Category: Congenital disorders

A study from the laboratory of Dr. Hugo J. Bellen, a distinguished service professor at Baylor College of Medicine and a principal investigator at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital, has discovered that gain-of-function variants in the DOT1L gene cause a new disorder. Further studies revealed that the majority of the symptoms in the patients were surprisingly due to an increase in the enzymatic activity of a histone methylase encoded by this gene. This study was published in the American Journal of Human Genetics. This project originated when the Undiagnosed Diseases Network, SickKids Complex Care Genomics project in Canada headed by Dr. Gregory Costain, and a search of the GeneMatcher database identified nine unrelated individuals with intellectual disability, developmental delays, distinctive facial features, and other overlapping features carried variants in DOT1L gene. We found this intriguing because this gene had not been previously associated with a genetic or neurological disorder.” Dr. Hugo J. Bellen, distinguished service professor at Baylor College of Medicine DOT1L is an evolutionarily conserved gene found in a broad range of species from yeast to man. It encodes an enzyme – lysine methyltransferase (KMT) – that adds methyl groups to a specific amino acid (lysine 79 aka K79) present on a particular histone (H3). Methylation of specific lysine residues within histones acts as a switch to turn ‘on’ or ‘off’ the expression of target genes. So far, only partial loss-of-function DOT1L variants in around half of KMT-encoding genes (16 of 34) have been shown to cause dominant human developmental disorders. “We found the variants in DOT1L cause a dominant disorder through a gain-of-function mechanism, which is different from other KMTs,” said Dr. Bellen. Although DOT1L is involved in several fundamental cellular processes, and its misregulation has been implicated in cancer, prior to this study it was not clear how variants in the DOT1L gene cause a congenital disorder. So, Dr. Zelha Nil, the first author and postdoctoral associate in the Bellen lab, turned to fruit flies to address that question. DOT1L and its fruit fly version, grappa (gpp) have similar protein sequences and are also likely to have overlapping functions. Most disease-causing human variants in DOT1L are located in its enzymatic domain. Furthermore, gpp is expressed in a large subset of neurons and some glial cells. The team generated a fly gpp mutant, which grew slowly and died in larval stages. Using these mutant flies and flies in which gpp RNA was knocked down, they found compelling evidence that gpp is essential for the survival of the flies and required for proper development as well as the development and function of the fly nervous system, and for H3K79 methylation. Related Stories “We attempted to suppress the lethality of gpp mutant flies by expressing the human DOT1L gene in flies,” Dr. Zelha Nil said. “To our surprise, expressing normal or variant versions of the human DOT1L gene in tissues where it occurs naturally in flies was not sufficient for gpp mutants who had lost both copies of the gene to survive. Surprisingly, flies with a partial loss of gpp that expressed the human DOT1L variants were less viable and had more profound morphological defects than the normal DOT1L expressing flies, suggesting the human DOT1L expression in flies was toxic.” Consistent with this observation, gpp mutant flies and cultured cells expressing variant versions of human DOT1L exhibited significantly higher levels of H3K79 methylation than normal DOT1L, suggesting that elevated levels of methylation are the likely molecular cause of the symptoms seen in the patients. “Based on our studies in flies, it appears that the variants result in excess enzymatic activity of DOT1Lin these patients,” Dr. Bellen said. “While additional studies are needed to unravel the exact mechanism of disease pathogenesis, our study suggests that reducing DOT1L activity is a viable therapeutic strategy that can be developed in the future to treat this new genetic condition.” Others involved in the study were Ashish R. Deshwar, Yan Huang, Scott Barish, Xi Zhang, Sanaa Choufani, Polona Le Quesne Stabej, Ian Hayes, Patrick Yap, Chad Haldeman-Englert, Carolyn Wilson, Trine Prescott, Kristian Tveten, Arve Vøllo, Devon Haynes, Patricia G. Wheeler, Jessica Zon, Cheryl Cytrynbaum, Rebekah Jobling, Moira Blyth, Siddharth Banka, Alexandra Afenjar, Cyril Mignot, Florence Robin-Renaldo, Boris Keren, Oguz Kanca, Xiao Mao, Daniel J. Wegner, Kathleen Sisco, Marwan Shinawi, Undiagnosed Disease Network, Michael F. Wangler, Rosanna Weksberg, Shinya Yamamoto, and Gregory Costain. Their institutional affiliations can be found here. The study was funded by a grant from the NIH Commonfund to the Model Organisms Screening Center of the UDN, the Office of Research Infrastructure Programs of the NIH, the Huffington Foundation, the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital to H.J.B, the Baylor College of Medicine IDDRC, through a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development for use of the Microscopy Core facilities, NIHR Manchester Biomedical Research Centre and Canadian Institutes of Health Research (CIHR) grants. Texas Children’s Hospital Journal reference: Nil, Z., et al. (2023). Rare de novo gain-of-function missense variants in DOT1L are associated with developmental delay and congenital anomalies. American Journal of Human Genetics. doi.org/10.1016/j.ajhg.2023.09.009.

