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Brody disease is a rare inherited myopathy due to reduced sarcoplasmic reticulum Ca(2+) ATPase (SERCA)1 activity caused by mutations in ATP2A1, which causes delayed muscle relaxation and silent cramps. So far the disease has mostly been diagnosed by measurement of SERCA1 activity. Since mutation analysis became more widely available, it has appeared that not all patients with reduced SERCA1 activity indeed have ATP2A1 mutations, and a distinction between Brody disease (with ATP2A1 mutations) and Brody syndrome (without ATP2A1 mutations) was proposed. We aim to compare the clinical features of patients with Brody disease and those with Brody syndrome and detect clinical features which help to distinguish between the two. In addition, we describe the Brody syndrome phenotype in more detail. We therefore performed a literature review on clinical features of both Brody disease and Brody syndrome and a cross-sectional clinical study consisting of questionnaires, physical examination, and a review of medical files in 17 Brody syndrome patients in our centre. The results showed that Brody disease presents with an onset in the 1st decade, a generalized pattern of muscle stiffness, delayed muscle relaxation after repetitive contraction on physical examination, and autosomal recessive inheritance. Patients with Brody syndrome more often report myalgia and experience a considerable impact on daily life. Future research should focus on the possible mechanisms of reduction of SERCA activity in Brody syndrome and other genetic causes, and on evaluation of treatment options.

We describe a new mutation in the tRNA(Ala) gene, a T-->C transition at nucleotide position 5628, in a 62-year-old woman with late onset chronic progressive external ophthalmoplegia, dysphagia and mild proximal myopathy. The mutation is heteroplasmic and disrupts a highly conserved A-U base pair within the anticodon stem of the tRNA(Ala). Cytochrome c oxidase-negative fibers harbor a significantly higher level of mutated mtDNA than cytochrome c oxidase-positive fibers. This is the first mutation in the tRNA(Ala) gene which satisfies accepted criteria for pathogenicity.

Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of immune-mediated muscle disorders characterized by muscle inflammation and weakness. They comprise inclusion body myositis (IBM), polymyositis (PM), juvenile dermatomyositis (JDM) and adult dermatomyositis (DM). Autophagic pathway impairment has been well documented in sporadic IBM, where it has been suggested to be responsible for the accumulation of multiple-protein aggregates, typical of the myopathy. The main candidates responsible for this impairment are suggested to be TLRs. We evaluated the autophagic process also in PM and DM, in particular the interaction between autophagosome maturation and innate immune system. LC3 and other autophagic molecules, together with TLR3, TLR4, HSP60 and HMGB1/2 were analyzed in IIM and control muscles by qPCR, immunohistochemistry and immunoblot. Myoblasts and myotubes from PM, DM and control muscle biopsies were analyzed to evaluate changes in TLR and HMGB1/2 expression after induction or inhibition of autophagy. Gene expression analysis showed a dysregulation of autophagy in all IIM subgroups. A tight correlation between autophagy and innate immunity in myopathic muscles compared to controls was highlighted by confocal microscopy; activation of stress response and the presence of bacterial infection were observed connected with an abnormal accumulation of autophagosomes in IIM myofibers. These findings demonstrate the involvement of the autophagic process in the pathogenesis of all subtypes of IIMs; it is not clear if this mechanism represents a consequence or a cause of the induction of immune response and inflammation. Autophagic machinery components might represent a possible target for new therapeutic approaches for IIM.

Frame-truncating mutations within the first five exons of the DMD gene typically do not result in Duchenne muscular dystrophy, but instead result in milder dystrophinopathy syndromes. This was first demonstrated in individuals carrying the c.9G > A (p.Trp3X) mutation, a North American founder allele associated with clinical severity ranging from a very mild Becker muscular dystrophy phenotype to a complete absence of symptoms. We have previously shown that the mild phenotype associated with this and similar 5’ exon mutations is due to alternative initiation of translation from methionines encoded in exon 6, a process mediated by the presence of a muscle-specific and glucocorticoid-inducible internal ribosomal entry site (IRES) found within exon 5. The resultant N-truncated dystrophin protein lacks the first calponin homology domain of the canonical actin binding domain 1. Nevertheless, it is highly functional, raising the possibility of the therapeutic use of this isoform. We hypothesized that disruption of the mRNA open reading frame via exon skipping – resulting in a downstream premature termination codon – would stimulate IRES utilization. The feasibility of this approach is supported by the recent identification of an asymptomatic patient harbouring an exon 2 deletion, and we designed U7snRNA vectors targeting exon 2 for use in both patient-derived cell lines and in a new DMD mouse model harbouring an exon 2 duplication. Both in vitro and in vivo we can stimulate IRES activity, and by combining exon-skipping and glucocorticoid treatment we are able to restore expression of a properly localized yet N-truncated dystrophin. These results not only provide evidence for the functionality of the dystrophin IRES – and, hence, for the presence of a novel N-truncated dystrophin isoform under yet to be clarified physiologic conditions – but also suggest that out-of-frame skipping is a promising therapeutic approach for DMD patients harbouring 5’ mutations.