Mutations in the DYSF gene lead to a complete or partial absence of the dysferlin protein in skeletal muscles and are at the origin of dysferlinopathies, a very heterogeneous group of rare autosomal recessive inherited neuromuscular disorders. A common clinical characteristic of all dysferlinopathy forms is a slowly progressive muscle wasting and weakness with variable distribution and severity, in association with highly increased serum CK levels (see the freely available review Urtizberea et al. 2008).
Different phenotypes have been reported for dysferlinopathies:
• Miyoshi myopathy (MM, MIM: 254130) is characterized by late teens or early adult onset and mainly affects the posterior distal calf muscles. Over time, muscle weakness can extend to pelvic muscles and to the upper limbs.
• Limb-girdle muscular dystrophy, type 2B (LGMD2B, MIM: 253601). LGMDs are characterized by a specific wasting of the proximal pelvic and shoulder girdle muscles. The LGMD2B form usually starts with increased muscle weakness in the late teens. Over time, distal muscles in the lower legs can be affected as well.
• Distal myopathy with anterior tibial onset (DMAT, MIM: 606768) (also referred to as distal anterior compartment myopathy -DACM) shows clinical signs similar to Miyoshi myopathy with the anterior tibial muscles being the first muscles to be affected. After progression of the disease, weakness extends to the posterior compartment of the lower legs (Illa et al. 2001).
• Proximodistal forms (PD) of dysferlinopathy (Ueyama et al. 2002 and Nguyen et al. 2007). While MM and LGMD2B represent 50% of all patients, as many as 35% of patients present at onset with a mixed phenotype combining proximal and distal myopathy of the lower limbs.
• More recently a congenital muscular dystrophy phenotype has also been described in one family, with patients showing weakness in proximal lower limbs and neck flexor muscles at birth (Paradas et al. 2009).
• Isolated and long-lasting hyperCKemia.
• Elevated CK levels and minimal clinical manifestations have also been anecdotally described in a few heterozygotes (Illa et al. 2007).
Age of onset and severity are highly variable, ranging from prolonged asymptomatic in adulthood to rapid worsening of the disease over a few years leading to severe functional disability. In addition, dysferlinopathies are also characterized by a high intrafamilial clinical heterogeneity (Ueyama et al. 2002). In all cases the genotype-phenotype relationship has always remained difficult to define.