What are dysferlinopathies?

Dysferlinopathies are a group of autosomal recessive muscular dystrophies caused by the loss of functional dysferlin protein due to mutations in the dysferlin gene. “Autosomal recessive” means that for the disease to occur, both copies of the dysferlin gene must contain a mutation. This usually occurs by inheriting one mutation from each parent. Since the term “dysferlinopathy” is a genetic diagnosis, it should only be used when pathogenic mutations in dysferlin have been identified. Although it is clear that dysferlinopathies are rare diseases, the exact incidence has not yet been determined.

Dysferlinopathies are characterized by progressive muscle wasting and are clinically divided into four main types:

Limb-Girdle Muscular Dystrophy type 2B (LGMD2B),
Miyoshi Myopathy,
Distal Myopathy with Anterior Tibial onset (DMAT),
Proximodistal weakness.

The specific clinical diagnosis given usually depends on the initial pattern of muscle involvement at diagnosis. For example, a diagnosis of LGMD2B is given when weakness initially presents in the proximal muscles (thighs and upper arms), while a diagnosis of Miyoshi myopathy is given when weakness initially presents in the distal muscles (calves and lower arms). It is not known how defects in the dysferlin gene give rise to all of these different clinical manifestations. However, patients normally begin to experience a combination of symptoms (i.e. weakness in both the proximal and distal limbs) as the disease progresses and in later stages, the symptoms are quite similar with overlap between the different types.

The symptoms of dysferlinopathies usually manifest in early adulthood between the ages of 16 and 25 and primarily affect the skeletal muscle of the limbs and the limb girdles (hips and shoulders), leaving critical muscles such as the heart and diaphragm largely unaffected. The rate of progression is fairly slow compared to most other types of muscular dystrophy; the majority of dysferlinopathy patients become non-ambulant within 10–20 years of diagnosis, but life expectancy is normal. However, there is a large amount of variability in the age of onset and progression of the disease.