Credit: Unsplash/CC0 Public Domain A study from the laboratory of Dr. Hugo J. Bellen, a distinguished service professor at Baylor College of Medicine and a principal investigator at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital, has discovered that gain-of-function variants in the DOT1L gene cause a new disorder. Further studies revealed that the majority of the symptoms in the patients were surprisingly due to an increase in the enzymatic activity of a histone methylase encoded by this gene. This study was published in the American Journal of Human Genetics. “This project originated when the Undiagnosed Diseases Network, SickKids Complex Care Genomics project in Canada headed by Dr. Gregory Costain, and a search of the GeneMatcher database identified nine unrelated individuals with intellectual disability, developmental delays, distinctive facial features, and other overlapping features carried variants in DOT1L gene,” said Dr. Bellen. “We found this intriguing because this gene had not been previously associated with a genetic or neurological disorder.” DOT1L is an evolutionarily conserved gene found in a broad range of species from yeast to man. It encodes an enzyme—lysine methyltransferase (KMT)—that adds methyl groups to a specific amino acid (lysine 79 aka K79) present on a particular histone (H3). Methylation of specific lysine residues within histones acts as a switch to turn ‘on’ or ‘off’ the expression of target genes. So far, only partial loss-of-function DOT1L variants in around half of KMT-encoding genes (16 of 34) have been shown to cause dominant human developmental disorders. “We found the variants in DOT1L cause a dominant disorder through a gain-of-function mechanism, which is different from other KMTs,” said Dr. Bellen. Although DOT1L is involved in several fundamental cellular processes, and its misregulation has been implicated in cancer, prior to this study it was not clear how variants in the DOT1L gene cause a congenital disorder. So, Dr. Zelha Nil, the first author and postdoctoral associate in the Bellen lab, turned to fruit flies to address that question. DOT1L and its fruit fly version, grappa (gpp) have similar protein sequences and are also likely to have overlapping functions. Most disease-causing human variants in DOT1L are located in its enzymatic domain. Furthermore, gpp is expressed in a large subset of neurons and some glial cells. The team generated a fly gpp mutant, which grew slowly and died in larval stages. Using these mutant flies and flies in which gpp RNA was knocked down, they found compelling evidence that gpp is essential for the survival of the flies and required for proper development as well as the development and function of the fly nervous system, and for H3K79 methylation. “We attempted to suppress the lethality of gpp mutant flies by expressing the human DOT1L gene in flies,” Dr. Zelha Nil said. “To our surprise, expressing normal or variant versions of the human DOT1L gene in tissues where it occurs naturally in flies was not sufficient for gpp mutants who had lost both copies of the gene to survive. Surprisingly, flies with a partial loss of gpp that expressed the human DOT1L variants were less viable and had more profound morphological defects than the normal DOT1L expressing flies, suggesting the human DOT1L expression in flies was toxic.” Consistent with this observation, gpp mutant flies and cultured cells expressing variant versions of human DOT1L exhibited significantly higher levels of H3K79 methylation than normal DOT1L, suggesting that elevated levels of methylation are the likely molecular cause of the symptoms seen in the patients. “Based on our studies in flies, it appears that the variants result in excess enzymatic activity of DOT1Lin these patients,” Dr. Bellen said. “While additional studies are needed to unravel the exact mechanism of disease pathogenesis, our study suggests that reducing DOT1L activity is a viable therapeutic strategy that can be developed in the future to treat this new genetic condition.” More information: Zelha Nil et al, Rare de novo gain-of-function missense variants in DOT1L are associated with developmental delay and congenital anomalies, The American Journal of Human Genetics (2023). DOI: 10.1016/j.ajhg.2023.09.009 Provided by Texas Children’s Hospital Citation: DOT1L gene variants associated with a new neurological disorder (2023, October 13) retrieved 13 October 2023 from https://medicalxpress.com/news/2023-10-dot1l-gene-variants-neurological-disorder.html This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.

Texas Children’s Hospital A study from the laboratory of Dr. Hugo J. Bellen, a distinguished service professor at Baylor College of Medicine and a principal investigator at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital, has discovered that gain-of-function variants in the DOT1L gene cause a new disorder. Further studies revealed that the majority of the symptoms in the patients were surprisingly due to an increase in the enzymatic activity of a histone methylase encoded by this gene. This study was published in the American Journal of Human Genetics. “This project originated when the Undiagnosed Diseases Network, SickKids Complex Care Genomics project in Canada headed by Dr. Gregory Costain, and a search of the GeneMatcher database identified nine unrelated individuals with intellectual disability, developmental delays, distinctive facial features, and other overlapping features carried variants in DOT1L gene,” said Dr. Bellen. “We found this intriguing because this gene had not been previously associated with a genetic or neurological disorder.” DOT1L is an evolutionarily conserved gene found in a broad range of species from yeast to man. It encodes an enzyme – lysine methyltransferase (KMT) – that adds methyl groups to a specific amino acid (lysine 79 aka K79) present on a particular histone (H3). Methylation of specific lysine residues within histones acts as a switch to turn ‘on’ or ‘off’ the expression of target genes. So far, only partial loss-of-function DOT1L variants in around half of KMT-encoding genes (16 of 34) have been shown to cause dominant human developmental disorders. “We found the variants in DOT1L cause a dominant disorder through a gain-of-function mechanism, which is different from other KMTs,” said Dr. Bellen. Although DOT1L is involved in several fundamental cellular processes, and its misregulation has been implicated in cancer, prior to this study it was not clear how variants in the DOT1L gene cause a congenital disorder. So, Dr. Zelha Nil, the first author and postdoctoral associate in the Bellen lab, turned to fruit flies to address that question. DOT1L and its fruit fly version, grappa (gpp) have similar protein sequences and are also likely to have overlapping functions. Most disease-causing human variants in DOT1L are located in its enzymatic domain. Furthermore, gpp is expressed in a large subset of neurons and some glial cells. The team generated a fly gpp mutant, which grew slowly and died in larval stages. Using these mutant flies and flies in which gpp RNA was knocked down, they found compelling evidence that gpp is essential for the survival of the flies and required for proper development as well as the development and function of the fly nervous system, and for H3K79 