Search

Drosophila melanogaster usage has provided substantial insights into the pathogenesis of several nucleotide repeat expansion diseases (NREDs), a group of genetic diseases characterized by the abnormal expansion of DNA repeats. Leveraging the genetic simplicity and manipulability of Drosophila, researchers have successfully modeled close to 15 NREDs such as Huntington's disease (HD), several spinocerebellar ataxias (SCA), and myotonic dystrophies type 1 and 2 (DM1/DM2). These models have been instrumental in characterizing the principal associated molecular mechanisms: protein aggregation, RNA toxicity, and protein function loss, thus recapitulating key features of human disease. Used in chemical and genetic screenings, they also enable us to identify promising small molecules and genetic modifiers that mitigate the toxic effects of expanded repeats. This review summarizes the close to 150 studies performed in this area during the last seven years. The relevant highlights are the achievement of the first fly-based models for some NREDs, the incorporation of new technologies such as CRISPR for developing or evaluating transgenic flies containing repeat expanded motifs, and the evaluation of less understood toxic mechanisms in NREDs such as RAN translation. Overall, Drosophila melanogaster remains a powerful platform for research in NREDs. [ABSTRACT FROM AUTHOR]

Lymphangioleiomyomatosis (LAM) is a rare genetic lung disease. Unfortunately, treatment with the mTORC1 inhibitor Rapamycin only slows disease progression, and incomplete responses are common. Thus, there remains an urgent need to identify new targets for the development of curative LAM treatments. Nitazoxanide (NTZ) is an orally bioavailable antiprotozoal small molecule drug approved for the treatment of diarrhea caused by Giardia lamblia or Cryptosporidium parvum in children and adults, with a demonstrated mTORC1 inhibitory effect in several human cell lines. NTZ's excellent safety profile characterized by its more than 20 years of clinical use makes it a promising candidate for repurposing. Our rationale for this study was to further investigate NTZ's effect using in vitro and in vivo LAM models and to elucidate the underlying molecular mechanism beyond mTORC1 inhibition. For this purpose, we investigated cell proliferation, cell viability, and changes in protein phosphorylation and expression in primary human cell cultures derived from LAM lung samples before translating our results into a syngeneic mouse model utilizing Tsc2-null cells. NTZ reduced cell growth for all tested cell lines at a dose of about 30 µM. Lower doses than that had no effect on cell viability, but doses above 45 µM lowered the viability by about 10 to 15% compared to control. Interestingly, our western blot revealed no inhibition of mTORC1 and only a mild effect on active ß-Catenin. Instead, NTZ had a pronounced effect on reducing pAkt. In the mouse model, prophylactic NTZ treatment via the intraperitoneal and oral routes had some effects on reducing lung lesions and improving body weight retention, but the results remain inconclusive. [ABSTRACT FROM AUTHOR]

Perry disease (PeD) is a rare, neurodegenerative, genetic disorder inherited in an autosomal dominant manner. The disease manifests as parkinsonism, with psychiatric symptoms on top, such as depression or sleep disorders, accompanied by unexpected weight loss, central hypoventilation, and aggregation of DNA-binding protein (TDP-43) in the brain. Due to the genetic cause, no causal treatment for PeD is currently available. The only way to improve the quality of life of patients is through symptomatic therapy. This work aims to review the latest data on potential PeD treatment, specifically from the medicinal chemistry and computer-aided drug design (CADD) points of view. We select proteins that might represent therapeutic targets for symptomatic treatment of the disease: monoamine oxidase B (MAO-B), serotonin transporter (SERT), dopamine D2 (D2R), and serotonin 5-HT1A (5-HT1AR) receptors. We report on compounds that may be potential hits to develop symptomatic therapies for PeD and related neurodegenerative diseases and relieve its symptoms. We use Phase pharmacophore modeling software (version 2023.08) implemented in Schrödinger Maestro as a ligand selection tool. For each of the chosen targets, based on the resolved protein–ligand structures deposited in the Protein Data Bank (PDB) database, pharmacophore models are proposed. We review novel, active compounds that might serve as either hits for further optimization or candidates for further phases of studies, leading to potential use in the treatment of PeD. [ABSTRACT FROM AUTHOR]

Neurocysticercosis (NCC), a parasitic infection of the central nervous system caused by the larval stage of Taenia solium, presents a diagnostic conundrum due to its rare and often nonspecific clinical manifestations. This paper aims to unravel the diagnostic mystery surrounding NCC, shedding light on its epidemiology, pathophysiology, clinical presentation, and the challenges encountered in its diagnosis. Despite being considered a rare disease, NCC is the leading cause of acquired epilepsy worldwide, underscoring its clinical significance. The complexity of NCC diagnosis lies in its diverse clinical presentations, which can range from headaches, dizziness, and seizures to more severe neurological cognitive deficits. This diversity often leads to misdiagnosis. Furthermore, the limitations of current diagnostic methods, including serological tests and neuroimaging, contribute to the diagnostic dilemma. This paper emphasises the need for improved diagnostic criteria and novel diagnostic tools to enable early and accurate detection of NCC. By enhancing our understanding of NCC, we can pave the way for better management strategies, ultimately improving patient outcomes in this under-recognised disease. [ABSTRACT FROM AUTHOR]

Gynecomastia in adolescence is a benign condition that mostly disappears spontaneously within approximately two years from onset. When it is associated with hypogonadism, it may suggest a disorder of sexual differentiation. We report the case of a young man (18 years old) with gynecomastia associated with azoospermia, small testes, hyperestrogenism and hypergonadotropic hypogonadism. A karyotype 46,XX was found, and searching for SRY (sex-determining region Y) by fluorescence in situ hybridization (FISH) highlighted the presence of the gene on the terminal region of the short arm, with breakpoints likely in Xp22.3 and Yp11.3. Implications of testosterone replacement therapy with respect to sex differentiation disorder and to physical performance are discussed. [ABSTRACT FROM AUTHOR]

Autosomal dominant retinitis pigmentosa (AD-RP) is caused by several genes, among which RHO is one of the most investigated. This article will be focused on RHO and its role in explaining AD-RP cases in the Italian population, taking advantage of the experience of the Genomic Medicine Laboratory UILDM at the Santa Lucia Foundation IRCCS. The retrospective evaluation of the distribution of RHO variants in the Italian patients with a clinical suspicion of RP pointed out eight variants. Of them, four variants (c.632A>T, c.1040C>T, c.1030C>T, c.383_392del) were pathogenic and made it possible to confirm the diagnosis of AD-RP in nine affected patients, highlighting a lower frequency (17%) of RHO variants compared to previous studies (30–40%). In addition, this study identified four variants classified as Variants of Uncertain Significance (VUS). In conclusion, the experience of the Genomic Medicine Laboratory provides an overview of the distribution of RHO variants in the Italian population, highlighting a slightly lower frequency of these variants in our cases series compared to previous reports. However, further studies on RHO variants are essential to characterize peculiar RP phenotypes and extend the spectrum of disease associated with this gene. [ABSTRACT FROM AUTHOR]

Feeding difficulties are constantly present in patients with Crisponi/cold-induced sweating syndrome type 1 (CS/CISS1). The aim of our study was to describe their prevalence and evolution from birth to adult age. We performed an observational study at the Department of Life Sciences and Public Health, Rome. Fourteen patients were included in this study (six M; mean age: 18 years; SD: 10.62 years; median age: 15 years; age range: 6–44 years); six were adults (43%). Data on oral motor abilities from birth were collected. Meal duration, presence of swallowing reflex, dysphagia symptoms, difficulty chewing, and drooling management were assessed. At birth, all patients needed enteral feeding. Introduction of solid food was postponed beyond the age of 18 months in 43% of patients. During childhood and adolescence, mealtime was characterized by increased duration (43%) accompanied by fatigue during chewing (43%), food spillage from the nasal cavities (21%), sialorrhea (86%), and poor/reduced appetite (57%). A mature rotatory chewing skill was never achieved. This report expands the phenotype description of CS/CISS1 and also improves the overall management and prevention of complications in this ultra-rare disease. [ABSTRACT FROM AUTHOR]

