Orphanet J Rare Dis. 2021 Nov 27;16(1):498. doi: 10.1186/s13023-021-02129-0.

ABSTRACT

BACKGROUND: COVID-19 has affected our society at large, particularly vulnerable groups, such as children suffering from rare diseases and their parents. However, the psychosocial influences of COVID-19 on these have yet to be investigated. As such, the study's goal was to evaluate the health-related quality of life (HRQoL), quality of life (QoL), and mental health of children with rare congenital surgical diseases and their parents during the COVID-19 pandemic and lockdown measures.

METHODS: A survey of n = 210 parents of children with rare congenital surgical diseases and a control group of n = 88 parents of children without rare diseases was conducted cross-sectionally between April 2020 to April 2021. Data on HRQoL, QoL, and mental health was collected using standardized psychometric questionnaires for children and parents presenting to the pediatric surgery department at a university hospital.

RESULTS: Mothers of children with rare pediatric surgical diseases showed significantly lower QoL and significantly higher impairment in mental health than a control group and norm data. For fathers, this was solely the case for their QoL. Children's parent-reported HRQoL and mental health were partially impaired. Social and disease-specific risk factors of the respective outcomes in affected families were identified through regression analysis models.

CONCLUSION: Parents of children with rare diseases report severe psychosocial impairment regarding themselves and their children during the COVID-19 pandemic. Therefore, affected families should receive attention and supportive care in the form of a family-center approach to alleviate the additional burden of the COVID-19 pandemic.

PMID:34838064 | PMC:PMC8626760 | DOI:10.1186/s13023-021-02129-0

Mob DNA. 2021 Nov 27;12(1):28. doi: 10.1186/s13100-021-00256-w.

ABSTRACT

BACKGROUND: Retrotransposons have been implicated as causes of Mendelian disease, but their role in autism spectrum disorder (ASD) has not been systematically defined, because they are only called with adequate sensitivity from whole genome sequencing (WGS) data and a large enough cohort for this analysis has only recently become available.

RESULTS: We analyzed WGS data from a cohort of 2288 ASD families from the Simons Simplex Collection by establishing a scalable computational pipeline for retrotransposon insertion detection. We report 86,154 polymorphic retrotransposon insertions-including > 60% not previously reported-and 158 de novo retrotransposition events. The overall burden of de novo events was similar between ASD individuals and unaffected siblings, with 1 de novo insertion per 29, 117, and 206 births for Alu, L1, and SVA respectively, and 1 de novo insertion per 21 births total. However, ASD cases showed more de novo L1 insertions than expected in ASD genes. Additionally, we observed exonic insertions in loss-of-function intolerant genes, including a likely pathogenic exonic insertion in CSDE1, only in ASD individuals.

CONCLUSIONS: These findings suggest a modest, but important, impact of intronic and exonic retrotransposon insertions in ASD, show the importance of WGS for their analysis, and highlight the utility of specific bioinformatic tools for high-throughput detection of retrotransposon insertions.

PMID:34838103 | DOI:10.1186/s13100-021-00256-w

Biomolecules. 2021 Nov 17;11(11):1713. doi: 10.3390/biom11111713.

ABSTRACT

The advent of next-generation sequencing (NGS) is heavily changing both the diagnosis of human conditions and basic biological research. It is now possible to dig deep inside the genome of hundreds of thousands or even millions of people and find both common and rare genomic variants and to perform detailed phenotypic characterizations of both physiological organs and experimental models. Recent years have seen the introduction of multiple techniques using NGS to profile transcription, DNA and chromatin modifications, protein binding, etc., that are now allowing us to profile cells in bulk or even at a single-cell level. Although rare and ultra-rare diseases only affect a few people, each of these diseases represent scholarly cases from which a great deal can be learned about the pathological and physiological function of genes, pathways, and mechanisms. Therefore, for rare diseases, state-of-the-art investigations using NGS have double valence: their genomic cause (new variants) and the characterize the underlining the mechanisms associated with them (discovery of gene function) can be found. In a non-exhaustive manner, this review will outline the main usage of NGS-based techniques for the diagnosis and characterization of neurodevelopmental disorders (NDDs), under whose umbrella many rare and ultra-rare diseases fall.

