J Allergy Clin Immunol. 2021 Jul 2:S0091-6749(21)01052-6. doi: 10.1016/j.jaci.2021.06.024. Online ahead of print.

ABSTRACT

BACKGROUND: Multisystem Inflammatory Syndrome in Children (MIS-C) is a pediatric complication of SARS-CoV-2 infection characterized by multiorgan inflammation and frequently, cardiovascular dysfunction. It occurs predominantly in otherwise healthy children. We previously reported haploinsufficiency of Suppressor of Cytokine Signaling 1 (SOCS1), a negative regulator of Type I and II interferons, as a genetic risk factor for MIS-C.

OBJECTIVES: We aimed to identify additional genetic mechanisms underlying susceptibility to SARS-CoV-2-associated MIS-C.

METHODS: In a single center, prospective cohort study, whole exome sequencing was performed on patients with MIS-C. The impact of candidate variants was tested using patients' peripheral blood mononuclear cells obtained at least seven months after recovery.

RESULTS: We enrolled 18 patients with MIS-C (median age: 8 years, IQR 5 - 12.25 years), of whom 89% had no conditions other than obesity. In two boys with no significant infection history, we identified and validated hemizygous, deleterious defects in XIAP, encoding X-linked inhibitor of apoptosis, and CYBB, encoding cytochrome b-245. Including the previously reported SOCS1 haploinsufficiency, a genetic diagnosis was identified in three (17%) of 18 patients. Even after recovery, patients with defects in SOCS1, XIAP, or CYBB exhibit an inflammatory immune cell transcriptome with enrichment of differentially expressed genes in pathways downstream of IL-18, oncostatin M, and NF-κB, compared to those with mild COVID-19.

CONCLUSIONS: Although inflammatory disorders are rare in the general population, our cohort of patients with MIS-C was enriched for monogenic susceptibility to inflammation. Our results support the use of next-generation sequencing in previously healthy children who develop MIS-C.

PMID:34224783 | DOI:10.1016/j.jaci.2021.06.024

Front Genet. 2021 Jun 17;12:674295. doi: 10.3389/fgene.2021.674295. eCollection 2021.

ABSTRACT

Rare genetic disorders, while individually rare, are collectively common. They represent some of the most severe disorders affecting patients worldwide with significant morbidity and mortality. Over the last decade, advances in genomic methods have significantly uplifted diagnostic rates for patients and facilitated novel and targeted therapies. However, many patients with rare genetic disorders still remain undiagnosed as the genetic etiology of only a proportion of Mendelian conditions has been discovered to date. This article explores existing strategies to identify novel Mendelian genes and how these discoveries impact clinical care and therapeutics. We discuss the importance of data sharing, phenotype-driven approaches, patient-led approaches, utilization of large-scale genomic sequencing projects, constraint-based methods, integration of multi-omics data, and gene-to-patient methods. We further consider the health economic advantages of novel gene discovery and speculate on potential future methods for improved clinical outcomes.

PMID:34220947 | PMC:PMC8248347 | DOI:10.3389/fgene.2021.674295

BMJ Open. 2021 Jul 2;11(7):e042856. doi: 10.1136/bmjopen-2020-042856.

ABSTRACT

OBJECTIVE: We aimed at developing a patient-centred self-help programme, tailored to the needs of patients with rare chronic diseases.

DESIGN: Multistage, multimethod development process including a survey with validated self-report scales and open-ended questions (phase 1) and focus groups (phase 2) for needs assessment and, consolidating the first phases and the literature, the intervention development (phase 3).

SETTING: Phase 1: nationwide online survey in Germany, phase 2: four separate and diagnostically homogeneous focus groups. The focus groups took place at a university medical centre in Germany.

PARTICIPANTS: Target group were patients with rare diseases that occur at a prevalence <1:2000. Phase 1: n=300 participants with different rare diseases. Phase 2: Individuals with neurofibromatosis type 1 (n=4), primary sclerosing cholangitis (n=5), pulmonary arterial hypertension (n=4) and Marfan syndrome (n=5).