Background/Objectives: Rubinstein–Taybi Syndrome (RSTS-OMIM, #180849) is a rare genetic disorder associated with distinctive clinical features, including a typical craniofacial appearance, global developmental delay, intellectual disability and broad, angular thumbs and fingers. The main aim of the study was to evaluate the health problems of children with RTST, their quality of life and the impact of the disease on family functioning. In addition, we investigate whether comorbidities, autistic behavior and eating problems affect the children's overall QOL. Methods: A cross-sectional study was performed, including a total of 13 caregivers of children diagnosed with RSTS. A self-reported questionnaire [SRQ], medical records and the Pediatric Impact Module PedsQLTM 2.0, the Pediatric Quality of Life PedsQLTM 4.0 were used to obtain data on QOL and the impact of the disease on family functioning. Results: The overall QOL score for children with RSTS was x = 52.40; SD 13.01. The highest QOL was in emotional functioning (EF; x = 59.23; SD 18.69), while the lowest QOL was in physical functioning (PF; x = 48.56; SD 16.32) and social functioning (SF; x = 48.85; SD 18.84). There was a statistically significant negative correlation (p < 0.03; r = −2.01) between the age of the child and their QOL, indicating that older children had lower QOL scores. The mean overall rating for the impact of RSTS on family functioning was x = 50.00; SD 10.91. Caregivers reported the highest scores for cognitive functioning (CF; x = 64.23; SD 23.70) and family relationships (FR; x = 60.00; SD 17.17). The lowest scores were for daily activities (DA; x = 41.03; SD 17.17) and worry (W; x = 37.69; SD 18.55). Conclusions: This study provides the first comprehensive exploration of the QOL of children with RSTS) and its impact on family functioning. [ABSTRACT FROM AUTHOR]

While artificial intelligence has successful and innovative applications in common medicine, could its application facilitate research on rare diseases? This study explores the application of artificial intelligence (AI) in orphan drug research, focusing on how AI can address three major barriers: high financial risk, development complexity, and low trialability. This paper begins with an overview of orphan drug development and AI applications, defining key concepts and providing a background on the regulatory framework of and AI's role in medical research. Next, it examines how AI can lower financial risks by streamlining drug discovery and development processes, analyzing complex data, and predicting outcomes to improve our understanding of rare diseases. This study then explores how AI can enhance clinical trials through simulations and virtual trials, compensating for the limited patient populations available for rare disease research. Finally, it discusses the broader implications of integrating AI in orphan drug development, emphasizing the potential for AI to accelerate drug discovery and improve treatment success rates, and highlights the need for ongoing innovation and regulatory support to maximize the benefits of AI-driven research in healthcare. Based on those results, we discuss the implications for traditional and AI-powered business in the drug industry. [ABSTRACT FROM AUTHOR]

Background: Chronic progressive external ophthalmoplegia (CPEO) belongs to the group of mitochondrial encephalomyopathies. Anaesthesia for patients with CPEO may be associated with an increased risk due to known drug effects on mitochondrial metabolism. Therefore, the aim of this analysis was to evaluate anaesthesiological concepts in patients with CPEO requiring ophthalmic surgery. Methods: This is a retrospective, monocentric cohort analysis of eleven patients with CPEO undergoing ophthalmic surgery either with general anaesthesia or local anaesthesia in a German university hospital from January 2012 to February 2022. Results: A total of twelve ophthalmic surgery procedures were performed in eleven adult patients with CPEO. Six patients underwent surgery after receiving local anaesthesia (LA cohort). Five patients underwent six surgical procedures under general anaesthesia (GA cohort). In five cases within the GA cohort, propofol and remifentanil were used for the maintenance of anaesthesia. In one case, balanced anaesthesia with desflurane and remifentanil was used. The median duration of general anaesthesia was 37.5 min (range, 25–65 min). Patients stayed in the recovery room for a median of 48.5 min (range, 35–70 min). All patients were discharged on the first postoperative day. No relevant complications occurred in either the LA or GA cohort. Conclusion: Both local and general anaesthesia are feasible concepts for patients with CPEO undergoing ophthalmic surgery. Propofol, at least with a short duration (less than one hour) of use, appears to be a feasible hypnotic drug in CPEO patients. [ABSTRACT FROM AUTHOR]

Background: Methylmalonic Aciduria (MA) without homocystinuria (or isolated MA) is a group of rare inherited metabolic disorders which leads to the accumulation of methylmalonic acid (MMA), a toxic molecule that accumulates in blood, urine, and cerebrospinal fluid, causing acute and chronic complications including metabolic crises, acute kidney injury (AKI), and chronic kidney disease (CKD). Detailed Case Description: Herein, we report a case of a 39-year-old male with MA and stage IV CKD who experienced acute metabolic decompensation secondary to gastrointestinal infection. The patient underwent a single hemodialysis (HD) session to correct severe metabolic acidosis unresponsive to medical therapy and to rapidly remove MMA. The HD session resulted in prompt clinical improvement and shortening of hospitalization. Discussion: MMA accumulation in MA patients causes acute and life-threatening complications, such as metabolic decompensations, and long-term complications such as CKD, eventually leading to renal replacement therapy (RRT). Data reported in the literature show that, overall, all dialytic treatments (intermittent HD, continuous HD, peritoneal dialysis) are effective in MMA removal. HD, in particular, can be useful in the emergency setting to control metabolic crises, even with GFR > 15 mL/min. Kidney and/or liver transplantations are often needed in MA patients. While a solitary transplanted kidney can be rapidly affected by MMA exposure, with a decline in renal function even in the first year of follow-up, the combined liver–kidney transplantation showed better long-term results due to a combination of reduced MMA production along with increased urinary excretion. Conclusions: Early diagnosis, multidisciplinary management and preventive measures are pivotal in MA patients to avoid recurrent AKI episodes and, consequently, to slow down CKD progression. [ABSTRACT FROM AUTHOR]

Obesity-related ciliopathies, as a group of ciliopathies including Alström Syndrome and Bardet–Biedl Syndrome, exhibit distinct genetic and phenotypic variability. The understanding of these diseases is highly significant for understanding the functions of primary cilia in the human body, particularly regarding the relationship between obesity and primary cilia. The diagnosis of these diseases primarily relies on clinical presentation and genetic testing. However, there is a significant lack of research on biomarkers to elucidate the variability in clinical manifestations, disease progression, prognosis, and treatment responses. Through an extensive literature review, the paper focuses on obesity-related ciliopathies, reviewing the advancements in the field and highlighting the potential roles of biomarkers in the clinical presentation, diagnosis, and prognosis of these diseases. [ABSTRACT FROM AUTHOR]

Brazil is a continent-size country with 203 million inhabitants, classified as a developing upper-middle-income country, although inequities remain significant. Most of the population is assisted by the public Unified Health System (SUS), along with a thriving private health sector. Congenital malformations are the second leading cause of infant mortality and chronic/genetic disorders and a significant burden in hospital admissions. The past two decades have been crucial for formalizing medical genetics as a recognized medical specialty in the SUS, as well as for implementing a new health policy by the Ministry of Health for comprehensive care for rare diseases. These public health policies had the broad support of the Brazilian Society of Medical Genetics and Genomics and patient organizations. Most comprehensive genetic services are concentrated in large urban centers in the South and Southeast regions of Brazil; with this new policy, new services throughout the country are progressively being integrated. The number of medical geneticists increased by 103% in a decade. Details on the policy and an overview of the availability of services, testing, human resources, newborn screening, research projects, patient organizations, and relevant issues regarding medical genetics in this vast and diverse country are presented. [ABSTRACT FROM AUTHOR]

