J Appl Genet. 2022 May;63(2):361-368. doi: 10.1007/s13353-022-00691-2. Epub 2022 Mar 24.

ABSTRACT

Rare disease datasets are typically structured such that a small number of patients (cases) are represented by multidimensional feature vectors. In this report, we considered a rare disease, mucopolysaccharidosis (MPS). This disease is divided into 11 types and subtypes, depending on the genetic defect, type of deficient enzyme, and nature of accumulated glycosaminoglycan(s). Among them, 7 types are known as possibly neuronopathic and 4 are non-neuronopathic, and in the case of the former group, prediction of the course of the disease is crucial for patient's treatment and the management. Here, we have used transcriptomic data available for one patient from each MPS type/subtype. The approach to gene grouping considered by us was based on the minimization of the perceptron criterion in the form of convex and piecewise linear function (CPL). This approach allows designing complexes of linear classifiers on the basis of small samples of multivariate vectors. As a result, distinguishing neuronopathic and non-neuronopathic forms of MPS was possible on the basis of bioinformatic analysis of gene expression patterns where each MPS type was represented by only one patient. This approach can be potentially used also for assessing other features of patients suffering from rare diseases, for which large body of data (like transcriptomic data) is available from only one or a few representatives.

PMID:35322332 | DOI:10.1007/s13353-022-00691-2

Nat Rev Neurosci. 2022 Mar 23. doi: 10.1038/s41583-022-00572-x. Online ahead of print.

ABSTRACT

Genetic mosaicism is the result of the accumulation of somatic mutations in the human genome starting from the first postzygotic cell generation and continuing throughout the whole life of an individual. The rapid development of next-generation and single-cell sequencing technologies is now allowing the study of genetic mosaicism in normal tissues, revealing unprecedented insights into their clonal architecture and physiology. The somatic variant repertoire of an adult human neuron is the result of somatic mutations that accumulate in the brain by different mechanisms and at different rates during development and ageing. Non-pathogenic developmental mutations function as natural barcodes that once identified in deep bulk or single-cell sequencing can be used to retrospectively reconstruct human lineages. This approach has revealed novel insights into the clonal structure of the human brain, which is a mosaic of clones traceable to the early embryo that contribute differentially to the brain and distinct areas of the cortex. Some of the mutations happening during development, however, have a pathogenic effect and can contribute to some epileptic malformations of cortical development and autism spectrum disorder. In this Review, we discuss recent findings in the context of genetic mosaicism and their implications for brain development and disease.

PMID:35322263 | DOI:10.1038/s41583-022-00572-x

Front Endocrinol (Lausanne). 2022 Mar 4;13:832063. doi: 10.3389/fendo.2022.832063. eCollection 2022.

ABSTRACT

Rare diseases, such as inherited metabolic diseases, have been identified as a health priority within the European Union more than 20 years ago and have become an integral part of EU health programs and European Reference Networks. Having the potential to pool data, to achieve sufficient sample size, to overcome the knowledge gap on rare diseases and to foster epidemiological and clinical research, patient registries are recognized as key instruments to evidence-based medicine for individuals with rare diseases. Patient registries can be used for multiple purposes, such as (1) describing the natural history and phenotypic diversity of rare diseases, (2) improving case definition and indication to treat, (3) identifying strategies for risk stratification and early prediction of disease severity (4), evaluating the impact of preventive, diagnostic, and therapeutic strategies on individual health, health economics, and the society, and (5) informing guideline development and policy makers. In contrast to clinical trials, patient registries aim to gather real-world evidence and to achieve generalizable results based on patient cohorts with a broad phenotypic spectrum. In order to develop a consistent and sustained framework for rare disease registries, uniform core principles have been formulated and have been formalized through the European Rare Disease Registration Infrastructure. Adherence to these core principles and compliance with the European general data protection regulations ensures that data collected and stored in patient registries can be exchanged and pooled in a protected environment. To illustrate the benefits and limitations of patient registries on rare disease research this review focuses on inherited metabolic diseases.

