PLoS One. 2024 Jul 31;19(7):e0308087. doi: 10.1371/journal.pone.0308087. eCollection 2024.

ABSTRACT

Rare cancers are defined by low incidence rates, and may lack evidence that supports uniform standards of care and relevant clinical guidelines. Rare cancers may represent up to 24% of all cancers, yet remain understudied and underappreciated in terms of their clinical and ultimately societal impact. The PLOS Rare Cancer Collection brings together a broad range of research endeavors that are being undertaken in rare cancers research ranging from basic biological evaluations to therapeutic drug development. This Overview presents a brief background to the Collection and highlights the contributions of included articles.

PMID:39083545 | DOI:10.1371/journal.pone.0308087

Int J Paleopathol. 2024 Sep;46:62-73. doi: 10.1016/j.ijpp.2024.07.002. Epub 2024 Jul 29.

ABSTRACT

OBJECTIVE: The first case of Legg-Calvé-Perthes disease (LCPD) in Greece is presented. LCPD, a rare disease, is discussed using the Digital Atlas of Ancient Rare Diseases (DAARD), which tests the benefits of the database for diagnosing and contextualizing the new case with 42 archaeological cases of LCPD recorded in the DAARD.

MATERIALS: A 30-40-year-old, probable male individual was found at the archaeological site of Olympia, Greece, dating to 500-700 CE.

METHODS: Biological sex, age-at-death and pathological changes were investigated using macroscopic and osteometric methods. The DAARD provided the typical characteristics of LCPD.

RESULTS: Pathological changes in both hip joints without any other related changes in the skeleton corresponded to the skeletal features of LCPD. The DAARD produced 42 cases of LCPD, most of which from Europe, with a preference for male sex and unilateral involvement of the hip joint.

CONCLUSIONS: The DAARD aids in diagnosing rare diseases and interpreting new cases in the context of already known studies.

SIGNIFICANCE: This study shows that the DAARD has the potential to help researchers move beyond the level of single case studies and create a broader picture of the history of rare diseases.

LIMITATIONS: This paper focuses on the benefits of the DAARD in relation to LCPD but not all rare diseases have been included in the database.

SUGGESTIONS FOR FURTHER RESEARCH: More rare diseases from archaeological contexts should be added to the DAARD to create a base for the interpretation of their history and expand our understanding of rare diseases in the past.

PMID:39079280 | DOI:10.1016/j.ijpp.2024.07.002

Am J Hum Genet. 2024 Jul 25:S0002-9297(24)00226-X. doi: 10.1016/j.ajhg.2024.07.002. Online ahead of print.

ABSTRACT

Recurrent copy-number variation represents one of the most well-established genetic drivers in neurodevelopmental disorders, including autism spectrum disorder. Duplication of 15q11-q13 (dup15q) is a well-described neurodevelopmental syndrome that increases the risk of autism more than 40-fold. However, the effects of this duplication on gene expression and chromatin accessibility in specific cell types in the human brain remain unknown. To identify the cell-type-specific transcriptional and epigenetic effects of dup15q in the human frontal cortex, we conducted single-nucleus RNA sequencing and multi-omic sequencing on dup15q-affected individuals (n = 6) as well as individuals with non-dup15q autism (n = 7) and neurotypical control individuals (n = 7). Cell-type-specific differential expression analysis identified significantly regulated genes, critical biological pathways, and differentially accessible genomic regions. Although there was overall increased gene expression across the duplicated genomic region, cellular identity represented an important factor mediating gene-expression changes. As compared to other cell types, neuronal subtypes showed greater upregulation of gene expression across a critical region within the duplication. Genes that fell within the duplicated region and had high baseline expression in control individuals showed only modest changes in dup15q, regardless of cell type. Of note, dup15q and autism had largely distinct signatures of chromatin accessibility but shared the majority of transcriptional regulatory motifs, suggesting convergent biological pathways. However, the transcriptional binding-factor motifs implicated in each condition implicated distinct biological mechanisms: neuronal JUN and FOS networks in autism vs. an inflammatory transcriptional network in dup15q microglia. This work provides a cell-type-specific analysis of how dup15q changes gene expression and chromatin accessibility in the human brain, and it finds evidence of marked cell-type-specific effects of this genetic driver. These findings have implications for guiding therapeutic development in dup15q syndrome, as well as understanding the functional effects of copy-number variants more broadly in neurodevelopmental disorders.