Moebius syndrome (MBS) is a rare congenital disorder characterized by non-progressive facial palsy and ocular abduction paralysis. Most cases are sporadic, but also rare familial cases with autosomal dominant transmission and incomplete penetrance/variable expressivity have been described. The genetic etiology of MBS is still unclear: de novo pathogenic variants in REV3L and PLXND1 are reported in only a minority of cases, suggesting the involvement of additional causative genes. With the aim to uncover the molecular causative defect and identify a potential genetic basis of this condition, we performed trio-WES on a cohort of 37 MBS and MBS-like patients. No de novo variants emerged in REV3L and PLXND1. We then proceeded with a cohort analysis to identify possible common causative genes among all patients and a trio-based analysis using an in silico panel of candidate genes. However, identified variants emerging from both approaches were considered unlikely to be causative of MBS, mainly due to the lack of clinical overlap. In conclusion, despite this large cohort, WES failed to identify mutations possibly associated with MBS, further supporting the heterogeneity of this syndrome, and suggesting the need for integrated omics approaches to identify the molecular causes underlying MBS development. [ABSTRACT FROM AUTHOR]

Inherited metabolic diseases (IMDs) are a group of heterogeneous genetic disorders resulting in substrate accumulation, energy deficiency, or complex molecular defects due to the failure of specific molecules to act as enzymes, cofactors, transporters, or receptors in specific metabolic pathways. The pathophysiological changes seen in IMDs are sometimes associated with intellectual disability (ID) or neurocognitive decline, necessitating multidisciplinary input. We here describe our experience at one tertiary metabolic centre in the UK. We reviewed the case prevalence and existing service provision in one adult IMD service covering a multi-ethnic population of 10 million in North England. In our cohort of 2268 IMD patients, 1598 patients had general metabolic conditions (70.5%), and 670 had lysosomal storage disease/disorders (LSD)s (29.5%). The overall prevalence of ID and neurocognitive decline was found to be 15.7% (n = 357), with patients with LSDs accounting for 23.5% (n = 84) of affected patients. Given the prevalence of ID in adults with IMDs, access to multidisciplinary input from neuropsychology and neuropsychiatry services is important. Education of healthcare professionals to diagnose IMDs in patients with ID, in addition to neurocognitive and neuropsychiatric presentations, will avoid missed diagnoses of IMD and will have a positive effect on patient outcomes. [ABSTRACT FROM AUTHOR]

The process of developing therapies to treat rare diseases is fraught with financial, regulatory, and logistical challenges that have limited our ability to build effective treatments. Recently, a novel type of therapy called antisense therapy has shown immense potential for the treatment of rare diseases, particularly through single-patient N-of-1 trials. Several N-of-1 antisense therapies have been developed recently for rare diseases, including the landmark study of milasen. In response to the success of N-of-1 antisense therapy, the Food and Drug Administration (FDA) has developed unique guidelines specifically for the development of antisense therapy to treat N-of-1 rare diseases. This policy change establishes a strong foundation for future therapy development and addresses some of the major limitations that previously hindered the development of therapies for rare diseases. [ABSTRACT FROM AUTHOR]

Background: Achondroplasia, the most prevalent skeletal dysplasia, stems from a functional mutation in the fibroblast growth factor receptor 3 gene, leading to growth impairment. This condition presents multifaceted medical, functional and psychosocial challenges throughout childhood, adolescence and adulthood. Current management strategies aim to minimise medical complications, optimise functional capabilities and provide comprehensive supportive care. Vosoritide (trade name: VOXZOGO®, BioMarin Pharmaceuticals) is the first disease-modifying pharmaceutical treatment approved for the management of patients with achondroplasia and became available in Australia in May 2023. Methods: Standardised clinical guidelines for its optimal use are not yet widely available. To address this gap, a multidisciplinary Australian Vosoritide Working Group, comprising 12 experts with experience in achondroplasia management from across Australia, developed recommendations to guide the use of vosoritide in clinical practice. Results: The recommendations, which are expert opinions of the Australian Vosoritide Working Group, aim to (i) standardise the use of vosoritide across Australia, (ii) support the safe clinical rollout of vosoritide and (iii) support universal access. Conclusions: These recommendations have been developed for healthcare professionals and institutions that are engaged in using vosoritide in the management of achondroplasia and will be revised using a formal framework for clinical guideline development once more evidence is available. [ABSTRACT FROM AUTHOR]

Background: The Angelman Syndrome Registry (RISA) was developed as a retrospective study with the following objectives: to evaluate the clinical history of individuals with Angelman Syndrome (AS) in Italy and compare it with the existing literature; to investigate the feasibility of gathering data by directly involving participants in the data collection process; and to explore the relationship between different symptoms and genotypes. Methods: Established in 2018, RISA enrolled a total of 82 participants, with 62 (75.6%) providing complete data. Demographic, clinical, and genetic information was collected using electronic case report forms. Descriptive statistics characterized the sample, while associations between genotype and clinical characteristics were examined. Results: Descriptive analysis revealed a median participant age of 8.0 years, with males comprising 48.8% of the sample. Deletion (58.1%) was the most common genotype. The majority (82.2%) experienced epilepsy, with seizures typically onset before 3 years of age. Most patients (86.2%) required multiple anti-epileptic drugs for control, with generalized tonic–clonic seizures and atypical absence seizures being most prevalent. The deletion group exhibited more severe developmental delays and a trend towards higher seizure severity. Sleep problems affected 69.4% of participants, characterized by difficulties in sleep onset and maintenance. Conclusions: This study offers valuable insights into the clinical history and genetic characteristics of AS in Italy, consistent with the prior literature. Additionally, it underscores the efficacy of patient registries in capturing comprehensive data on rare diseases such as AS, highlighting their potential to advance research and enhance patient care. [ABSTRACT FROM AUTHOR]

Background/Objectives: Huntington's disease (HD) is an autosomal dominant genetic disorder causing progressive neurodegeneration which, aside from symptomatic therapies for controlling psychological and motor problems, currently has no effective treatment. People who receive this diagnosis often feel disoriented and lost without guidance. Furthermore, HD patients are estimated to have a two to seven times greater risk of suicide death compared to the general population. The current review investigates the complex relationship between HD and suicide, seeking to identify key risk factors influencing suicidal ideation and behaviour in affected individuals. Methods: We conducted a systematic review following the PRISMA guidelines. Studies were searched for on the PubMed, Cochrane, and Web of Science databases, and 17 articles met the inclusion criteria. Results: The findings reveal that emotional strain, neuropsychiatric symptoms, and the absence of a cure contribute to heightened suicidal tendencies in HD patients. Critical periods for suicide risk coincide with early symptomatic stages of disease or the successive phase, with the loss of independence impacting on daily functioning. Risk factors associated with HD include a depressive mood, cognitive impairments, and a history of suicide attempts. Conclusions: From a prevention perspective, a comprehensive multidisciplinary and multidimensional approach could enhance the overall well-being of people with HD. In particular, screening for suicidal thoughts in people with HD could mitigate suicide risk. [ABSTRACT FROM AUTHOR]