RESULTS: The central results of phases 1 and 2 were requests for more information about the disease and contact with other affected persons. Patients also expressed support needs in dealing with difficult emotions and identified acceptance of the disease as a turning point for quality of life. In phase 3, we identified acceptance and commitment therapy (ACT) as a suitable therapeutic approach and determined details about implementation and execution of self-management programmes. A 6-week self-help concept led by peer counsellors was developed, which includes disease-specific information and ACT-based exercises.

CONCLUSION: Based on a multistage needs assessment, we developed a peer-guided self-help intervention for patients with rare chronic diseases. Combining self-management, peer-counselling and ACT may help living with a rare condition. Further research needs to test the programme's efficacy.

TRIAL REGISTRATION NUMBER: ISRCTN13738704.

PMID:34215596 | PMC:PMC8256734 | DOI:10.1136/bmjopen-2020-042856

Int J Environ Res Public Health. 2021 Jun 25;18(13):6830. doi: 10.3390/ijerph18136830.

ABSTRACT

Aim: The current study aims to assess levels of knowledge among Israeli dentists about rare diseases with orofacial manifestations, and whether occupational, regional and social factors influence those levels. Materials and Methods: A total of 309 Israeli dentists participated in an online survey that provided basic demographic information pertaining to their knowledge about rare diseases, their clinical experience with rare diseases, what further information they considered necessary, and which sources of information they most frequently utilize. Results: Young age, country of dental education, practicing in both public and private settings, as well as the number of hours allocated to dental studies and the opportunity to acquire information on rare diseases with orofacial manifestations, all seem to affect the level of knowledge. Conclusions: Developments in the field of rare disease are constantly ongoing, and improvements in post-graduate dental studies about them should keep pace. The results of the current study reveal the areas upon which such curricula should focus with respect to dental practitioners.

PMID:34202149 | PMC:PMC8297074 | DOI:10.3390/ijerph18136830

Int J Environ Res Public Health. 2021 Jun 17;18(12):6538. doi: 10.3390/ijerph18126538.

ABSTRACT

Rare diseases produce multiple impacts for the people who suffer from them, but they also have repercussions for their families, education and healthcare. The objective of this study is to analyze the coordination between healthcare and education professionals who intervene with children and adolescents with rare diseases. It is a qualitative study designed with a critical paradigm, and it was carried out through focus group discussions. A total of 50 people participated in the study, including healthcare professionals, teachers and families. The results suggest that poor communication and coordination negatively impact minors with rare diseases, placing an extra burden on their families, who take on an intermediary role in communication. Participants in the study recognized coordination as an area for improvement as it can compromise equitable social and health services and inclusive education. Other measures must also be put into action at the public administration level not only to establish protocols for intersectoral coordination, but also to increase the knowledge and awareness of staff involved in health and education interventions for children with rare diseases.

PMID:34204503 | PMC:PMC8296368 | DOI:10.3390/ijerph18126538

Biomolecules. 2021 Jun 28;11(7):953. doi: 10.3390/biom11070953.

ABSTRACT

Primary Sjögren's syndrome (pSS) is a systemic autoimmune disorder characterized by very heterogeneous features. The spectrum of this disorder may vary from benign but disabling symptoms such as dryness, due to lachrymal and salivary involvement, pain and fatigue, to systemic, potentially severe, manifestations that may involve any organ. In recent decades, the arrival of biotechnological therapy has offered new opportunities for the treatment of this-until now-orphan disease. Currently, the possible use of these new drugs in therapeutic trials has made it necessary to have reliable outcome measures to evaluate their efficacy in this disease. A great effort has been made in multicenter, often multinational, studies to develop and validate instruments capable of assessing the different disease-related features. The adoption in therapeutic trials of the newly developed outcome measures aimed at assessing systemic features and patient reported symptoms has often yielded disappointing results. These negative data have been ascribed, on the one hand, to the trial design not being completely appropriate, and, on the other hand, to the fact that a single instrument may be not sufficient to cover the great clinical heterogeneity of the disease features. There is now growing belief that composite end points that include instruments that are able to assess the various aspects of the disease may be more properly and successfully used in future therapeutic trials.

