Int J Environ Res Public Health. 2023 Sep 29;20(19):6863. doi: 10.3390/ijerph20196863.

ABSTRACT

The COVID-19 pandemic took a toll on everyone's lives, and patients with rare diseases (RDs) had to pay an even higher price. In this systematic review, we explored the impact of the COVID-19 pandemic on individuals with RDs from a psychological perspective. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we retrieved articles from the Google Scholar, Scopus, and PubMed databases focusing on 'COVID-19,' 'psychology,' and 'rare diseases.' Seventeen primary articles were identified (mainly from continental Europe). The results revealed the psychological effects of the pandemic on rare disease patients, including increased anxiety, stress, and depressive moods. This review also highlighted the increased vulnerability and reduced quality of life of rare disease patients during the pandemic, as well as the importance of telecare and psychological support as critical interventions for improving their well-being. There is an urgent need for multidisciplinary research and stronger healthcare systems to meet the unique challenges of rare disease patients, who represent 3.5-5.9% of the global population.

PMID:37835133 | PMC:PMC10573057 | DOI:10.3390/ijerph20196863

Orphanet J Rare Dis. 2023 Oct 13;18(1):324. doi: 10.1186/s13023-023-02947-4.

ABSTRACT

BACKGROUND: In the European Union, a disease is defined as rare when it affects fewer than 1 in 2000 people. Currently, there are up to 8000 described rare diseases (RDs), collectively affecting 30 million people in the European Union. In 2004 Tuscany region (Italy) established a Regional Network of hospital units to ensure highly specialised medical care in the field of RDs. Shortly after the Rare Diseases Registry of Tuscany (Registro Toscano Malattie Rare-RTMR) was implemented. Here we describe the analysis performed on RTMR data which has recently allowed to remap the Network based on European Reference Networks' model.

RESULTS: Data analysis was performed on 60,367 cases registered in RTMR, regarding 628 RDs. Two-hundred and fifteen active presidia have been evaluated. The assignment of each RD to the suitable European Reference Network has been made considering not only the number of registered cases, certifications and treatment plans for each Regional Presidium but also the competence in multidisciplinary management of the patient, from diagnosis to treatment. This evaluation has led to the establishment of twenty-one Regional Coordination Centres. They aggregate and coordinate Hospital Units which diagnose and treat one or a group of related RDs. In case of wide groups of RDs, Clinical Subnets are instituted. Updated statistics regarding RDs in Tuscany, list of RDs and Coordination Centres, as well as information about single Presidia are published and freely available on a designated webpage. Regional Decrees are regularly updated according to the network evolution.

CONCLUSIONS: The Rare Diseases Regional Network in Tuscany, based on the ERN model, has played a pivotal role in enhancing RD management and research. The remapping has led to a dynamic system, following not only scientific research but also the development of Presidia's expertise. By pooling resources and expertise, the network has improved the availability and accessibility of specialized care for patients with RDs. Collaborative efforts, data sharing, and standardized registries are crucial for advancing RD research, improving diagnosis and treatment, and ultimately enhancing the quality of life for individuals living with RDs.

PMID:37833795 | PMC:PMC10576286 | DOI:10.1186/s13023-023-02947-4

EBioMedicine. 2023 Oct 12;97:104829. doi: 10.1016/j.ebiom.2023.104829. Online ahead of print.

ABSTRACT

BACKGROUND: Malignant peripheral nerve sheath tumour (MPNST) is an aggressive orphan disease commonly affecting adolescents or young adults. Current knowledge of molecular tumour biology has been insufficient for development of rational treatment strategies. We aimed to discover molecular subtypes of potential clinical relevance.

METHODS: Fresh frozen samples of MPNSTs (n = 94) and benign neurofibromas (n = 28) from 115 patients in a European multicentre study were analysed by DNA copy number and/or transcriptomic profiling. Unsupervised transcriptomic subtyping was performed and the subtypes characterized for genomic aberrations, clinicopathological associations and patient survival.

