Nat Neurosci. 2021 Mar 22. doi: 10.1038/s41593-021-00830-8. Online ahead of print.

NO ABSTRACT

PMID:33753946 | DOI:10.1038/s41593-021-00830-8

BMJ Case Rep. 2021 Mar 18;14(3):e235976. doi: 10.1136/bcr-2020-235976.

ABSTRACT

Riga-Fede disease (RFD), also known as traumatic eosinophilic granuloma, is a benign inflammatory condition of the oral cavity that may mimic a malignant tumour. It's a rare condition mainly reported in infants. We present a unique case report of a 57-year-old man who presented to our outpatient department with foreign body sensation in the throat and swelling over the dorsum of the tongue for a period of 1 month. He gave no history of trauma, especially due to sharp teeth. Video laryngoscopy done revealed an ulceroproliferative growth on the midline of the dorsum of the tongue. With clinical suspicion of malignancy, the patient underwent wide local excision of the tongue lesion. Histopathological examination was suggestive of RFD. The postoperative follow-up was uneventful with good wound healing. The patient was followed up with no evidence of recurrence.

PMID:33737272 | PMC:PMC7978262 | DOI:10.1136/bcr-2020-235976

Science. 2021 Mar 19;371(6535):1249-1253. doi: 10.1126/science.abe1544.

ABSTRACT

Although cell lineage information is fundamental to understanding organismal development, very little direct information is available for humans. We performed high-depth (250×) whole-genome sequencing of multiple tissues from three individuals to identify hundreds of somatic single-nucleotide variants (sSNVs). Using these variants as "endogenous barcodes" in single cells, we reconstructed early embryonic cell divisions. Targeted sequencing of clonal sSNVs in different organs (about 25,000×) and in more than 1000 cortical single cells, as well as single-nucleus RNA sequencing and single-nucleus assay for transposase-accessible chromatin sequencing of ~100,000 cortical single cells, demonstrated asymmetric contributions of early progenitors to extraembryonic tissues, distinct germ layers, and organs. Our data suggest onset of gastrulation at an effective progenitor pool of about 170 cells and about 50 to 100 founders for the forebrain. Thus, mosaic mutations provide a permanent record of human embryonic development at very high resolution.

PMID:33737485 | DOI:10.1126/science.abe1544

Ann Oncol. 2021 Mar 15:S0923-7534(21)00877-2. doi: 10.1016/j.annonc.2021.02.025. Online ahead of print.

ABSTRACT

Small cell lung cancer (SCLC) is an aggressive malignancy accounting for 15% of all diagnosed cases of lung cancer. After more than 15 years without any clinically relevant therapeutic advances, extensive disease SCLC has become the second thoracic malignancy for which immune checkpoint inhibitors (ICIs) have shifted the treatment paradigm to improve overall survival. Today, atezolizumab or durvalumab in combination with platinum-etoposide chemotherapy is considered the new standard of care in the first-line setting in SCLC. However, the magnitude of benefit with this immune-chemotherapy strategy in SCLC is more modest than that observed in metastatic non-small cell lung cancer patients. The immunosuppressive phenotype of SCLC plays an important role in hampering ICI efficacy, and may explain the differences in outcomes between these two types of lung cancer. In this review, we provide a summary of recent therapeutic advances in SCLC in light of ICI, as well as current challenges of this strategy in patients who are elderly, have poor performance status or brain metastases. We also address future perspectives of immunotherapeutic strategies currently in clinical development for these patients.

PMID:33737119 | DOI:10.1016/j.annonc.2021.02.025

Kardiologiia. 2021 Feb 10;61(1):72-77. doi: 10.18087/cardio.2021.1.n1475.