PMID:39079538 | DOI:10.1016/j.ajhg.2024.07.002

Genes (Basel). 2024 Jun 21;15(7):821. doi: 10.3390/genes15070821.

ABSTRACT

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.

PMID:39062600 | PMC:PMC11275492 | DOI:10.3390/genes15070821

Int J Biol Macromol. 2024 Oct;277(Pt 2):134097. doi: 10.1016/j.ijbiomac.2024.134097. Epub 2024 Jul 25.

ABSTRACT

A considerable fraction of population in the world suffers from rare diseases. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and its related Cas proteins offer a modern form of curative gene therapy for treating the rare diseases. Hereditary transthyretin amyloidosis, hereditary angioedema, duchenne muscular dystrophy and Rett syndrome are a few examples of such rare diseases. CRISPR/Cas9, for example, has been used in the treatment of β-thalassemia and sickle cell disease (Frangoul et al., 2021; Pavani et al., 2021) [1,2]. Neurological diseases such as Huntington's have also been focused in some studies involving CRISPR/Cas (Yang et al., 2017; Yan et al., 2023) [3,4]. Delivery of these biologicals via vector and non vector mediated methods depends on the type of target cells, characteristics of expression, time duration of expression, size of foreign genetic material etc. For instance, retroviruses find their applicability in case of ex vivo delivery in somatic cells due to their ability to integrate in the host genome. These have been successfully used in gene therapy involving X-SCID patients although, incidence of inappropriate activation has been reported. On the other hand, ex vivo gene therapy for β-thalassemia involved use of BB305 lentiviral vector for high level expression of CRISPR biological in HSCs. The efficacy and safety of these biologicals will decide their future application as efficient genome editing tools as they go forward in further stages of human clinical trials. This review focuses on CRISPR/Cas based therapies which are at various stages of clinical trials for treatment of rare diseases and the constraints and ethical issues associated with them.

PMID:39059527 | DOI:10.1016/j.ijbiomac.2024.134097

CNS Drugs. 2024 Jul 26. doi: 10.1007/s40263-024-01105-z. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: CDKL5 deficiency disorder presents as a challenging condition with early-onset refractory seizures, severe developmental delays, and a range of other neurological symptoms. Our study aimed to explore the benefits and side effects of anti-seizure medications (ASMs) in managing seizures among individuals with CDKL5 deficiency disorder, drawing on data from the International CDKL5 Disorder Database.

METHODS: Data for this retrospective cohort study were obtained from the International CDKL5 Disorder Database, which contains responses from a baseline questionnaire administered between 2012 and 2022 and a follow-up questionnaire administered between 2018 and 2019. Families of eligible individuals were asked to provide information on ASMs that were previously and currently taken, the dose prescribed, the age at starting the medications, and the age at discontinuation for past medications. The outcome variables of interest were perceived seizure-related benefits for the current and past use of ASMs and caregiver-reported side effects. Rescue medications and infrequently used ASMs were excluded from the analysis. Descriptive statistics were used to summarise the characteristics of the study population.

RESULTS: The study included 399 children and adults with CDKL5 deficiency disorder, descriptively analysing the perceived benefits and side effects of 23 unique ASMs based on caregiver reports. The study identified levetiracetam, topiramate, sodium valproate, vigabatrin, phenobarbital and clobazam as the most used ASMs. Notably, cannabidiol showed highly beneficial outcomes with few side effects, whereas levetiracetam and phenobarbital exhibited less favourable benefit-to-side-effect ratios. Dual therapy involving sodium valproate and levetiracetam was only used a small number (n = 5) of times but appeared effective in reducing seizure activity with relatively few side effects. Compared with monotherapy, polytherapy had a relatively higher likelihood of reported side effects than benefits.