Tissue biopsy remains the standard for diagnosing gastrointestinal stromal tumors (GISTs), although liquid biopsy is emerging as a promising alternative in oncology. In this pilot study, we advocate for droplet digital PCR (ddPCR) to diagnose GIST in tissue samples and explore its potential for early diagnosis via liquid biopsy, focusing on the PDGFRA D842V mutation and SEPT9 hypermethylated gene. We utilized ddPCR to analyze the predominant PDGFRA mutation (D842V) in surgical tissue samples from 15 GIST patients, correlating with pathologists' diagnoses. We expanded our analysis to plasma samples to compare DNA alterations between tumor tissue and plasma, also investigating SEPT9 gene hypermethylation. We successfully detected the PDGFRA D842V mutation in GIST tissues by ddPCR. Despite various protocols to enhance mutation detection in early-stage disease, it remained challenging, likely due to the low concentration of DNA in plasma samples. Additionally, the results of Area Under the Curve (AUC) for the hypermethylated SEPT9 gene, analyzing concentration, ratio, and abundance were 0.74 (95% Confidence Interval (CI): 0.52 to 0.97), 0.77 (95% CI: 0.56 to 0.98), and 0.79 (95% CI: 0.59 to 0.99), respectively. As a rare disease, the early detection of GIST through such biomarkers is particularly crucial, offering significant potential to improve patient outcomes. [ABSTRACT FROM AUTHOR]

Pseudoxanthoma elasticum (PXE) is a rare inherited systemic disease responsible for a juvenile peripheral arterial calcification disease. The clinical diagnosis of PXE is only based on a complex multi-organ phenotypic score and/or genetical analysis. Reduced plasma inorganic pyrophosphate concentration [PPi]p has been linked to PXE. In this study, we used a novel and accurate method to measure [PPi]p in one of the largest cohorts of PXE patients, and we reported the valuable contribution of a cutoff value to PXE diagnosis. Plasma samples and clinical records from two French reference centers for PXE (PXE Consultation Center, Angers, and FAVA-MULTI South Competent Center, Nice) were assessed. Plasma PPi were measured in 153 PXE and 46 non-PXE patients. The PPi concentrations in the plasma samples were determined by a new method combining enzymatic and ion chromatography approaches. The best match between the sensitivity and specificity (Youden index) for diagnosing PXE was determined by ROC analysis. [PPi]p were lower in PXE patients (0.92 ± 0.30 µmol/L) than in non-PXE patients (1.61 ± 0.33 µmol/L, p < 0.0001), corresponding to a mean reduction of 43 ± 19% (SD). The PPi cutoff value for diagnosing PXE in all patients was 1.2 µmol/L, with a sensitivity of 83.3% and a specificity of 91.1% (AUC = 0.93), without sex differences. In patients aged <50 years (i.e., the age period for PXE diagnosis), the cutoff PPi was 1.2 µmol/L (sensitivity, specificity, and AUC of 93%, 96%, and 0.97, respectively). The [PPi]p shows high accuracy for diagnosing PXE; thus, quantifying plasma PPi represents the first blood assay for diagnosing PXE. [ABSTRACT FROM AUTHOR]

Alkaptonuria (AKU) is a genetic disorder that affects connective tissues of several body compartments causing cartilage degeneration, tendon calcification, heart problems, and an invalidating, early-onset form of osteoarthritis. The molecular mechanisms underlying AKU involve homogentisic acid (HGA) accumulation in cells and tissues. HGA is highly reactive, able to modify several macromolecules, and activates different pathways, mostly involved in the onset and propagation of oxidative stress and inflammation, with consequences spreading from the microscopic to the macroscopic level leading to irreversible damage. Gaining a deeper understanding of AKU molecular mechanisms may provide novel possible therapeutical approaches to counteract disease progression. In this review, we first describe inflammation and oxidative stress in AKU and discuss similarities with other more common disorders. Then, we focus on HGA reactivity and AKU molecular mechanisms. We finally describe a multi-purpose digital platform, named ApreciseKUre, created to facilitate data collection, integration, and analysis of AKU-related data. [ABSTRACT FROM AUTHOR]

Background: Modulator therapies improve weight and body mass index (BMI) in cystic fibrosis (CF) patients. We aimed to compare the nutritional risk index (NRI) in adult CF patients receiving modulator (MT) or only non-modulator (conventional) therapies (non-MT). Methods: A single-center prospective cohort study was conducted between June and December 2023. The NRI based on weight gain and albumin was calculated at beginning and end of a 12-week period in both groups. This design was pragmatic, since it was based on individual patient access to MT for 12 weeks. Results: In total, 107 patients were included [mean (SD) age: 23.85 (4.98) years, 54.7% male, 46.7% MT]. In the MT group, mean (SD) weight (kg) and albumin (g/dL) increased significantly [changes: +3.09 (2.74) and +0.17 (0.37); p < 0.001]. In the non-MT group, weight and albumin decreased significantly [changes: −0.99 (1.73) and −0.12 (0.30); p < 0.001]. Compared to the MT group, baseline mean (SD) NRI in the non-MT group was significantly higher [100.65 (11.80) vs. 104.10 (10.10); p = 0.044]. At the end of the 12 weeks, mean (SD) NRI in the MT group was higher than in the non-MT group [104.18 (10.40) vs. 102.58 (12.39); p = 0.145]. In the MT group, the NRI category improved in 22 (44%), and worsened in 3 (6%) patients (p < 0.001). In the non-MT group, the NRI category improved in 2 (3.5%), and worsened in 10 (17.5%) patients (p < 0.001). Conclusions: This is the first study reporting on a positive effect of MT on NRIs, based on weight gain and albumin. Personalized nutrition and routine follow-up of adults with CF based on NRI is recommended prior to MT initiation. [ABSTRACT FROM AUTHOR]

Introduction: Pain perception, far from being a pathological mechanism, is a crucial protective stimulus to prevent additional injuries. Any disturbance in this complex system poses significant risks to individuals, affecting their quality of life and even their survival. Objective: This review aims to explore congenital insensitivity to pain, an extremely rare genetic disorder with an autosomal recessive pattern that results in the inability to perceive pain. We will focus on the well-known subtype, congenital insensitivity to pain with anhidrosis (CIPA). Our research seeks to update existing knowledge through a comprehensive literature review. Methodology: The review employs a systematic literature review, analyzing various sources and scientific documents, primarily emphasizing CIPA. The review follows the PROSPERO protocol, registered under CRD42023394489. The literature search was performed on the Scopus, PubMed, and Cinahl databases. Results: Our review reveals secondary complications associated with CIPA, such as recurrent bone fractures, temperature insensitivity, self-mutilation, and, occasionally, intellectual disabilities. The limited available information underscores the need for expanding our knowledge. Conclusions: In summary, CIPA, particularly, presents a significant medical challenge with adverse impacts on quality of life. Early diagnosis, education for families and healthcare professionals, and appropriate nursing care are essential for effective management. This review highlights the necessity of further research and awareness to enhance support for those affected. [ABSTRACT FROM AUTHOR]

Background/Objectives: Pycnodysostosis is a rare genetic disorder causing skeletal dysplasia. It is determined by a gene mutation leading to cathepsin K deficiency and predisposes a patient to osteosclerosis, resulting in increased bone fragility. The altered bone quality typical of this disease is responsible for an increased risk of fractures. The purpose of our study was to evaluate the orthopedic manifestations and potential pitfalls in the surgical treatments of pathological fractures in a series of patients treated in our institution who were affected by pycnodysostosis. Methods: We retrospectively evaluated clinical and radiographic characteristics of five patients with pycnodysostosis treated for pathological fractures at our hospital in the past 5 years. Results: Two male and three female patients were included in this study. Four patients had a family history of pycnodysostosis. All the patients were of short stature, but only two underwent growth hormone treatment. All the patients experienced fractures, mostly in their lower limbs and occurring as a result of low-energy trauma. Most of the patients experienced either consolidation delay or nonunion. Conclusions: The orthopedic management of fractures in patients with pycnodysostosis poses an ongoing challenge for orthopedic surgeons. The fact that the bone is simultaneously sclerotic and brittle makes any orthopedic surgical treatment challenging and at a high risk of nonunion in any case. [ABSTRACT FROM AUTHOR]

