Founder mutations exist in only a few small communities (6, 9, 10). Dysferlinopathy can be diagnosed mainly by Western blotting and, in fact, although the Trametinib clinical diagnostic process by which dysferlinopathy is diagnosed is variable, most laboratories still rely on the diagnosis by muscle immunoblotting as the most reliable method, versus immunohistochemistry (11-13). Some laboratories carry

out protein testing on monocytes as an alternative screening methodology (14). The gold standard for dysferlinopathy diagnosis is however Inhibitors,research,lifescience,medical DNA testing, with sequencing carried out in a small number of laboratories in Europe and the USA (7, 17). A limitation of all LGMD2B studies however is that, with few exceptions, long-term follow-up data are not presented and data on clinical progression are collected in different ways, making precise comparisons between their conclusions difficult. Klinge et al. Inhibitors,research,lifescience,medical (5, 8) have observed that a unique

finding within the spectrum of muscular dystrophies is that the majority of patients with dysferlin deficiency appear to have good muscle strength before onset of symptoms, leading to good performance at sports or to the ability to cope well with physically demanding activities; 53% of the patients were very active in sports before onset of clinical symptoms,which makes the clinical course of dysferlinopathy unusual and provides Inhibitors,research,lifescience,medical a challenge to understanding the underlying pathogenesis in this disease. Material and methods Natural history Recently, two studies have addressed more systematically the topic of the natural history of dysferlinopathy. A study Inhibitors,research,lifescience,medical of 9 genetically confirmed LGMD2B and MM patients studied over 18 months, demonstrated a significant decline in muscle strength in a set of muscle groups measured by manual muscle testing, and in knee flexion Inhibitors,research,lifescience,medical measured by quantitative muscle testing, accompanied by a detectable deterioration on MRI in biceps femoris and tibialis posterior (15). It is likely that in dysferlinopathy there are changes detectable

with time that either could address the design of future clinical trials, but the optimal measurements have yet to be defined representing the entire clinical spectrum of this diverse disease group. Aims of the study The primary aims of this study are the following: To describe a cohort of patients with dysferlinopathy in terms of clinical, functional, strength and quality of life assessments, as well as for MRI results, and to explore associations between these assessments and gender, age, clinical distribution of muscle involvement/ mode of presentation, physical activity (in sports) versus non active prior to onset (cut-off 1000 hours) relationship of onset and deterioration. To describe changes over time in these parameters over a eight year period and define the outcome measures capable of capturing this information most reliably.