FINDINGS: MPNSTs were classified into two transcriptomic subtypes defined primarily by immune signatures and proliferative processes. "Immune active" MPNSTs (44%) had sustained immune signals relative to neurofibromas, were more frequently low-grade (P = 0.01) and had favourable prognostic associations in a multivariable model of disease-specific survival with clinicopathological factors (hazard ratio 0.25, P = 0.003). "Immune deficient" MPNSTs were more aggressive and characterized by proliferative signatures, high genomic complexity, aberrant TP53 and PRC2 loss, as well as high relative expression of several potential actionable targets (EGFR, ERBB2, EZH2, KIF11, PLK1, RRM2). Integrated gene-wise analyses suggested a DNA copy number-basis for proliferative transcriptomic signatures in particular, and the tumour copy number burden further stratified the transcriptomic subtypes according to patient prognosis (P < 0.01).

INTERPRETATION: Approximately half of MPNSTs belong to an "immune deficient" transcriptomic subtype associated with an aggressive disease course, PRC2 loss and expression of several potential therapeutic targets, providing a rationale for molecularly-guided intervention trials.

FUNDING: Research grants from non-profit organizations, as stated in the Acknowledgements.

PMID:37837931 | DOI:10.1016/j.ebiom.2023.104829

J Neurodev Disord. 2023 Oct 13;15(1):33. doi: 10.1186/s11689-023-09502-z.

ABSTRACT

OBJECTIVE: Recent advances in the understanding of neurodevelopmental disorders such as Rett syndrome (RTT) have enabled the discovery of novel therapeutic approaches that require formal clinical evaluation of efficacy. Clinical trial success depends on outcome measures that assess clinical features that are most impactful for affected individuals. To determine the top concerns in RTT and RTT-related disorders we asked caregivers to list the top caregiver concerns to guide the development and selection of appropriate clinical trial outcome measures for these disorders.

METHODS: Caregivers of participants enrolled in the US Natural History Study of RTT and RTT-related disorders (n = 925) were asked to identify the top 3 concerning problems impacting the affected participant. We generated a weighted list of top caregiver concerns for each of the diagnostic categories and compared results between the disorders. Further, for classic RTT, caregiver concerns were analyzed by age, clinical severity, and common RTT-causing mutations in MECP2.

RESULTS: The top caregiver concerns for classic RTT were effective communication, seizures, walking/balance issues, lack of hand use, and constipation. The frequency of the top caregiver concerns for classic RTT varied by age, clinical severity, and specific mutations, consistent with known variation in the frequency of clinical features across these domains. Caregivers of participants with increased seizure severity often ranked seizures as the first concern, whereas caregivers of participants without active seizures often ranked hand use or communication as the top concern. Comparison across disorders found commonalities in the top caregiver concerns between classic RTT, atypical RTT, MECP2 duplication syndrome, CDKL5 deficiency disorder, and FOXG1 syndrome; however, distinct differences in caregiver concerns between these disorders are consistent with the relative prevalence and impact of specific clinical features.

CONCLUSION: The top caregiver concerns for individuals with RTT and RTT-related disorders reflect the impact of the primary clinical symptoms of these disorders. This work is critical in the development of meaningful therapies, as optimal therapy should address these concerns. Further, outcome measures to be utilized in clinical trials should assess these clinical issues identified as most concerning by caregivers.

PMID:37833681 | PMC:PMC10571464 | DOI:10.1186/s11689-023-09502-z

F1000Res. 2023 Nov 13;12:741. doi: 10.12688/f1000research.130388.1. eCollection 2023.