PMID:35317224 | PMC:PMC8934440 | DOI:10.3389/fendo.2022.832063

J Pak Med Assoc. 2022 Mar;72(3):598. doi: 10.47391/JPMA.4671.

NO ABSTRACT

PMID:35320261 | DOI:10.47391/JPMA.4671

Haemophilia. 2022 Mar;28 Suppl 2:5-8. doi: 10.1111/hae.14439.

ABSTRACT

To prepare for the introduction of gene therapies in haemophilia care, healthcare frameworks for evaluation and valuation will need to evolve to address the unique requirements of current and future innovations for treating this rare disease. The papers in this supplement provide an insightful and comprehensive state-of-the-art assessment of these requirements and challenges. In terms of evaluation, the definition of a patient-defined value framework that captures multi-dimensional, patient-centered outcomes is an important first step for determining the full benefit of gene therapy for persons with haemophilia. In terms of valuation and rewards for innovation, health systems will need to develop alternative payment models for risk-sharing that will allow payers and society to address uncertainties about the ultimate clinical and economic value of these innovations. And health technology assessment authorities will need to exercise greater flexibility in evidence requirements given the unique features of data collection for a potentially curative therapy for a rare disease with long-term uncertainties about durability of impact. Collaboration among stakeholders will be essential for developing the critical evidence requirements and providing the incentives needed to achieve sustainable budgets and broad access for persons with haemophilia worldwide.

PMID:35318781 | DOI:10.1111/hae.14439

Ugeskr Laeger. 2022 Mar 14;184(11):V71095.

NO ABSTRACT

PMID:35315764

Acta Gastroenterol Belg. 2022 Jan-Mar;85(1):97-101. doi: 10.51821/85.1.9793.

ABSTRACT

Acute esophageal necrosis is a rare syndrome classically characterized by black distal esophagus with a complex pathophysiology that usually involves a combination of esophageal ischemia, gastroesophageal reflux and impaired mucosal reparative mechanisms. We retrospectively analyzed the main risk factors, clinical characteristics and outcome in all patients diagnosed with acute esophageal necrosis between January 2015 and December 2020 at our center. Ten patients were identified in a total of 26854 upper digestive endoscopies (0.04%). Most patients were male (8/10) and the mean age of presentation was 71.1 years. The most common presenting symptoms were melena and hematemesis and half the patients required red blood cell transfusion. The most common risk factors were hypertension, diabetes mellitus, dyslipidemia, chronic kidney disease, peripheral artery disease, coronary artery disease, cerebrovascular disease, heart failure and malignancy. Compromised hemodynamic state was the most common precipitating event in four patients. Other recognized precipitating events included surgical interventions, decompensated heart failure, gastrointestinal bleeding from gastric malignancy and methotrexate. Endoscopic findings revealed diffuse and circumferential black distal esophagus with abrupt transition at gastroesophageal junction and variable proximal extension at presentation. The 1-month mortality rate was 30%, mostly from severe underlying illness. In conclusion, acute esophageal necrosis is a rare cause of upper gastrointestinal bleeding that should be suspected in older patients with multiple comorbidities. Although associated with a high mortality rate, appropriate treatment may result in favorable outcome in most patients.

PMID:35305000 | DOI:10.51821/85.1.9793

Genet Med. 2022 Mar 15:S1098-3600(22)00655-4. doi: 10.1016/j.gim.2022.02.009. Online ahead of print.

ABSTRACT

PURPOSE: Genetic disorders often present in the neonatal intensive care unit (NICU), and detecting or confirming these diagnoses has been shown to impact care. However, the availability and use of genetic testing, particularly exome or genome sequencing, among NICUs varies widely. We therefore sought to investigate practice patterns related to genetic testing in NICUs around the country to identify and quantify potential discrepancies.

METHODS: We designed a survey that was distributed to neonatologists via email. The survey contained questions related to test availability and desirability, the process of test ordering in NICU, and general comfort with ordering and interpreting genetic testing. Demographic data related to the survey participants and characteristics of their NICU were also obtained.