CONCLUSIONS: The study, leveraging a large sample size that exceeds that of previous research, emphasises the complex nature of seizure management in CDKL5 deficiency disorder. Our findings underscore the necessity of ongoing research to optimise treatment strategies, considering both the efficacy of seizure control and the potential for adverse effects. The study also points to the need for future investigations into the therapeutic potential of emerging treatments such as ganaxolone and the unresolved efficacy of cannabis products in seizure management.

PMID:39060900 | DOI:10.1007/s40263-024-01105-z

Br J Gen Pract. 2024 Jul 25;74(745):340-341. doi: 10.3399/bjgp24X738789. Print 2024 Aug.

NO ABSTRACT

PMID:39054086 | DOI:10.3399/bjgp24X738789

Orphanet J Rare Dis. 2024 Jul 24;19(1):277. doi: 10.1186/s13023-024-03280-0.

ABSTRACT

BACKGROUND: The history of rare diseases is largely unknown. Research on this topic has focused on individual cases of prominent (historical) individuals and artistic (e.g., iconographic) representations. Medical collections include large numbers of specimens that exhibit signs of rare diseases, but most of them date to relatively recent periods. However, cases of rare diseases detected in mummies and skeletal remains derived from archaeological excavations have also been recorded. Nevertheless, this direct evidence from historical and archaeological contexts is mainly absent from academic discourse and generally not consulted in medical research on rare diseases.

RESULTS: This desideratum is addressed by the Digital Atlas of Ancient Rare Diseases (DAARD: https://daard.dainst.org ), which is an open access/open data database and web-based mapping tool that collects evidence of different rare diseases found in skeletons and mummies globally and throughout all historic and prehistoric time periods. This easily searchable database allows queries by diagnosis, the preservation level of human remains, research methodology, place of curation and publications. In this manuscript, the design and functionality of the DAARD are illustrated using examples of achondroplasia and other types of stunted growth.

CONCLUSIONS: As an open, collaborative repository for collecting, mapping and querying well-structured medical data on individuals from ancient times, the DAARD opens new avenues of research. Over time, the number of rare diseases will increase through the addition of new cases from varied backgrounds such as museum collections and archaeological excavations. Depending on the research question, phenotypic or genetic information can be retrieved, as well as information on the general occurrence of a rare disease in selected space-time intervals. Furthermore, for individuals diagnosed with a rare disease, this approach can help them to build identity and reveal an aspect of their condition they might not have been aware of. Thus, the DAARD contributes to the understanding of rare diseases from a long-term perspective and adds to the latest medical research.

PMID:39044201 | DOI:10.1186/s13023-024-03280-0

HNO. 2024 Sep;72(9):668-672. doi: 10.1007/s00106-024-01503-1. Epub 2024 Jul 22.

ABSTRACT

An isolated fracture of the handle of the malleus is a rare entity in otorhinolaryngology and manifests clinically as acute-onset unilateral hearing loss. Several factors may cause this injury, including acute barotraumatic pressure changes or traumatic events. Various therapeutic approaches such as tympanoplasty, autologous graft, or application of bone cement are discussed. We report the case of a 46-year-old female patient who developed acute hearing loss in her left ear after finger manipulation. Clinical evaluation revealed axial displacement of the handle of the malleus and audiometry indicated conductive hearing loss. After otoscopy, audiometry, and computed tomography, tympanoscopy was indicated due to suspicion of ossicular chain disruption. Intraoperatively, an isolated fracture of the handle of malleus was found, which was treated with glass ionomer cement. Following postoperative examination, there was progressive improvement in the acoustic transmission component, such that a normal hearing threshold was observed 4 months postoperatively. This case report underlines the importance of precise diagnosis and individualized treatment for rare middle ear injuries.

PMID:39037485 | DOI:10.1007/s00106-024-01503-1

Orphanet J Rare Dis. 2024 Jul 22;19(1):275. doi: 10.1186/s13023-024-03286-8.

