Int J Mol Sci. 2024 Aug 28;25(17):9320. doi: 10.3390/ijms25179320.

ABSTRACT

Glomerular kidney diseases typically begin insidiously and can progress to end stage kidney failure. Early onset of therapy can slow down disease progression. Early diagnosis is required to ensure such timely therapy. The goal of our study was to evaluate protein biomarkers (BMs) for common nephropathies that have been described for children with Alport syndrome. Nineteen candidate BMs were determined by commercial ELISA in children with congenital anomalies of the kidneys and urogenital tract, inflammatory kidney injury, or diabetes mellitus. It is particularly essential to search for kidney disease BMs in children because they are a crucial target group that likely exhibits early disease stages and in which misleading diseases unrelated to the kidney are rare. Only minor differences in blood between affected individuals and controls were found. However, in urine, several biomarker candidates alone or in combination seemed to be promising indicators of renal injury in early disease stages. The BMs of highest sensitivity and specificity were collagen type XIII, hyaluronan-binding protein 2, and complement C4-binding protein. These proteins are unrelated to inflammation markers or to risk factors for and signs of renal failure. In conclusion, our study evaluated several strong candidates for screening for early stages of kidney diseases and can help to establish early nephroprotective regimens.

PMID:39273271 | PMC:PMC11395411 | DOI:10.3390/ijms25179320

Int J Mol Sci. 2024 Aug 25;25(17):9229. doi: 10.3390/ijms25179229.

ABSTRACT

Brody disease (BD) is an "ultra-rare" human genetic disorder of skeletal muscle function due to defects in the atp2a1 gene causing deficiency of the SERCA protein, isoform1. The main clinical signs are exercise-induced stiffness and delayed muscular relaxation after physical exercises, even mild ones. No mouse model nor specific therapies exist for Brody myopathy, which is therefore considered an orphan disease. Bovine congenital pseudomyotonia (PMT) is a muscular disorder characterized by an impairment of muscle relaxation and is the only mammalian model of human BD. The pathogenetic mechanism underlying bovine PMT has been recently clarified. These findings prompted us to purpose a potential pharmacological approach addressing a specific population of BD patients who exhibit reduced expression but still exhibit activity of the SERCA1 pump. Preclinical research involving in vivo studies is essential and necessary before clinical trials can be pursued and SERCA protein shows a high degree of conservation among species. So far, the only animal models available to study BD in vivo are a group of zebrafish mutant lines known as accordion zebrafish (acc). In this paper, we focused on a comprehensive characterization of the "acctq206" zebrafish variant. Our aim was to use this mutant line as an experimental animal model for testing the novel therapeutic approach for BD.

PMID:39273176 | PMC:PMC11395142 | DOI:10.3390/ijms25179229

Cells. 2024 Sep 9;13(17):1508. doi: 10.3390/cells13171508.

ABSTRACT

Most rare diseases are caused by mutations and can have devastating consequences. Precise gene editing by CRISPR/Cas is an exciting possibility for helping these patients, if no irreversible developmental defects have occurred. To optimize gene editing therapy, reporter mice for gene editing have been generated which, by expression of reporter genes, indicate the efficiency of precise and imprecise gene editing. These mice are important tools for testing and comparing novel gene editing methodologies. This review provides a comprehensive overview of reporter mice for gene editing which all have been used for monitoring CRISPR/Cas-mediated gene editing involving DNA double-strand breaks (DSBs). Furthermore, we discuss how reporter mice can be used for quickly checking genetic alterations by base editing (BE) or prime editing (PE).

PMID:39273078 | PMC:PMC11394079 | DOI:10.3390/cells13171508

Orphanet J Rare Dis. 2024 Sep 13;19(1):345. doi: 10.1186/s13023-024-03352-1.

ABSTRACT

OBJECTIVE: To conduct a comprehensive bibliometric analysis of the application of artificial intelligence (AI) in Rare diseases (RDs), with a focus on analyzing publication output, identifying leading contributors by country, assessing the extent of international collaboration, tracking the emergence of research hotspots, and detecting trends through keyword bursts.

