Dominant LGMD2A: alternative diagnosis or hidden digenism?

Sir, We read with great interest the work recently published in Brain (Vissing et al. , 2016), in which the findings on limb girdle muscular dystrophy families from the UK, Denmark and Sweden are described. The cases showed a segregation pattern compatible with a dominant transmission. All the affected cases except for one share a heterozygous mutation in the CAPN3 gene previously described in recessive forms of limb girdle muscular dystrophy 2A (LGMD2A) (Richard et al. , 1997; Groen et al. , 2007). The mutation located within a common haplotype, suggests a common ancestral origin of these families, probably spread over a territory that shared a past Viking settlement as described for other mutations (Pliner et al. , 2014). The possibility of an alternative inheritance pattern of the same phenotype, associated with mutations in the same gene, is a well-known scenario in several myopathies. Besides the myotonia congenita, the collagen-related myopathies and the desminopathies referred to by the authors (Vissing et al. , 2016), there are also other well characterized examples such as RYR1 mutations associated to a central core myopathy (Klein et al. , 2012; Snoeck et al. , 2015) and mutations in the TTN gene responsible for dominant distal myopathy or a recessive variant of limb girdle muscular dystrophy (LGMD2J) (Hackman et al. , 2002, 2003; Udd et al. , 2005). Furthermore, in other recessive limb girdle muscular dystrophies, heterozygous carriers may present subclinical symptoms [creatine kinase (CK) elevations and/or alterations in MRI] associated with a reduction of the protein (Fischer et al. , 2003; Brummer et al. , 2005; Illa et al. , 2007). In this context, the understanding of this phenomenon in LGMD2A would be of great interest to shed some light on the knowledge of its pathophysiology, …