ABSTRACT

Aim To analyze cases of idiopathic recurrent pericarditis (IRP) in the structure of pericardial diseases of various origins from patient visits to the Multidisciplinary Federal Center.Material and methods A retrospective analysis of case records was performed for patients admitted to the V.A. Almazov National Medical Research Center from January 1, 2015 through January 1, 2020 for pericardial effusion of different etiologies.Results For the study period, 4 981 new cases of pericardial damage of different etiologies were found. Among these cases, postpericardiotomy syndrome accounted for 4 360 cases and pericarditis for 621 cases. IRP was detected in 34 cases, which amounted to 5.4 %. Based on the study data, the estimated IRP prevalence in the Russian Federation can be 1.1 cases per 100 thousand population.Conclusion IRP should be regarded as a new autoinflammatory disease, the prevalence of which borders on that of adult Still disease and should be addressed within the concept of orphan diseases. Current knowledge of the pathogenesis and data from recent studies demonstrated a great importance of interleukin-1 blockade as a leading mechanism for achieving remission. This has justified conduction of a randomized clinical study at the Center.

PMID:33734057 | DOI:10.18087/cardio.2021.1.n1475

Mov Disord. 2021 May;36(5):1119-1124. doi: 10.1002/mds.28560. Epub 2021 Mar 16.

NO ABSTRACT

PMID:33724530 | DOI:10.1002/mds.28560

Laryngorhinootologie. 2021 May;100(5):372-381. doi: 10.1055/a-1402-0543. Epub 2021 Mar 15.

ABSTRACT

OBJECTIVE: Hereditary Hemorrhagic Telangiectasia (HHT) is a rare and systemic disorder which is characterized by recurrent epistaxis, mucocutaneous telangiectases, and visceral arteriovenous malformations (AVM). An interdisciplinary concept is recommended.

MATERIAL AND METHODS: We performed a retrospective review of consecutive patients who were referred to our newly established HHT Center of Excellence (HHT COE) for evaluation and treatment between April 2014 and August 2019.

RESULTS: A network of over 20 departments was established at the University Hospital Essen. In 261 of the 282 patients (93 %), who were referred to the hospital's COE, the HHT diagnosis was at least possible. Most patients suffered from several symptoms (epistaxis and / or telangiectasia: > 80 %, visceral involvement: 65 %) and received a variety of treatments, often in a multidisciplinary setting. Alongside this direct treatment, the COE leader manages the coordination of the center and its public relations, which involves more than 900 e-mails per year. International collaboration and exchanges of expertise within the European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN) can improve the treatment of patients with HHT particularly where these cases are complex.

CONCLUSIONS: An HHT COE provides an interdisciplinary network where highly specialized diagnostic and therapeutic processes can be updated and optimized continuously.

PMID:33723832 | DOI:10.1055/a-1402-0543

J Med Internet Res. 2021 Mar 16;23(3):e21023. doi: 10.2196/21023.

ABSTRACT

BACKGROUND: 16p13.11 microduplication syndrome has a variable presentation and is characterized primarily by neurodevelopmental and physical phenotypes resulting from copy number variation at chromosome 16p13.11. Given its variability, there may be features that have not yet been reported. The goal of this study was to use a patient "self-phenotyping" survey to collect data directly from patients to further characterize the phenotypes of 16p13.11 microduplication syndrome.

OBJECTIVE: This study aimed to (1) discover self-identified phenotypes in 16p13.11 microduplication syndrome that have been underrepresented in the scientific literature and (2) demonstrate that self-phenotyping tools are valuable sources of data for the medical and scientific communities.

METHODS: As part of a large study to compare and evaluate patient self-phenotyping surveys, an online survey tool, Phenotypr, was developed for patients with rare disorders to self-report phenotypes. Participants with 16p13.11 microduplication syndrome were recruited through the Boston Children's Hospital 16p13.11 Registry. Either the caregiver, parent, or legal guardian of an affected child or the affected person (if aged 18 years or above) completed the survey. Results were securely transferred to a Research Electronic Data Capture database and aggregated for analysis.

RESULTS: A total of 19 participants enrolled in the study. Notably, among the 19 participants, aggression and anxiety were mentioned by 3 (16%) and 4 (21%) participants, respectively, which is an increase over the numbers in previously published literature. Additionally, among the 19 participants, 3 (16%) had asthma and 2 (11%) had other immunological disorders, both of which have not been previously described in the syndrome.