Fibrous dysplasia (FD) is a rare bone disorder characterized by the replacement of normal bone with benign fibro-osseous tissue. Developments in our understanding of the pathophysiology and treatment options are impeded by the lack of suitable research models. In this study, we developed an in vitro organotypic model capable of recapitulating key intrinsic and phenotypic properties of FD. Initially, transcriptomic profiling of individual cells isolated from patient lesional tissues unveiled intralesional molecular and cellular heterogeneity. Leveraging these insights, we established patient-derived organoids (PDOs) using primary cells obtained from patient FD lesions. Evaluation of PDOs demonstrated preservation of fibrosis-associated constituent cell types and transcriptional signatures observed in FD lesions. Additionally, PDOs retained distinct constellations of genomic and metabolic alterations characteristic of FD. Histological evaluation further corroborated the fidelity of PDOs in recapitulating important phenotypic features of FD that underscore their pathophysiological relevance. Our findings represent meaningful progress in the field, as they open up the possibility for in vitro modeling of rare bone lesions in a three-dimensional context and may signify the first step towards creating a personalized platform for research and therapeutic studies. [ABSTRACT FROM AUTHOR]

Holoprosencephaly is a complex human brain malformation resulting from incomplete cleavage of the prosencephalon into both hemispheres. Congenital nasal pyriform aperture stenosis (CNPAS) is sometimes found in patients with mild forms of holoprosencephaly. Surgical treatment is required. Low-invasive surgical approaches involve balloon dilation of the pyriform opening. We present the case of an 8-day-old girl diagnosed with holoprosencephaly, CNPAS, and the presence of a solitary median maxillary central incisor. Once examined by neonatologist, geneticist, pneumologist, otolaryngologist, and pediatric dentist, a combined otolaryngological–orthodontic approach was used. The obstruction of the right nasal cavity was treated by widening the nasal cavities and stabilizing them with a balloon dilation technique. After surgery, the respiratory space was increased by applying a neonatal palatal expander plate (NPEP) considering the palatal deformity: ogival shaped, anterior vertex growth direction, reduction of transverse diameters. The NPEP promoted distraction of the median palatine suture and assisted the nasal dilation. Therefore, after the insertion of NPEP, the physiological sucking–swallowing mechanism was activated. In infants with CNPAS, NPEP can be useful to ensure the safe stability of nasal dilation. A multidisciplinary approach is fundamental. In our experience, the close collaboration between an otolaryngologist and orthodontist is essential for the management of the patient with CNPAS. [ABSTRACT FROM AUTHOR]

Simple Summary: Sarcomas are a group of rare heterogeneous neoplasms of mesenchymal origin. Despite attendant difficulties in study of such disease states, there has been at least one US Federal Drug Administration (FDA) treatment approval for sarcomas in 8 of the last 11 years since 2013. The relative costs, as well as trends in the marketplace, for medications approved for sarcoma have heretofore been unexplored. Given the expansion of medical treatments for sarcoma subtypes in the past decade, it is vital to assess the current status of the landscape to better comprehend achieved successes, challenges, and future directions. Herein, we provide an overview of some of the trends in FDA approvals as well as their associated costs and correlations with incidence as well as outcomes. Sarcomas represent a diverse set of both malignant and benign subtypes consisting of often rare and ultra-rare conditions. Over the course of the last decade, there have been numerous FDA approvals for agents treating various sarcoma subtypes. Given this burgeoning landscape of sarcoma treatments, we seek to review current FDA-approved agents with respect to their rates of incidence, approval rates, and financial costs. We gathered clinical trial data by searching FDA approval announcements from 2013 to 2023. We determined the 30 day and one year cost of therapy for patients of FDA-approved sarcoma treatments in the aforementioned timeframe. From 2013 to 2023, 14 medications have been FDA-approved for sarcoma subtypes. The 30-day dosing prices for these medications range from $11,162.86 to $46,926.00. Since 2013, the rates of approval for sarcoma medications have been higher than in prior decades. Nonetheless, there remains the potential for significant financial toxicity for patients living with sarcoma. [ABSTRACT FROM AUTHOR]

Coenzyme Q (CoQ) is a lipidic compound that is widely distributed in nature, with crucial functions in metabolism, protection against oxidative damage and ferroptosis and other processes. CoQ biosynthesis is a conserved and complex pathway involving several proteins. COQ2 is a member of the UbiA family of transmembrane prenyltransferases that catalyzes the condensation of the head and tail precursors of CoQ, which is a key step in the process, because its product is the first intermediate that will be modified in the head by the next components of the synthesis process. Mutations in this protein have been linked to primary CoQ deficiency in humans, a rare disease predominantly affecting organs with a high energy demand. The reaction catalyzed by COQ2 and its mechanism are still unknown. Here, we aimed at clarifying the COQ2 reaction by exploring possible substrate binding sites using a strategy based on homology, comprising the identification of available ligand-bound homologs with solved structures in the Protein Data Bank (PDB) and their subsequent structural superposition in the AlphaFold predicted model for COQ2. The results highlight some residues located on the central cavity or the matrix loops that may be involved in substrate interaction, some of which are mutated in primary CoQ deficiency patients. Furthermore, we analyze the structural modifications introduced by the pathogenic mutations found in humans. These findings shed new light on the understanding of COQ2's function and, thus, CoQ's biosynthesis and the pathogenicity of primary CoQ deficiency. [ABSTRACT FROM AUTHOR]

Access to healthcare is multifaceted and poses significant challenges for individuals with chronic and rare diseases (RDs). This study aimed to conduct a psychometric evaluation of the German version of the Perception of Access to Healthcare Questionnaire (PAHQ) among individuals with RDs. We conducted an evaluation of the PAHQ using a sample of 271 adults with an RD diagnosis. The 31-item instrument underwent evaluation including a comparison of three different confirmatory factor models (CFA). Subsequent steps involved item removal, reliability analysis (computation of Cronbach's alpha), and analysis of criterion-related validity. The six-factor model showed the best fit to the data and was selected for further examination. Subsequently, six items were removed. Fit indices for the final model were acceptable. Cronbach's alpha ranged from 0.75 to 0.91 for the six subscales, except for the availability subscale which exhibited the lowest value (0.64). In terms of criterion-related validity, different skills relating to the navigation of access dimensions were significantly correlated with corresponding PAHQ subscales, thus confirming validity. The capacity of the PAHQ to guide targeted interventions and facilitate cross-population comparisons positions it as a valuable instrument for advancing healthcare access research and promoting equitable access to care, particularly for individuals with rare and chronic diseases. [ABSTRACT FROM AUTHOR]