methylation. “We attempted to suppress the lethality of gpp mutant flies by expressing the human DOT1L gene in flies,” Dr. Zelha Nil said. “To our surprise, expressing normal or variant versions of the human DOT1L gene in tissues where it occurs naturally in flies was not sufficient for gpp mutants who had lost both copies of the gene to survive. Surprisingly, flies with a partial loss of gpp that expressed the human DOT1L variants were less viable and had more profound morphological defects than the normal DOT1L expressing flies, suggesting the human DOT1L expression in flies was toxic.” Consistent with this observation, gpp mutant flies and cultured cells expressing variant versions of human DOT1L exhibited significantly higher levels of H3K79 methylation than normal DOT1L, suggesting that elevated levels of methylation are the likely molecular cause of the symptoms seen in the patients. “Based on our studies in flies, it appears that the variants result in excess enzymatic activity of DOT1Lin these patients,” Dr. Bellen said. “While additional studies are needed to unravel the exact mechanism of disease pathogenesis, our study suggests that reducing DOT1L activity is a viable therapeutic strategy that can be developed in the future to treat this new genetic condition.” Others involved in the study were Ashish R. Deshwar, Yan Huang, Scott Barish, Xi Zhang, Sanaa Choufani, Polona Le Quesne Stabej, Ian Hayes, Patrick Yap, Chad Haldeman-Englert, Carolyn Wilson, Trine Prescott, Kristian Tveten, Arve Vøllo, Devon Haynes, Patricia G. Wheeler, Jessica Zon, Cheryl Cytrynbaum, Rebekah Jobling, Moira Blyth, Siddharth Banka, Alexandra Afenjar, Cyril Mignot, Florence Robin-Renaldo, Boris Keren, Oguz Kanca, Xiao Mao, Daniel J. Wegner, Kathleen Sisco, Marwan Shinawi, Undiagnosed Disease Network, Michael F. Wangler, Rosanna Weksberg, Shinya Yamamoto, and Gregory Costain. Their institutional affiliations can be found here. The study was funded by a grant from the NIH Commonfund to the Model Organisms Screening Center of the UDN, the Office of Research Infrastructure Programs of the NIH, the Huffington Foundation, the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital to H.J.B, the Baylor College of Medicine IDDRC, through a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development for use of the Microscopy Core facilities, NIHR Manchester Biomedical Research Centre and Canadian Institutes of Health Research (CIHR) grants. /Public Release. This material from the originating organization/author(s) might be of the point-in-time nature, and edited for clarity, style and length. Mirage.News does not take institutional positions or sides, and all views, positions, and conclusions expressed herein are solely those of the author(s).View in full here.

MIAMI SHORES, Fla., Sept. 5, 2023 /PRNewswire/ — Prominently featured in The Inner Circle, Dr. Nirat Beohar is acknowledged as a Pinnacle Life Member for his contributions to the fields of Interventional Cardiology and Medical Education. Dr. Beohar pursued higher education at the Maulana Azad Medical College in 1990 where he earned a Medical Degree. He relocated to the United States and attended Baylor College of Medicine where he completed a residency in Internal Medicine in 1994 and was a visiting fellow at the Laboratory of Molecular Cardiology at the National Heart, Lung, and Blood Institute. He then attended George Washington University where he finished his fellowship in cardiovascular disease in 1998 and concluded a second fellowship in Interventional Cardiology at the Feinberg Medical School in 1999. The doctor holds multiple board certifications from the American Board of Internal Medicine (ABIM) in Cardiovascular Disease; Interventional Cardiology; Nuclear Cardiology; CT Angiography; and Internal Medicine and notes that ABIM is a physician-led non-profit independent evaluation organization driven by doctors who want to achieve higher standards for better care in a rapidly changing world. He explained that cardiology is a branch of medicine that deals with the disorders of the heart, as well as some parts of the circulatory system. The field includes medical diagnosis and treatment of congenital heart defects, coronary artery disease, heart failure, valvular heart disease, and electrophysiology. He notes that cardiologists are doctors who diagnose, assess, and treat patients with diseases and defects of the heart and blood vessels (the cardiovascular system). A Fellow of the American College of Cardiology (FACC), Dr. Beohar asserts that he has devoted his career to the use and development of catheter-based therapies for the treatment of heart disease. He currently serves in many leadership positions including Vice Chief of the Columbia University Division of Cardiology at Mount Sinai Medical Center; Director of the hospital’s Cardiac Catheterization Lab; Medical Director of the hospital’s Structural Heart Disease Program; Director of the hospital’s Interventional Cardiology Fellowship Program; and a Professor at Columbia University Medical Center. The doctor is an expert in many specialties including implanting catheter-delivered heart aortic valves; treating complex coronary conditions, such as left main and multi-vessel disease as well as chronic total occlusions; and devices to close atrial septal defects; PFOs; and other intracardiac shunts. Dr. Beohar implants left ventricular assist devices such as the Tandem heart and Impella for patients in cardiogenic shock and is skilled in transseptal catheterization, a highly specialized technique used to access the left side of the heart to treat structural heart disease. He has also had experience with percutaneous therapies for peripheral vascular disease. Prior to his current posts, Dr. Beohar worked at Mount Sinai-Columbia; was an interventional cardiologist at Northwestern Memorial Hospital in Chicago; an Associate Professor of Medicine at Northwestern University’s Feinberg School of Medicine; and the Director of the Cardiac Catheterization Laboratory at the Veterans Administration Lakeside Hospital in Chicago. Dr. Beohar’s illustrious career has been punctuated by many awards and honors including the Top Doctor Award by Coral Gables Magazine in 2019. He is also highly sought after for his lectures to fellows and also assists with medical education in India. He would like to dedicate this honor in loving memory of his parents, Prakash C. and Sushma Beohar, and his mentors, Robert Bonow, MD, and Charles J. Davidson, MD. Contact: Katherine Green516-825-5634[email protected] View original content to download multimedia:https://www.prnewswire.com/news-releases/the-inner-circle-acknowledges-dr-nirat-beohar-as-a-pinnacle-life-member-for-his-contributions-to-the-fields-of-interventional-cardiology-and-medical-education-301918305.html SOURCE The Inner Circle

