Progress and challenges in diagnosis of dysferlinopathy

Abstract

Dysferlin-deficient limb girdle muscular dystrophy type 2B, distal Miyoshi myopathy, and other less frequent phenotypes are a group of recessive disorders called dysferlinopathies. They are characterized by wide clinical heterogeneity. To diagnose dysferlinopathy, a clinical neuromuscular workup, including electrophysiological and muscle imaging investigations, is essential to support subsequent laboratory testing. Increased serum creatine kinase levels, distal or proximal muscle weakness, and myalgia with onset in the second or third decades are the main clinical features of the disease. In muscle biopsies, severe dysferlin deficiency by immunoblot or its abnormal localization by immunohistochemistry are the gold standard, as they have a high diagnostic value. Dysferlin testing on monocytes is a valuable alternative to muscle immunoblotting. Molecular techniques for gene mutation detection, such as next generation sequencing, have improved the genetic diagnosis, which is crucial for treatment and genetic counselling. Muscle Nerve 54: 821-835, 2016.

Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients

“…LGMD have more than 30 different subtypes linked to specific gene loci, which manifest in very overlapping and heterogeneous phenotypes 1, 2, 3. This is likely the result of a tight link between associated muscle proteins within the sarcomere‐sarcolemma‐sarcoplasm‐extracellular‐matrix network (Fig.…”

Novel duplication mutation of the DYSF gene in a Pakistani family with Miyoshi Myopathy

“…The rate of progression can be quite variable with some individuals progressing rapidly over a few years to being non-ambulatory, however one-third of affected cases were found wheelchair bound after 10 years of onset 21. Katz et al22 described patients with a Miyoshi phenotype that did not have a primary dysferlinopathy. These patients differed from those with dysferlinopathy by their later age of onset (usually after 30 years of age) and discreetly raised serum CK level 22.…”

“…Katz et al22 described patients with a Miyoshi phenotype that did not have a primary dysferlinopathy. These patients differed from those with dysferlinopathy by their later age of onset (usually after 30 years of age) and discreetly raised serum CK level 22. In the present study, the clinical phenotype of Miyoshi myopathy is consistent with already reported phenotypes 4,8…”

“…Miyoshi myopathy (MM-MIM #254130) is a recessively inherited distal type of muscular dystrophy that presents at early adulthood. It clinically resembles other myopathies which involves the distal musculature, especially the muscles of lower legs 3. The mutations in the DYSF gene are a major cause of this disease 4.…”

A novel mutation in the DYSF gene in a patient with a presumed inflammatory myopathy

“…Dysferlin enhances calcium-mediated membrane fusion and sarcolemmal repair. 3 Targeted sequencing remains the gold standard in the precise diagnosis of dysferlinopathy. 2 Predominantly, proximal and distal muscles are implicated in dysferlinopathy which is most pronounced in the pelvic and shoulder girdle muscles (Limbgirdle muscular dystrophy type 2B, LGMD2B), or in distal parts of the legs involving either the gastrocnemius and soleus muscles in cases of Miyoshi myopathy (MM), or the anterior tibial muscles, as in distal anterior compartment myopathy (DACM).…”