Portrait of Dysferlinopathy: Diagnosis and Development of Therapy

Abstract

Dysferlinopathy is a disease caused by a dysferlin deficiency due to mutations in the DYSF gene. Dysferlin is a membrane protein in the sarcolemma and is involved in different functions, such as membrane repair and vesicle fusion, T-tubule development and maintenance, Ca2+ signalling, and the regulation of various molecules. Miyoshi Myopathy type 1 (MMD1) and Limb–Girdle Muscular Dystrophy 2B/R2 (LGMD2B/LGMDR2) are two possible clinical presentations, yet the same mutations can cause both presentations in the same family. They are therefore grouped under the name dysferlinopathy. Onset is typically during the teenage years or young adulthood and is characterized by a loss of Achilles tendon reflexes and difficulty in standing on tiptoes or climbing stairs, followed by a slow progressive loss of strength in limb muscles. The MRI pattern of patient muscles and their biopsies show various fibre sizes, necrotic and regenerative fibres, and fat and connective tissue accumulation. Recent tools were developed for diagnosis and research, especially to evaluate the evolution of the patient condition and to prevent misdiagnosis caused by similarities with polymyositis and Charcot–Marie–Tooth disease. The specific characteristic of dysferlinopathy is dysferlin deficiency. Recently, mouse models with patient mutations were developed to study genetic approaches to treat dysferlinopathy. The research fields for dysferlinopathy therapy include symptomatic treatments, as well as antisense-mediated exon skipping, myoblast transplantation, and gene editing.

The Dysferlinopathies Conundrum: Clinical Spectra, Disease Mechanism and Genetic Approaches for Treatments

“…Elevated CK levels along with muscle weakness, particularly in distal regions, historically served as a key diagnostic criterion for diagnosing most of the recessive muscular dystrophies, and dysferlinopathies were no exception [ 22 , 31 , 43 ]. However, with advancements in diagnostic modalities, the reliance on CK levels as a diagnostic metric for dysferlinopathy has receded [ 22 , 23 , 43 ].…”

“…Structurally, it is composed of seven lipid-responsive C2 domains, an inner DysF (iDysF) domain, two Fer domains, and a transmembrane anchor—featuring a very sophisticated architecture [ 9 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. Interactome studies reveal that dysferlin has synergistic interactions with proteins, e.g., affixin, caveolin-3, and calpain-3, which are all crucial for muscle membrane repair and integrity, thus broadening its role in muscle cell function [ 21 , 22 , 23 ]. Dysferlin is almost ubiquitously expressed but is most abundant in muscular structures, e.g., skeletal and cardiac muscles [ 9 , 24 ].…”

“…Clinically, dysferlinopathies manifest in multiple forms, including Miyoshi myopathy (MM), limb-girdle muscular dystrophy recessive type 2 (LGMDR2, also known as limb-girdle muscular dystrophy type 2B or LGMD2B), and the less common distal myopathy with anterior tibial onset (DMAT) [ 2 , 6 , 22 , 28 , 29 , 30 , 31 ]. Onset is typically in adolescence or early adulthood, with significant difficulties including tiptoe standing or stair climbing [ 4 , 23 , 31 , 32 , 33 , 34 ]. While muscle weakness tends to progress slowly over years, some rare cases report a rapid decline in mobility within approximately 5 years [ 34 ].…”

“…While muscle weakness tends to progress slowly over years, some rare cases report a rapid decline in mobility within approximately 5 years [ 34 ]. Modern medical modalities—including MRI, electromyography, and histopathological investigations—provide important insights into muscle fiber variations, necrosis, regeneration, and the accumulation of fat and connective tissue [ 23 ].…”

“…Historically, although dysferlinopathies have been under study since their initial documentation in Japan in the 1970s, our understanding of the molecular intricacies of these conditions remains elusive, largely due to the incomplete understanding of dysferlin’s core functions [ 22 , 35 , 36 , 37 , 38 ]. Nonetheless, contemporary breakthroughs, especially the development of dysferlin-deficient mouse models, offer important insights and spearhead potential therapeutic strategies [ 22 , 23 , 35 ]. Emerging therapeutic approaches span from anti-sense-mediated exon skipping to myoblast transplantation and avant-garde gene therapies.…”