suggest RYR1 involvement also in cases with more unusual features or equivocal histopathological findings. Initial mutational hotspot analysis is recommended in typical CCD but screening of the entire RYR1 coding sequence may be required in atypical cases. The main pathogenetic mechanisms implicated in typical CCD are altered excitability ("Excitation-contraction uncoupling hypothesis") and changes in calcium homeostasis ("Leaky channel hypothesis") within muscle cells but may be distinct in other RYR1-related myopathies. Further evaluation of the precise molecular basis of these conditions may provide the basis for future rational pharmacological treatment.
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