PMID:34203480 | DOI:10.3390/biom11070953

Orphanet J Rare Dis. 2021 Jun 30;16(1):292. doi: 10.1186/s13023-021-01925-y.

ABSTRACT

BACKGROUND: The number of market approvals of orphan medicinal products (OMPs) has been increasing steadily in the last 3 decades. While OMPs can offer a unique chance for patients suffering from rare diseases, they are usually very expensive. The growing number of approved OMPs increases their budget impact despite their low prevalence, making it pressing to find solutions to ethical challenges on how to fairly allocate scarce healthcare resources under this context. One potential solution could be to grant OMPs special status when considering them for reimbursement, meaning that they are subject to different, and less stringent criteria than other drugs. This study aims to provide a systematic analysis of moral reasons for and against such a special status for the reimbursement of OMPs in publicly funded healthcare systems from a multidisciplinary perspective.

RESULTS: With a systematic review of reasons, we identified 39 reasons represented in 243 articles (scientific and grey literature) for and against special status for the reimbursement of OMPs, then categorized them into nine topics. Taking a multidisciplinary perspective, we found that most articles came from health policy (n = 103) and health economics (n = 49). More articles took the position for a special status of OMPs (n = 97) than those against it (n = 31) and there was a larger number of reasons identified in favour (29 reasons) than against (10 reasons) this special status.

CONCLUSION: Results suggest that OMP reimbursement issues should be assessed and analysed from a multidisciplinary perspective. Despite the higher occurrence of reasons and articles in favour of a special status, there is no clear-cut solution for this ethical challenge. The binary perspective of whether or not OMPs should be granted special status oversimplifies the issue: both OMPs and rare diseases are too heterogeneous in their characteristics for such a binary perspective. Thus, the scientific debate should focus less on the question of disease prevalence but rather on how the important variability of different OMPs concerning e.g. target population, cost-effectiveness, level of evidence or mechanism of action could be meaningfully addressed and implemented in Health Technology Assessments.

PMID:34193232 | PMC:PMC8247078 | DOI:10.1186/s13023-021-01925-y

Brain Pathol. 2021 Jul;31(4):e12958. doi: 10.1111/bpa.12958.

ABSTRACT

Focal epilepsies are the largest epilepsy subtype and associated with significant morbidity. Somatic variation is a newly recognized genetic mechanism underlying a subset of focal epilepsies, but little is known about the processes through which somatic mosaicism causes seizures, the cell types carrying the pathogenic variants, or their developmental origin. Meanwhile, the inception of single cell biology has completely revolutionized the study of neurological diseases and has the potential to answer some of these key questions. Focusing on single cell genomics, transcriptomics, and epigenomics in focal epilepsy research, circumvents the averaging artifact associated with studying bulk brain tissue and offers the kind of granularity that is needed for investigating the consequences of somatic mosaicism. Here we have provided a brief overview of some of the most developed single cell techniques and the major considerations around applying them to focal epilepsy research.

PMID:34196990 | DOI:10.1111/bpa.12958

Am J Hum Genet. 2021 Jun 19:S0002-9297(21)00227-5. doi: 10.1016/j.ajhg.2021.06.003. Online ahead of print.

ABSTRACT

The genetic causes of global developmental delay (GDD) and intellectual disability (ID) are diverse and include variants in numerous ion channels and transporters. Loss-of-function variants in all five endosomal/lysosomal members of the CLC family of Cl- channels and Cl-/H+ exchangers lead to pathology in mice, humans, or both. We have identified nine variants in CLCN3, the gene encoding CIC-3, in 11 individuals with GDD/ID and neurodevelopmental disorders of varying severity. In addition to a homozygous frameshift variant in two siblings, we identified eight different heterozygous de novo missense variants. All have GDD/ID, mood or behavioral disorders, and dysmorphic features; 9/11 have structural brain abnormalities; and 6/11 have seizures. The homozygous variants are predicted to cause loss of ClC-3 function, resulting in severe neurological disease similar to the phenotype observed in Clcn3-/- mice. Their MRIs show possible neurodegeneration with thin corpora callosa and decreased white matter volumes. Individuals with heterozygous variants had a range of neurodevelopmental anomalies including agenesis of the corpus callosum, pons hypoplasia, and increased gyral folding. To characterize the altered function of the exchanger, electrophysiological analyses were performed in Xenopus oocytes and mammalian cells. Two variants, p.Ile607Thr and p.Thr570Ile, had increased currents at negative cytoplasmic voltages and loss of inhibition by luminal acidic pH. In contrast, two other variants showed no significant difference in the current properties. Overall, our work establishes a role for CLCN3 in human neurodevelopment and shows that both homozygous loss of ClC-3 and heterozygous variants can lead to GDD/ID and neuroanatomical abnormalities.