Q: Are Purebred or Mixed-Breed Dogs Healthier? A: “While any breed of pet can become ill, some purebred dogs are closely inbred and can have a greater risk of developing genetic diseases or congenital issues that come from inbreeding,” said Dr. Liff. While every pet’s health is unique, purebred dogs have less genetic diversity than mixed-breed dogs and are generally at a higher risk for genetic or inherited medical conditions. Mixed-breed dogs have a more diverse genetic pool, so if one dog has a health issue, the chances are higher it will disappear in the next generation. Responsible breeders can reduce the risk of some of the more prevalent genetic diseases by doing specific disease testing before breeding a dog, but not all breeders invest the time and money to do this. Only buy from reputable breeders who test for common genetic diseases to ensure your puppy is healthy. Q: What Health Problems Do Purebred Dogs Have? A: Purebred dogs are at a higher risk for a variety of hereditary and congenital conditions. “Some examples are that Cavalier King Charles spaniels have a higher risk of heart disease, as do boxers, Great Danes and Doberman pinschers,” said Dr. Liff. “Doberman pinschers also often have a blood clotting disorder called Von Willebrand’s disease. Purebred poodles can have increased prevalence of epilepsy and Addison’s disease.” Hereditary conditions are genetically inherited, and may not appear until later life. Congenital defects develop while the pet is still in utero, and while these conditions are present at birth, they may not be apparent without a veterinary exam. Common hereditary conditions — Hip and elbow dysplasia, heart disease, epilepsy and certain eye conditions Common congenital conditions — Heart defects, liver abnormalities and cleft palate Q: Are Purebred or Mixed-Breed Dogs More Expensive To Own? A: Owning any pet is a big financial commitment. While the cost of owning a dog varies, popular breeds, such as French bulldogs, are expensive to purchase and are more prone to certain genetic disorders, which can increase their healthcare costs. Breed-related conditions can range from mild to severe and may require costly lifelong medical management (i.e., medication, rehabilitation or weight management) or surgical correction. Q: Are Purebred Dogs More Expensive To Insure? A: While breed is factored into the cost of coverage, pet insurance premiums are based on multiple other factors. “Insurance is typically based on the pet’s age, breed and size and the location in which you are seeking insurance, so it may not be as price sensitive by breed,” said Dr. Liff. “For example, a 100-pound, mixed-breed dog living in New York City would cost more to insure than a Havanese living in Cleveland, Ohio.” Q: Which Insurance Plans Are Best for Purebred Dogs? A: Dr. Liff recommends that all pets have accident and illness coverage with an 80% to 90% reimbursement rate and a minimum annual coverage limit of $25,000, whether they’re purebred or not. Additional wellness coverage can often save you money on preventive care, which can help keep your purebred dog healthy. When investigating pet insurance plans for your purebred dog, research hereditary or congenital conditions common to your pet’s breed, consider their health history and review each policy carefully to ensure your dog is well-protected. Q: Which Insurance Plans Are Best for Mixed-Breed Dogs? A: While mixed-breed dogs have a lower risk for genetic or inherited medical conditions, quality veterinary care, especially for unexpected illnesses and injuries, is expensive. The right pet insurance plan can cut the cost of all your mixed-breed dog’s health needs, from routine veterinary services to emergency care. Coverage and plan options — as well as cost — can vary widely depending on the provider and the specific policy, so it’s important to spend time researching your options to help you find the best pet insurance plan for your mixed-breed dog. Q: What Tips Do You Have For Owners of Purebred Dogs? A: “All pets — regardless of breed — need regular veterinary care to stay healthy,” said Dr. Liff. She advises following your veterinarian’s recommendations regarding your pet’s preventive care and annual diagnostics to monitor your pet’s health and identify problems before they become more serious. She also recommends keeping your pet up-to-date on their vaccinations and parasite screenings, and administering year-round flea, tick and heartworm preventives to protect your pet. Q: What Tips Do You Have for Owners of Mixed-Breed Dogs? A: Many pet insurance providers cover pets as young as 8 weeks old, so purchase pet insurance for your mixed-breed dog when they are young and healthy. Most pet insurance plans do not cover pre-existing conditions, and purchasing coverage for your young pet means your plan will likely cover future health conditions. Regardless of whether you bring a purebred or mixed-breed dog into your home and heart, you want to ensure they live a long, healthy life by your side. Purchasing a health insurance policy can help you provide for their medical needs, from routine to unexpected, so they stay in excellent health.

Agammaglobulinemia is a set of inherited immunological disorders marked by low antibody levels in the blood due to a lack of certain lymphocytes in the blood and lymph. Agammaglobulinemia is a set of inherited immunological disorders marked by low antibody levels in the blood due to a lack of certain lymphocytes in the blood and lymph. Image Credit: Kateryna Kon/Shutterstock.com While X-linked agammaglobulinemia (XLA) is the most frequent cause of congenital agammaglobulinemia, accounting for about 85% of cases, other genetic types of agammaglobulinemia have been discovered. X-linked agammaglobulinemia (XLA), autosomal recessive agammaglobulinemia (ARAG), and autosomal dominant agammaglobulinemia are the three kinds of agammaglobulinemia. Serial bacterial infections are the main symptoms of agammaglobulinemia, which are caused by deficiencies in certain immunological responses caused by abnormalities in B-lymphocytes. Infections commonly occur in the gastrointestinal tract, lungs, skin, joints, and upper respiratory tracts. XLA A mutation in Bruton’s tyrosine kinase (BTK) causes this X-linked agammaglobulinemia. BTK is a cytoplasmic tyrosine kinase that is mostly expressed in hematopoietic cells. There have been over 600 mutations discovered in BTK, with the bulk of them involving 1–4 base pairs. Recurrent, pyogenic bacterial infections in young boys and a near-complete absence of all immunoglobulin isotypes are among the clinical manifestations of XLA. Streptococcus pneumoniae, Staphylococcus spp., Pseudomonas spp., and Haemophilus influenzae are among the most prevalent pathogens found in XLA. Prior to diagnosis, recurrent otitis is the most frequent infection. In addition, conjunctivitis, sinopulmonary infections, diarrhea, and skin infections are common. When people with XLA acquire a serious, life-threatening condition such as pneumonia, empyema, meningitis, sepsis, or septic arthritis, they are diagnosed with immunodeficiency. Neutropenia has been identified as a prevalent XLA symptom. The prevalence of XLA varies between 1:100,000 and 1:200,000. There is no known ethnic predilection, but the White race has the highest documented occurrence. Males with early-onset bacterial infections, substantial reductions in all classes of blood immunoglobulins, and missing B cells are suspected of having XLA. The prognosis for people with XLA has improved dramatically in the last 25 years as a result of earlier diagnosis, the discovery of gammaglobulin preparations that allow for normal blood IgG concentrations, and more liberal antibiotic use. Autosomal recessive and autosomal dominant agammaglobulinemia In comparison to XLA, autosomal recessive