PMID:34827709 | PMC:PMC8616022 | DOI:10.3390/biom11111713

Cells. 2021 Nov 13;10(11):3158. doi: 10.3390/cells10113158.

ABSTRACT

The modification of genes in animal models has evidently and comprehensively improved our knowledge on proteins and signaling pathways in human physiology and pathology. In this review, we discuss almost 40 monogenic rare diseases that are enriched in the Finnish population and defined as the Finnish disease heritage (FDH). We will highlight how gene-modified mouse models have greatly facilitated the understanding of the pathological manifestations of these diseases and how some of the diseases still lack proper models. We urge the establishment of subsequent international consortiums to cooperatively plan and carry out future human disease modeling strategies. Detailed information on disease mechanisms brings along broader understanding of the molecular pathways they act along both parallel and transverse to the proteins affected in rare diseases, therefore also aiding understanding of common disease pathologies.

PMID:34831381 | PMC:PMC8621025 | DOI:10.3390/cells10113158

Int J Environ Res Public Health. 2021 Nov 15;18(22):11968. doi: 10.3390/ijerph182211968.

ABSTRACT

Rare disease (RD) registries aim to promote data collection and sharing, and facilitate multidisciplinary collaboration with the overall aim of improving patient care. Recommendations relating to the minimum standards necessary to develop and maintain high quality registries are essential to ensure high quality data and sustainability of registries. The aim of this international study was to survey RD registry leaders to ascertain the level of consensus amongst the RD community regarding the quality criteria that should be considered essential features of a disease registry. Of 35 respondents representing 40 RD registries, over 95% indicated that essential quality criteria should include establishment of a good governance system (ethics approval, registry management team, standard operating protocol and long-term sustainability plan), data quality (personnel responsible for data entry and procedures for checking data quality) and construction of an IT infrastructure complying with Findable, Accessible, Interoperable and Reusable (FAIR) principles to maintain registries of high quality, with procedures for authorized user access, erasing personal data, data breach procedures and a web interface. Of the 22 registries that performed a self-assessment, over 80% stated that their registry had a leader, project management group, steering committee, active funding stream, website, and user access policies. This survey has acceptability amongst the RD community for the self-quality evaluation of RD registries with high levels of consensus for the proposed quality criteria.

PMID:34831724 | PMC:PMC8620980 | DOI:10.3390/ijerph182211968

Medicina (Kaunas). 2021 Nov 4;57(11):1205. doi: 10.3390/medicina57111205.

ABSTRACT

Anal canal duplication (ACD) is a very rare condition, diagnosed and treated mostly in childhood. Less than 90 cases have been reported in the literature so far. We are presenting a case of a young woman who underwent surgical excision of the duplication when she was 27 years old. The patient was unaware of her condition and was referred from a gynaecological office to the surgical department with a history of perianal discomfort and mucus discharge. Local examination showed an external orifice posterior to the anal opening, on the median line, which had the macroscopic appearance of a secondary anal orifice. The opening was about 0.5 cm in diameter. Exploration of the tract revealed a length of about 4 cm. MRI described the aforementioned tract, parallel to the anal canal, with no other anomalies mentioned. Under spinal anesthesia, with the patient in jackknife position, the accessory anal canal was surgically excised. The pathology report showed the presence of smooth muscle fibers and typical anal glands in the specimen. After a five-year follow-up, the patient showed no recurrence or any other related local symptoms. Absence of perianal abscess from the patient history, along with the macroscopic aspect of the opening similar to a secondary anal orifice on the midline, should raise the suspicion of ACD. Due to the lack of bothersome symptomatology, the patient did not seek any special investigations for her condition until she was in her late twenties. ACD is a very rare condition in adults that might pass unnoticed, but a midline opening posterior to the anus should always raise the suspicion of a secondary anal canal. Surgery is the only cure for this condition with good results after a proper pre-operative workout to reveal others simultaneous malformations.