PMID:34186028 | DOI:10.1016/j.ajhg.2021.06.003

Mol Genet Metab. 2021 Jun 24:S1096-7192(21)00735-6. doi: 10.1016/j.ymgme.2021.06.006. Online ahead of print.

ABSTRACT

Early-onset forms of hereditary spastic paraplegia and inborn errors of metabolism that present with spastic diplegia are among the most common "mimics" of cerebral palsy. Early detection of these heterogenous genetic disorders can inform genetic counseling, anticipatory guidance, and improve outcomes, particularly where specific treatments exist. The diagnosis relies on clinical pattern recognition, biochemical testing, neuroimaging, and increasingly next-generation sequencing-based molecular testing. In this short review, we summarize the clinical and molecular understanding of: 1) childhood-onset and complex forms of hereditary spastic paraplegia (SPG5, SPG7, SPG11, SPG15, SPG35, SPG47, SPG48, SPG50, SPG51, SPG52) and, 2) the most common inborn errors of metabolism that present with phenotypes that resemble hereditary spastic paraplegia.

PMID:34183250 | DOI:10.1016/j.ymgme.2021.06.006

Ann Neurol. 2021 Jun 28. doi: 10.1002/ana.26149. Online ahead of print.

NO ABSTRACT

PMID:34180075 | DOI:10.1002/ana.26149

BMJ Case Rep. 2021 Jun 23;14(6):e243411. doi: 10.1136/bcr-2021-243411.

ABSTRACT

Generalised eruptive histiocytosis is a rare proliferative disease that typically presents with indolent cutaneous eruptions. We describe the case of a 73-year-old man presenting with diffuse, asymptomatic crops of pink to dusky red papules preceded by general malaise, myalgias, fluctuating fever, chills, and weight loss. Histological evaluation revealed a non-Langerhans cell histiocytic dermal infiltrate with spindle cell features and chronic inflammation, reactive for CD68 and negative for both S100 and CD1a. Malignancy screening was negative. This report aims to highlight a unique presentation of generalised eruptive histiocytosis, emphasise histological findings, and discuss considerations for malignancy screening.

PMID:34162620 | DOI:10.1136/bcr-2021-243411

Proc Natl Acad Sci U S A. 2021 Jun 22;118(25):e2023333118. doi: 10.1073/pnas.2023333118.

ABSTRACT

Osmotic equilibrium and membrane potential in animal cells depend on concentration gradients of sodium (Na+) and potassium (K+) ions across the plasma membrane, a function catalyzed by the Na+,K+-ATPase α-subunit. Here, we describe ATP1A3 variants encoding dysfunctional α3-subunits in children affected by polymicrogyria, a developmental malformation of the cerebral cortex characterized by abnormal folding and laminar organization. To gain cell-biological insights into the spatiotemporal dynamics of prenatal ATP1A3 expression, we built an ATP1A3 transcriptional atlas of fetal cortical development using mRNA in situ hybridization and transcriptomic profiling of ∼125,000 individual cells with single-cell RNA sequencing (Drop-seq) from 11 areas of the midgestational human neocortex. We found that fetal expression of ATP1A3 is most abundant to a subset of excitatory neurons carrying transcriptional signatures of the developing subplate, yet also maintains expression in nonneuronal cell populations. Moving forward a year in human development, we profiled ∼52,000 nuclei from four areas of an infant neocortex and show that ATP1A3 expression persists throughout early postnatal development, most predominantly in inhibitory neurons, including parvalbumin interneurons in the frontal cortex. Finally, we discovered the heteromeric Na+,K+-ATPase pump complex may form nonredundant cell-type-specific α-β isoform combinations, including α3-β1 in excitatory neurons and α3-β2 in inhibitory neurons. Together, the developmental malformation phenotype of affected individuals and single-cell ATP1A3 expression patterns point to a key role for α3 in human cortex development, as well as a cell-type basis for pre- and postnatal ATP1A3-associated diseases.