RESULTS: In total, 162 neonatologists completed the survey, representing 40 states and 112 distinct NICUs. Although nearly all (93.2%) neonatologists attributed a high level of importance to identifying a genetic diagnosis for their patients, genetic consultations were only available at 78% of NICUs and exome or genome sequencing was not available on a regular basis (69% of NICUs).

CONCLUSION: Although, among US neonatologists surveyed, most feel that genetic tests are indicated for their patients, these are not always clinically available. Further research into implementation barriers is warranted.

PMID:35304021 | DOI:10.1016/j.gim.2022.02.009

J Allergy Clin Immunol. 2022 Mar 15:S0091-6749(22)00299-8. doi: 10.1016/j.jaci.2022.03.002. Online ahead of print.

ABSTRACT

BACKGROUND: Allergic skin inflammation elicited in mice by epicutaneous (EC) sensitization with antigen shares characteristics with human atopic dermatitis (AD).

OBJECTIVE: To characterize gene expression by single cells in mouse skin undergoing antigen-driven allergic inflammation and compare the results with findings in AD skin lesions.

METHODS: Mice were EC sensitized by application of ovalbumin (OVA) or saline to tape stripped skin. Single-cell RNA-Seq (scRNA-Seq) was performed on skin cells twelve days later. Flow cytometry analysis was performed to validate results.

RESULTS: scRNA-Seq identified seven nonhematopoietic and six hematopoietic cell subsets in EC sensitized mouse skin. OVA sensitization resulted in the expansion in the skin of T cells, dendritic cells (DCs), macrophages, mast cell/basophils, fibroblasts and myocytes cell clusters, and in upregulation of Th2 cytokine gene expression in CD4+ T cells and mast/cell basophils. Genes differentially expressed in OVA sensitized skin included genes important for inflammation in DCs and macrophages, collagen deposition and leukocyte migration in fibroblasts, chemotaxis in endothelial cells and skin barrier integrity and differentiation in KCs, findings that recapitulate those in AD skin lesions. Unexpectedly, mast/cell basophils, rather than T cells, were the major source of Il4 and ll13 in OVA sensitized mouse skin. In addition, our results suggest novel pathways in fibroblast and endothelial cells that may contribute to allergic skin inflammation.

CONCLUSION: The gene expression profile of single cells in mouse skin undergoing antigen-driven shares many features with that in AD skin lesions, and unveils novel pathways that may be involved in allergic skin inflammation.

PMID:35300986 | DOI:10.1016/j.jaci.2022.03.002

Ann Clin Transl Neurol. 2022 Mar 16. doi: 10.1002/acn3.51531. Online ahead of print.

ABSTRACT

CAPN1-associated hereditary spastic paraplegia (SPG76) is a rare and clinically heterogenous syndrome due to loss of calpain-1 function. Here we illustrate a translational approach to the case of an 18-year-old patient who first presented with psychiatric symptoms followed by spastic gait, intention tremor, and neurogenic bladder dysfunction, consistent with a complex form of HSP. Exome sequencing showed compound-heterozygous missense variants in CAPN1 (NM_001198868.2: c.1712A>G (p.Asn571Ser)/c.1991C>T (p.Ser664Leu)) and a previously reported heterozygous stop-gain variant in RCL1. In silico analyses of the CAPN1 variants predicted a deleterious effect and in vitro functional studies confirmed reduced calpain-1 activity and dysregulated downstream signaling. These findings support a diagnosis of SPG76 and highlight that the psychiatric symptoms can precede the motor symptoms in HSP. Our results also suggest that multiple genes can potentially contribute to complex neuropsychiatric diseases.

PMID:35297214 | DOI:10.1002/acn3.51531

J Biomed Semantics. 2022 Mar 15;13(1):9. doi: 10.1186/s13326-022-00264-6.

