Abstract:
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RYR1-related diseases include malignant hyperthermia and structural congenital myopathies among which the most common are core myopathies. Other forms such as centronuclear myopathies and myopathies with predominance of type I fibres or with disproportion of type fibres were also evidenced although less frequently, in patients. However it is not clear whether some of these later forms can represent an early expression of core myopathies. We have analyzed 299 unrelated MH patients. Limited exonic screening has allowed the identification a dominant mutation in 50 % of the families. When performed, histological investigations have revealed the presence of cores in a significant number of MH patients. This caused some confusion as this type of patients were originally referred as MH/CCD patients although they did not present with myopathic symptoms. We have investigated 294 unrelated patients presenting with structural congenital myopathies ranging from congenital onset with severe phenotype to milder non or slowly progressive forms.191 patients were sporadic cases. Muscle biopsies were characterized by core lesions showing highly variable localisation, size, length and number within the muscle fibres suggesting a continuum from classical unique central cores to multiple small diffuse cores. A dominant mutation was identified in 70 cases while 37 families harboured two recessive mutations. A single mutation was also characterized in 23 other families with unknown AD/AR status. Mapping of the mutations showed a different distribution depending on the nature of diseases and inheritance. Noticeably, more than 40% of the recessive mutations led to silencing of allele expression through various mechanisms. Interestingly, a second mutation has been identified after extensive analysis of the RYR1 gene in sporadic cases originally classified as dominant myopathies. This was of importance for the genetic counseling in these families. Myopathic phenotypes will be discussed in relation with the nature of the RYR1 mutations.
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