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

Challenges of diagnostic exome sequencing in an inbred founder population

Exome sequencing was used as a diagnostic tool in a Roma/Gypsy family with three subjects (one deceased) affected by lissencephaly with cerebellar hypoplasia (LCH), a clinically and genetically heterogeneous diagnostic category. Data analysis identified high levels of unreported inbreeding, with multiple rare/novel "deleterious" variants occurring in the homozygous state in the affected individuals. Step‐wise filtering was facilitated by the inclusion of parental samples in the analysis and the availability of ethnically matched control exome data. We identified a novel mutation, p.Asp487Tyr, in the VLDLR gene involved in the Reelin developmental pathway and associated with a rare form of LCH, the Dysequilibrium Syndrome. p.Asp487Tyr is the third reported missense mutation in this gene and the first example of a change affecting directly the functionally crucial β‐propeller domain. An unexpected additional finding was a second unique mutation (p.Asn494His) with high scores of predicted pathogenicity in KCNV2, a gene implicated in a rare eye disorder, retinal cone dystrophy type 3B. This result raised diagnostic and counseling challenges that could be resolved through mutation screening of a large panel of healthy population controls. The strategy and findings of this study may inform the search for new disease mutations in the largest European genetic isolate

Rare disease research workflow using multilayer networks elucidates the molecular determinants of severity in Congenital Myasthenic Syndromes

\ua9 The Author(s) 2024.Exploring the molecular basis of disease severity in rare disease scenarios is a challenging task provided the limitations on data availability. Causative genes have been described for Congenital Myasthenic Syndromes (CMS), a group of diverse minority neuromuscular junction (NMJ) disorders; yet a molecular explanation for the phenotypic severity differences remains unclear. Here, we present a workflow to explore the functional relationships between CMS causal genes and altered genes from each patient, based on multilayer network community detection analysis of complementary biomedical information provided by relevant data sources, namely protein-protein interactions, pathways and metabolomics. Our results show that CMS severity can be ascribed to the personalized impairment of extracellular matrix components and postsynaptic modulators of acetylcholine receptor (AChR) clustering. This work showcases how coupling multilayer network analysis with personalized -omics information provides molecular explanations to the varying severity of rare diseases; paving the way for sorting out similar cases in other rare diseases

The TREAT-NMD DMD Global Database: Analysis of more than 7,000 Duchenne Muscular Dystrophy mutations

Analyzing the type and frequency of patient-specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning, and improved clinical care. Locus-specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations)

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

Пациент с вродена миопатия в резултат на мутация в CRYAB гена, водеща до развитието на алфа-в кристалинопатия

Миофибриларни миопатии (MFM) са група от доминантни, наследствени, дегенеративни заболявания на скелетния и сърдечния мускул, характеризиращи се с вътреклетъчно натрупване на протеин, разпадане на миофибрили, десмин-реактивна агрегация на разградени нишки в плеоморфни гранулирани или хиалинни включвания, и ектопична експресия на множество свързани с Z-диск и други протеини. Молекулярната основа на MFM е хетерогенна и са идентифицирани мутации в гени, кодиращи саркомерни Z-диск протеини, включително десмин (DES), алфа-В кристалин (CRYAB), миотилин (TTID), ZASP (LDB3), филамин С (FLNC) и Bcl-2-свързан атаноген-3 протеин (BAG3). Представяме болен на 34 години с начало на болестта от кърмаческа възраст, проявяваща се с хипомимичен фациес, носов говор, мускулна хипотония, мускулна слабост предимно за проксималните мускули на горните крайници, със засягане на сърдечна и дихателната функция

Проследяване на ефекта от лечението със Spinraza (Nusinersen) при български пациенти със спинална мускулна атрофия (СМА) над 18 г.

Въведение: 5q спиналната мускулна атрофия (СMA) е генетично невродегенеративно заболяване, обусловено от хомозиготна делеция или други мутации в survival motor neuron 1 (SMN1) гена, характеризиращо се със засягане на периферния двигателен неврон. Nusinersen, е антисенс олигонуклеотид, порвата терапия, одобрена за лечение на СМА след доказано подобрение в преживяемостта и моторните функции при деца и в изследвания от реалната клинична практика при възрастни. Цел: Целта на настоящото изследване е да се оцени ефективността и безопасността при лечението с nusinersen на български пациенти над 18 г. със СМА. Методи: Седемнадесет пациента със СМА над 18 г., преминали натоварващия период на лечение са оценени със следните Скали: Hammersmith Functional Motor Scale Expanded, HFMSE; Revised Upper Limb Module, RULM и 6 Minutes walking test). Профилът на безопасност е оценен при тези болни. Резултати: Дванадесет пациента демонстрират значимо подобрение с 2 или повече точки по отношение на RULM, а 11 са с подобрение по HFMSE. От 11 болни със запазена самостоятелна походка 9 демонстрират по-голямо разстояние по отношение на 6MWT. Останалите пациенти показват стабилизация по отношение на моторните функции за периода на проследяване. Не са наблюдавани сериозни нежелани лекарствени реакции. Заключение: Лечението с Nusinersen води до стабилизиране или подобрение на моторните функции при българските пациенти над 18 г

Association Between Loss of Dp140 and Cognitive Impairment in Duchenne and Becker Dystrophies

The presence of variable degrees of non progressive cognitive impairment is recognized as a clinical feature of patients with Duchenne and Becker muscular dystrophies (DMD and BMD), but its pathogenesis still remains a matter of debate. A number of findings have proved that rearrangements located in the second part of the dystrophin (DMD) gene seem to be preferentially associated with cognitive impairment. Dp140 is a distal dystrophin isoform, mainly expressed during fetal brain development, whose role for neuropsychological functioning was suggested