The EA-QOL questionnaire measures quality-of-life specifically for children born with esophageal atresia (EA) aged 8–18 and was completed in Sweden and Germany. This study aimed to describe an international collaborative initiative to establish a semantically equivalent linguistic version of the EA-QOL questionnaires in 12 new countries. The 24-item EA-QOL questionnaire was translated into the target languages and the translated questionnaire was evaluated through cognitive debriefing interviews with children with EA aged 8–18 and their parents in each new country. Participants rated an item as to whether an item was easy to understand and sensitive/uncomfortable to answer. They could choose not to reply to a non-applicable/problematic item and provide open comments. Data were analyzed using predefined psychometric criteria; item clarity ≥80%, item sensitive/uncomfortable to answer ≤20%, item feasibility(missing item responses ≤5%). Decision to improve any translation was made by native experts–patient stakeholders and the instrument developer. Like in Sweden and Germany, all items in the cross-cultural analysis of child self-report (ntot = 82, 4–10 children/country) met the criteria for item clarity in all 12 new countries, and in parent-report (ntot = 86, 5–10 parents/country) in 8/12 countries. All items fulfilled the criteria for sensitive/uncomfortable to answer (child-report 1.2–9.9%; parent-report 0–11.6%) and item feasibility. Poor translations were resolved. Hence, this study has established semantically equivalent linguistic versions of the EA-QOL questionnaire for use in children aged 8–18 with repair of EA in and across 14 countries. [ABSTRACT FROM AUTHOR]

Parietal thinning was detected in a 72-year-old with recurrent headaches. Quantification of bone loss was performed applying two- and three-dimensional methods using computerized tomographies. Two-dimensional methods provided accurate measurements using single-line analyses of bone thicknesses (2.13 to 1.65 and 1.86 mm on the left and 4.44 to 3.08 and 4.20 mm on the right side), single-point analyses of bone intensities (693 to 375 and 403 on the left and 513 to 393 and 411 Houndsfield Units on the right side) and particle-size analyses of low density areas (16 to 22 and 12 on the left and 18 to 23 and 14 on the right side). Deteriorations between days 0 and 220 followed by bone stability on day 275 were paralleled using the changed volumes of bone defects to 1200 and finally 1133 mm3 on the left side and to 331 and finally 331 mm3 on the right side. Interfolding as measurement of the bones' shape provided changes to −1.23 and −1.72 mm on the left and to −1.42 and −1.30 mm on the right side. These techniques suggest a stabilizing effect of corticosteroids between days 220 and 275. Reconstruction of computerized tomographies appears justified to allow for quantification of bone loss during long-term follow-up. [ABSTRACT FROM AUTHOR]

With technological applications, especially in genetic testing, new diseases have been discovered and new disease concepts have been proposed in recent years; however, the pathogenesis and treatment of these rare diseases are not as well established as those of common diseases. To demonstrate the importance of rare disease research, in this paper we focus on our research topic, Perry disease (Perry syndrome). Perry disease is a rare autosomal dominant neurodegenerative disorder clinically characterized by parkinsonism, depression/apathy, weight loss, and respiratory symptoms including central hypoventilation and central sleep apnea. The pathological classification of Perry disease falls under TAR DNA-binding protein 43 (TDP-43) proteinopathies. Patients with Perry disease exhibit DCTN1 mutations, which is the causative gene for the disease; they also show relatively uniform pathological and clinical features. This review summarizes recent findings regarding Perry disease from both basic and clinical perspectives. In addition, we describe technological innovations and outline future challenges and treatment prospects. We discuss the expansion of research from rare diseases to common diseases and the importance of collaboration between clinicians and researchers. Here, we highlight the importance of researching rare diseases as it contributes to a deeper understanding of more common diseases, thereby opening up new avenues for scientific exploration. [ABSTRACT FROM AUTHOR]

More than 20 years have passed since the identification of SLC3A1 and SLC7A9 as causative genes for cystinuria. However, cystinuria patients exhibit significant variability in the age of lithiasis onset, recurrence, and response to treatment, suggesting the presence of modulatory factors influencing cystinuria severity. In 2016, a second renal cystine transporter, AGT1, encoded by the SLC7A13 gene, was discovered. Although it was discarded as a causative gene for cystinuria, its possible effect as a modulatory gene remains unexplored. Thus, we analyzed its function in mouse models of cystinuria, screened the SLC7A13 gene in 34 patients with different lithiasic phenotypes, and functionally characterized the identified variants. Mice results showed that AGT1/rBAT may have a protective role against cystine lithiasis. In addition, among the four missense variants detected in patients, two exhibited a 25% impairment in AGT1/rBAT transport. However, no correlation between SLC7A13 genotypes and lithiasis phenotypes was observed in patients, probably because these variants were found in heterozygous states. In conclusion, our results, consistent with a previous study, suggest that AGT1/rBAT does not have a relevant effect on cystinuria patients, although an impact in patients carrying homozygous pathogenic variants cannot be discarded. [ABSTRACT FROM AUTHOR]

Genome sequencing is available as a clinical test in the UK through the Genomic Medicine Service (GMS). The GMS analytical strategy predominantly filters genome data on preselected gene panels. Whilst this reduces variants requiring assessment by reporting laboratories, pathogenic variants outside applied panels may be missed, and variants in genes without established disease–gene relationships are largely ignored. This study compares the analysis of a research exome to a GMS clinical genome for the same patients. For the research exome, we applied a panel-agnostic approach filtering for variants with High Pathogenic Potential (HiPPo) using ClinVar, allele frequency, and in silico prediction tools. We then restricted HiPPo variants to Gene Curation Coalition (GenCC) disease genes. These results were compared with the GMS genome panel-based approach. Twenty-four participants from eight families underwent parallel research exome and GMS genome sequencing. Exome HiPPo analysis identified a similar number of variants as the GMS panel-based approach. GMS genome analysis returned two pathogenic variants and one de novo variant. Exome HiPPo analysis returned the same variants plus an additional pathogenic variant and three further de novo variants in novel genes, where case series are underway. When HiPPo was restricted to GenCC disease genes, statistically fewer variants required assessment to identify more pathogenic variants than reported by the GMS, giving a diagnostic rate per variant assessed of 20% for HiPPo versus 3% for the GMS. With UK plans to sequence 5 million genomes, strategies are needed to optimise genome analysis beyond gene panels whilst minimising the burden of variants requiring clinical assessment. [ABSTRACT FROM AUTHOR]

Background: The benefits of preventive interventions lack comprehensive evaluation in standard health technology assessments (HTA), particularly for rare and transmissible diseases. Objective: To identify possible considerations for future HTA using analogies between the treatment and prevention of rare diseases. Study design: An Expert panel meeting assessed whether one HTA assessment framework can be applied to assess both rare disease treatments and preventive interventions. Experts also evaluated the range of value elements currently included in HTAs and their applicability to rare, transmissible, and/or preventable diseases. Results: A broad range of value should be considered when assessing rare, transmissible disease prevention. Although standard HTA can be applied to transmissible diseases, the risk of local outbreaks and the need for large-scale prevention programs suggest a modified assessment framework, capable of incorporating prevention-specific value elements in HTAs. A 'Rule of Prevention' framework was proposed to allow broader value considerations anchored to severity, equity, and prevention benefits in decision-making for preventive interventions for rare transmissible diseases. Conclusion: The proposed prevention framework introduces an explicit initial approach to consistently assess rare transmissible diseases, and to incorporate the broader value of preventive interventions compared with treatment. [ABSTRACT FROM AUTHOR]

Background: Like many developing countries, Colombia faces difficulties in financing health-care services as well as programs for health promotion and health education and there is evidence that its health-care system is underperforming. Objective: To provide evidence-based estimates of potential funding levels and assess the strengths, weaknesses, and viability of innovative funding mechanisms with a focus on treating rare diseases in Colombia. Methods: The strategy involved evidence-based projections of potential funding levels and a qualitative viability assessment using an expert panel. Results: Crowdfunding, corporate donation, and social impact bonds (SIBs) were deemed to be the most viable of numerous potential strategies. Expected funding levels over 10 years for rare diseases in Colombia from crowdfunding, corporate donations, and SIBs were roughly $7,200, $23,000, and $12,400, respectively. Conclusions: Based on the combination of projected funding potential along with expert consensus regarding viability and operability, crowdfunding, corporate donations, and SIBs, especially in combination, have the potential to substantially improve funding for vulnerable patient populations in Colombia. [ABSTRACT FROM AUTHOR]

