Mesoangioblasts of inclusion-body myositis: a twofold tool to study pathogenic mechanisms and enhance defective muscle regeneration

Mesoangioblasts are a class of adult stem cells of mesoderm origin, potentially useful for the treatment of primitive myopathies of different etiology. Extensive in vitro and in vivo studies in animal models of muscular dystrophy have demonstrated the ability of mesoangioblast to repair skeletal muscle when injected intra-arterially. In a previous work we demonstrated that mesoangioblasts obtained from diagnostic muscle biopsies of IBM patients display a defective differentiation down skeletal muscle and this block can be corrected in vitro by transient MyoD transfection. We are currently investigating different pathways involved in mesoangioblasts skeletal muscle differentiation and exploring alternative stimulatory approaches not requiring extensive cell manipulation. This will allow to obtain safe, easy and efficient molecular or pharmacological modulation of pro-myogenic pathways in IBM mesoangioblasts. It is of crucial importance to identify factors (ie. cytokines, growth factors) produced by muscle or inflammatory cells and released in the surrounding milieu that are able to regulate the differentiation ability of IBM mesoangioblasts. To promote myogenic differentiation of endogenous mesoangioblasts in IBM muscle, the modulation of such target molecules selectively dysregulated would be a more handy approach to enhance muscle regeneration compared to transplantation techniques

Hereditary inclusion-body myopathy with sparing of the quadriceps: the many tiles of an incomplete puzzle

The hereditary inclusion-body myopathies encompass several syndromes with autosomal recessive or dominant inheritance. Despite a different clinical presentation they all have a progressive course leading to severe disability and share similar pathologic findings at the muscle biopsy. Quadriceps-sparing autosomal recessive hereditary inclusion-body myopathy (h-IBM) is the commonest form and is tied to mutations of the UDP-Nacetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) that codes for a rate-limiting enzyme in the sialic acid biosynthetic pathway. Despite the identification of the causative gene defect, it has not been clarified how mutations of the GNE gene impair muscle homeostasis. Although several lines of evidence argue in favor of an abnormal sialylation of muscle glycoproteins playing a key role in h-IBM pathogenesis, others studies have demonstrated new functions of the GNE gene, outside the sialic acid biosynthetic pathway, that may also be relevant. This review illustrates the clinical and pathologic characteristics of h- IBM and the main clues available to date concerning the possible pathogenic mechanisms of this disorder. Understanding the molecular mechanism underlying h-IBM pathology is a fundamental requisite to plan a future attempt to therapy

Limb-Girdle Muscular Dystrophies (LGMDs): The Clinical Application of NGS Analysis, a Family Case Report

The diagnosis of LGMD2A (calpainopathy) can be challenging due to genetic heterogeneity and to high similarity with other LGMDs or neuromuscular disorders. In this setting, NGS panels are highly recommended to perform differential diagnosis, identify new causative mutations and enable genotype-phenotype correlations. In this manuscript, the case of a patient affected by LGMD2A is reported, for which the application of a defined custom designed NGS panel allowed to confirm the diagnosis of calpainopathy linked with two heterozygous variants in CAPN3, namely c.550delA and c.1813G>C. The first variant has been extensively described in relation to calpainopathy. The second variant c.1813G>C, instead, is novel and has been predicted to be probably damaging. In addition, NGS analysis on the proband revealed a heterozygous variant (c.550C>T) in the LMNA gene, which is associated with dilated cardiomyopathy. The variant is novel and has been predicted to be deleterious by subsequent bioinformatic analysis. Successively, segregation analysis was performed on family members. Interestingly, none of them showed neuromuscular symptoms but the mother was diagnosed with bradycardia and syncopal episodes and showed a positive family history for cardiomyopathy. The segregation analysis reported that the proband inherited the c.1813G>C (CAPN3) from the father who was a healthy carrier. The mother was positive for c.550delA (CAPN3) and c.550C>T (LMNA), suggesting thereby a possible genetic explanation for her cardiovascular problems. Segregation analysis, therefore, confirmed the inheritance pattern of the variants carried by the proband and highlighted a familiarity for cardiomyopathy which should not be neglected. The NGS analysis was further performed on the partner of the proband, to estimate the reproductive risk of the couple. The partner was negative to NGS screening, suggesting thereby a low risk to have an affected child with calpainopathy and 50% probability inherit the LMNA variant. This case report showed the clinical utility of the NGS panel in providing accurate LGMD2A diagnosis and identifying complex phenotypes originating from mutations in multiple genes. However, NGS results should always be accomplished by a dedicated genetic counseling, not only to evaluate the recurrence and reproductive risks but also to uncover unexpected findings which can be clinically significant