METHODS: In this bibliometric study, we identified and retrieved publications on AI applications in RDs spanning 2003 to 2023 from the Web of Science (WoS). We conducted a global research landscape analysis and utilized CiteSpace to perform keyword clustering and burst detection in this field.

RESULTS: A total of 1501 publications were included in this study. The evolution of AI applications in RDs progressed through three stages: the start-up period (2003-2010), the steady development period (2011-2018), and the accelerated growth period (2019-2023), reflecting this field's increasing importance and impact at the time of the study. These studies originated from 85 countries, with the United States as the leading contributor. "Mutation", "Diagnosis", and "Management" were the top three keywords with high frequency. Keyword clustering analysis identified gene identification, effective management, and personalized treatment as three primary research areas of AI applications in RDs. Furthermore, the keyword burst detection indicated a growing interest in the areas of "biomarker", "predictive model", and "data mining", highlighting their potential to shape future research directions.

CONCLUSIONS: Over two decades, research on the AI applications in RDs has made remarkable progress and shown promising results in the development. Advancing international transboundary cooperation is essential moving forward. Utilizing AI will play a more crucial role across the spectrum of RDs management, encompassing rapid diagnosis, personalized treatment, drug development, data integration and sharing, and continuous monitoring and care.

PMID:39272071 | PMC:PMC11401438 | DOI:10.1186/s13023-024-03352-1

Nat Commun. 2024 Sep 14;15(1):8043. doi: 10.1038/s41467-024-52443-x.

ABSTRACT

The neocortex varies in size and complexity among mammals due to the tremendous variability in the number and diversity of neuronal subtypes across species. The increased cellular diversity is paralleled by the expansion of the pool of neocortical progenitors and the emergence of indirect neurogenesis during brain evolution. The molecular pathways that control these biological processes and are disrupted in neurological disorders remain largely unknown. Here we show that the transcription factors BRN1 and BRN2 have an evolutionary conserved function in neocortical progenitors to control their proliferative capacity and the switch from direct to indirect neurogenesis. Functional studies in mice and ferrets show that BRN1/2 act in concert with NOTCH and primary microcephaly genes to regulate progenitor behavior. Analysis of transcriptomics data from genetically modified macaques provides evidence that these molecular pathways are conserved in non-human primates. Our findings thus demonstrate that BRN1/2 are central regulators of gene expression programs in neocortical progenitors critical to determine brain size during evolution.

PMID:39271675 | PMC:PMC11399407 | DOI:10.1038/s41467-024-52443-x

JAMA Netw Open. 2024 Sep 3;7(9):e2427219. doi: 10.1001/jamanetworkopen.2024.27219.

NO ABSTRACT

PMID:39269710 | DOI:10.1001/jamanetworkopen.2024.27219

Orphanet J Rare Dis. 2024 Sep 12;19(1):340. doi: 10.1186/s13023-024-03347-y.

ABSTRACT

BACKGROUND: The Pareto Principle asserts that a large portion of results can be achieved with a small amount of effort. Wakap et al. found that around 80% of individuals with rare diseases (RD) suffer from one of 149 specific rare diseases. A significant challenge in the RD domain is the lack of information, compounded by the fact that most RD are not specifically codifiable in the ICD-10, leading to a deficit in reliable epidemiological data. Additionally, time constraints in medical education hinder the comprehensive teaching of all RD, contributing to the diagnostic odyssey problem through failure of recognizing diseases. We identified the most and second most prevalent RD (prevalences of 1-5/10,000 and 1-9/100,000, respectively) from the Orphanet Epidemiology File, totaling 454 diseases. We investigated the feasibility of specific coding using ICD-10-GM and whether these diseases were explicitly listed in the subject catalog (GK) of the second state examination in human medicine in Germany. A two-sided chi-square test was employed to identify statistically significant differences between prevalence groups.

RESULTS: Out of 454 diseases, a total of 34% could be specifically coded in ICD-10-GM, with 49% of diseases in the 1-5/10,000 prevalence range (153 RD) and 26% in the 1-9/100,000 range (301 RD) having specific codes. Approximately 15% of all investigated diseases were part of the GK, with 25% of the most prevalent and 10% of the second most prevalent RD group, respectively. Statistically significant differences were observed between prevalence groups concerning the presence of a specific ICD-10-GM code and inclusion in the GK.

