These alterations,

which were less conspicuous and affected fewer fibres in younger patients, were nonetheless the right clue to direct molecular testing. Our data significantly enlarges also the spectrum of RYR1 mutations since; among the 13 variants identified, nine are novel (Table 2 and Figure 7b). Compound heterozygous mutations were identified in six unrelated patients and a homozygous mutation in patient 6. Compound missense mutations were present in five patients while amorphic/hypomorphic mutations leading to RyR1 depletion were found in two patients (patients 1 and 5). In six patients recessive inheritance was confirmed by familial studies. In patient 6 for whom parental samples were not available, familial consanguinity, homozygosity of the mutation and the absence of familial history were strongly suggestive of a recessive inheritance. Seven missense BMN 673 nmr variants were novel. All of them were absent in 200 unrelated controls and affected highly conserved residues. The p.Thr4709Met variant has been already reported in a recessive form of core myopathy

Selleckchem Dabrafenib [28] while the p.Arg3772Trp change has been identified as the single change in RYR1 in an MHS patient [30]. This last variant, which is clearly recessive with respect to the myopathy, could confer dominant MHS susceptibility. This could be also the case of the p.Arg2336Cys variant that mapped to the MH2 domain of the protein, a hot spot for malignant hyperthermia mutations, and whose position has already been involved in a malignant hyperthermia-causing mutation (Arg2336His) [30]. Most of the variants present in this study were located in the cytoplasmic PAK6 region spanning from the MH2 domain to the Ca2+ pore domain whose functions remain mostly unknown.

Moreover, the pathophysiological pathways associated with recessive missense mutations in RYR1 are generally unknown and are likely to be mutation specific [38]. No malignant hyperthermia reactions were documented in these patients or among their relatives; however, in vitro contracture testing was not carried out in this series. Nevertheless, awareness about the potential risk of MHS is advisable before affected patients or their possible carrier relatives. Patient 1 was compound heterozygous for a null mutation (c.8342_8343delTA) on one allele and for a hypomorphic splicing mutation (c.10348-6C>G) associated with a missense variant (p.Val4842Met) on the second allele. Only a low amount of Met4842 mutant RyR1 protein was detected in muscle biopsy. Interestingly, a low amount of Met4842-RyR1 protein has previously been observed in two affected sisters who were compound heterozygous for the same missense and other null mutations [c.10348-6C>G, p.Val4842Met] and a c.7324-1G>T [19]. They also presented a severe neonatal form of congenital myopathy. In contrast, patient 6 was homozygous for the hypomorphic c.8692+131G>A mutation.