PMID:34161264 | DOI:10.1073/pnas.2023333118

Expert Opin Drug Saf. 2021 Jun 17. doi: 10.1080/14740338.2021.1945031. Online ahead of print.

ABSTRACT

INTRODUCTION: Waldenström's macroglobulinemia (WM), an orphan disease, is a rare low-grade B-cell lymphoplasmacytic lymphoma with unique clinical features and monoclonal IgM production. Rituximab remains to this date the backbone of most commonly used treatment combinations. The FDA/EMA approval of Ibrutinib, the first-in-class BTK inhibitor, either as monotherapy or in combination with rituximab, changed the treatment landscape of the disease.

AREAS COVERED: Clinical trial data that demonstrate mode of action, efficacy and the safety profile of each agent will be covered. A safety analysis of the combination treatment will also be performed to point out its high efficacy and overall favorable toxicity profile. The disadvantages and treatment gaps that still exist in the treatment of WM which relate to the need for long-term ibrutinib administration and the lack of deep remissions and subsequent disease relapse, will also be reviewed.

EXPERT OPINION: The ibrutinib-rituximab combination is both effective and safe, in the newly-diagnosed and relapsed-refractory disease setting. The optimal therapeutic approach for WM patients remains however to be established. The question of which combinatory (or synergistic) regimen can allow for a fixed-treatment duration, deep and durable responses with a safe toxicity profile is being addressed in ongoing clinical trials.

PMID:34137347 | DOI:10.1080/14740338.2021.1945031

Orphanet J Rare Dis. 2021 Jun 14;16(1):275. doi: 10.1186/s13023-021-01907-0.

ABSTRACT

BACKGROUND: Rare diseases (RDs) encompass a heterogeneous group of life-threatening or chronically debilitating conditions that individually affect a small number of subjects but overall represent a major public health issue globally. There are still limited data on RD burden due to the paucity of large population-based epidemiological studies. The aim of this research was to provide survival estimates of patients with a RD residing in Tuscany, Italy.

METHODS: Cases collected in the Rare Diseases Registry of Tuscany with diagnosis between 1st January 2000 and 31th December 2018 were linked to the regional health databases in order to retrieve information on mortality of all subjects. Survival at 1, 5 and 10 years from diagnosis with 95% confidence intervals (CI) was estimated by sex, age class, nosological group and subgroup using the Kaplan-Meier method. The effect of sex, age and period of diagnosis (years 2000-2009 or 2010-2018) on survival was estimated using Cox proportional hazards regression.

RESULTS: Survival at 1, 5 and 10 years from diagnosis was 97.3%, 88.8% and 80.8%, respectively. Respiratory diseases and peripheral and central nervous system disorders were characterized by the lowest survival at 5 and 10 years. Despite a modest higher prevalence of RDs among females (54.0% of the total), male cases had a significant increased risk of death (hazard ratio, HR 1.48, 95% CI 1.38-1.58). Cases diagnosed during 2010-2018 period had a risk of death significantly lower than those diagnosed during 2000-2009 (HR 0.81, 95% CI 0.82-0.96), especially for immune system disorders (HR 0.48, 95% CI 0.26-0.87), circulatory system diseases (HR 0.61, 95% CI 0.45-0.84) and diseases of the musculoskeletal system and connective tissue (HR 0.64, 95% CI 0.49-0.84).

CONCLUSIONS: An earlier diagnosis as well as the improvement in the efficacy of treatment resulted in a decreased risk of death over the years for specific RDs. The linkage between a population-based registry and other regional databases exploited in this study provides a large and accurate mass of data capable of estimating patients' life-expectancy and increasing knowledge on the collective burden of RDs.