agammaglobulinemia is a rare cause of agammaglobulinemia. Mutations have been found in the mu heavy chain, Lambda 5, Ig alpha, Ig beta, BLNK, PI3K, and TCF3 genes so far. Due to mu heavy chain mutations, BLNK insufficiency, and Ig alpha deficit, neutropenia has been found in some ARA patients. These diseases are more severe and manifest earlier than XLA instances. Some patients with early B cell developmental abnormalities have yet to be diagnosed with a genetic etiology, though this is changing because of breakthroughs in diagnostic and genetic testing. Mutations in numerous different genes have been linked to autosomal recessive agammaglobulinemia, including the heavy chain gene, 5, Ig, Ig, BLNK, PIK3R, and TCF3. Mutations in the LRRC8A gene on chromosome 9q34 and the TCF3 gene on 19p13.3 have been linked to autosomal dominant agammaglobulinemia. Diagnosis and treatment Immunoglobulin levels are measured in blood tests to confirm the condition. Flow cytometry, immunoelectrophoresis, and nephelometry to quantify immunoglobulins (IgG, IgA, IgM) are among the tests used to determine the number of circulating B lymphocytes. The presence of a missing B cell in a maternal uncle or male cousin essentially guarantees the diagnosis. Males with a hemizygous BTK pathogenic mutation and females with a heterozygous BTK pathogenic variant have their XLA diagnosis confirmed. Treatment entails taking actions to limit the number of infections and their severity. Bacterial infections frequently necessitate the use of antibiotics. Immunoglobulins are injected or given through a vein to enhance the immune system. A bone marrow transplant is a possibility. Molecular genetic testing of at-risk male relatives as soon as feasible after delivery guarantees that affected individuals receive gammaglobulin substitution therapy as soon as possible. Corticosteroids and other immune-suppressing medicines (immunosuppressant drugs) should be avoided as much as possible. Patients should also avoid strenuous activity that could harm their spleen, such as harsh contact sports. Immunoglobulin replacement comes in a variety of forms and can be given intravenously or subcutaneously. The patient receives intravenous immunoglobulin replenishment every 3–4 weeks. Although no current published guidelines exist, prophylactic antibiotics can be used to avoid infection. Prophylactic antibiotics may be considered, especially if patients continue to get infections despite receiving appropriate immunoglobulin replacement therapy. X linked agammaglobulinemia | Agammaglobulinemia | XLA |USMLE step 1Play Agammaglobulinemia in COVID-19 patients With the outbreak of the SARS-CoV-2 pandemic in 2019, it is expected that immunocompromised patients will be particularly vulnerable. Patients with agammaglobulinemia with coronavirus disease 2019 (COVID-19) infection have been described in a small number of cases. Seven patients, one with XLA, one with autosomal recessive agammaglobulinemia, and five with CVID (common variable immune deficiency) with COVID, were described by a group of researchers. The investigators reported that the two patients with agammaglobulinemia had mild clinical outcomes, but the five with CVID had severe disease and one fatality. Another study identified two patients with XLA who developed COVID-19 with a complete lack of B lymphocytes in their peripheral blood. According to their findings, XLA patients are at a higher risk of developing pneumonia as a result of SARS-CoV-2 infection, but they can recover. While additional research is needed, observations and case reports have revealed that certain people with XLA had a milder type of COVID-19 than those with other underlying immunodeficiencies. References Cardenas-Morales M, & Hernandez-Trujillo, VP (2021). Agammaglobulinemia: from X-linked to Autosomal Forms of Disease. Clinical Reviews in Allergy & Immunology, 1–14. Advance online publication. doi: https://doi.org/10.1007/s12016-021-08870-5 Lackey AE, Ahmad F. X-linked Agammaglobulinemia. [Updated 2021 Jul 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK549865/ Soresina A, Moratto D, Chiarini M, et al. (2020). Two X-linked agammaglobulinemia patients develop pneumonia as COVID-19 manifestation but recover. Pediatric Allergy and Immunology: Official Publication of the European Society of Pediatric Allergy and Immunology, 31(5), 565–569. doi: https://doi.org/10.1111/pai.13263 El-Sayed ZA,

You can get PIP even if you’re working, have savings or are getting most other benefits. PIP is made up of two components – a daily living rate and a mobility rate – and you can be entitled to both or just one of these. These are then split again, into the standard rate and the enhanced rate. For the daily living rate, you can either get £68.10 or £101.75 a week and for mobility, you can either get £26.90 or £71. If you are eligible for both enhanced rates you can get £172.75 a week or £691 every month. DWP pays out £11million to thousands of people who were denied PIP payments https://t.co/6p19cnbj0R — John E Jefferson (@JohnEJefferson) March 17, 2023 Daily living part You might get the daily living part of PIP if you need help with: preparing food eating and drinking managing your medicines or treatments washing and bathing using the toilet dressing and undressing reading managing your money socialising and being around other people talking, listening and understanding Mobility part You might get the mobility part of PIP if you need help with: working out a route and following it physically moving around leaving your home You do not have to have a physical disability to get the mobility part. You might also be eligible if you have difficulty getting around because of a cognitive or mental health condition, like anxiety. DWP autumn cost of living payments and cash boosts to claim as price cap changes#Autumn | #Living | #Payments | #Boostshttps://t.co/Lu04OnQTbx — Mia (@miatweets83) September 2, 2023 If you have one of these stomach conditions, you may be entitled to claim PIP: Diseases of the oesophagus, stomach and duodenum Hiatus hernia / gastroesophageal reflux disease / reflux oesophagitis Oesophageal varices Oesophagus, stomach and duodenum – Other diseases of / type not known Peptic ulcer (gastric and duodenal)/gastritis Diseases of the small bowel Coeliac disease Small bowel – Other diseases of / type not known Inflammatory bowel disease Crohn’s disease Ulcerative colitis Diseases of the colon Colon – Other diseases of / type not known Constipation Diverticular disease / diverticulitis Diseases of the rectum and anus Anorectal abscess Fistula in anus Haemorrhoids Rectal prolapse Rectum/anus – Other diseases of / type not known Irritable bowel syndrome (IBS) Benign tumours of the gastrointestinal tract Abdominal hernias Hernia Congenital disorders of the GI tract Cleft lip Cleft lip with cleft palate Hirschprung Disease Tracheo-oesophageal fistula/atresia Other diseases of the gastrointestinal tract Attention to artificial opening colostomy/ileostomy/ stoma – no underlying diagnosis Gastrointestinal tract – Other diseases of / type not known Latest Personal Independence Payment (PIP) statistics show that as at 31st October 2022 there were 2.8 million claimants entitled to PIP (caseload) in England & Wales, with just over one in three cases (35%) receiving the highest level of award.

