Distal myopathies: from clinical classification to molecular understanding

Abstract

The distal myopathies are a group of rare diseases that in the past were primarily classified by eponyms. Classification criteria were the beginning of the disease, the distribution of the muscle weakness, the course of the disease, the prognosis, and histological changes in the muscle biopsy. Advances of molecular genetics have identified various genes and mutations in many of the clinical phenotypes. This led to modifications and extensions of the existing clinical classification. Our own study on 42 patients with distal myopathy including 15 patients from six families with matrin-3 mutation suggests that in distal myopathies (1) there seem to be no monogenetic classical phenotypes; (2) there are phenotypes with different genotypes and (3) phenotypes with genotypes that are usually associated with other than distal phenotypes. Some of these phenotypes could not be classified according to the traditional clinical classification. In matrin-3 associated myopathy most but not all patients had predominant distal weakness. Also in the initial families distal weakness myopathy was associated with vocal cord and pharyngeal weakness, this was observed in half of our patients. Three of 15 patients met the criteria of Welander-phenotype. The recent classification by Udd distinguishes major groups of myopathies based on age of onset, mode of inheritance, and morphological changes in muscle biopsy. In many but not all subforms of these major groups the genotype has been established so far.