PMID:34127030 | PMC:PMC8201697 | DOI:10.1186/s13023-021-01907-0

Pharmacol Rev. 2021 Jul;73(3):968-1000. doi: 10.1124/pharmrev.120.000171.

ABSTRACT

Activation of the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome drives release of the proinflammatory cytokines interleukin (IL)-1β and IL-18 and induces pyroptosis (lytic cell death). These events drive chronic inflammation, and as such, NLRP3 has been implicated in a large number of human diseases. These range from autoimmune conditions, the simplest of which is NLRP3 gain-of-function mutations leading to an orphan disease, cryopyrin-associated period syndrome, to large disease burden indications, such as atherosclerosis, heart failure, stroke, neurodegeneration, asthma, ulcerative colitis, and arthritis. The potential clinical utility of NLRP3 inhibitors is substantiated by an expanding list of indications in which NLRP3 activation has been shown to play a detrimental role. Studies of pharmacological inhibition of NLRP3 in nonclinical models of disease using MCC950 in combination with human genetics, epigenetics, and analyses of the efficacy of biologic inhibitors of IL-1β, such as anakinra and canakinumab, can help to prioritize clinical trials of NLRP3-directed therapeutics. Although MCC950 shows excellent (nanomolar) potency and high target selectivity, its pharmacokinetic and toxicokinetic properties limited its therapeutic development in the clinic. Several improved, next-generation inhibitors are now in clinical trials. Hence the body of research in a plethora of conditions reviewed herein may inform analysis of the potential translational value of NLRP3 inhibition in diseases with significant unmet medical need. SIGNIFICANCE STATEMENT: The nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is one of the most widely studied and best validated biological targets in innate immunity. Activation of NLRP3 can be inhibited with MCC950, resulting in efficacy in more than 100 nonclinical models of inflammatory diseases. As several next-generation NLRP3 inhibitors are entering proof-of-concept clinical trials in 2020, a review of the pharmacology of MCC950 is timely and significant.

PMID:34117094 | DOI:10.1124/pharmrev.120.000171

Genet Med. 2021 Jun 10. doi: 10.1038/s41436-021-01218-6. Online ahead of print.

ABSTRACT

PURPOSE: ADP ribosylation factor guanine nucleotide exchange factors (ARFGEFs) are a family of proteins implicated in cellular trafficking between the Golgi apparatus and the plasma membrane through vesicle formation. Among them is ARFGEF1/BIG1, a protein involved in axon elongation, neurite development, and polarization processes. ARFGEF1 has been previously suggested as a candidate gene for different types of epilepsies, although its implication in human disease has not been well characterized.

METHODS: International data sharing, in silico predictions, and in vitro assays with minigene study, western blot analyses, and RNA sequencing.

RESULTS: We identified 13 individuals with heterozygous likely pathogenic variants in ARFGEF1. These individuals displayed congruent clinical features of developmental delay, behavioral problems, abnormal findings on brain magnetic resonance image (MRI), and epilepsy for almost half of them. While nearly half of the cohort carried de novo variants, at least 40% of variants were inherited from mildly affected parents who were clinically re-evaluated by reverse phenotyping. Our in silico predictions and in vitro assays support the contention that ARFGEF1-related conditions are caused by haploinsufficiency, and are transmitted in an autosomal dominant fashion with variable expressivity.

CONCLUSION: We provide evidence that loss-of-function variants in ARFGEF1 are implicated in sporadic and familial cases of developmental delay with or without epilepsy.

PMID:34113008 | DOI:10.1038/s41436-021-01218-6

Orphanet J Rare Dis. 2021 Jun 9;16(1):265. doi: 10.1186/s13023-021-01901-6.

ABSTRACT

BACKGROUND: Orphan drug designations are a useful proxy to investigate trends in rare disease drug development. Drug developers must receive a designation before they are eligible for the economic incentives of the Orphan Drug Act in the United States. We created a database of all orphan drugs designated between 1983 and 2019 that included numerous drug characteristics, including therapeutic area. In addition, we constructed a "broad disease" categorization of designations as an alternative to therapeutic area, based on disease etiology and age of onset rather than organ system. By looking at the pattern of orphan drug designations over the past four decades, this analysis studied the impact of the evolving rare disease drug development landscape and considers the future of rare disease therapies over the coming decades.