CONCLUSION: Only 49% of the most prevalent RD can be specifically coded, highlighting the challenge of limited epidemiological data on RD. In Germany, the Alpha-ID was introduced in addition to ICD-10 in the inpatient setting to obtain more valid epidemiological data on RD. Recognizing the Pareto Principle's applicability, the study emphasizes the importance of including the most common rare diseases in medical education. While recognizing the limitations, especially in covering ultra-rare diseases, the study underscores the potential benefits of enhancing medical curricula to improve rare disease awareness and diagnostic accuracy.

PMID:39267157 | PMC:PMC11396778 | DOI:10.1186/s13023-024-03347-y

Orphanet J Rare Dis. 2024 Sep 12;19(1):336. doi: 10.1186/s13023-024-03341-4.

ABSTRACT

BACKGROUND: SATURN (Systematic Accumulation of Treatment practices and Utilisation, Real world evidence, and Natural history data) for the rare condition osteogenesis imperfecta (OI) has the objective to create a common core dataset by utilising existing, well-established data sources to meet the needs of the various stakeholders (physicians, registry/dataset owners, patients and patient associations, OI community leaders, European [EU] policymakers, regulators, health technology assessments [HTA]s, and healthcare systems including payers). This paper describes the steps taken to assess the feasibility of one existing OI registry (i.e., the Registry of OI [ROI]) as a candidate for SATURN. The same methodology will be applied to other existing OI registries in the future and this same concept could be utilised for other rare disease registries.

METHODS: The approach to assessing the feasibility of the ROI registry consisted of three steps: (1) an assessment of the registry characteristics using the Registry Evaluation and Quality Standards Tool (REQueST); (2) a gap analysis comparing SATURN required Core Variables to those being captured in the registry's Case Report Form (CRF); and (3) a compliance check on the data exchange process following the Title 21 of Code of Federal Regulations (CFR) Part 11/EudraLex Annex 11 Compliance Checklist. The first registry that SATURN has assessed is the ROI database at the Istituto Ortopedico Rizzoli (IOR) in Italy.

RESULTS: The results from the ROI REQueST have demonstrated satisfactory complete responses in terms of methodology, essential standards, interpretability, and interoperability-readiness for data linkage, data sources, and ethics to meet the needs of data customers. However, the ROI data is from a tertiary referral centre which may limit the ability to understand the full patient journey. The gap analysis has revealed that an exact or logical match between SATURN requested variables and the ROI current variables exists for the following items: patient characteristics, treatment of OI (medical and surgical) and treatment of pain (with the exception of frequency of treatment and reasons for discontinuation), fracture history and bone density. However, data on safety was missing. The compliance check has implied that the ROI implemented appropriate controls for the web-based platform (i.e., Genotype-phenotype Data Integration Platform [GeDI]) that is involved in processing the electronic patient data, and GeDI is a validated/compliant application that follows relevant 21 CFR Part 11/EudraLex Annex 11 regulations.

CONCLUSIONS: This robust feasibility process highlights potential limitations and opportunities to develop and to refine the collaboration with the ROI as the SATURN programme moves forward. It also ensures that the existing datasets in the rare condition OI are being maximised to respond to the needs of patients, data customers and decision-makers. This feasibility process has allowed SATURN to build a compliant methodology that aligns with the requirements from the European Medicines Agency (EMA) and HTAs. More data variables will continue to be developed and refined along the way with more registries participating in SATURN. As a result, SATURN will become a meaningful and truly collaborative core dataset, which will also contribute to advancing understanding of OI diagnosis, treatment, and care.

PMID:39267100 | PMC:PMC11391597 | DOI:10.1186/s13023-024-03341-4

J Coll Physicians Surg Pak. 2024 Sep;34(9):1139-1140. doi: 10.29271/jcpsp.2024.09.1139.

ABSTRACT

Null.

PMID:39262023 | DOI:10.29271/jcpsp.2024.09.1139

Healthc Policy. 2024 Aug;19(4):27-31. doi: 10.12927/hcpol.2024.27353.