ABSTRACT

This article aims to synthesize the existing literature on the implementation of public policies to incentivize the development of treatments for rare diseases, (diseases with very low prevalence and therefore with low commercial interest) otherwise known as orphan drugs. The implementation of these incentives in the United States (US), Japan, and in the European Union (EU) seems to be related to a substantial increase in treatments for these diseases, and has influenced the way the pharmaceutical research & development (R&D) system operates beyond this policy area. Despite the success of the Orphan Drug model, the academic literature also highlights the negative implications that these public policies have on affordability and access to orphan drugs, as well as on the prioritization of certain disease rare areas over others. The synthesis focuses mostly on the United States' Orphan Drug Act (ODA) as a model for subsequent policies in other regions and countries. It starts with a historical overview of the creation of the term "rare diseases", continues with a summary of the evidence available on the US ODA's positive and negative impacts, and provides a summary of the different proposals to reform these incentives in light of the negative outcomes described. Finally, it describes some key aspects of the Japanese and European policies, as well as some of the challenges captured in the literature related to their impact in Low- and Middle-Income Countries (LMICs).

PMID:37822316 | PMC:PMC10562777 | DOI:10.12688/f1000research.130388.1

Orphanet J Rare Dis. 2023 Oct 12;18(1):321. doi: 10.1186/s13023-023-02943-8.

ABSTRACT

BACKGROUND: Generalized pairwise comparisons (GPC) can be used to assess the net benefit of new treatments for rare diseases. We show the potential of GPC through simulations based on data from a natural history study in mucopolysaccharidosis type IIIA (MPS IIIA).

METHODS: Using data from a historical series of untreated children with MPS IIIA aged 2 to 9 years at the time of enrolment and followed for 2 years, we performed simulations to assess the operating characteristics of GPC to detect potential (simulated) treatment effects on a multi-domain symptom assessment. Two approaches were used for GPC: one in which the various domains were prioritized, the other with all domains weighted equally. The net benefit was used as a measure of treatment effect. We used increasing thresholds of clinical relevance to reflect the magnitude of the desired treatment effects, relative to the standard deviation of the measurements in each domain.

RESULTS: GPC were shown to have adequate statistical power (80% or more), even with small sample sizes, to detect treatment effects considered to be clinically worthwhile on a symptom assessment covering five domains (expressive language, daily living skills, and gross-motor, sleep and pain). The prioritized approach generally led to higher power as compared with the non-prioritized approach.

CONCLUSIONS: GPC of prioritized outcomes is a statistically powerful as well as a patient-centric approach for the analysis of multi-domain scores in MPS IIIA and could be applied to other heterogeneous rare diseases.

PMID:37828533 | PMC:PMC10571482 | DOI:10.1186/s13023-023-02943-8

Front Public Health. 2023 Sep 26;11:1248260. doi: 10.3389/fpubh.2023.1248260. eCollection 2023.

ABSTRACT

BACKGROUND: Patients, families, the healthcare system, and society as a whole are all significantly impacted by rare diseases (RDs). According to various classifications, there are currently up to 9,000 different rare diseases that have been recognized, and new diseases are discovered every month. Although very few people are affected by each uncommon disease individually, millions of people are thought to be impacted globally when all these conditions are considered. Therefore, RDs represent an important public health concern. Although crucial for clinical care, early and correct diagnosis is still difficult to achieve in many nations, especially those with low and middle incomes. Consequently, a sizeable amount of the overall burden of RD is attributable to undiagnosed RD (URD). Existing barriers and policy aspects impacting the care of patients with RD and URD remain to be investigated.

METHODS: To identify unmet needs and opportunities for patients with URD, the Developing Nations Working Group of the Undiagnosed Diseases Network International (DNWG-UDNI) conducted a survey among its members, who were from 20 different nations. The survey used a mix of multiple choice and dedicated open questions covering a variety of topics. To explore reported needs and analyze them in relation to national healthcare economical aspects, publicly available data on (a) World Bank ranking; (b) Current health expenditure per capita; (c) GDP per capita; (d) Domestic general government health expenditure (% of GDP); and (e) Life expectancy at birth, total (years) were incorporated in our study.

RESULTS: This study provides an in-depth evaluation of the unmet needs for 20 countries: low-income (3), middle-income (10), and high-income (7). When analyzing reported unmet needs, almost all countries (N = 19) indicated that major barriers still exist when attempting to improve the care of patients with UR and/or URD; most countries report unmet needs related to the availability of specialized care and dedicated facilities. However, while the countries ranked as low income by the World Bank showed the highest prevalence of referred unmet needs across the different domains, no specific trend appeared when comparing the high, upper, and low-middle income nations. No overt trend was observed when separating countries by current health expenditure per capita, GDP per capita, domestic general government health expenditure (% of GDP) and life expectancy at birth, total (years). Conversely, both the GDP and domestic general government health expenditure for each country impacted the presence of ongoing research.

