Cardiac and pulmonary findings in dysferlinopathy: A 3‐year, longitudinal study

Abstract

Introduction/Aims: There is debate about whether and to what extent either respiratory or cardiac dysfunction occurs in patients with dysferlinopathy. This study aimed to establish definitively whether dysfunction in either system is part of the dysferlinopathy phenotype. Methods: As part of the Jain Foundation's International Clinical Outcome Study (COS) for dysferlinopathy, objective measures of respiratory and cardiac function were collected twice, with a 3-y interval between tests, in 188 genetically confirmed patients aged 11-86 y (53% female). Measures included forced vital capacity (FVC), electrocardiogram (ECG), and echocardiogram (echo).Results: Mean FVC was 90% predicted at baseline, decreasing to 88% at year 3. FVC was less than 80% predicted in 44 patients (24%) at baseline and 48 patients (30%) by year 3, including ambulant participants. ECGs showed P-wave abnormalities indicative of delayed trans-atrial conduction in 58% of patients at baseline, representing a risk for developing atrial flutter or fibrillation. The prevalence of impaired left ventricular function or hypertrophy was comparable to that in the general population.Discussion: These results demonstrate clinically significant respiratory impairment and abnormal atrial conduction in some patients with dysferlinopathy. Therefore, we recommend that annual or biannual follow-up should include FVC measurement, enquiry about arrhythmia symptoms and peripheral pulse palpation to assess cardiac rhythm. However, periodic specialist cardiac review is probably not warranted unless prompted by symptoms or abnormal pulse findings.

Epidemiology and natural history in 101 subjects with FKRP-related limb-girdle muscular dystrophy R9. The Norwegian LGMDR9 cohort study (2020)

“…Perhaps the clearest overlap is with the sarcoglycanopathies [ 39 , 40 ], although these tend to show earlier loss of ambulation [39] . In contrast, dilated cardiomyopathy and ventilatory needs are uncommon in subtype R1 [ 41 , 42 ], R2 [43] and R12 [44][45][46] . Furthermore, anoctaminopathy and dysferlinopathy are associated with a later onset; median 35 years (common type) [44] and 19 years [47] , respectively.…”

On the role of dysferlin in striated muscle: membrane repair, t‐tubules and Ca2+ handling

“…Therefore, given that dysferlin has been implicated in multiple mechanisms known to support skeletal muscle physiology, it is clear why dysferlin mutations primarily manifest in skeletal myopathy (Bushby et al., 1998; Liu et al., 1998). However, clinical observations showed that some dysferlinopathy patients presented with a cardiac phenotype (Moore et al., 2022; Nishikawa et al., 2016; Wenzel et al., 2007). Like skeletal muscle, cardiac muscle contains extensive t‐tubule networks with associated EC coupling proteins, which facilitate the fast and synchronous rise in intracellular Ca 2+ necessary for a healthy heartbeat (Fig.…”

Gene-edited primary muscle stem cells rescue dysferlin-deficient muscular dystrophy

“…9,10 Dysferlin deficiency leads to progressive skeletal muscle degeneration and atrophy. 11,12 Restoring dysferlin expression is likely the only curative solution and clustered regularly interspaced short palindromic repeats – associated protein 9 (CRISPR/Cas9) methodology would have the greatest utility.…”