ABSTRACT

Lexchin and Sirrs (2024) proposed five relevant principles to guide the use of federal funding for expensive drugs for rare diseases, including funding of outcomes-based risk-sharing agreements (OBRSAs) and proactive commitment and participation in the generation of high-quality evidence in a transparent way. This rejoinder, however, questions whether the federal funding should be used only to buy new drugs or whether it could be used to develop new drugs as well. It also examines what OBRSAs would require in terms of institutional capacities to allow the collection of real-world evidence.

PMID:39229660 | DOI:10.12927/hcpol.2024.27353

Healthc Policy. 2024 Aug;19(4):19-26. doi: 10.12927/hcpol.2024.27334.

ABSTRACT

The number of expensive drugs for rare diseases (EDRDs) approved by Health Canada and their contribution to healthcare costs have been rapidly increasing. The federal government has announced a three-year funding commitment of $1.4 billion for EDRDs, but principles need to be developed for how that funding will be allocated, especially in cases where insufficient data are available to guide decision making. Here, we review the role of evidence quality in making choices and draw on the experience from other countries to put forward five principles about how the money should be spent.

PMID:39229659 | DOI:10.12927/hcpol.2024.27334

Cancer Discov. 2024 Sep 4;14(9):1574-1576. doi: 10.1158/2159-8290.CD-24-0752.

ABSTRACT

Juvenile myelomonocytic leukemia (JMML) is a rare pediatric hematologic malignancy with a high relapse rate and a poor prognosis hallmarked by RAS pathway mutations. Stieglitz and colleagues conducted a phase II clinical trial using the MEK inhibitor trametinib to treat patients with relapsed and refractory juvenile myelomonocytic leukemia and observed an objective response rate of 50% and an overall survival of 80% after 4 years. See related article by Stieglitz et al., p. 1590 (4) .

PMID:39228296 | DOI:10.1158/2159-8290.CD-24-0752

Nat Commun. 2024 Sep 2;15(1):7640. doi: 10.1038/s41467-024-51961-y.

ABSTRACT

Genetic parasites, including viruses and transposons, exploit components from the host for their own replication. However, little is known about virus-transposon interactions within host cells. Here, we discover a strategy where human cytomegalovirus (HCMV) hijacks L1 retrotransposon encoded protein during its replication cycle. HCMV infection upregulates L1 expression by enhancing both the expression of L1-activating transcription factors, YY1 and RUNX3, and the chromatin accessibility of L1 promoter regions. Increased L1 expression, in turn, promotes HCMV replicative fitness. Affinity proteomics reveals UL44, HCMV DNA polymerase subunit, as the most abundant viral binding protein of the L1 ribonucleoprotein (RNP) complex. UL44 directly interacts with L1 ORF2p, inducing DNA damage responses in replicating HCMV compartments. While increased L1-induced mutagenesis is not observed in HCMV for genetic adaptation, the interplay between UL44 and ORF2p accelerates viral DNA replication by alleviating replication stress. Our findings shed light on how HCMV exploits host retrotransposons for enhanced viral fitness.

PMID:39223139 | DOI:10.1038/s41467-024-51961-y

Orphanet J Rare Dis. 2024 Aug 31;19(1):319. doi: 10.1186/s13023-024-03327-2.

ABSTRACT

BACKGROUND: Research on rare diseases focuses less on caregivers, who play an important role in meeting the medical and social needs of the people they care for. Caregivers of people with rare diseases face negative outcomes due to problems with diagnosis, caring for complex conditions and expensive treatments. However, the factors that affect their quality of life are poorly understood. Poor mental and physical health of caregivers has a direct impact on the person they are caring for.

METHODS: To explore the literature on this topic, we conducted a scoping review in which we identified and analysed relevant studies to find out how extensively this topic has been researched. The articles were retrieved from the bibliographic databases PubMed, Ovid Medline and Ebsco Cinahl.

RESULTS: We initially identified 299 references and then included thirty-four articles. The included articles address three main topics, namely caregiver quality of life, health care accessibility, and the impact of health care accessibility on caregiver QOL.

CONCLUSION: This study provides information that is important to multiple providers of services as it can help to better understand caregivers and people with rare diseases and improve the quality of services offered. It highlights areas with the greatest need for change and offers insight into the complexity of caring for people with rare diseases, assisting policymakers in developing policies to support informal caregivers.