CONCLUSION: We found that policy characteristics varied greatly with the type of health system and country. No overall pattern in terms of referral for unmet needs when separating countries by main economic or health indicators were observed. Our findings highlight the importance of identifying actionable points (e.g., implemented orphan drug acts or registries where not available) in order to improve the care and diagnosis of RDs and URDs on a global scale.

PMID:37822540 | PMC:PMC10562568 | DOI:10.3389/fpubh.2023.1248260

Nat Commun. 2023 Oct 12;14(1):6403. doi: 10.1038/s41467-023-41980-6.

ABSTRACT

Rare Mendelian disorders pose a major diagnostic challenge and collectively affect 300-400 million patients worldwide. Many automated tools aim to uncover causal genes in patients with suspected genetic disorders, but evaluation of these tools is limited due to the lack of comprehensive benchmark datasets that include previously unpublished conditions. Here, we present a computational pipeline that simulates realistic clinical datasets to address this deficit. Our framework jointly simulates complex phenotypes and challenging candidate genes and produces patients with novel genetic conditions. We demonstrate the similarity of our simulated patients to real patients from the Undiagnosed Diseases Network and evaluate common gene prioritization methods on the simulated cohort. These prioritization methods recover known gene-disease associations but perform poorly on diagnosing patients with novel genetic disorders. Our publicly-available dataset and codebase can be utilized by medical genetics researchers to evaluate, compare, and improve tools that aid in the diagnostic process.

PMID:37828001 | PMC:PMC10570269 | DOI:10.1038/s41467-023-41980-6

Hum Gene Ther. 2023 Oct;34(19-20):980-981. doi: 10.1089/hum.2023.29248.rwh. Epub 2023 Oct 12.

NO ABSTRACT

PMID:37823804 | DOI:10.1089/hum.2023.29248.rwh

Database (Oxford). 2023 Oct 11;2023:baad066. doi: 10.1093/database/baad066.

ABSTRACT

In recent years, a huge amount of data on ncRNA interactions has been described in scientific papers and databases. Although considerable effort has been made to annotate the available knowledge in public repositories, there are still significant discrepancies in how different resources capture and interpret data on ncRNA functional and physical associations. In the present paper, we present a collection of microRNA-mRNA interactions annotated from the scientific literature following recognized standard criteria and focused on microRNAs, which regulate genes associated with rare diseases as a case study. The list of protein-coding genes with a known role in specific rare diseases was retrieved from the Genome England PanelApp, and associated microRNA-mRNA interactions were annotated in the IntAct database and compared with other datasets. RNAcentral identifiers were used for unambiguous, stable identification of ncRNAs. The information about the interaction was enhanced by a detailed description of the cell types and experimental conditions, providing a computer-interpretable summary of the published data, integrated with the huge amount of protein interactions already gathered in the database. Furthermore, for each interaction, the binding sites of the microRNA are precisely mapped on a well-defined mRNA transcript of the target gene. This information is crucial to conceive and design optimal microRNA mimics or inhibitors to interfere in vivo with a deregulated process. As these approaches become more feasible, high-quality, reliable networks of microRNA interactions are needed to help, for instance, in the selection of the best target to be inhibited and to predict potential secondary off-target effects. Database URL https://www.ebi.ac.uk/intact.

PMID:37819683 | PMC:PMC10566539 | DOI:10.1093/database/baad066

Lakartidningen. 2023 Oct 3;120:23082.