Cerebellar atrophy (CA) is a frequent neuroimaging finding in paediatric neurology, usually associated with cerebellar ataxia. The list of genes involved in hereditary forms of CA is continuously growing and reveals its genetic complexity. We investigated ten cases with early-onset cerebellar involvement with and without ataxia by exome sequencing or by a targeted panel with 363 genes involved in ataxia or spastic paraplegia. Novel variants were investigated by in silico or experimental approaches. Seven probands carry causative variants in well-known genes associated with CA or cerebellar hypoplasia: SETX, CACNA1G, CACNA1A, CLN6, CPLANE1, and TBCD. The remaining three cases deserve special attention; they harbour variants in MAST1, PI4KA and CLK2 genes. MAST1 is responsible for an ultrarare condition characterised by global developmental delay and cognitive decline; our index case added ataxia to the list of concomitant associated symptoms. PIK4A is mainly related to hypomyelinating leukodystrophy; our proband presented with pure spastic paraplegia and normal intellectual capacity. Finally, in a patient who suffers from mild ataxia with oculomotor apraxia, the de novo novel CLK2 c.1120T>C variant was found. The protein expression of the mutated protein was reduced, which may indicate instability that would affect its kinase activity. [ABSTRACT FROM AUTHOR]

Fibrous dysplasia (FD) is a rare, non-hereditary skeletal disorder characterized by its chronic course of non-neoplastic fibrous tissue buildup in place of healthy bone. A myriad of factors have been associated with its onset and progression. Perturbation of cell–cell signaling networks and response outputs leading to disrupted building blocks, incoherent multi-level organization, and loss of rigid structural motifs in mineralized tissues are factors that have been identified to participate in FD induction. In more recent years, novel insights into the unique biology of FD are transforming our understandings of its pathology, natural discourse of the disease, and treatment prospects. Herein, we built upon existing knowledge with recent findings to review clinical, etiologic, and histological features of FD and discussed known and potential mechanisms underlying FD manifestations. Subsequently, we ended on a note of optimism by highlighting emerging therapeutic approaches aimed at either halting or ameliorating disease progression. [ABSTRACT FROM AUTHOR]

Phenotypicheterogeneity is a phenomenon in which distinct phenotypes can develop in individuals bearing pathogenic variants in the same gene. Genetic factors, gene interactions, and environmental factors are usually considered the key mechanisms of this phenomenon. Phenotypic heterogeneity may impact the prognosis of the disease severity and symptoms. In our work, we used publicly available data on the association between genetic variants and Mendelian disease to investigate the genetic factors (such as the intragenic localization and type of a variant) driving the heterogeneity of gene–disease relationships. First, we showed that genes linked to multiple rare diseases (GMDs) are more constrained and tend to encode more transcripts with high levels of expression across tissues. Next, we assessed the role of variant localization and variant types in specifying the exact phenotype for GMD variants. We discovered that none of these factors is sufficient to explain the phenomenon of such heterogeneous gene–disease relationships. In total, we identified only 38 genes with a weak trend towards significant differences in variant localization and 30 genes with nominal significant differences in variant type for the two associated disorders. Remarkably, four of these genes showed significant differences in both tests. At the same time, our analysis suggests that variant localization and type are more important for genes linked to autosomal dominant disease. Taken together, our results emphasize the gene-level factors dissecting distinct Mendelian diseases linked to one common gene based on open-access genetic data and highlight the importance of exploring other factors that contributed to phenotypic heterogeneity. [ABSTRACT FROM AUTHOR]

(1) Background: Identification of typical behavioral manifestations in patients with DEAD-Box Helicase 3 X-linked gene (DDX3X) variants plays a crucial role in accurately diagnosing and managing the syndrome. The objective of this paper was to carry out a review of medical and public databases and assess the behavioral features of the DDX3X syndrome (DDX3X), with a particular focus on psycho-pathological symptoms. (2) Methods: An extensive computerized search was conducted in various databases, including PubMed, Medline Complete, Science Direct, Scopus, and Web of Science. Specific keywords and Medical Subject Headings were used to ensure the inclusion of relevant studies. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were applied to assess the methodological quality of the manuscripts. (3) Results: Only nine papers out of the 272 assessed met the inclusion criteria. These articles revealed various psycho-pathological manifestations in patients with the DDX3X syndrome. Intellectual disability (ID) or developmental disability (DD), speech delay, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), generalized anxiety disorder (GAD), self-injurious behaviors (SIBs), sensory symptoms and sleep disturbance were demonstrated to be the most common psycho-pathological behavior manifestations. (4) Conclusions: Patients with the DDX3X syndrome manifest a wide spectrum of psycho-pathological symptoms. A comprehensive investigation of these symptoms in patients is essential for early diagnosis and effective therapy. [ABSTRACT FROM AUTHOR]

The COVID-19 vaccination campaign has been fortified by the positive effects of immunization: data from official government organizations and communication channels show that infection rates, hospitalizations, and deaths have continued to fall since its implementation. In Brazil, the effective and free National Vaccination Program has failed to prioritize patients with rare diseases, who have extreme comorbidities, and who adhere to the calendar prepared by the government. The question is why these "rare people" were not considered priorities during the vaccination program. This study aims to understand the reasoning behind this decision and to resume the debate around the rights of patients with rare diseases based on regular descriptors issued by official government agencies and by critics of rare disease issues in scientific articles. The objectives of this study were as follows: to analyze the dispensed care of rare disease patients in the COVID-19 vaccination campaign; to identify the procedures implemented by the National Vaccination Plan for the Brazilian population over 18 years of age and to evaluate the effectiveness of the plan implemented from the perspective of a "rare person". [ABSTRACT FROM AUTHOR]

Lysinuric protein intolerance (LPI) is a rare inborn error of metabolism (IEM), classified as an inherited aminoaciduria, caused by mutations in the SLC7A7 gene, leading to a defective cationic amino acid transport. The metabolic adaptations to the demands of pregnancy and delivery cause significant physiological stress, so those patients affected by IEM are at greater risk of decompensation. A 28-year-old woman with LPI had experienced 3 early miscarriages. While pregnancy was finally achieved, diverse nutritional and medical challenges emerged (food aversion, intrauterine growth restriction, bleeding risk, and preeclampsia suspicion), which put both the mother and the fetus at risk. Moreover, the patient requested a natural childbirth (epidural-free, delayed cord clamping). Although the existence of multiple safety concerns rejected this approach at first, the application of novel strategies made a successful delivery possible. This case reinforces that the woman's wish for a non-medicated, low-intervention natural birth should not be automatically discouraged because of an underlying complex metabolic condition. Achieving a successful pregnancy is conceivable thanks to the cooperation of interdisciplinary teams, but it is still important to consider the risks beforehand in order to be prepared for possible additional complications. [ABSTRACT FROM AUTHOR]

Renal hypouricemia (RHUC) is a rare hereditary disorder caused by loss-of-function mutations in the SLC22A12 (RHUC type 1) or SLC2A9 (RHUC type 2) genes, encoding urate transporters URAT1 and GLUT9, respectively, that reabsorb urate in the renal proximal tubule. The characteristics of this disorder are low serum urate levels, high renal fractional excretion of urate, and occasional severe complications such as nephrolithiasis and exercise-induced acute renal failure. In this study, we report two Spanish (Caucasian) siblings and a Pakistani boy with clinical characteristics compatible with RHUC. Whole-exome sequencing (WES) analysis identified two homozygous variants: a novel pathogenic SLC22A12 variant, c.1523G>A; p.(S508N), in the two Caucasian siblings and a previously reported SLC2A9 variant, c.646G>A; p.(G216R), in the Pakistani boy. Our findings suggest that these two mutations cause RHUC through loss of urate reabsorption and extend the SLC22A12 mutation spectrum. In addition, this work further emphasizes the importance of WES analysis in clinical settings. [ABSTRACT FROM AUTHOR]

