Epidemiology of seropositive myasthenia gravis in Sardinia: A population-based study in the district of Sassari.

INTRODUCTION/AIMS: The global incidence and prevalence of myasthenia gravis (MG) range between 6-31/million and 10-37/100,000, respectively. Sardinia is a high-risk region for different immune-mediated disorders, but the epidemiology of MG remains unclear. We determined the epidemiology of MG with acetylcholine receptor (AChR)-immunoglobulin G (IgG) and muscle-specific tyrosine kinase (MuSK)-IgG in the district of Sassari (North-Western Sardinia; population, 325,288). METHODS: From the laboratory of the University Hospital of Sassari (reference for AChR/MuSK-IgG testing in Sardinia since 1998) and the main neurology units in Sardinia, we retrospectively identified MG patients with (1) AChR-IgG and/or MuSK-IgG positivity by radioimmunoprecipitation assay; and (2) residency in the district of Sassari. Incidence (January 2010-December 2019) and prevalence (December 31, 2019) were calculated. RESULTS: A total of 202 patients were included (incident, 107; prevalent, 180). Antibody specificities were AChR (n = 187 [93%]) and MuSK (n = 15 [7%]). The crude MG incidence (95% confidence interval) was 32.6 (26.8-39.2)/million, while prevalence was 55.3 (47.7-63.9)/100,000. After age-standardization to the world population, incidence decreased to 18.4 (14.3-22.5)/million, while prevalence decreased to 31.6 (26.1-37.0)/100,000. Among incident cases, age strata (years) at MG onset were: <18 (2%), 18-49 (14%), 50-64 (21%), and ≥65 (63%). DISCUSSION: Sardinia is a high-risk region for MG, with a prevalence that exceeds the European threshold for rare disease. Identification of the environmental and genetic determinants of this risk may improve our understanding of disease pathophysiology.

X-Linked Emery-Dreifuss Muscular Dystrophy: Study Of X-Chromosome Inactivation and Its Relation with Clinical Phenotypes in Female Carriers.

X-linked Emery-Dreifuss muscular dystrophy (EDMD1) affects approximately 1:100,000 male births. Female carriers are usually asymptomatic but, in some cases, they may present clinical symptoms after age 50 at cardiac level, especially in the form of conduction tissue anomalies. The aim of this study was to evaluate the relation between heart involvement in symptomatic EDMD1 carriers and the X-chromosome inactivation (XCI) pattern. The XCI pattern was determined on the lymphocytes of 30 symptomatic and asymptomatic EDMD1 female carriers-25 familial and 5 sporadic cases-seeking genetic advice using the androgen receptor (AR) methylation-based assay. Carriers were subdivided according to whether they were above or below 50 years of age. A variance analysis was performed to compare the XCI pattern between symptomatic and asymptomatic carriers. The results show that 20% of EDMD1 carriers had cardiac symptoms, and that 50% of these were ≥50 years of age. The XCI pattern was similar in both symptomatic and asymptomatic carriers. Conclusions: Arrhythmias in EDMD1 carriers poorly correlate on lymphocytes to a skewed XCI, probably due to (a) the different embryological origin of cardiac conduction tissue compared to lymphocytes or (b) the preferential loss of atrial cells replaced by fibrous tissue.

Cardiac and Neuromuscular Features of Patients With LMNA-Related Cardiomyopathy.

Background: Mutations in the LMNA (lamin A/C) gene have been associated with neuromuscular and cardiac manifestations, but the clinical implications of these signs are not well understood. Objective: To learn more about the natural history of LMNA-related disease. Design: Observational study. Setting: 13 clinical centers in Italy from 2000 through 2018. Patients: 164 carriers of an LMNA mutation. Measurements: Detailed cardiologic and neurologic evaluation at study enrollment and for a median of 10 years of follow-up. Results: The median age at enrollment was 38 years, and 51% of participants were female. Neuromuscular manifestations preceded cardiac signs by a median of 11 years, but by the end of follow-up, 90% of the patients had electrical heart disease followed by structural heart disease. Overall, 10 patients (6%) died, 14 (9%) received a heart transplant, and 32 (20%) had malignant ventricular arrhythmias. Fifteen patients had gait loss, and 6 had respiratory failure. Atrial fibrillation and second- and third-degree atrioventricular block were observed, respectively, in 56% and 51% of patients with combined cardiac and neuromuscular manifestations and 37% and 33% of those with heart disease only. Limitations: Some of the data were collected retrospectively. Neuromuscular manifestations were more frequent in this analysis than in previous studies. Conclusion: Many patients with an LMNA mutation have neurologic symptoms by their 30s and develop progressive cardiac manifestations during the next decade. A substantial proportion of these patients will have life-threatening neurologic or cardiologic conditions. Primary Funding Source: None.