ABSTRACT

Umbilical pilonidal sinus is a rare diagnosis which is characterized by an inflammatory granulomatous reaction to hair shafts penetrating the epidermis. It is most often seen in adolescent male with a hairy abdomen. The patients often present with a history of pain and umbilical discharge. Conservative treatment with hair extraction and personal hygiene is prioritized and surgery is only recommended in recurrent cases. Here one such case is presented, which was resistant to conservative treatment and where surgical excision and primary repair was indicated. No recurrence was observed 6 months postoperatively.

PMID:37818822

Ann Hematol. 2023 Dec;102(12):3299-3309. doi: 10.1007/s00277-023-05439-4. Epub 2023 Oct 10.

ABSTRACT

ABP 959 is being developed as a biosimilar to Soliris® (eculizumab) reference product (RP), which was approved under orphan designation for a group of rare diseases including paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), generalized myasthenia gravis (gMG), and neuromyelitis optica spectrum disorder (NMOSD). Development of biosimilars for therapeutics approved for rare disease indications must provide scientific rationale based on the totality of evidence (TOE). To support the TOE and the scientific justification for extrapolation to all approved indications for eculizumab RP, including but not limited to aHUS and NMOSD, we utilized simulated ex-vivo pharmacodynamic (PD) assessments to compare the complement component 5 (C5) inhibitory activity of ABP 959 and the RP. Hemolysis activity of CH50 and AH50, and Wieslab CP, AP, and LP endpoints represent the three complement activation pathways (classical, alternative, and lectin), all of which share the terminal pathway and require C5 for activity. These endpoints were evaluated in normal serum, simulated aHUS serum, and simulated NMOSD serum to provide a robust comparison. The results support the conclusion that ABP 959 and eculizumab RP exhibit highly similar inhibition of C5 function regardless of the type of serum used. This work presents a full comparison of the effect of C5 inhibition across five complement functional assays. Using this approach to confirm functional similarity of ABP 959 with eculizumab RP contributes to the TOE for biosimilarity and provides support for extrapolation based on inhibition of C5 function to other rare disease indications approved for eculizumab RP.

PMID:37817009 | DOI:10.1007/s00277-023-05439-4

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2023 Nov;66(11):1249-1258. doi: 10.1007/s00103-023-03772-7. Epub 2023 Oct 10.

ABSTRACT

Newborn screening (NBS) is a highly successful secondary prevention program with the goal of preventing severe sequelae of congenital, mostly genetic, diseases by identifying them as early as possible, ideally in the pre-symptomatic period. Studies to date have shown the important achievements of NBS programs but also reveal a number of relevant weaknesses. These include the often incompletely understood natural history and phenotypic diversity of rare diseases as well as the inadequate ability to accurately predict individual disease severity at an early stage and thus the uncertainties in case definition, risk stratification, and treatment indication.In light of the rapid developments in high-throughput genetic technologies and the associated opportunities for substantial future expansion of NBS programs, it seems overdue to make structured long-term follow-up and the subsequent evaluation of the long-term health benefits mandatory for individuals with rare diseases identified through NBS. This article explains the importance of long-term follow-up for the evaluation and continuous optimization of the screening. Long-term clinical outcomes of people with inherited metabolic diseases identified by NBS are presented as examples.

PMID:37815612 | DOI:10.1007/s00103-023-03772-7

Arch Clin Neuropsychol. 2023 Oct 20;38(7):1499. doi: 10.1093/arclin/acad067.335.

ABSTRACT

OBJECTIVE: Approximately 80% of rare diseases in childhood have a genetic cause. Neuropsychological assessments offer a greater understanding of the clinical presentation and trajectory of neurogenetic disorders. Given the rarity of the conditions, the limited funding allocated to study psychosocial factors, the diversity within the patient populations (e.g., country of origin, clinical phenotypes), and the limitations of our tools, there are no clear guidelines for evaluations. We aim to present a systematic approach to create assessment protocols that track disease progression and/or efficacy of therapeutic interventions.

METHOD: Our gene therapy program has created nine assessment protocols to evaluate conditions ranging from epileptic encephalopathies, lysosomal storage, neuromuscular, and mitochondrial diseases. Through review of past protocols, we created a neuropsychological assessment selection checklist (NASC) and standard operating procedure (SOP) checklist.

