Hypertrophic cardiomyopathy associated with damaging variants in the ALPK3 gene is a fairly recent discovery, and only a small number of patients have been described thus far. Here we present two additional patients with hypertrophic cardiomyopathy caused by biallelic variants in ALPK3. Genetic investigation was performed using a targeted gene panel consisting of known cardiomyopathy-associated genes and whole exome sequencing. The patients showed a large difference in the age of onset, and both presented with extracardiac features that are often seen in ALPK3 patients. The patient with the later onset showed milder extracardiac symptoms, such as decreased muscle tone and distal muscular dystrophy, but had fast progression of cardiac complications leading to the need of heart transplantation. This study further elucidates the variability of both symptoms and age of onset among these patients.

Even though genetic studies of individuals with neuromuscular diseases have uncovered the molecular background of many cardiac disorders such as cardiomyopathies and inherited arrhythmic syndromes, the genetic cause of a proportion of cardiomyopathies associated with neuromuscular phenotype still remains unknown. Here, we present an individual with a combination of cardiomyopathy and limb-girdle type muscular dystrophy where whole exome sequencing identified myoferlin (MYOF)—a member of the Ferlin protein family and close homolog of DYSF—as the most likely candidate gene. The disease-causative role of the identified variant c.[2576delG; 2575G>C], p.G859QfsTer8 is supported by functional studies in vitro using the primary patient’s skeletal muscle mesenchymal progenitor cells, including both RNA sequencing and morphological studies, as well as recapitulating the muscle phenotype in vivo in zebrafish. We provide the first evidence supporting a role of MYOF in human muscle disease.

Background and Objectives Infiltrating T cells is a typical histopathologic feature in muscles of patients with myositis and they play important roles in the disease development. In contrast to macrophages which usually can be reduced extensively after glucocorticoid (GC) treatment, T cells often persist, and the reasons are still unclear. Autophagy helps cells to survive under variable cellular stresses. In this context the effects of endogenous, cytosolic high mobility group box 1 (HMGB1) protein is of interest as HMGB1 can induce autophagy by binding Beclin1 (an upstream protein initiating autophagy) and thereby contribute to cell survival. In this study, we will investigate whether autophagy initiated by HMGB1-Beclin1 binding can contribute to T cell survival in the muscles of patients with myositis, and whether these homeostatic T cells are related to GC treatment resistance. Materials and Methods Muscle biopsies were obtained from poly- and dermato- myositis patients with no or limited clinical response to GC and from patients with good response to GC. Biopsies were investigated by immunohistochemistry for macrophages (CD163, CD68), T cells (CD3), HMGB1 and Beclin1. Computer image analysis was performed for each marker. Co-localization of HMGB1, Beclin1 and T cells was done by consecutive section staining and was confirmed by double fluorescence staining. Results Both HMGB1 and Beclin1 expression was detected in muscle tissue of patients with myositis; furthermore, the expression co-localised to the infiltrating T cells as demonstrated by consecutive section staining and double fluorescence staining. Moreover, the expression of autophagy marker Beclin1 correlated with both HMGB1 and T cells (p<0.05). In nine patients who are good responders to GC, the number of T cells in the muscles was decreased after treatment, and simultaneously the HMGB1 and Beclin1 expression was decreased. Analyses are ongoing on the non-responders. According to our hypothesis in these patients T cells will not be reduced as much as good responders after treatment and HMGB1 and Beclin1 expression will maintain at high levels too. Conclusions Markers of autophagy are present in the invading T cells in muscle tissue of myositis patients. Autophagy initiated by HMGB1-Beclin1 binding may contribute to T cell survival in the muscles of patients with myositis. And this homeostasis in T cells could be a factor that contributes to the GC resistance.