Esophageal atresia (EA) is the most common malformation of the upper gastrointestinal tract. The estimated incidence of EA is 1 in 3500 births. EA is more frequently observed in boys and in twins. The exact cause of isolated EA remains unknown; a multifactorial etiology, including epigenetic gene expression modifications, is considered. The study included six pairs of twins (three pairs of monozygotic twins and three pairs of dizygotic twins) in which one child was born with EA as an isolated defect, while the other twin was healthy. DNA samples were obtained from the blood and esophageal tissue of the child with EA as well as from the blood of the healthy twin. The reduced representation bisulfite sequencing (RRBS) technique was employed for a whole-genome methylation analysis. The analyses focused on comparing the CpG island methylation profiles between patients with EA and their healthy siblings. Hypermethylation in the promoters of 219 genes and hypomethylation in the promoters of 78 genes were observed. A pathway enrichment analysis revealed the statistically significant differences in methylation profile of 10 hypermethylated genes in the Rho GTPase pathway, previously undescribed in the field of EA (ARHGAP36, ARHGAP4, ARHGAP6, ARHGEF6, ARHGEF9, FGD1, GDI1, MCF2, OCRL, and STARD8). [ABSTRACT FROM AUTHOR]

Hemophilia is a chronic, congenital/hereditary and X-linked disease, characterized by an insufficiency of factors VIII or IX, which are necessary for blood clotting. Those affected by hemophilia often suffer from particular psychosocial problems, both in the acceptance, coping, treatment and self-management of their disease and in their family and social relationships, which are often mediated by these circumstances. The aim of this study was to explore the experiences of people with hemophilia or their family members, of in a specific region of Spain, regarding the impact of having hemophilia. Structured interviews were conducted and developed, using the studies of the World Federation of Hemophilia and Osorio-Guzmán et al. as a guide, as well as a literature review of qualitative work on hemophilia. Data were analyzed using a six-step thematic analysis. A total of 34 interviews were thematically analyzed. The results showed that three key themes emerged from the data: (1) the daily impact of having hemophilia, (2) uncertainty about the disease, (3) the role of associations and (4) support from institutions. The results make it clear that the disease has a major impact on their lives (work, family, leisure and personal environment). The main conclusion is that hemophilia has a negative impact on the daily lives of patients, families and caregivers. [ABSTRACT FROM AUTHOR]

Tay–Sachs disease is classified as a rare paediatric disease of metabolic origin. It is an autosomal recessive inherited disease. The gene responsible for the disease is known as HEXA, and it is located on chromosome 15(15q23). There is currently no effective treatment for Tay–Sachs disease; hence, it is an incurable disease in which patients do not live for more than five years, meaning that nursing care takes on greater importance to maintain quality of life. The main objective of this work is to develop a specific standard nursing care plan by applying an inductive research method supported by nursing methodology using the NANDA-NIC-NOC taxonomy and validated by the Delphi method. This care plan will improve the knowledge of health professionals on this topic and support future studies on the disease. Following its implementation, the care plan proposed in this study aims to increase the quality of life of patients diagnosed with this disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Two papillon puppies (a stillborn and a live pup) were born with severe syndromic developmental abnormalities, involving incomplete fusion of the chest and abdominal wall with extrusion of internal organs. A similarly affected stillborn pup from the dam's previous litter was reported, suggesting a possible familial inheritance. This study describes the results of advanced imaging (by computed tomography) and postmortem examinations of the two affected puppies compared to an unaffected stillborn papillon puppy from a separate litter. The results confirmed a diagnosis of Pentalogy of Cantrell, a rare syndrome, which is proposed to be inherited in humans. There are infrequent reports of this congenital condition in domestic animals with variable expression of the typical five signs of this syndrome, without any identified cause or confirmed genetic familial basis. Developmental anomalies are an important cause of stillbirth and early perinatal death in companion animals. Many of these disorders remain poorly understood and provide an opportunity as a spontaneous animal model for human disease. Pentalogy of Cantrell is a rare congenital syndrome described in human neonates. It is a ventral midline closure defect with a proposed familial inheritance in humans. This syndrome involves five defects, including the thoracoabdominal wall, sternal, diaphragmatic, pericardial and cardiac malformations. Diverse expressions of these defects have been described in humans and sporadically in domestic animals. This severe syndrome commonly harbors a poor prognosis, posing an ethical and surgical dilemma. To better understand this syndrome and its presentation in dogs, we describe two rare cases of Pentalogy of Cantrell in a litter of papillon dogs. The affected puppies had anomalies compatible with the Pentalogy of Cantrell, including thoracoabdominal schisis, ectopia cordis, sternal cleft, pericardial agenesis, and diaphragmatic defects. The diagnosis was confirmed by advanced imaging (computed tomography) and postmortem examinations. The family history of this litter was explored and other cases in domestic animals were reviewed. This is the first report of the complete Pentalogy of Cantrell with ectopia cordis in the dog and the only report on papillons. Similar to human cases, possible familial inheritance and suspected male gender bias were observed. Further research on this novel animal model, its pathogenesis and its hereditary basis, may be helpful in better understanding this rare developmental disorder. [ABSTRACT FROM AUTHOR]

Background: 22q11 deletion syndrome (SD22Q11) is a neurogenetic condition that is associated with a high risk of neurodevelopmental disorders and intellectual disability. People with SD22Q11, both children and adults, often experience significant difficulties in social interactions, as well as neurocognitive deficits, and have elevated rates of autism spectrum disorder (ASD). Despite this, the relationship between basic cognitive processes and cognitive ability in this population has not been well investigated. Methods: the main objective of the present research is to describe the neurocognitive profile of people with SD22Q11 using standardized neuropsychological assessment instruments. For this purpose, a sample of 10 participants aged between 7 and 15 years was administered an assessment battery with the following tests: WISC-V, CELF-5, NEPSY-II, CSAT-R, CARAS-R, TP, MABC-2, BRIEF-2, SENA, DABAS, ABAS-II, SCQ, and ADOS-2. Results: the results showed IQ scores in the borderline normal range, as well as difficulties in language functions, social skills, motor skills, and executive functions. Conclusions: an individualized assessment taking into account the globality of its expression, and a therapeutic approach adapted to the specific needs of children with this syndrome is essential. [ABSTRACT FROM AUTHOR]

Myotonic dystrophy type 1 (DM1) is a complex rare disorder characterized by progressive muscle dysfunction, involving weakness, myotonia, and wasting, but also exhibiting additional clinical signs in multiple organs and systems. Central dysregulation, caused by an expansion of a CTG trinucleotide repeat in the DMPK gene's 3' UTR, has led to exploring various therapeutic approaches in recent years, a few of which are currently under clinical trial. However, no effective disease-modifying treatments are available yet. In this study, we demonstrate that treatments with boldine, a natural alkaloid identified in a large-scale Drosophila-based pharmacological screening, was able to modify disease phenotypes in several DM1 models. The most significant effects include consistent reduction in nuclear RNA foci, a dynamic molecular hallmark of the disease, and noteworthy anti-myotonic activity. These results position boldine as an attractive new candidate for therapy development in DM1. [ABSTRACT FROM AUTHOR]