CONCLUSIONS: Several phenotypes might be underrepresented in the previous 16p13.11 microduplication literature, and new possible phenotypes have been identified. Whenever possible, patients should continue to be referenced as a source of complete phenotyping data on their condition. Self-phenotyping may lead to a better understanding of the prevalence of phenotypes in genetic disorders and may identify previously unreported phenotypes.

PMID:33724192 | DOI:10.2196/21023

Stem Cell Res. 2021 Mar 5;53:102276. doi: 10.1016/j.scr.2021.102276. Online ahead of print.

ABSTRACT

CDKL5 Deficiency Disorder (CDD) is a rare X-linked monogenic developmental encephalopathy that is estimated to affect 1:42,000 live births. CDD is caused by pathogenic variants in the CDKL5 gene and is observed in both male and female patients. Here, we report the generation and characterization of induced pluripotent stem cells (iPSCs) derived from fibroblasts of six unrelated CDD patients-three males and three females. These patients are clinically diagnosed to present with classic CDD phenotypes, including refractory epilepsy and global developmental delay, and are being followed in a longitudinal clinical study.

PMID:33714067 | DOI:10.1016/j.scr.2021.102276

BMJ Case Rep. 2021 Mar 10;14(3):e239331. doi: 10.1136/bcr-2020-239331.

ABSTRACT

A 75-year-old man was referred to our urology service with painless haematuria. The delayed phase on a subsequent computed tomography (CT) abdomen and pelvis showed a filling defect in the left renal pelvicalyceal system, suspicious for a transitional cell carcinoma. The patient underwent ureteroscopic biopsy suggestive of a papillary neoplasia, before progressing to a laparoscopic radical left nephrouretectomy. Final histology revealed a fumarate hydratase-deficient renal cell carcinoma with clear margins. The patient was subsequently referred for genetic counselling.

PMID:33692051 | PMC:PMC7949369 | DOI:10.1136/bcr-2020-239331

J Nutr. 2021 Mar 9:nxab005. doi: 10.1093/jn/nxab005. Online ahead of print.

ABSTRACT

BACKGROUND: Maternal iron deficiency (ID) is associated with poor pregnancy and fetal outcomes. The effect is thought to be mediated by the placenta but there is no comprehensive assessment of placental responses to maternal ID. Additionally, whether the influence of maternal ID on the placenta differs by fetal sex is unknown.

OBJECTIVES: To identify gene and protein signatures of ID mouse placentas at mid-gestation. A secondary objective was to profile the expression of iron genes in mouse placentas across gestation.

METHODS: We used a real-time PCR-based array to determine the mRNA expression of all known iron genes in mouse placentas at embryonic day (E) 12.5, E14.5, E16.5, and E19.5 (n = 3 placentas/time point). To determine the effect of maternal ID, we performed RNA sequencing and proteomics in male and female placentas from ID and iron-adequate mice at E12.5 (n = 8 dams/diet).

RESULTS: In female placentas, 6 genes, including transferrin receptor (Tfrc) and solute carrier family 11 member 2, were significantly changed by maternal ID. An additional 154 genes were altered in male ID placentas. A proteomic analysis quantified 7662 proteins in the placenta. Proteins translated from iron-responsive element (IRE)-containing mRNA were altered in abundance; ferritin and ferroportin 1 decreased, while TFRC increased in ID placentas. Less than 4% of the significantly altered genes in ID placentas occurred both at the transcriptional and translational levels.

CONCLUSIONS: Our data demonstrate that the impact of maternal ID on placental gene expression in mice is limited in scope and magnitude at mid-gestation. We provide strong evidence for IRE-based transcriptional and translational coordination of iron gene expression in the mouse placenta. Finally, we discover sexually dimorphic effects of maternal ID on placental gene expression, with more genes and pathways altered in male compared with female mouse placentas.

PMID:33693820 | DOI:10.1093/jn/nxab005

Front Neurol. 2021 Feb 22;12:642228. doi: 10.3389/fneur.2021.642228. eCollection 2021.