—QOL-B Respiratory Domain Shown to Work Effectively as Patient-Reported Outcome Tool in Patients with MAC Lung Disease; to be Proposed to FDA as Primary Endpoint in ENCORE with No Modifications— —Patients Treated with ARIKAYCE Plus Macrolide-Based Background Regimen Had Meaningfully Larger Improvements in QOL-B Respiratory Score with Strong Trend Toward Significance vs. Macrolide-Based Background Regimen Alone— —ARIKAYCE-Treated Patients Had Nominally Statistically Significantly Higher Culture Conversion Rates at Month 7 vs. Comparator (78.8% vs. 47.1%, p=0.0010); Culture Conversion Began Earlier and Was More Likely to Persist Through Month 7 with ARIKAYCE Regimen— —No New or Unexpected Safety Signals Observed— —Insmed to Explore Accelerating Filing for ARIKAYCE in Newly Infected MAC Lung Disease Patients with Global Regulators on Basis of ARISE Data— —Insmed to Host Investor Call at 8:30 a.m. ET on Tuesday, September 5— BRIDGEWATER, N.J., Sept. 5, 2023 /PRNewswire/ — Insmed Incorporated (Nasdaq: INSM), a global biopharmaceutical company on a mission to transform the lives of patients with serious and rare diseases, today announced positive topline results from its Phase 3 ARISE study of ARIKAYCE in patients with newly diagnosed or recurrent nontuberculous mycobacterial (NTM) lung infection caused by Mycobacterium avium complex (MAC) who had not started antibiotics. The study met its primary objective of demonstrating that the Quality of Life – Bronchiectasis (QOL-B) respiratory domain works effectively as a patient-reported outcome (PRO) instrument in patients with MAC lung disease. Based on these results, Insmed plans to propose to the U.S. Food and Drug Administration (FDA) that the QOL-B respiratory domain PRO be the primary endpoint for the ENCORE study without any modifications. Patients in ARISE (N=99) were randomized 1:1 to treatment with ARIKAYCE plus macrolide-based background regimen (ARIKAYCE arm) or placebo plus macrolide-based background regimen (comparator arm) for six months, followed by one month off treatment. ARIKAYCE-treated patients performed better than those in the comparator arm as measured by the QOL-B instrument, with 43.8% of patients achieving an improvement in QOL-B respiratory score above the estimated meaningful within-subject score difference of 14.8, compared with 33.3% of patients in the comparator arm. While the study was not powered to show a statistically significant difference between treatment arms, a strong trend toward significance was observed for improvement from baseline at Month 7 (12.24 vs. 7.76, p=0.1073). Patients in the ARIKAYCE arm also achieved nominally statistically significantly higher culture conversion rates at Month 7 versus patients in the comparator arm (78.8% vs. 47.1%, p=0.0010), and culture conversion was faster and more likely to persist through Month 7 for the ARIKAYCE arm. “The ARISE study represents a clear and unambiguous win for the entire NTM community. We are thrilled that these results not only validate a PRO tool in NTM lung disease, but also show that patients treated with an ARIKAYCE-based regimen felt better versus patients in the comparator arm, as measured by this instrument. Coupled with extraordinary culture conversion outcomes, these findings give us great confidence that our Phase 3 registrational trial, ENCORE, is well-positioned to achieve both statistically and clinically meaningful results, leading to a sizeable increase in the number of patients who could hope to benefit from ARIKAYCE,” said Martina Flammer, M.D., MBA, Chief Medical Officer of Insmed. Based on the results of ARISE, Insmed plans to explore with global regulators accelerating the filing for approval of ARIKAYCE in newly infected patients with MAC lung disease. In parallel, the Company continues to enroll patients in ENCORE, which will use the PRO tool that has been validated in ARISE, with 250 patients expected to be enrolled by the end of 2023. Enrollment in ENCORE is expected to continue into 2024 to ensure a high degree of statistical powering and Insmed anticipates reporting topline data from ENCORE in 2025. “I want to thank the many patients, caregivers, and investigators who participated in ARISE and made this impressive outcome possible. We look forward to discussing these excellent results from this well-executed study in the near future with regulators,” noted Kevin Mange, M.D., M.S.C.E., Chief Development Officer of Insmed. Additional ARISE Study Findings Insmed reported the following additional results from the ARISE study: Culture ConversionConsistent with prior clinical studies, a higher proportion of patients in the ARIKAYCE arm achieved culture conversion by Month 6 (defined as negative cultures at Months 5 and 6) compared to patients in the comparator arm (80.6% vs. 63.9%, p=0.0712). Among patients who achieved culture conversion by Month 6, more patients in the ARIKAYCE arm achieved the first of their two required monthly negative cultures for clinical conversion at Month 1 versus the comparator arm (74.3% vs. 46.7%). As reported above, at Month 7 (one month following the cessation of treatment), 47.1% of patients in the comparator arm were culture-converted vs. 78.8% of patients in the ARIKAYCE arm, suggesting that ARIKAYCE-treated patients are more likely to remain negative. Correlation Between Culture Conversion and QOL-B PerformancePatients in the ARIKAYCE arm who achieved culture conversion at both Month 6 and Month 7 had nominally statistically significantly greater improvements in QOL-B respiratory domain scores at Month 7 compared to patients in the ARIKAYCE arm who did not achieve culture conversion (15.74 vs. 3.53, p=0.0167 at Month 6 and 14.89 vs. 4.50, p=0.0416 at Month 7). PROMIS Fatigue-Short Form 7aThe Patient-Reported Outcome Measurement Information System (PROMIS) Fatigue-Short Form 7a was also assessed in the study. While both treatment arms showed improvements in the PROMIS Fatigue scores from Baseline to Month 7, the difference between treatment groups was not significant, with 35.5% of ARIKAYCE patients achieving a within-subject meaningful difference of at least a 4-unit decrease (a negative change signifies improvement) compared to 29.4% of subjects in the comparator arm. As previously noted, the study was not powered to show a statistically significant difference between treatment arms. Safety and TolerabilityThe discontinuation rate of ARIKAYCE or the placebo used in the comparator arm was 22.9% in the ARIKAYCE arm and 7.8% in the comparator arm. Study completion rates were 91.7% in the ARIKAYCE arm and 94.1% in the comparator arm. No new safety events were