RESULTS: Between 1983 and 2019, a total of 5099 drugs and biologics received orphan drug designation. Designations more than doubled between the 1980s and 1990s, almost doubled between the 1990s and 2000s, and almost tripled in number between the 2000s and 2010s. The top three therapeutic areas represented in the orphan drug designations were: oncology (1910, 37%), neurology (674, 13%), and infectious diseases (436, 9%). The broad disease categorization found that the proportion of designations for pediatric-onset diseases has increased in the most recent decade to 27%.

CONCLUSIONS: Analysis of the last four decades of orphan drug designation indicates seismic shifts have occurred in the rare disease drug development space. The number of designations granted more than quadrupled between the 1990s and 2010s. While these substantial increases led to growth in the absolute number of designations within all therapeutic areas (bar one) and broad disease categories, the relative proportions have seen considerable change over time. In the most recent decade, there have been notable increases in the proportion of drugs in oncology, pediatric-onset diseases, and neurologic disorders. The dramatic rise in overall orphan designations over the past four decades suggests we may continue to see an upward trajectory in designations leading to an increased number of approvals for drugs and biologics designed specifically for diagnosing, preventing, and treating rare diseases in the coming decades.

PMID:34107994 | PMC:PMC8191002 | DOI:10.1186/s13023-021-01901-6

Chemistry. 2021 Aug 5;27(44):11291-11297. doi: 10.1002/chem.202101408. Epub 2021 Jul 2.

ABSTRACT

Mucopolysaccharidosis type IIIB is a devastating neurological disease caused by a lack of the lysosomal enzyme, α-N-acetylglucosaminidase (NAGLU), leading to a toxic accumulation of heparan sulfate. Herein we explored a pharmacological chaperone approach to enhance the residual activity of NAGLU in patient fibroblasts. Capitalizing on the three-dimensional structures of two modest homoiminosugar-based NAGLU inhibitors in complex with bacterial homolog of NAGLU, CpGH89, we have synthesized a library of 17 iminosugar C-glycosides mimicking N-acetyl-D-glucosamine and bearing various pseudo-anomeric substituents of both α- and β-configuration. Elaboration of the aglycon moiety results in low micromolar selective inhibitors of human recombinant NAGLU, but surprisingly it is the non-functionalized and wrongly configured β-homoiminosugar that was proved to act as the most promising pharmacological chaperone, promoting a 2.4 fold activity enhancement of mutant NAGLU at its optimal concentration.

PMID:34106504 | DOI:10.1002/chem.202101408

Andes Pediatr. 2021 Apr;92(2):309-315. doi: 10.32641/andespediatr.v92i2.3716.

ABSTRACT

In the framework of the vaccination campaign against the SARS-CoV-2 virus, the Chilean Ministry of Health requested advice from the Genetics Branch of the Chilean Society of Pediatrics, to define the level of prioritization for people with Down Syndrome . A panel of geneticists worked on the development of this consensus, in which not only patients with Down syndrome were included, but the search was extended to patients with other types of disabilities, in both pediatric and adult ages in or der to contribute to the development of public health measures against the COVID-19 pandemic. The consensus concludes that, given the prevalence of comorbidities associated with Down syndrome, the higher incidence of cases with severe COVID-19 in this population group and a higher mortality, individuals with trisomy 21 should be considered as a high-risk population, and therefore, vaccina tion against SARS-CoV-2 should have a high priority for all people with Down syndrome regardless of their age (except for the age limit established by the clinical trials of each vaccine), and should be preceded only by the groups of health personnel and adults aged > 60-65 years. Likewise, this group of experts urges health authorities to include people with intellectual disabilities and related conditions as a priority population (other chromosomal abnormalities other than Down syndrome, intellectual disability, congenital anomalies and conditions that cause disability with microcephaly), as well as the caregivers of people with this type of conditions. Vaccination in children with this type of disorders should be considered as part of the first priority group, once safe vaccines against SARS-CoV-2 are available for use in children and adolescents.

PMID:34106172 | DOI:10.32641/andespediatr.v92i2.3716