ABSTRACT

BACKGROUND: The European Platform on Rare Disease Registration (EU RD Platform) aims to address the fragmentation of European rare disease (RD) patient data, scattered among hundreds of independent and non-coordinating registries, by establishing standards for integration and interoperability. The first practical output of this effort was a set of 16 Common Data Elements (CDEs) that should be implemented by all RD registries. Interoperability, however, requires decisions beyond data elements - including data models, formats, and semantics. Within the European Joint Programme on Rare Diseases (EJP RD), we aim to further the goals of the EU RD Platform by generating reusable RD semantic model templates that follow the FAIR Data Principles.

RESULTS: Through a team-based iterative approach, we created semantically grounded models to represent each of the CDEs, using the SemanticScience Integrated Ontology as the core framework for representing the entities and their relationships. Within that framework, we mapped the concepts represented in the CDEs, and their possible values, into domain ontologies such as the Orphanet Rare Disease Ontology, Human Phenotype Ontology and National Cancer Institute Thesaurus. Finally, we created an exemplar, reusable ETL pipeline that we will be deploying over these non-coordinating data repositories to assist them in creating model-compliant FAIR data without requiring site-specific coding nor expertise in Linked Data or FAIR.

CONCLUSIONS: Within the EJP RD project, we determined that creating reusable, expert-designed templates reduced or eliminated the requirement for our participating biomedical domain experts and rare disease data hosts to understand OWL semantics. This enabled them to publish highly expressive FAIR data using tools and approaches that were already familiar to them.

PMID:35292119 | PMC:PMC8922780 | DOI:10.1186/s13326-022-00264-6

Malawi Med J. 2021 Dec;33(4):300-302. doi: 10.4314/mmj.v33i4.12.

ABSTRACT

Castleman's disease was first described by Castleman et al. in 1956 as a non-lymphoproliferative disease.1 Castleman's disease (CD), or angiofollicular lymphoid hyperplasia, is a rare disease with unknown etiology that can be easily misdiagnosed as lymphoma, neoplasm, or infection. Very few cases of pelvic origin and observed in pregnancy have been reported in the literature and are usually asymptomatic. Preoperative diagnosis is very difficult due to nonspecific imaging findings and rarity; most cases are diagnosed based on postoperative pathological examination. In this paper, a case of a 36-year-old pregnant woman suspected of adnexal origin in the uterine posterolateral, which was detected incidentally by ultrasound, was presented. The patient underwent a successful mass excision. Pathology of mass observed to be in the pelvic retroperitoneum was detected as localized unicentric and hyaline vascular CD. The study was conducted to discuss the diagnostic tools and perioperative management needed to identify the retroperitoneal unicentric Castleman case.

PMID:35291389 | PMC:PMC8893006 | DOI:10.4314/mmj.v33i4.12

Cell Rep. 2022 Mar 15;38(11):110517. doi: 10.1016/j.celrep.2022.110517.

ABSTRACT

Individuals with autism spectrum disorder (ASD) exhibit an increased burden of de novo mutations (DNMs) in a broadening range of genes. While these studies have implicated hundreds of genes in ASD pathogenesis, which DNMs cause functional consequences in vivo remains unclear. We functionally test the effects of ASD missense DNMs using Drosophila through "humanization" rescue and overexpression-based strategies. We examine 79 ASD variants in 74 genes identified in the Simons Simplex Collection and find 38% of them to cause functional alterations. Moreover, we identify GLRA2 as the cause of a spectrum of neurodevelopmental phenotypes beyond ASD in 13 previously undiagnosed subjects. Functional characterization of variants in ASD candidate genes points to conserved neurobiological mechanisms and facilitates gene discovery for rare neurodevelopmental diseases.

PMID:35294868 | DOI:10.1016/j.celrep.2022.110517

BMC Pediatr. 2022 Mar 14;22(1):135. doi: 10.1186/s12887-022-03179-4.

ABSTRACT

BACKGROUND: Strokes in the paediatric age group have their own epidemiology and aetiology and are frequently misdiagnosed. As in the adult population, they present some risk factors that must be identified. Cerebral arteriopathies as a cause of paediatric ischaemic stroke present a very diverse aetiology and morphology. In this article we report a paediatric stroke in a patient who was diagnosed during his first months of life of Hutchinson-Gilford´s Progeria (HGP). This is a rare genetic condition caused by mutations in the LMNA gene, producing an aberrant lamin A protein. The disease leads to premature aging, and cardiovascular complications are the first cause of morbidity and mortality in these patients.

