Challenges for the genetic screening in dysferlin deficiency--report of an instructive case and review of the literature.

The homozygous or compound heterozygous mutation of the alleles of DYSF gene causes dysferlinopathy resulting in limb girdle muscular dystrophy Type 2B (LGMD 2B) or Miyoshi myopathy. However, patients with only 1 (heterozygous) mutation on 1 allele are increasingly recognized. Based on the Leiden database (www.dmd.nl) among 257 different mutations resulting in dysferlin-deficient muscular dystrophy, pathogenic mutations were detected only on 1 allele in 45 cases, while the exons of the other allele did not show any pathological alterations. The relatively high number of these so-called heterozygous cases raises the question if present routine molecular techniques are sufficient alone for confirming the diagnosis of dysferlin deficiency. In fact, the heterogenous genetic background of the disease makes it impossible to make the correct diagnosis without Western blot of the muscle dysferlin. This paper presents the clinical, myopathological and molecular genetic results of a 30-year-old male with dysferlinopathy as an instructive case. The cDNA sequencing of the dysferlin gene revealed a single C5302T heterozygous mutation resulting in Arg1768Trp exchange. The paper highlights the importance of the protein analysis in the diagnosis of dysferlin deficiency, discusses the difficulties of the complete genomic analysis of the dysferlin gene alterations and the possible etiopathogenetic role of the noncoding DNA sequence of the dysferlin gene in dysferlin deficiencies.