RESULTS: The NASC systematizes updated multidisciplinary disease knowledge and relevant desirable outcomes (e.g., cognitive, motor, quality of life). Cultural elements (e.g., beliefs around health, disease, testing) and necessary accommodations (e.g., interpreters, sensory impairments) must be considered. Additional sociocultural and socioeconomic information of the sample is germane not only to contextualize results but also to help narrow possible tools. The SOP aims to increase standardization (e.g., starting points) and maximize use of the data collected (e.g., deferment reasons.).

CONCLUSIONS: Neuropsychological assessments offer a wealth of cognitive, behavioral, emotional, and adaptive functioning data that is crucial to better understand the progression and treatment of rare neurogenetic diseases. Cultural considerations and in-depth clinical and assessment skills are essential to creating evaluation protocols that are valid, useful, and comprehensive.

PMID:37807538 | DOI:10.1093/arclin/acad067.335

medRxiv. 2023 Sep 28:2023.09.27.23294269. doi: 10.1101/2023.09.27.23294269. Preprint.

ABSTRACT

Heterozygous missense variants and in-frame indels in SMC3 are a cause of Cornelia de Lange syndrome (CdLS), marked by intellectual disability, growth deficiency, and dysmorphism, via an apparent dominant-negative mechanism. However, the spectrum of manifestations associated with SMC3 loss-of-function variants has not been reported, leading to hypotheses of alternative phenotypes or even developmental lethality. We used matchmaking servers, patient registries, and other resources to identify individuals with heterozygous, predicted loss-of-function (pLoF) variants in SMC3, and analyzed population databases to characterize mutational intolerance in this gene. Here, we show that SMC3 behaves as an archetypal haploinsufficient gene: it is highly constrained against pLoF variants, strongly depleted for missense variants, and pLoF variants are associated with a range of developmental phenotypes. Among 13 individuals with SMC3 pLoF variants, phenotypes were variable but coalesced on low growth parameters, developmental delay/intellectual disability, and dysmorphism reminiscent of atypical CdLS. Comparisons to individuals with SMC3 missense/in-frame indel variants demonstrated a milder presentation in pLoF carriers. Furthermore, several individuals harboring pLoF variants in SMC3 were nonpenetrant for growth, developmental, and/or dysmorphic features, some instead having intriguing symptomatologies with rational biological links to SMC3 including bone marrow failure, acute myeloid leukemia, and Coats retinal vasculopathy. Analyses of transcriptomic and epigenetic data suggest that SMC3 pLoF variants reduce SMC3 expression but do not result in a blood DNA methylation signature clustering with that of CdLS, and that the global transcriptional signature of SMC3 loss is model-dependent. Our finding of substantial population-scale LoF intolerance in concert with variable penetrance in subjects with SMC3 pLoF variants expands the scope of cohesinopathies, informs on their allelic architecture, and suggests the existence of additional clearly LoF-constrained genes whose disease links will be confirmed only by multi-layered genomic data paired with careful phenotyping.

PMID:37808847 | PMC:PMC10557843 | DOI:10.1101/2023.09.27.23294269

Kathmandu Univ Med J (KUMJ). 2023 Jan-Mar;21(81):98-99.

ABSTRACT

Male infertility may be due to low sperm concentration, poor sperm motility, or abnormal morphology. Among the factors involved in male infertility, there is a rare morphology disorder called "Globozoospermia". This condition is primarily characterized by the presence of round-headed spermatozoa, absence of acrosomal cap and cytoskeleton defects around the nucleus. The morphological characteristics of globozoospermia are formed during spermiogenesis. We report here a case of male infertility due to morphological disorder Globozoospermia. Assessment of semen by observing macroscopic and microscopic parameters are not sufficient for sperm analysis. In present case, macroscopic and microscopic assessment was within normal range. Morphological assessment showed 80% of spermatozoa with round head and absence of acrosomal cap. The absence of acrosome makes fertilization impossible since these sperm are unable to bind to the zona pellucida. By using Intracytoplasmic Sperm Injection (ICSI), conception is possible; however, the fertilization rate remains very low.