PMID:34833422 | PMC:PMC8618150 | DOI:10.3390/medicina57111205

Epilepsia. 2021 Nov 27. doi: 10.1111/epi.17125. Online ahead of print.

ABSTRACT

OBJECTIVE: The study investigated the effect of seizure and medication burden at initial contact with the International CDKL5 Disorder Database on subsequent development and clinical severity and compared quality of life among those whose development progressed, remained stable, or regressed between baseline and follow-up.

METHODS: The effects of seizure and medication burden at baseline (high or low) on the CDKL5 Disorder Severity Scores and CDKL5 Developmental Score (CDS) at follow-up were assessed using linear and negative binomial regressions, respectively, with adjustment for age at baseline, gender, and follow-up duration with and without genotype. Seizure and medication burden were defined by average daily seizure count (high, ≥5/day; low, <5/day) and number of antiseizure medications (high, ≥3/day; low, <3/day), respectively. The effects of change in CDS over time (improved, stable, or deteriorated) on Quality of Life Inventory-Disability (QI-Disability) total and domain scores at follow-up were assessed in those aged at least 3 years at follow-up using linear regression models with adjustment for baseline CDS, gender, and follow-up duration.

RESULTS: The expected follow-up CDS was lower for individuals with high compared to low seizure burden at baseline (β = -.49, 95% confidence interval [CI] = -.84 to -.13). The average total QI-Disability score was 5.6 (95% CI = -.2 to 11.5) points higher among those with improved compared with stable or deteriorating CDS and 8.5 (95% CI = 3.1-13.8) points lower for those with deteriorating compared to stable or improved CDS.

SIGNIFICANCE: Our finding that later development showed slight improvement in those with better earlier seizure control even after adjustment for genotype suggests that the trajectory for an individual child is not necessarily predetermined and could possibly be influenced by optimal seizure management. This has implications for children's quality of life.

PMID:34837650 | DOI:10.1111/epi.17125

J Neurooncol. 2021 Nov 26. doi: 10.1007/s11060-021-03902-8. Online ahead of print.

ABSTRACT

INTRODUCTION: Glioblastoma multiforme (GBM) constitutes one of the deadliest tumors to afflict humans, although it is still considered an orphan disease. Despite testing multiple new and innovative therapies in ongoing clinical trials, the median survival for this type of malignancy is less than two years after initial diagnosis, regardless of therapy. One class of promising new therapies are chimeric antigen receptor T cells or CAR-T which have been shown to be very effective at treating refractory liquid tumors such as B-cell malignancies. However, CAR-T effectivity against solid tumors such as GBM has been limited thus far.

METHODS: A Pubmed, Google Scholar, Directory of Open Access Journals, and Web of Science literature search using the terms chimeric antigen receptor or CAR-T, GBM, solid tumor immunotherapy, immunotherapy, and CAR-T combination was performed for publication dates between January 1987 and November 2021.

RESULTS: In the current review, we present a comprehensive list of CAR-T cells developed to treat GBM, we describe new possible T-cell engineering strategies against GBM while presenting a short introductory history to the reader regarding the origin(s) of this cutting-edge therapy. We have also compiled a unique list of anti-GBM CAR-Ts with their specific protein sequences and their functions as well as an inventory of clinical trials involving CAR-T and GBM.

CONCLUSIONS: The aim of this review is to introduce the reader to the field of T-cell engineering using CAR-Ts to treat GBM and describe the obstacles that may need to be addressed in order to significantly delay the relentless growth of GBM.

PMID:34825292 | DOI:10.1007/s11060-021-03902-8

Br J Hosp Med (Lond). 2021 Nov 2;82(11):1-9. doi: 10.12968/hmed.2020.0537. Epub 2021 Nov 23.