PMID:39217366 | DOI:10.1186/s13023-024-03327-2

Eur J Paediatr Dent. 2024 Sep 3;25(3):171-171. doi: 10.23804/ejpd.2024.25.03.01. Epub 2024 Sep 1.

ABSTRACT

Rare diseases are an often an overlooked public health problem. Although they are infrequent, occurring on average in 100-500 people per million, these diseases represent a significant challenge in paediatric dentistry due to their complex manifestations and the need for specialised care. Conditions such as X-linked hypophosphatemic rickets (XLH), hypophosphatasia (HPP), and osteogenesis imperfecta (OI) exemplify the intersection of systemic health issues and oral health, requiring a multidisciplinary approach for their effective management. Dentists frequently play a crucial role in identifying genetic alterations through their dental manifestations and then referring patients to the geneticist for a definitive diagnosis. X-linked hypophosphatemia is the most common genetic form of rickets, with a prevalence of 1/20,000 - 1/60,000. XLH is characterised by stunted growth with disproportionate short stature, bowing of the lower limbs associated with reduced motor skills, osteoarticular pain, hypotonia, and dental and periodontal anomalies. XLH is due to inactivating mutations in the PHEX gene which cause excessive production of fibroblast growth factor 23 (FGF23). Increased concentration of FGF23 represents the main pathogenetic mechanism of XLH, stimulating urinary phosphate loss and renal 24-hydroxylase activity, and reducing renal 1α-hydroxylase activity with insufficient production of 1,25 -dihydroxy-vitamin D (1,25(OH)2D). PHEX protein is also expressed in osteoblasts, osteocytes, and odontoblasts. Regardless of FGF23's systemic effects on phosphate homeostasis, odontoblast differentiation, and dentin formation, its overexpression directly reduces osteoblast differentiation and matrix mineralisation. In patients with XLH, the deficit of 1,25(OH)2D induced by FGF23 causes poor enamel mineralisation with presence of cracks on teeth surface. XLH patients have recurrent dental abscesses with fistulas. Radiographic investigations highlight a generalised enlargement of the pulp chambers, molars with short roots, and a taurodontic appearance. Hypophosphatasia (HPP) is another condition in which dental manifestations precede systemic symptoms; it is a rare genetic disease (1/300,000 for severe forms, 1/100,000 for moderate forms. The incidence is perhaps underestimated due to missed diagnosis of moderate forms of the disease). It mainly affects bone and dental mineralisation. It is caused by pathogenic variant mutations in the ALPL gene which is located on the short arm of chromosome 1 and encodes the non-tissue-specific alkaline phosphatase (TNSALP) enzyme. TNSALP deficiency results in vitamin B6 (pyridoxine) deficiency and pathological accumulation of alkaline phosphatase substrates which may be responsible for extra-osseous manifestations, such as neurologic ones (pyridoxine sensitive seizures) as well as involvement of muscles and joints (arthropathies, muscle fatigue/hypotonia). Early non-traumatic loss of primary teeth between the ages of 2 and 4 years (and sometimes earlier) with an intact, non-resorbed root is a sign of disease. Tooth mobility precedes exfoliation of the tooth/teeth, most often without associated gum inflammation or pain. The primary incisors are the most affected teeth, and the number and type of primary teeth lost are proportional to the severity of the disease. From a radiologic perspective, characteristic signs include localised or generalised horizontal alveolar bone loss, large pulp chambers, intrapulpal calcifications, and reduced enamel thickness. Osteogenesis imperfecta, or brittle bone disease, is a rare condition characterised by bone fragility and osteopenia. It combines skeletal signs of varying severity (mainly fractures, hyperlaxity, and ligament deformities) and extra skeletal signs (bluish sclera, deafness, vascular fragility). It may also involve dentinogenesis imperfecta. The severity of clinical manifestations is highly variable, ranging from moderate forms that can go unnoticed to major forms that are lethal in the perinatal period. The birth prevalence of osteogenesis imperfecta is approximately 1 in 10,000 people. In approximately 90% of cases, it is an autosomal dominant disease due to monoallelic mutations in the COL1A1, COL1A2 or IFITM5 genes. Ten percent of cases are recessive forms characterised by dentinogenesis imperfecta, where the dental manifestations include teeth discoloration and weakness. The timely recognition of dental manifestations of these rare genetic diseases can allow providers to make an early diagnosis even prior to the development of systemic complications, and for this reason paediatric dentists have a key role in the recognition and management of these patients. Once the diagnosis is suspected, the dentist should refer patients for a genetic evaluation so as to ensure multidisciplinary management and initiation of medical therapies with the collaboration of paediatricians, endocrinologists and other health specialists. The role of dental professionals is not limited to the diagnosis of these rare diseases, but it also encompasses delivering specific, patient-tailored treatments, encouraging preventive care with regular dental visits and educating patients with the ultimate goal to promote not only oral health but the patient's overall wellbeing.