Neuroblastoma image-defined risk factors in adrenal neuroblastoma: role of radiologist.

Neuroblastoma, one of the most common extracranial solid malignancies in children, is often localized in the adrenal glands (49%). The staging system for prognostic purpose was one of the first points of disagreement, which led to the International Neuroblastoma Staging System (INSS) of 1986, revised in 1989, which relies on surgical staging. The limit of this classification was the different surgical resection, also done at interval times from diagnosis. To overcome this difficulty, a new staging system was made based on preoperative imaging by the International Neuroblastoma Risk Group (INRG) in 2009. This new staging system uses 20 Image-Defined Risk Factors (IDRFs) across multiple organ systems. The scope of this IDRFs is to predict surgical outcomes and, in addition with clinical data, to provide risk stratification. The INRG Staging System (INRGSS) relies on Imaging-Defined Risk Factors (IDRFs) that are determined before surgery or other therapy. With the application of the INRGSS the radiologist's role in staging children with neuroblastoma increased. The review provides an overview of the INRGSS and the IDRFs in adrenal neuroblastoma.

Elevated TGF ß2 serum levels in Emery-Dreifuss Muscular Dystrophy: Implications for myocyte and tenocyte differentiation and fibrogenic processes.

Among rare diseases caused by mutations in LMNA gene, Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B are characterized by muscle weakness and wasting, joint contractures, cardiomyopathy with conduction system disorders. Circulating biomarkers for these pathologies have not been identified. Here, we analyzed the secretome of a cohort of patients affected by these muscular laminopathies in the attempt to identify a common signature. Multiplex cytokine assay showed that transforming growth factor beta 2 (TGF ß2) and interleukin 17 serum levels are consistently elevated in the vast majority of examined patients, while interleukin 6 and basic fibroblast growth factor are altered in subgroups of patients. Levels of TGF ß2 are also increased in fibroblast and myoblast cultures established from patient biopsies as well as in serum from mice bearing the H222P Lmna mutation causing Emery-Dreifuss Muscular Dystrophy in humans. Both patient serum and fibroblast conditioned media activated a TGF ß2-dependent fibrogenic program in normal human myoblasts and tenocytes and inhibited myoblast differentiation. Consistent with these results, a TGF ß2 neutralizing antibody avoided fibrogenic marker activation and myogenesis impairment. Cell intrinsic TGF ß2-dependent mechanisms were also determined in laminopathic cells, where TGF ß2 activated AKT/mTOR phosphorylation. These data show that TGF ß2 contributes to the pathogenesis of Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B and can be considered a potential biomarker of those diseases. Further, the evidence of TGF ß2 pathogenetic effects in tenocytes provides the first mechanistic insight into occurrence of joint contractures in muscular laminopathies.

The empowerment of translational research: lessons from laminopathies.

The need for a collaborative approach to complex inherited diseases collectively referred to as laminopathies, encouraged Italian researchers, geneticists, physicians and patients to join in the Italian Network for Laminopathies, in 2009. Here, we highlight the advantages and added value of such a multidisciplinary effort to understand pathogenesis, clinical aspects and try to find a cure for Emery-Dreifuss muscular dystrophy, Mandibuloacral dysplasia, Hutchinson-Gilford Progeria and forms of lamin-linked cardiomyopathy, neuropathy and lipodystrophy.

Aberrant splicing in the LMNA gene caused by a novel mutation on the polypyrimidine tract of intron 5.

INTRODUCTION: Familial dilated cardiomyopathy with conduction system defects variably associated with skeletal muscle abnormalities is frequently caused by LMNA gene mutations. METHODS: A family affected by cardiac abnormalities, either isolated or variably associated with skeletal muscle compromise, was identified. LMNA gene analysis was applied to all family members. RESULTS: A novel intron 5 (c.937-11 C > G) mutation was identified. mRNA transcription analysis was subsequently performed, and cDNA was obtained from mutated patients. It displayed an aberrant splice product featuring the insertion of 40 nucleotides from intron 5, leading to a frameshift. Computational predictions identified a cryptic splice site 40 bp upstream from the canonical site; this alternative splicing event was elicited by intronic mutation, which seems to interfere with the polypyrimidine tract of the canonical site. CONCLUSIONS: We have described the first mutation on the LMNA gene interfering with the polypyrimidine tract. Our findings underline the importance of including introns in the search for mutations.