ABSTRACT

Hereditary haemorrhagic telangiectasia is a rare, genetic disorder that can present at any age. It is characterised by epistaxis, mucocutaneous telangiectasia and visceral arteriovenous malformations, which can affect multiple organs. Early diagnosis and management reduces the morbidity and mortality associated with the disease. There is a well-established hereditary haemorrhagic telangiectasia clinic in London, and excellent links across Europe via the European Reference Network. However, local coordinated care for patients with hereditary haemorrhagic telangiectasia across the UK can be variable and often absent for children and young people. Some patients travel long distances to receive care in London, while others are referred to local clinicians or lost to follow up entirely. This article presents the experience to date from two regional UK centres (Liverpool and Dundee) where care for patients with hereditary haemorrhagic telangiectasia is being coordinated and streamlined. While there is still a lot to learn, this article highlights some of the successes and challenges identified so far, with suggestions for how these could be addressed. Collaborative regional networks such as these can facilitate the sharing of best practice and ensure that all patients with hereditary haemorrhagic telangiectasia are able to access safe, high-quality care.

PMID:34817258 | DOI:10.12968/hmed.2020.0537

N Engl J Med. 2021 Nov 25;385(22):2090-2091. doi: 10.1056/NEJMe2114846.

NO ABSTRACT

PMID:34818485 | DOI:10.1056/NEJMe2114846

N Engl J Med. 2021 Nov 25;385(22):2059-2065. doi: 10.1056/NEJMoa2110051.

ABSTRACT

The integration of genomic testing into clinical care enables the use of individualized approaches to the management of rare diseases. We describe the use of belzutifan, a potent and selective small-molecule inhibitor of the protein hypoxia-inducible factor 2α (HIF2α), in a patient with polycythemia and multiple paragangliomas (the Pacak-Zhuang syndrome). The syndrome was caused in this patient by somatic mosaicism for an activating mutation in EPAS1. Treatment with belzutifan led to a rapid and sustained tumor response along with resolution of hypertension, headaches, and long-standing polycythemia. This case shows the application of a targeted therapy for the treatment of a patient with a rare tumor-predisposition syndrome. (Funded by the Morin Family Fund for Pediatric Cancer and Alex's Lemonade Stand Foundation.).

PMID:34818480 | DOI:10.1056/NEJMoa2110051

Autophagy. 2021 Nov 24:1-13. doi: 10.1080/15548627.2021.1990671. Online ahead of print.

ABSTRACT

WDR45-related neurodevelopmental disorder (NDD) is a clinically-heterogenous congenital disorder of macroautophagy/autophagy. The natural history of this ultra-orphan disease remains incompletely understood, leading to delays in diagnosis and lack of quantifiable outcome measures. In this cross-sectional study, we model quantitative natural history data for WDR45-related NDD using a standardized analysis of 160 published cases, representing the largest cohort to date. The primary outcome of this study was survival. Age at disease onset, diagnostic delay and geographic distribution were quantified as secondary endpoints. Our tertiary aim was to explore and quantify the spectrum of WDR45-related phenotypes. Survival estimations showed low mortality until 39 years of age. Median age at onset was 10 months, with a median diagnostic delay of 6.2 years. Geographic distribution appeared worldwide with clusters in North America, East Asia, Western Europe and the Middle East. The clinical spectrum was highly variable with a bi-phasic evolution characterized by early-onset developmental and epileptic encephalopathy during childhood followed by a progressive dystonia-parkinsonism syndrome along with cognitive decline during early adulthood. Female individuals showed milder disease severity. The majority of pathogenic WDR45 variants were predicted to result in a loss of WDR45 expression, without clear genotype-phenotype associations. Our results provide clinical and epidemiological data that may facilitate an earlier diagnosis, enable anticipatory guidance and counseling of affected families and provide the foundation for endpoints for future interventional trials.Abbreviations: BPAN: beta-propeller protein-associated neurodegeneration; CNS: central nervous system; DEE: developmental and epileptic encephalopathy; MRI: magnetic resonance imaging; NBIA: neurodegeneration with brain iron accumulation; NDD: neurodevelopmental disorder; NGS: next-generation sequencing; WDR45/WIPI4: WD repeat domain 45.