PMID:39212455 | DOI:10.23804/ejpd.2024.25.03.01

Genes (Basel). 2024 Aug 6;15(8):1033. doi: 10.3390/genes15081033.

ABSTRACT

Bi-allelic disruptive variants (nonsense, frameshift, and splicing variants) in KDM5B have been identified as causative for autosomal recessive intellectual developmental disorder type 65. In contrast, dominant variants, usually disruptive as well, have been more difficult to implicate in a specific phenotype, since some of them have been found in unaffected controls or relatives. Here, we describe individuals with likely pathogenic variants in KDM5B, including eight individuals with dominant missense variants. This study is a retrospective case series of 21 individuals with variants in KDM5B. We performed deep phenotyping and collected the clinical information and molecular data of these individuals' family members. We compared the phenotypes according to variant type and to those previously described in the literature. The most common features were developmental delay, impaired intellectual development, behavioral problems, autistic behaviors, sleep disorders, facial dysmorphism, and overgrowth. DD, ASD behaviors, and sleep disorders were more common in individuals with dominant disruptive KDM5B variants, while individuals with dominant missense variants presented more frequently with renal and skin anomalies. This study extends our understanding of the KDM5B-related neurodevelopmental disorder and suggests the pathogenicity of certain dominant KDM5B missense variants.

PMID:39202393 | DOI:10.3390/genes15081033

Genes (Basel). 2024 Jul 25;15(8):984. doi: 10.3390/genes15080984.

ABSTRACT

Wolfram syndrome 1 (WS1) is an uncommon autosomal recessive neurological disorder that is characterized by diabetes insipidus, early-onset non-autoimmune diabetes mellitus, optic atrophy, and deafness (DIDMOAD). Other clinical manifestations are neuropsychiatric symptoms, urinary tract alterations, and endocrinological disorders. The rapid clinical course of WS1 results in death by the age of 30. Severe brain atrophy leads to central respiratory failure, which is the main cause of death in WS1 patients. Mutations in the WFS1 gene, located on chromosome 4p16, account for approximately 90% of WS1 cases. The gene produces wolframin, a transmembrane glycoprotein widely distributed and highly expressed in retinal, neural, and muscular tissues. Wolframin plays a crucial role in the regulation of apoptosis, insulin signaling, and ER calcium homeostasis, as well as the ER stress response. WS1 has been designated as a neurodegenerative and neurodevelopmental disorder due to the numerous abnormalities in the ER stress-mediated system. WS1 is a devastating neurodegenerative disease that affects patients and their families. Early diagnosis and recognition of the initial clinical signs may slow the disease's progression and improve symptomatology. Moreover, genetic counseling should be provided to the patient's relatives to extend multidisciplinary care to their first-degree family members. Regrettably, there are currently no specific drugs for the therapy of this fatal disease. A better understanding of the etiology of WS1 will make possible the development of new therapeutic approaches that may enhance the life expectancy of patients. This review will examine the pathogenetic mechanisms, development, and progression of neuropsychiatric symptoms commonly associated with WS1. A thorough understanding of WS1's neurophysiopathology is critical for achieving the goal of improving patients' quality of life and life expectancy.

PMID:39202345 | DOI:10.3390/genes15080984

Int J Mol Sci. 2024 Aug 15;25(16):8891. doi: 10.3390/ijms25168891.

