Dysferlinopathies: Clinical and genetic variability

Abstract

Dysferlinopathies are a clinically heterogeneous group of diseases caused by mutations in the DYSF gene encoding the dysferlin protein. Dysferlin is mostly expressed in muscle tissues and is localized in the sarcolemma, where it performs its main function of resealing and maintaining of the integrity of the cell membrane. At least four forms of dysferlinopathies have been described: Miyoshi myopathy, limb‐girdle muscular dystrophy type 2B, distal myopathy with anterior tibial onset, and isolated hyperCKemia. Here we review the clinical features of different forms of dysferlinopathies and attempt to identify genotype–phenotype correlations. Because of the great clinical variability and rarety of the disease and mutations little is known, how different phenotypes develop as a result of different mutations. However, missense mutations seem to induce more severe disease than LoF, which is typical for many muscle dystrophies. The role of several specific mutations and possible gene modifiers is also discussed in the paper.

Miyoshi Muscular Dystrophy Due to Novel Splice Site Variants in DYSF Gene

“…[6][7][8] The absence of a clear correlation between phenotype and genotype even exists within first degree family members. 2 Here, we describe a teenage girl with MMD phenotype due to novel splice site variants in the DYSF gene.…”

“…The phenotypic spectrum of dysferlinopathy includes Miyoshi muscular dystrophy (MMD) or Miyoshi myopathy, limb-girdle muscular dystrophy type R2 (LGMDR2, previously designated as LGMD2B), distal myopathy with anterior tibial onset (DMAT), and isolated hyperCKemia (elevated serum creatinine kinase). 1 , 2 MMD is characterized by muscle weakness and atrophy predominantly affecting the calf muscles (gastrocnemius and soleus muscles). Patients typically present with difficulties walking or standing on tiptoes.…”

“…Dysferlin is critical for muscle repair as well as for maintaining the integrity of the muscle membrane. 2 The diagnosis of dysferlinopathy is established in a patient when there is typical phenotype associated with biallelic pathogenic variants in DYSF . Pathological assessment of dysferlinopathy by immunohistochemistry and immunoblotting using anti-dysferlin antibodies commonly reveals an absence or deficiency of dysferlin.…”

“… 6 – 8 The absence of a clear correlation between phenotype and genotype even exists within first degree family members. 2 …”

“…Serum CK level can be highly elevated (typically between 5000 and 20000 IU/L) in dysferlinopathy. 1,2 Cardiac and pulmonary involvement have been noted in some patients with dysferlinopathy. 1,3 The DYSF gene that encodes dysferlin is located at the 2p13.2 locus.…”