Ichthyosis vulgaris (IV)X-linked recessive ichthyosis (XLRI)Autosomal recessive congenital ichthyosisKeratinopathic ichthyosisOther rare formsReferencesFurther reading Ichthyosis is an inherited group of skin disorders characterized by xerosis and scaling. Other common phenotypic characteristics are hyperkeratosis, keratosis pilaris, palmar, and plantar hyperlinearity. It is also known as fish scale disease or the disorders of keratinization (DOK). Ichthyosis vulgaris. Image Credit: TANAPAT LEK.JIW/Shutterstock.com The clinical symptoms often appear at birth or within the first few years of life. The Ichthyosis Consensus Conference produced a consensus classification for ichthyosis in 2009 based on pathophysiology, clinical symptoms, and manner of inheritance. It is classified into two types according to this naming system: nonsyndromic forms (clinical symptoms limited to the skin) and syndromic forms (involvement of other organ systems). Ichthyosis Vulgaris and X-linked recessive ichthyosis are the most frequent, both caused by well-known genetic abnormalities. Depending on the severity of the ichthyosis, treatment should include hydration and lubrication, as well as keratolytic and keratinocyte differentiation modulators. Although oral retinoids are not normally required in the care of common ichthyoses, they are a staple in the systemic management of severe disease. The majority of ichthyosis treatments try to increase the skin’s barrier function. Bathing and carefully applying creams and ointments are important components of an ichthyosis patient’s daily regimen. Ichthyosis vulgaris (IV) The most prevalent form of ichthyosis is Ichthyosis Vulgaris (IV), which has an incidence of 1:250 to 1:1000. IV is also the mildest form of inherited nonsyndromic ichthyosis, with xerosis, scaling, eczema, and pruritus, and it is strongly linked to atopic symptoms. The phenotypic manifestations usually arise around an age of 2 months and improve in the summer. The extensor sides of the lower legs and the back are usually afflicted; the chest and abdomen are rarely impacted. Keratosis pilaris and palmoplantar hyperlinearity are both common IV complications. IV is caused by autosomal dominant mutations in the filaggrin gene (FLG), which is required for epidermal development and skin barrier formation. Population-specific FLG variants of IV have been found in Europeans, Asians, and Africans. Patients with IVs are more likely to develop atopic dermatitis, asthma, and allergies. This increased risk is likely due to a breakdown in barrier function, which may allow possible allergens to penetrate deeper into the epidermis. X-linked recessive ichthyosis (XLRI) XLRI is the second most frequent form of hereditary ichthyosis, with a male incidence ranging from 1:2000 to 1:6000. Clinical manifestations of XLRI are frequently indistinguishable from those of IV. Symptoms often begin in the neonatal period as generalized desquamation and xerosis, progressing to fine scaling of the trunk and extremities in infancy. Patients develop a brownish, polygonal, plate-like scale that tightly adheres to the skin over time. Mutations in the STS gene, which codes for steroid sulfatase, on the X chromosome cause XLRI. Some mild and severe XLRI phenotypes may be clinically difficult to distinguish from IV and ARCI (autosomal recessive congenital ichthyosis), respectively. Because around 90% of XLRI patients have substantial deletions, including STS and surrounding DNA, with contiguous gene loss in certain cases, fluorescence in situ hybridization (FISH) analysis is a valuable tool for detecting XLRI patients and carriers who have such deletions. Nonetheless, while FISH is useful in these circumstances, it is not useful in detecting other persons with partial deletions or point mutations. Autosomal recessive congenital ichthyosis ARCI refers to a collection of genetically and phenotypically diverse illnesses that includes harlequin ichthyosis (HI), lamellar ichthyosis (LI), and congenital ichthyosiform erythroderma (CIE). The incidence of ARCI has been estimated to be one in every 200,000 births. Loss-of-function mutations in ABCA12, which encodes an ATP-binding cassette (ABC) transporter, induce HI. ABCA12 is required for lipid transport into lamellar granules and is important in cornification and lipid barrier formation. Interestingly, while homozygous loss-of-function mutations in ABCA12 result in HI, missense mutations in ABCA12 result in milder LI/CIE symptoms. LI and CIE can be caused by mutations in one of nine genes – TGM1, NIPAL4/ICHTHYIN, ALOX12B, ALOXE3, CYP4F22, ABCA12, PNPLA1, CERS3, and LIPN16. TGM1 mutations are the most frequent and account for roughly 32% of ARCI17 heritability. A CIE baby is frequently born as a collodion baby. Erythroderma and scaling emerge after the collodion membrane is removed. The scales in CIE are often fine and white or light grey. The erythroderma in severe cases of CIE is systemic and permanent. However, erythroderma improves in childhood, especially in milder forms. Another minor form of ARCI is bathing suit ichthyosis (BSI). It is distinguished by a distinct pattern of lesions on the trunk, the most proximal sections of the upper limbs, the scalp, and the neck, but not on the central face and extremities. In South Africa, the term “bathing suit” ichthyosis was introduced to describe this peculiar phenotypic of lamellar ichthyosis. TGM1 missense mutations have been found in 20 BSI cases. Related Stories Neonates with HI have thick, armor-like scales on their skin, as well as significant ectropion (eversion of the eyelids), eclabium (eversion of the lips), and ear flattening. Some neonatal HI patients