The Clinical Outcome Study for dysferlinopathy

Abstract

Objective:To describe the baseline clinical and functional characteristics of an international cohort of 193 patients with dysferlinopathy.Methods:The Clinical Outcome Study for dysferlinopathy (COS) is an international multicenter study of this disease, evaluating patients with genetically confirmed dysferlinopathy over 3 years. We present a cross-sectional analysis of 193 patients derived from their baseline clinical and functional assessments.Results:There is a high degree of variability in disease onset, pattern of weakness, and rate of progression. No factor, such as mutation class, protein expression, or age at onset, accounted for this variability. Among patients with clinical diagnoses of Miyoshi myopathy or limb-girdle muscular dystrophy, clinical presentation and examination was not strikingly different. Respiratory impairment and cardiac dysfunction were observed in a minority of patients. A substantial delay in diagnosis was previously common but has been steadily reducing, suggesting increasing awareness of dysferlinopathies.Conclusions:These findings highlight crucial issues to be addressed for both optimizing clinical care and planning therapeutic trials in dysferlinopathy. This ongoing longitudinal study will provide an opportunity to further understand patterns and variability in disease progression and form the basis for trial design.

The genetic profile of dysferlinopathy in a cohort of 209 cases: Genotype–phenotype relationship and a hotspot on the inner DysF domain

“…Korea (Shin et al, 2015), China (Jin et al, 2016;Xi et al, 2014), Iran (Fatehi et al, 2015), France (Krahn et al, 2009), as well as from an international multicenter study (Harris et al, 2016), demonstrating the genetic character in each population including the existence of have been reported to be located deep in intronic regions (Dominov et al, 2019). Hence, RNA analysis combined with genomic DNA will be needed to characterize undiagnosed cases.…”

Diltiazem improves contractile properties of skeletal muscle in dysferlin-deficient BLAJ mice, but does not reduce contraction-induced muscle damage

“…Since a large percentage of patients with dysferlinopathies are known to have athletic prowess during the years prior to onset of muscle weakness, it is not uncommon for patients to exercise more, when they start developing symptoms (Harris et al. ; Moore et al. ; Jain Foundation Inc., ).…”

“…Our studies also serve to emphasize the value of muscle-injury-prevention in patients with dysferlinopathies. Since a large percentage of patients with dysferlinopathies are known to have athletic prowess during the years prior to onset of muscle weakness, it is not uncommon for patients to exercise more, when they start developing symptoms (Harris et al 2016;Moore et al 2018;Jain Foundation Inc., 2017). The evidence so far suggests that, like most other muscular dystrophies (other than some congenital muscular dystrophies), dysferlinopathies are progressive conditions, and therefore, cannot be reversed by exercise.…”

“…; Harris et al. ). Dysferlinopathies are caused by mutations in the dysferlin (DYSF) gene, resulting in complete or partial absence of the protein dysferlin (Liu et al.…”

“…Dysferlin-linked muscular dystrophies (a.k.a. dysferlinopathies) are a group of inherited diseases that cause progressive skeletal muscle weakness and wasting, with onset in the late-teen years (Urtizberea et al 2008;Harris et al 2016). Dysferlinopathies are caused by mutations in the dysferlin (DYSF) gene, resulting in complete or partial absence of the protein dysferlin (Liu et al 1998).…”