CASE PRESENTATION: We report the case of a 5-year-old patient with HGP (missense mutation-de novo-c.1822G > A in heterozygosis, LMNA gene). The patient was diagnosed during his first year of life and presented distinct phenotypical features. No other relevant comorbidities were present. He was admitted to the emergency department for right hemiparesis with at least 4 h of evolution, with inability to open the hand and slight decrease in the level of consciousness (pedNIHSS 5-6). Cranial-CT and angio-CT showed findings indicative of left carotid dissection. Consensus was reached on conservative medical management with anticoagulation and antiplatelet therapy. In the first few days, the patient had a favourable evolution with resolution of the right lower limb hemiparesis and, one month after discharge, of the hand paresis.

CONCLUSIONS: The clinical manifestations, the vascular phenotype of the genetic mutation and the location of the radiological signs on a specific vascular morphology are indicative of carotid dissection. Spontaneous dissections occur under a predisposing risk factor or disease and are an exceptional finding in patients with HGP.

PMID:35287606 | PMC:PMC8922814 | DOI:10.1186/s12887-022-03179-4

Front Pediatr. 2022 Feb 23;10:841051. doi: 10.3389/fped.2022.841051. eCollection 2022.

ABSTRACT

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare orphan disease caused by dysregulated complement activation resulting in thrombotic microangiopathy. Although complement-mediated endothelial injury predominantly affects the renal microvasculature, extra-renal manifestations are present in a significant proportion of patients. While eculizumab has significantly improved the morbidity and mortality of this rare disease, optimizing therapeutic regimens of this highly expensive drug remains an active area of research in the treatment of aHUS.

CASE PRESENTATION: This report describes the case of a previously healthy 4 year-old male who presented with rhabdomyolysis preceding the development of aHUS with anuric kidney injury requiring dialysis. Clinical stabilization required increased and more frequent eculizumab doses compared with the standardized weight-based guidelines. In the maintenance phase of his disease, pharmacokinetic analysis indicated adequate eculizumab levels could be maintained with an individualized dosing regimen every 3 weeks, as opposed to standard 2 week dosing, confirmed in this patient over a 4 year follow up period. Cost analyses show that weight-based maintenance dosing costs $312,000 per year, while extending the dosing interval to every 3 weeks would cost $208,000, a savings of $104,000 per year, relative to the cost of $72,000 from more frequent eculizumab dosing during his initial hospitalization to suppress his acute disease.

CONCLUSION: This case exemplifies the potential of severe, multisystem involvement of aHUS presenting with extra-renal manifestations, including rhabdomyolysis as in this case, and highlights the possibility for improved clinical outcomes and higher value care with individualized eculizumab dosing in patients over the course of their disease.

PMID:35281224 | PMC:PMC8906567 | DOI:10.3389/fped.2022.841051

Int J Environ Res Public Health. 2022 Mar 1;19(5):2857. doi: 10.3390/ijerph19052857.

ABSTRACT

(1) Background: Drug lag, the delay between the first global regulatory approval and approval by the national health authorities in other countries, impacts the accessibility of drugs. Although the Korean pharmaceutical market has grown significantly, most of its innovative drugs for public health depend on imports from foreign pharmaceutical markets. (2) Methods: We extracted data from the official websites of the Korean Ministry of Food and Drug Safety (MFDS) and the US Food and Drug Administration. Information on new molecule entity drugs, approved as imported drugs by MFDS from 2000 to 2019, was extracted. Multivariate Cox proportional hazard models on drug approval were estimated. (3) Results: In total, 424 drugs were analyzed. Orphan drugs designated by MFDS were less likely to receive approval (HR = 0.731, 95% CI: 0.572-0.934). The drugs with Korean MAHs were less likely to obtain drug approval than those with MAHs of subsidiaries of multinational pharmaceutical companies (HR = 0.524, 95% CI: 0.371-0.738). In the analyses for non-orphan drugs (n = 37), oncology drugs that need local clinical study (HR = 0.247, 95% CI: 0.093-0.657) and drugs that need more patients in a local clinical study (HR = 0.993, 95% CI: 0.988-0.999) were less likely to receive approval, with longer drug lag. The higher number of clinical studies in Korea was associated with a shorter drug lag (HR = 2.133, 95% CI: 1.196-3.805). (4) Conclusions: Our findings imply that Korean pharmaceutical companies should augment their research capabilities for new drug development. Furthermore, consideration of orphan drugs used in rare diseases is needed for drug approval to ensure the availability of these drugs in the market without approval delays.