ABSTRACT

In order to improve clinical care, coordinate research activities and raise awareness for the ultra-orphan Neurodegeneration with Brain Iron Accumulation (NBIA) disorders, a group of NBIA clinicians and researchers, industry partners and patient advocacies from six European countries, Canada and the US joined forces in 2010 to set-up the collaborative initiative TIRCON (Treat Iron-Related Childhood-Onset Neurodegeneration). As a research project, TIRCON received funding in the 7th Framework Programme (FP7) of the European Union (EU) from 2011 to 2015. After successful and timely completion of the initial FP7 project, funding and donations from industry and patient organizations have sustained the further development of TIRCON's dedicated clinical research infrastructure and its governance architecture, as well as the ongoing efforts undertaken in the NBIA community to establish a network of care. From the beginning, the University Hospital of the Ludwig-Maximilians-University in Munich, Germany has been coordinating the TIRCON initiative. It consists of 8 work packages, of which the first double-blind, placebo-controlled, randomized, multi-site clinical trial in NBIA (deferiprone in PKAN, completed) and a global patient registry and biobank, currently comprising baseline and follow-up data of > 400 NBIA patients have gained particular importance. Here we describe TIRCON's history with all the challenges and achievements in diagnosing and treating NBIA. Today, TIRCON lays the ground for future clinical care and research. In these times, it may also serve as a good example of well-directed governmental funding and fruitful international scientific collaboration.

PMID:33692746 | PMC:PMC7937633 | DOI:10.3389/fneur.2021.642228

J Eur Acad Dermatol Venereol. 2021 Apr;35(4):783-784. doi: 10.1111/jdv.17165.

NO ABSTRACT

PMID:33689185 | DOI:10.1111/jdv.17165

Wien Med Wochenschr. 2021 Apr;171(5-6):94-101. doi: 10.1007/s10354-021-00820-2. Epub 2021 Mar 10.

ABSTRACT

Skeletal disorders are inherited disorders with significant skeletal involvement and most of them are rare or extremely rare. Based on the clinical, radiological and genetic phenotype, the group of skeletal disorder comprises more than 450 different and highly heterogeneous disorders. In skeletal disorders rapid and precise diagnoses are urgently needed for patient care and are based on the combination of clinical, radiological and genetic analysis. Novel genetic techniques have revolutionized diagnostics and have a huge impact on counseling of patients and families. Disease-specific long-term management in a multidisciplinary healthcare team in highly specialized centers is recommended to optimize care for these patients. Here we describe a multidisciplinary postnatal approach for the diagnosis and management of patients and families with rare skeletal disorders at the Vienna Bone and Growth Center. We discuss the value of a multidisciplinary diagnostic and management approach in the postnatal setting and provide a diagnostic flowchart for rare skeletal disorders.

PMID:33689085 | DOI:10.1007/s10354-021-00820-2

Pharmacol Rev. 2021 Apr;73(2):792-827. doi: 10.1124/pharmrev.120.000072.