PMID:34818117 | DOI:10.1080/15548627.2021.1990671

Pediatrics. 2021 Dec 1;148(6):e2021050990. doi: 10.1542/peds.2021-050990.

ABSTRACT

Inflammatory myofibroblastic tumor (IMT) is a rare, mesenchymal tumor that has an increased incidence in childhood. Tumors are usually isolated to the chest, abdomen, and retroperitoneum, but metastatic presentations can be seen. Presenting symptoms are nonspecific and include fever, weight loss, pain, shortness of breath, and cough. Approximately 85% of IMTs harbor actionable kinase fusions. The diagnosis can be delayed because of overlapping features with inflammatory disorders, such as elevated inflammatory markers, increased immunoglobin G levels, fever, weight loss, and morphologic similarity with nonmalignant conditions. We present a girl aged 11 years with a TFG-ROS1 fusion-positive tumor of the lung that was initially diagnosed as an immunoglobin G4-related inflammatory pseudotumor. She underwent complete left-sided pneumonectomy and later recurred with widely metastatic disease. We then report the case of a boy aged 9 years with widely metastatic TFG-ROS1 fusion-positive IMT with rapid molecular diagnosis. In both children, there was an excellent response to oral targeted therapy. These cases reveal that rapid molecular testing of inflammatory tumors is not only important for diagnosis but also reveals therapeutic opportunities. Targeted inhibitors produce significant radiologic responses, enabling potentially curative treatment approaches for metastatic ROS1 fusion IMT with previously limited treatment options. Primary care pediatricians and pediatric subspecialists have a crucial role in the early consultation of a pediatric oncology center experienced in molecular diagnostics to facilitate a comprehensive evaluation for children with inflammatory tumors.

PMID:34814185 | DOI:10.1542/peds.2021-050990

Rofo. 2021 Dec;193(12):1480-1481. doi: 10.1055/a-1651-8344. Epub 2021 Nov 23.

NO ABSTRACT

PMID:34814205 | DOI:10.1055/a-1651-8344

PET Clin. 2022 Jan;17(1):13-29. doi: 10.1016/j.cpet.2021.09.009.

ABSTRACT

Almost 1 in 10 individuals can suffer from one of many rare diseases (RDs). The average time to diagnosis for an RD patient is as high as 7 years. Artificial intelligence (AI)-based positron emission tomography (PET), if implemented appropriately, has tremendous potential to advance the diagnosis of RDs. Patient advocacy groups must be active stakeholders in the AI ecosystem if we are to avoid potential issues related to the implementation of AI into health care. AI medical devices must not only be RD-aware at each stage of their conceptualization and life cycle but also should be trained on diverse and augmented datasets representative of the end-user population including RDs. Inability to do so leads to potential harm and unsustainable deployment of AI-based medical devices (AIMDs) into clinical practice.

PMID:34809862 | DOI:10.1016/j.cpet.2021.09.009

Bull Cancer. 2021 Dec;108(12):1077-1084. doi: 10.1016/j.bulcan.2021.09.008. Epub 2021 Nov 18.

ABSTRACT

INTRODUCTION: Overseas France represents 18 % of French territory and is home to 4 % of its population for whom there is unequal treatment in the field of rare/complex cancer.

AIM: To report our experience of intercontinental multidisciplinary videoconferencing between the French mainland and Pacific territories.

METHODS: Every other friday, three centers located in Papeete, Nouméa and Paris-Villejuif connected between 6:30 AM and 8:00 AM GMT to discuss cases of rare/complex cancers.