ABSTRACT

Cyclin-dependent kinase-like 5 (CDKL5) is a serine/threonine protein kinase involved in human brain development and functioning. Mutations in CDKL5, especially in its catalytic domain, cause a severe developmental condition named CDKL5 deficiency disorder. Nevertheless, molecular studies investigating the structural consequences of such mutations are still missing. The CDKL5 catalytic domain harbors different sites of post-translational modification, such as phosphorylations, but their role in catalytic activity, protein folding, and stability has not been entirely investigated. With this work, we describe the expression pattern of the CDKL5 catalytic domain in Escherichia coli demonstrating that it predominantly aggregates. However, the use of solubility tags, the lowering of the expression temperature, the manual codon optimization to overcome an internal translational start, and the incubation of the protein with K+ and MgATP allow the collection of a soluble catalytically active kinase. Interestingly, the resulting protein exhibits hypophosphorylation compared to its eukaryotic counterpart, proving that bacteria are a useful tool to achieve almost unmodified CDKL5. Posing questions about the CDKL5 autoactivation mechanism and the determinants for its stability, this research provides a valuable platform for comparative biophysical studies between bacterial and eukaryotic-expressed proteins, contributing to our understanding of neurodevelopmental disorders associated with CDKL5 dysfunction.

PMID:39201578 | DOI:10.3390/ijms25168891

JMIR Public Health Surveill. 2024 Aug 27;10:e57353. doi: 10.2196/57353.

ABSTRACT

BACKGROUND: Rare diseases (RDs) affect millions of individuals collectively worldwide, contributing to significant burdens on patients and families in various aspects. However, there is a lack of evidence on the underlying patterns of burdens among diverse RDs for informing targeted social and health policies to address the unmet needs of this vulnerable population.

OBJECTIVE: This study aimed to examine the underlying patterns of the health and economic burden of 33 different RDs in China and identify the potential determinants.

METHODS: A nationwide internet-based cross-sectional survey was conducted in China between 2019 and 2020. Physical and mental health burden was measured by health-related quality of life. Economic burden was evaluated based on the proportions of direct medical, direct nonmedical, and indirect costs relative to household income. We used cluster analysis to identify patterns of health and economic burdens and conducted multinomial logistic regression to explore potential predictors of cluster membership.

RESULTS: The study included 8454 adults and 8491 children affected by 33 RDs. The following 3 clusters were identified: "extremely high burden" (representing 92/8454, 1.1% and 19/8491, 0.2% of adult and pediatric patients, respectively), "overall high burden" (5933/8454, 70.2% and 4864/8491, 57.3%, respectively), and "overall low burden" (2429/8454, 28.7% and 3608/8491, 42.5%, respectively). Wilson disease, Marfan syndrome, and Langerhans cell histiocytosis more likely resulted in an "extremely high burden" than others. Poverty was significantly associated with being in this extremely high burden group. Diseases causing neuromuscular symptoms and requiring long-term treatment (eg, amyotrophic lateral sclerosis, spinocerebellar ataxia, and Dravet syndrome) were prevalent in the "overall high burden" group. Key predictors of this group included older age, lower socioeconomic status, diagnostic delay, and comorbidity.

CONCLUSIONS: This study provides novel and valuable evidence on the burden of RDs in developing regions like China. The findings reveal significant disparities in the impact of RDs, emphasizing the need for targeted health care interventions and policies.

PMID:39190906 | DOI:10.2196/57353

Stud Health Technol Inform. 2024 Aug 22;316:894-898. doi: 10.3233/SHTI240556.

ABSTRACT

With the objective of extracting new knowledge about rare diseases from social media messages, we evaluated three models on a Named Entity Recognition (NER) task, consisting of extracting phenotypes and treatments from social media messages. We trained the three models on a dataset with social media messages about Developmental and Epileptic Encephalopathies and more common diseases. This preliminary study revealed that CamemBERT and CamemBERT-bio exhibit similar performance on social media testimonials, slightly outperforming DrBERT. It also highlighted that their performance was lower on this type of data than on structured health datasets. Limitations, including a narrow focus on NER performance and dataset-specific evaluation, call for further research to fully assess model capabilities on larger and more diverse datasets.

PMID:39176937 | DOI:10.3233/SHTI240556