SOCIAL STRATIFICATION IN THE 21ST CENTURY

Social stratification is a phenomenon that still exists in the 21st century. Historically and sociologically, there is no classless society. All societies have forms of ranking in which their members are categorized into positions as the driving force is competition for a better life. As a result, there is social mobility with a constant movement of units between individual layers, as well as a desire to preserve the higher positions. A profession is not only a way of earning money but also a display of style and prestige, as in advanced societies professions are associated with social status and remain the most widely used measure of the class system of stratification. Wealth is the total worth of an individual or family, including income and investments, and prestige includes the social respect, admiration and recognition with a certain social status that gives rise to feelings and power by which others are compelled to do what they would not normally want to do, they do. High positions are less pleasant or desirable to occupy, but more important to the survival of society and require more special abilities and talents. Therefore, society must create a certain reward system that it can use to induce members to take certain positions

Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness

Several hundred genetic muscle diseases have been described, all of which are rare. Their clinical and genetic heterogeneity means that a genetic diagnosis is challenging. We established an international consortium, MYO-SEQ, to aid the work-ups of muscle disease patients and to better understand disease etiology. Exome sequencing was applied to 1001 undiagnosed patients recruited from more than 40 neuromuscular disease referral centers; standardized phenotypic information was collected for each patient. Exomes were examined for variants in 429 genes associated with muscle conditions. We identified suspected pathogenic variants in 52% of patients across 87 genes. We detected 401 novel variants, 116 of which were recurrent. Variants in CAPN3, DYSF, ANO5, DMD, RYR1, TTN, COL6A2, and SGCA collectively accounted for over half of the solved cases; while variants in newer disease genes, such as BVES and POGLUT1, were also found. The remaining well-characterized unsolved patients (48%) need further investigation. Using our unique infrastructure, we developed a pathway to expedite muscle disease diagnoses. Our data suggest that exome sequencing should be used for pathogenic variant detection in patients with suspected genetic muscle diseases, focusing first on the most common disease genes described here, and subsequently in rarer and newly characterized disease genes

EMQN best practice guidelines for genetic testing in dystrophinopathies.

Dystrophinopathies are X-linked diseases, including Duchenne muscular dystrophy and Becker muscular dystrophy, due to DMD gene variants. In recent years, the application of new genetic technologies and the availability of new personalised drugs have influenced diagnostic genetic testing for dystrophinopathies. Therefore, these European best practice guidelines for genetic testing in dystrophinopathies have been produced to update previous guidelines published in 2010.These guidelines summarise current recommended technologies and methodologies for analysis of the DMD gene, including testing for deletions and duplications of one or more exons, small variant detection and RNA analysis. Genetic testing strategies for diagnosis, carrier testing and prenatal diagnosis (including non-invasive prenatal diagnosis) are then outlined. Guidelines for sequence variant annotation and interpretation are provided, followed by recommendations for reporting results of all categories of testing. Finally, atypical findings (such as non-contiguous deletions and dual DMD variants), implications for personalised medicine and clinical trials and incidental findings (identification of DMD gene variants in patients where a clinical diagnosis of dystrophinopathy has not been considered or suspected) are discussed

Неврологични усложнения при хроничната употреба на райски газ в юношеска възраст

Хроничната злоупотреба с райски газ сред юношите се превръща в сериозен проблем, тъй като води до функционален дефицит на витамин В12 с последващи миелоневропатии. Представяме кохорта от 5 пациента на възраст от 15 до 18 г. с анамнестични данни за хронична злоупотреба на райски газ до 10-12 пълнителя на ден – един до два пъти седмично за период между 3 месeца и 2 г. При всички пациенти се установяват парестезии по дистален тип, сензорна атаксия, а при една болна и силно смутена походка. Електроневрографското изследване е с данни да смесен тип полиневропатия, по-изразена в долните крайници. Серумните нива на витамин В12 са намалени при 4/5, докато нивата на хомоцистеин и метилмалонова киселина са увеличени над 7 пъти над нормата при всички. Магнотнорезонансната томография е с данни за хиперинтензни лезии, засягащи задните стълбци на гръбначния мозък при една болна. Пациентите са лекувани с витамин В12 с различна степен на подобрение. Хроничната злоупотреба с райски газ води до обратима подост ро прогресираща миелоневропатия. Преустановяването на приема и приложението на витамин В12 е с добър ефект

POGLUT1 biallelic mutations cause myopathy with reduced satellite cells, α-dystroglycan hypoglycosylation and a distinctive radiological pattern.

Protein O-glucosyltransferase 1 (POGLUT1) activity is critical for the Notch signaling pathway, being one of the main enzymes responsible for the glycosylation of the extracellular domain of Notch receptors. A biallelic mutation in the POGLUT1 gene has been reported in one family as the cause of an adult-onset limb-girdle muscular dystrophy (LGMD R21; OMIM# 617232). As the result of a collaborative international effort, we have identified the first cohort of 15 patients with LGMD R21, from nine unrelated families coming from different countries, providing a reliable phenotype-genotype and mechanistic insight. Patients carrying novel mutations in POGLUT1 all displayed a clinical picture of limb-girdle muscle weakness. However, the age at onset was broadened from adult to congenital and infantile onset. Moreover, we now report that the unique muscle imaging pattern of "inside-to-outside" fatty degeneration observed in the original cases is indeed a defining feature of POGLUT1 muscular dystrophy. Experiments on muscle biopsies from patients revealed a remarkable and consistent decrease in the level of the NOTCH1 intracellular domain, reduction of the pool of satellite cells (SC), and evidence of α-dystroglycan hypoglycosylation. In vitro biochemical and cell-based assays suggested a pathogenic role of the novel POGLUT1 mutations, leading to reduced enzymatic activity and/or protein stability. The association between the POGLUT1 variants and the muscular phenotype was established by in vivo experiments analyzing the indirect flight muscle development in transgenic Drosophila, showing that the human POGLUT1 mutations reduced its myogenic activity. In line with the well-known role of the Notch pathway in the homeostasis of SC and muscle regeneration, SC-derived myoblasts from patients' muscle samples showed decreased proliferation and facilitated differentiation. Together, these observations suggest that alterations in SC biology caused by reduced Notch1 signaling result in muscular dystrophy in LGMD R21 patients, likely with additional contribution from α-dystroglycan hypoglycosylation. This study settles the muscular clinical phenotype linked to POGLUT1 mutations and establishes the pathogenic mechanism underlying this muscle disorder. The description of a specific imaging pattern of fatty degeneration and muscle pathology with a decrease of α-dystroglycan glycosylation provides excellent tools which will help diagnose and follow up LGMD R21 patients