RESULTS: Between November 2019 and December 2020, 323 presentations implicating 233 patients involved sarcoma (n=93), digestive pathology (n=60), neuroendocrine tumors (n=35), urology (n=24), gynecology (n=24), neurology (n=16), thyroid pathology (n=14), dermatology (n=14), senology (n=11), hematology (n=11), ENT pathology (n=10), pathology thoracic (n=10) and pediatrics (n=1). Of the 233 patients, 134 (57.5 %) living in New Caledonia and 99 (42.5 %) in French Polynesia, 117 (50.5 %) had metastatic disease. 39 patients (16.7 %) were transferred to French mainland (EVASAN), for surgery (n=25), vectorized radiotherapy (n=7), biopsy (n=5), chemotherapy (n=1) or inclusion in a clinical trial (n=1). 195 patients (83.7 %) were treated at home, 15 (6.4 %) are still awaiting a decision and 4 (1.7 %) lost to follow-up.

CONCLUSION: The use of videoconferencing to discuss rare/complex cancer cases was effective in guaranteeing French overseas population access to innovative therapies and clinical trials, limiting the need for intercontinental transfer to 16.7 %.

PMID:34802717 | DOI:10.1016/j.bulcan.2021.09.008

Am J Bioeth. 2021 Dec;21(12):1-3. doi: 10.1080/15265161.2021.1996801.

NO ABSTRACT

PMID:34806973 | DOI:10.1080/15265161.2021.1996801

F1000Res. 2021 Jun 2;10:434. doi: 10.12688/f1000research.53134.1. eCollection 2021.

ABSTRACT

Based on its prevalence, Tourette syndrome cannot be considered a rare disease. However, in this opinion article, we make the claim that it should nonetheless be considered as an orphan or neglected disease.

PMID:34804496 | PMC:PMC8567683 | DOI:10.12688/f1000research.53134.1

Exp Mol Med. 2021 Nov 19. doi: 10.1038/s12276-021-00693-w. Online ahead of print.

ABSTRACT

Photoreceptor degeneration caused by genetic defects leads to retinitis pigmentosa, a rare disease typically diagnosed in adolescents and young adults. In most cases, rod loss occurs first, followed by cone loss as well as altered function in cells connected to photoreceptors directly or indirectly. There remains a gap in our understanding of retinal cellular responses to photoreceptor abnormalities. Here, we utilized single-cell transcriptomics to investigate cellular responses in each major retinal cell type in retinitis pigmentosa model (P23H) mice vs. wild-type littermate mice. We found a significant decrease in the expression of genes associated with phototransduction, the inner/outer segment, photoreceptor cell cilium, and photoreceptor development in both rod and cone clusters, in line with the structural changes seen with immunohistochemistry. Accompanying this loss was a significant decrease in the expression of genes involved in metabolic pathways and energy production in both rods and cones. We found that in the Müller glia/astrocyte cluster, there was a significant increase in gene expression in pathways involving photoreceptor maintenance, while concomitant decreases were observed in rods and cones. Additionally, the expression of genes involved in mitochondrial localization and transport was increased in the Müller glia/astrocyte cluster. The Müller glial compensatory increase in the expression of genes downregulated in photoreceptors suggests that Müller glia adapt their transcriptome to support photoreceptors and could be thought of as general therapeutic targets to protect against retinal degeneration.

PMID:34799683 | DOI:10.1038/s12276-021-00693-w

Stud Health Technol Inform. 2021 Nov 18;287:114-118. doi: 10.3233/SHTI210827.

ABSTRACT

Undiagnosed rare diseases include diseases with a well-characterised phenotype, diseases with unknown molecular causes or due to non-genetic factors, and pathological condition that cannot be named. Several initiatives have been launched for healthcare of patients with undiagnosed rare diseases. A project for development of medical records with special reference to the HL7 standards is being carried out in Genoa (Italy), taking into account regional and national regulations. The project is based on the integration of functionality related to patient diagnostics, taking into account omic sciences for disease prevention and risk assessment. Considering the evolution of standards, the use of FHIR is being considered in order to increase the elasticity of the system also in view of foreseeable adoption of this standard by the Italian healthcare system.

PMID:34795093 | DOI:10.3233/SHTI210827