die; however, survival has improved with advances in neonatal intensive care and early treatment with systemic retinoids. Retinoids can help patients with lamellar ichthyosis, epidermolytic hyperkeratosis, or congenital ichthyosiform erythroderma because the drugs’ keratolytic properties allow shedding and prevent future hyperproliferation. It is recommended that these medications be provided in low, effective doses because their use in ichthyosis patients could be lifelong. Ichthyosis Vulgaris | Causes, Signs & Symptoms, Diagnosis, TreatmentPlay Keratinopathic ichthyosis Keratinopathic ichthyosis refers to disorders caused by gene mutations in the keratin family. Epidermolytic ichthyosis, or EI, is the most common type. Minor varieties include superficial EI (SEI), annular EI (AEI), and Curth-Macklin ichthyosis. Mutations in the keratin family genes KRT1, KRT2, and KRT10 cause all kinds of keratinopathic ichthyosis. EI is the most common keratinopathic ichthyotic phenotype, with extensive blister formation and numerous erosions with erythroderma. At birth, the patients have blistering and erythema, which fade with age, and in adulthood, they have extensive epidermolytic hyperkeratosis. Because there is so much phenotypic heterogeneity in EI,

BROOKLYN, NY, USA, September 5, 2023/EINPresswire.com/ — The report offers a comprehensive analysis of the leber congenital amaurosis market in the United States, EU5 (including Germany, Spain, Italy, France, and the United Kingdom), and Japan. It covers aspects such as treatment methods, drugs available in the market, drugs in development, the proportion of various therapies, and the market’s performance in the seven major regions. Additionally, the report evaluates the performance of leading companies and their pharmaceutical products. Current and projected patient numbers across these key markets are also detailed in the report. This study is essential for manufacturers, investors, business planners, researchers, consultants, and anyone interested or involved in the leber congenital amaurosis market. Request for a Sample Copy of this Report: https://www.imarcgroup.com/leber-congenital-amaurosis-market/requestsample Market Overview: The 7 major Leber congenital amaurosis markets are expected to exhibit a CAGR of 3.36% during 2023-2033. The Leber congenital amaurosis market is being driven by the growing prevalence of inherited eye disorders and the increasing demand for treatments that can decelerate the progression of vision loss. Besides this, the adoption of non-invasive imaging tests, including optical coherence tomography, which provides detailed retinal images and aids in the diagnosis of retinal diseases like LCA, is further accelerating market growth. Major players in the market are investing heavily in research to understand the genetic causes of LCA and develop new therapies, resulting in a positive impact on the market. Moreover, the use of low-vision devices such as magnifiers, large print books, and electronic aids to assist individuals with LCA in maximizing their remaining vision is also contributing to market expansion. Additionally, the increasing popularity of occupational therapy and rehabilitation services among LCA patients, helping them acquire the skills and techniques necessary for everyday activities like reading and navigating their surroundings, is expected to drive the Leber congenital amaurosis market in the forecasted period. Countries Covered: • United States• Germany• France• United Kingdom• Italy• Spain• Japan Analysis Covered Across Each Country: • Historical, current, and future epidemiology scenario• Historical, current, and future performance of the leber congenital amaurosis market• Historical, current, and future performance of various therapeutic categories in the market• Sales of various drugs across the leber congenital amaurosis market• Reimbursement scenario in the market• In-market and pipeline drugs This report also provides a detailed analysis of the current leber congenital amaurosis marketed drugs and late-stage pipeline drugs. In-Market Drugs: • Drug Overview• Mechanism of Action• Regulatory Status• Clinical Trial Results• Drug Uptake and Market Performance Late-Stage Pipeline Drugs: • Drug overview• Mechanism of action• Regulatory status• Clinical trial results• Drug uptake and market performance Competitive Landscape With Key Players: The competitive landscape of the leber congenital amaurosis market has been studied in the report with the detailed profiles of the key players operating in the market. Ask Analyst for Customization and Explore Full Report With TOC & List of Figures: https://www.imarcgroup.com/request?type=report&id=6909&flag=C If you need specific information that is not currently within the scope of the report, we will provide it to you as a part of the customization. About Us IMARC Group is a leading market research company that offers management strategy and market research worldwide. We partner with clients in all sectors and regions to identify their highest-value opportunities, address their most critical challenges, and transform their businesses. IMARC’s information products include major market, scientific, economic and technological developments for business leaders in pharmaceutical, industrial, and high technology organizations. Market forecasts and industry analysis for biotechnology, advanced materials, pharmaceuticals, food and beverage, travel and tourism, nanotechnology and novel processing methods are at the top of the company’s expertise. Elena AndersonIMARC Services Private Limited+1 631-791-1145email us here You just read: News Provided By September 05, 2023, 09:24 GMT Share This Article EIN Presswire’s priority is source transparency. We do not allow opaque clients, and our editors try to be careful about weeding out false and misleading content. As a user, if you see something we have missed, please do bring it to our attention. Your help is welcome. EIN Presswire, Everyone’s Internet News Presswire™, tries to define some of the boundaries that are reasonable in today’s world. Please see our Editorial Guidelines for more information. Submit your press release