PMID:35270550 | PMC:PMC8910054 | DOI:10.3390/ijerph19052857

Nat Genet. 2022 Mar;54(3):219-222. doi: 10.1038/s41588-022-01027-w.

NO ABSTRACT

PMID:35256804 | DOI:10.1038/s41588-022-01027-w

Nature. 2022 Mar;603(7900):354. doi: 10.1038/d41586-022-00654-x.

NO ABSTRACT

PMID:35256814 | DOI:10.1038/d41586-022-00654-x

Curr Opin Pharmacol. 2022 Apr;63:102201. doi: 10.1016/j.coph.2022.102201. Epub 2022 Mar 4.

ABSTRACT

The greatest challenge of current biomedicine is to identify curative therapies for every disease in a personalized way so that every individual gets benefit. To that end, however, we need fully understand mechanisms of disease that will drive the design of novel therapies and innovative approaches. For rare diseases (RDs) which individually affect low numbers of people (< 1:2000), but together, affect 300 million (∼10% of the world population) the constraints are greater. This is because: 1) there is limited knowledge on RD physiopathology; 2) the low number of patients strongly limits clinical trials; 3) there is low commercial interest by pharma; 4) when specific drugs reach the market, their high cost precludes their reaching all those who need them. Several possibilities that can help mitigate these barriers are discussed here, including orphan drug designation, drug repurposing, break-down into theratypes (as currently in place for Cystic Fibrosis), or novel precision-medicine-based approaches.

PMID:35255452 | DOI:10.1016/j.coph.2022.102201

JAMA Neurol. 2022 Mar 7. doi: 10.1001/jamaneurol.2022.0067. Online ahead of print.

ABSTRACT

IMPORTANCE: Infants with hypotonia can present with a variety of potentially severe clinical signs and symptoms and often require invasive testing and multiple procedures. The wide range of clinical presentations and potential etiologies leaves diagnosis and prognosis uncertain, underscoring the need for rapid elucidation of the underlying genetic cause of disease.

OBSERVATIONS: The clinical application of exome sequencing or genome sequencing has dramatically improved the timely yield of diagnostic testing for neonatal hypotonia, with diagnostic rates of greater than 50% in academic neonatal intensive care units (NICUs) across Australia, Canada, the UK, and the US, which compose the International Precision Child Health Partnership (IPCHiP). A total of 74% (17 of 23) of patients had a change in clinical care in response to genetic diagnosis, including 2 patients who received targeted therapy. This narrative review discusses the common causes of neonatal hypotonia, the relative benefits and limitations of available testing modalities used in NICUs, and hypotonia management recommendations.

CONCLUSIONS AND RELEVANCE: This narrative review summarizes the causes of neonatal hypotonia and the benefits of prompt genetic diagnosis, including improved prognostication and identification of targeted treatments which can improve the short-term and long-term outcomes. Institutional resources can vary among different NICUs; as a result, consideration should be given to rule out a small number of relatively unique conditions for which rapid targeted genetic testing is available. Nevertheless, the consensus recommendation is to use rapid genome or exome sequencing as a first-line testing option for NICU patients with unexplained hypotonia. As part of the IPCHiP, this diagnostic experience will be collected in a central database with the goal of advancing knowledge of neonatal hypotonia and improving evidence-based practice.

PMID:35254387 | DOI:10.1001/jamaneurol.2022.0067