ABSTRACT

The complement system was discovered at the end of the 19th century as a heat-labile plasma component that "complemented" the antibodies in killing microbes, hence the name "complement." Complement is also part of the innate immune system, protecting the host by recognition of pathogen-associated molecular patterns. However, complement is multifunctional far beyond infectious defense. It contributes to organ development, such as sculpting neuron synapses, promoting tissue regeneration and repair, and rapidly engaging and synergizing with a number of processes, including hemostasis leading to thromboinflammation. Complement is a double-edged sword. Although it usually protects the host, it may cause tissue damage when dysregulated or overactivated, such as in the systemic inflammatory reaction seen in trauma and sepsis and severe coronavirus disease 2019 (COVID-19). Damage-associated molecular patterns generated during ischemia-reperfusion injuries (myocardial infarction, stroke, and transplant dysfunction) and in chronic neurologic and rheumatic disease activate complement, thereby increasing damaging inflammation. Despite the long list of diseases with potential for ameliorating complement modulation, only a few rare diseases are approved for clinical treatment targeting complement. Those currently being efficiently treated include paroxysmal nocturnal hemoglobinuria, atypical hemolytic-uremic syndrome, myasthenia gravis, and neuromyelitis optica spectrum disorders. Rare diseases, unfortunately, preclude robust clinical trials. The increasing evidence for complement as a pathogenetic driver in many more common diseases suggests an opportunity for future complement therapy, which, however, requires robust clinical trials; one ongoing example is COVID-19 disease. The current review aims to discuss complement in disease pathogenesis and discuss future pharmacological strategies to treat these diseases with complement-targeted therapies. SIGNIFICANCE STATEMENT: The complement system is the host's defense friend by protecting it from invading pathogens, promoting tissue repair, and maintaining homeostasis. Complement is a double-edged sword, since when dysregulated or overactivated it becomes the host's enemy, leading to tissue damage, organ failure, and, in worst case, death. A number of acute and chronic diseases are candidates for pharmacological treatment to avoid complement-dependent damage, ranging from the well established treatment for rare diseases to possible future treatment of large patient groups like the pandemic coronavirus disease 2019.

PMID:33687995 | PMC:PMC7956994 | DOI:10.1124/pharmrev.120.000072

Internist (Berl). 2021 Apr;62(4):441-448. doi: 10.1007/s00108-021-00986-2. Epub 2021 Mar 9.

ABSTRACT

Patients with rare diseases often receive insufficient medical care. The European Reference Networks (ERNs) were initiated by the European Union to improve healthcare for patients with rare and complex diseases within Europe. The Reference Network on Hepatological Diseases (ERN RARE-LIVER), which consists of hepatological centres, scientific societies and numerous patient organizations, is one of 24 ERNs. The aim of ERN RARE-LIVER is high-quality healthcare for patients suffering from rare liver diseases, regardless of their place of residence. Standardization of treatment, coordination of research projects as well as training and teaching of patients, patient representatives and healthcare professionals are means to reach this goal. Virtual case discussions are offered via a web-based platform (Clinical Patient Management System), in which experts from the ERNs advise treating physicians on the diagnosis and therapy of rare diseases.

PMID:33687527 | DOI:10.1007/s00108-021-00986-2

Epilepsia Open. 2021 Jan 13;6(1):160-170. doi: 10.1002/epi4.12459. eCollection 2021 Mar.

ABSTRACT

OBJECTIVE: Clinical care of rare and complex epilepsies is challenging, because evidence-based treatment guidelines are scarce, the experience of many physicians is limited, and interdisciplinary treatment of comorbidities is required. The pathomechanisms of rare epilepsies are, however, increasingly understood, which potentially fosters novel targeted therapies. The objectives of our survey were to obtain an overview of the clinical practice in European tertiary epilepsy centers treating patients with 5 arbitrarily selected rare epilepsies and to get an estimate of potentially available patients for future studies.

METHODS: Members of the European Reference Network for rare and complex epilepsies (EpiCARE) were invited to participate in a web-based survey on clinical practice of patients with Dravet syndrome, tuberous sclerosis complex (TSC), autoimmune encephalitis, and progressive myoclonic epilepsies including Unverricht Lundborg and Unverricht-like diseases. A consensus-based questionnaire was generated for each disease.

RESULTS: Twenty-six of 30 invited epilepsy centers participated. Cohorts were present in most responding centers for TSC (87%), Dravet syndrome (85%), and autoimmune encephalitis (71%). Patients with TSC and Dravet syndrome represented the largest cohorts in these centers. The antiseizure drug treatments were rather consistent across the centers especially with regard to Dravet syndrome, infantile spasms in TSC, and Unverricht Lundborg / Unverricht-like disease. Available, widely used targeted therapies included everolimus in TSC and immunosuppressive therapies in autoimmune encephalitis. Screening for comorbidities was routinely done, but specific treatment protocols were lacking in most centers.