PMID:37800435

Methods Mol Biol. 2024;2719:79-98. doi: 10.1007/978-1-0716-3461-5_5.

ABSTRACT

Modern high-throughput genomic testing using next-generation sequencing (NGS) has led to a significant increase in the successful diagnosis of rare genetic disorders. Recent advances in NGS tools and techniques have led to accurate and timely diagnosis of a large proportion of genetic diseases by finding sequence variations in clinical samples. One of the NGS techniques, exome sequencing (ES), is considered as a powerful and easily approachable method for genetic disorders in terms of rapid and cost-effective diagnostic yields. In this chapter, we describe an overview of whole exome sequencing (ES) in the context of experimental and analytical methodologies. Approaches to ES include sequencing capture technique, quality control processes at various stages of sequencing analysis, exome data filtering strategy that incorporates both primary and secondary filtering, and prioritization of candidate variants in diagnosing genetic diseases.

PMID:37803113 | DOI:10.1007/978-1-0716-3461-5_5

Am J Hum Genet. 2023 Oct 3:S0002-9297(23)00321-X. doi: 10.1016/j.ajhg.2023.09.008. Online ahead of print.

ABSTRACT

Certain classes of genetic variation still escape detection in clinical sequencing analysis. One such class is retroelement insertion, which has been reported as a cause of Mendelian diseases and may offer unique therapeutic implications. Here, we conducted retroelement profiling on whole-genome sequencing data from a cohort of 237 individuals with ataxia telangiectasia (A-T). We found 15 individuals carrying retroelement insertions in ATM, all but one of which integrated in noncoding regions. Systematic functional characterization via RNA sequencing, RT-PCR, and/or minigene splicing assays showed that 12 out of 14 intronic insertions led or contributed to ATM loss of function by exon skipping or activating cryptic splice sites. We also present proof-of-concept antisense oligonucleotides that suppress cryptic exonization caused by a deep intronic retroelement insertion. These results provide an initial systematic estimate of the contribution of retroelements to the genetic architecture of recessive Mendelian disorders as ∼2.1%-5.5%. Our study highlights the importance of retroelement insertions as causal variants and therapeutic targets in genetic diseases.

PMID:37802069 | DOI:10.1016/j.ajhg.2023.09.008

Clin Nucl Med. 2023 Nov 1;48(11):994-996. doi: 10.1097/RLU.0000000000004835. Epub 2023 Sep 18.

ABSTRACT

Intravenous (IV) leiomyomatosis is a rare IV disease. Our case presents 68 Ga-FAPI and 18 F-FDG PET/CT findings of IV leiomyomatosis in a 37-year-old woman. Intravenous leiomyomatosis shows only mild FDG but intense 68 Ga-FAPI activity on PET/CT studies. In this case, 68 Ga-FAPI was superior to 18 F-FDG PET/CT in detecting IV leiomyomatosis.

PMID:37796170 | DOI:10.1097/RLU.0000000000004835

J Biosci. 2023;48:37.

ABSTRACT

Rare diseases (RDs) are those that affect a small fraction of the total population. In India, where resources are scarce, the healthcare infrastructure and policy framework are focused on mitigating diseases that affect a large number of people. As a result,many cases ofRDs remain unreported, undiagnosed, and untreated. To understandthe currentlevel of RD awareness among healthcare professionals (HCPs) and researchers, as they are key stakeholders in diagnosis, treatment, policy making, and drug development, we conducted a survey based on identification of an RD, time for diagnosis, treatment options, and relationship with family history and geographic location. The survey was divided into two parts, one for researchers and the other for healthcare professionals, each consisting of 22 questions. We observed that among all our respondents, 31% of researchers and 29% of HCPs did not know the time required for diagnosis of a rare disease they mentioned in the survey. They identified the importance of family history but failed to realize its association with geographic location. The results from the exploratory study can provide information for enabling larger studies to develop recommendations and policies that can improve awareness about RDs in healthcare communities.

PMID:37795705