CACNA1S mutation associated with a case of juvenile-onset congenital myopathy

We present the case of an Italian family, whose affected members showed different degrees of muscle involvement and histopathological features compatible with congenital myopathies (CM), in the presence of a rare CACNA1S heterozygous mutation. CMs are a heterogeneous group of genetic muscle disorders ranging from severe and life-threatening neonatal manifestations to adult-onset milder forms [ [1] Schorling D.C. Kirschner J. Bönnemann C.G. Congenital muscular dystrophies and myopathies: an overview and update. Neuropediatrics. 2017; 48: 247-261 Crossref PubMed Scopus (28) Google Scholar ] and classified according to specific histological and ultrastructural muscle biopsy features [ [2] Ravenscroft G. Laing N.G. Bönnemann C.G. Pathophysiological concepts in the congenital myopathies: blurring the boundaries, sharpening the focus. Brain. 2015; 138: 246-268 Crossref PubMed Scopus (62) Google Scholar ]. Main clinical characteristics include hypotonia and weakness of proximal and facial muscles, often associated with respiratory failure and cardiac involvement [ [1] Schorling D.C. Kirschner J. Bönnemann C.G. Congenital muscular dystrophies and myopathies: an overview and update. Neuropediatrics. 2017; 48: 247-261 Crossref PubMed Scopus (28) Google Scholar ]. Disease course is slowly progressive and serum creatine-kinase (CK) levels are normal to mildly elevated [ [1] Schorling D.C. Kirschner J. Bönnemann C.G. Congenital muscular dystrophies and myopathies: an overview and update. Neuropediatrics. 2017; 48: 247-261 Crossref PubMed Scopus (28) Google Scholar ]. Over the last decades, many disease-causing genes have been associated with CMs [ [2] Ravenscroft G. Laing N.G. Bönnemann C.G. Pathophysiological concepts in the congenital myopathies: blurring the boundaries, sharpening the focus. Brain. 2015; 138: 246-268 Crossref PubMed Scopus (62) Google Scholar ]. Genes belonging to the CACNA1 family encode for tissue-specific alpha subunits of the voltage-gated calcium channel and have been associated with ataxias, hemiplegic migraine, blindness and deafness [ [3] Jurkat-Rott K. Lehmann-Horn F. The impact of splice isoforms on voltage-gated calcium channel alpha1 subunits. J. Physiol. 2004; 554: 609-619 Crossref PubMed Scopus (65) Google Scholar , [4] Wu J. Yan Z. Li Z. Yan C. Lu S. Dong M. et al. Structure of the voltage-gated calcium channel Cav1.1 complex. Science. 2015; 350: 2395 Crossref Scopus (206) Google Scholar ]. CACNA1S expressed in skeletal muscle encodes for Cav1.1 protein, the pore-forming subunit of the dihydropyridine receptor (DHPR) which is coupled to the Ryanodine receptor Ca2+-release channel-1 (RYR1) in muscle excitation-contraction [ [4] Wu J. Yan Z. Li Z. Yan C. Lu S. Dong M. et al. Structure of the voltage-gated calcium channel Cav1.1 complex. 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