SIGNIFICANCE: The survey summarizes the current clinical practice for selected rare epilepsies in tertiary European epilepsy centers and demonstrates consistency as well as heterogeneity in the treatment, underscoring the need for controlled trials and recommendations. The survey also provides estimates for potential participants of clinical trials recruited via EpiCARE, emphasizing the great potential of Reference Networks for future studies to evaluate new targeted therapies and to identify novel biomarkers.

PMID:33681659 | PMC:PMC7918306 | DOI:10.1002/epi4.12459

Int J Mol Sci. 2021 Feb 25;22(5):2308. doi: 10.3390/ijms22052308.

ABSTRACT

Warsaw breakage syndrome (WABS) is a genetic disorder characterized by sister chromatid cohesion defects, growth retardation, microcephaly, hearing loss and other variable clinical manifestations. WABS is due to biallelic mutations of the gene coding for the super-family 2 DNA helicase DDX11/ChlR1, orthologous to the yeast chromosome loss protein 1 (Chl1). WABS is classified in the group of "cohesinopathies", rare hereditary diseases that are caused by mutations in genes coding for subunits of the cohesin complex or protein factors having regulatory roles in the sister chromatid cohesion process. In fact, among the cohesion regulators, an important player is DDX11, which is believed to be important for the functional coupling of DNA synthesis and cohesion establishment at the replication forks. Here, we will review what is known about the molecular and cellular functions of human DDX11 and its role in WABS etiopathogenesis, even in light of recent findings on the role of cohesin and its regulator network in promoting chromatin loop formation and regulating chromatin spatial organization.

PMID:33669056 | PMC:PMC7956524 | DOI:10.3390/ijms22052308

Nat Methods. 2021 Mar;18(3):224-225. doi: 10.1038/s41592-021-01089-4.

NO ABSTRACT

PMID:33674793 | DOI:10.1038/s41592-021-01089-4

Orphanet J Rare Dis. 2021 Mar 5;16(1):119. doi: 10.1186/s13023-021-01766-9.

ABSTRACT

BACKGROUND: This study assesses the areas and extent of impact of the Coronavirus Disease of 2019 (COVID-19) pandemic on rare disease (RD) organisations in the Asia Pacific region. There is no existing literature that focuses on such impact on RD organisations in any jurisdictions, nor RD populations across multiple jurisdictions in the Asia Pacific region. A cross-sectional survey was distributed to RD organisations between April and May 2020. Quantitative and qualitative data on the impact of COVID-19 on RD organisations and patients were collected from the organisation representative's perspective. Qualitative data was analysed using thematic analysis. A follow-up focus group meeting was conducted in August 2020 to validate the survey findings and to discuss specific needs, support and recommendations for sustainable healthcare systems during the pandemic.

RESULTS: A total of 80 RD organisations from Australia, Hong Kong Special Administrative Region of China, India, Japan, mainland China, Malaysia, New Zealand, the Philippines, Singapore and Taiwan participated in the study. Of all, 89% were concerned about the impact of pandemic on their organisations. Results indicate that 63% of the organisations functioned at a reduced capacity and 42% stated a decrease in funding as their biggest challenge. Overall, 95% believed their patients were impacted, particularly in healthcare access, social lives, physical health, psychological health and financial impact. Specifically, 43% identified the reduced healthcare access as their top impact, followed by 26% about the impact on daily living and social life. Focus group meeting discussed differential impact across jurisdictions and point towards telemedicine and digitalisation as potential solutions.

CONCLUSIONS: This serves as the first study to assess the impact of COVID-19 on RD patients and organisations across multiple jurisdictions in the Asia Pacific region, identifying major themes on the impact on both RD patients and organisations. By including 80 organisations from ten jurisdictions, our study presents the most comprehensive assessment of the pandemic's impact to date. It highlights the need for mental health support and sheds light on moving towards telemedicine and digitalisation of organisation operation, which constitutes a sustainable model in times of pandemics and beyond.

PMID:33673852 | PMC:PMC7935006 | DOI:10.1186/s13023-021-01766-9