Prevalence and predictor factors of respiratory impairment in a large cohort of patients with Myotonic Dystrophy type 1 (DM1): A retrospective, cross sectional study

Introduction: Respiratory complications are relevant in DM1, leading to a significantly increased morbidity and mortality risk in these patients; however, so far only few studies concerning respiratory function have been conducted in DM1 patients. We report a retrospective, multicenter, cross sectional study on a large cohort of DM1 patients widely characterized in the phenotype, to assess prevalence and identify predictors of restrictive respiratory syndrome. Methods: 268 DM1 subjects aged >18 years, who had recently performed spirometric tests were included; restrictive syndrome was diagnosed if forced vital capacity (FVC) <80% of predicted. This cut-off was used for statistical univariate and multivariate analysis. Results: 51.9% patients showed a restrictive syndrome, and half of them had indication to non-invasive ventilation (NIV), yet only 50% resulted compliant to NIV. CTG expansion size in leukocytes, clinical muscle severity, most functional parameters of respiratory muscle involvement, presence of cardiac conduction disturbances, pacemaker (PMK), exertion dyspnea, obstructive sleep apnea, and indication and compliance to NIV were all significantly associated with restrictive syndrome at the univariate analysis; in the multivariate model only the first two factors resulted independent predictors. Discussion: A high prevalence of restrictive syndrome in our DM1 cohort, mainly due to respiratory muscles weakness, was observed and documented; the severity of muscle impairment and the CTG expansion size confirmed to be independent predictors of respiratory restriction. Our data suggest that optimization of respiratory therapeutic management, particularly regarding launching of NIV, might help to reduce the rate of deaths due to respiratory complications in DM1

Supporting the Design of Data Preparation Pipelines

The availability of a large amount of data facilitates spreading a data-driven culture in which data are used and analyzed to support decision-making. However, data-based decisions are effective only if the considered input data sources are not affected by poor quality and biases. For this reason, the data preparation phase is crucial for guaranteeing an appropriate output quality. There is a strong evidence in the literature that dealing with data preparation is not simple: it is the most resource consuming step in data analysis and most of the times it is performed using a trial and error approach. Considering this, we aim to support users in the design of data preparation pipelines by identifying the most suitable data transformation/cleaning operations to apply and the order in which they have to be executed. In order to achieve such a goal, using different datasets and ML algorithms, we conducted a series of experiments designed to assess the impact of different types of errors on the quality of the output. The idea is to develop a framework that provides users with guidelines that recommend to address the data quality issues with the highest negative impact first. A preliminary validation has confirmed that following the system suggestions yields better results

Frequency of Cerebrovascular Abnormalities in Patients with Late-Onset Pompe Disease: Our Experience

No abstract available

Genetic counseling and ngs screening for recessive lgmd2a families

Genetic counseling applied to limb\u2013girdle muscular dystrophies (LGMDs) can be very challenging due to their clinical and genetic heterogeneity and the availability of different molecular assays. Genetic counseling should therefore be addressed to select the most suitable approach to increase the diagnostic rate and provide an accurate estimation of recurrence risk. This is particularly true for families with a positive history for recessive LGMD, in which the presence of a known pathogenetic mutation segregating within the family may not be enough to exclude the risk of having affected children without exploring the genetic background of phenotypically unaffected partners. In this work, we presented a family with a positive history for LGMD2A (OMIM #253600, also known as calpainopathy) characterized by compound heterozygosity for two CAPN3 mutations. The genetic specialist suggested the segregation analysis of both mutations within the family as a first-level analysis. Sequentially, next-generation sequencing (NGS) analysis was performed in the partners of healthy carriers to provide an accurate recurrence/reproductive risk estimation considering the genetic background of the couple. Finally, this work highlighted the importance of providing a genetic counseling/testing service even in unaffected individuals with a carrier partner. This approach can support genetic counselors in estimating the reproductive/recurrence risk and eventually, suggesting prenatal testing, early diagnosis or other medical surveillance strategies