ABSTRACT

BACKGROUND: An estimated 3.5 million people in the UK live with a rare disease however due to the rarity of each individual condition this is not currently reflected in mainstream medical education. As a result, common features of living with a rare condition include diagnostic delay, poor coordination of health and social care and lack of access to specialist care and treatment. This is well documented in reports published by patient advocacy groups collating the patient experience and has been highlighted by the Department of Health and Social Care in its UK Rare Diseases Framework. One of the four priority areas outlined in this policy published in 2021 is 'increasing awareness amongst healthcare professionals'. Medics4RareDiseases (M4RD), a charity based in the UK, has proposed a disease-agnostic approach to educating doctors about rare disease, focusing on the common challenges experienced across this heterogeneous collection of conditions, rather than on the minutiae of each of the > 7000 rare conditions. A literature search using MEDLINE, PubMed Central and Bookshelf confirmed a lack of broad rare disease teaching in medical literature; none of the 10 final resources identified focused on the topic as a whole.

RESULTS: To address this, M4RD created the course 'Rare Disease 101'. It is accessed online using a learning management system that is free, contains interactive lessons, hosts a discussion board and is easily updated. In the 29 months since going live, 942 individuals have registered with 204 having completed the course; early feedback from 33 respondents was unanimously positive (all participants rated at least good (76%: excellent)) demonstrating that both clinicians and patients can benefit from broad rare disease education. The course is freely available to all at https://learn.m4rd.org/ .

CONCLUSIONS: Disease-agnostic training about rare disease as a large patient population, focusing on its unique profile of unmet needs, is required. Rare Disease 101 provides a pragmatic approach to an educational challenge that leads to poor patient outcomes. Early results suggest that the educational programme is well-received but further evaluation and assessment is needed.

PMID:39039494 | DOI:10.1186/s13023-024-03286-8

Clin Pharmacol Ther. 2024 Jul 22. doi: 10.1002/cpt.3393. Online ahead of print.

NO ABSTRACT

PMID:39039619 | DOI:10.1002/cpt.3393

Drug Discov Today. 2024 Sep;29(9):104102. doi: 10.1016/j.drudis.2024.104102. Epub 2024 Jul 18.

ABSTRACT

Characterization analysis of 87 pivotal clinical trials for 72 novel orphan drugs (76 orphan indications) approved by the FDA from 2017 to 2023 revealed that the clinical trial evidence supporting FDA orphan drug approvals often lacked high-quality designs, which frequently did not incorporate randomization, blinding, placebo or no treatment control, or clinical endpoint-driven methodologies. Additionally, regulatory flexibility was observed in the quantity of clinical trial evidence required, which included choices such as a single trial plus confirmatory evidence, one large multicenter trial or at least two trials. Furthermore, the overall strength of the clinical trial evidence exhibited variations across different orphan drugs and indications, influenced by features such as the therapeutic area and whether the orphan drug was granted accelerated approvals.

PMID:39032812 | DOI:10.1016/j.drudis.2024.104102

Pediatr Neurol. 2024 Sep;158:100-112. doi: 10.1016/j.pediatrneurol.2024.06.009. Epub 2024 Jun 24.

ABSTRACT

BACKGROUND: ZC4H2-associated rare disorder (ZARD) is caused by pathogenic variations in the ZC4H2 gene on the X chromosome. This gene codes for a zinc finger protein involved in neural development. ZARD is characterized by highly variable symptoms, potentially influenced by the sex of the individual.

METHODS: The ZC4H2-Associated Rare Disorder Natural History Study is a prospective natural history study conducted among individuals with ZARD that consists of standardized interviews, developmental assessments, and neurological examinations conducted every six months for two years. In this article, we present data from baseline visits with 40 participants, the largest ZARD cohort studied thus far, focusing on genotype-phenotype correlations and sex differences. Fisher exact, maximum likelihood χ2, and Mann-Whitney tests were utilized.

RESULTS: Males tended to have maternally inherited ZC4H2 pathogenic variations, whereas females tended to have de novo variations (P < 0.001). Female participants were more likely to have contractures at birth (P < 0.01), arthrogryposis multiplex congenita (P < 0.001), spasticity on examination (P < 0.1), and lower limb muscle atrophy (P < 0.05). Male participants were more likely to have seizures (P < 0.1), intermittent pain (P < 0.01), severe vision impairment (P < 0.05), dysphagia for solids (P < 0.01), and generalized muscle atrophy (P < 0.05).

CONCLUSIONS: Our study suggests there is significant overlap in severity and range of symptoms between males and females, although several symptoms are more common in one sex than the other. Further analysis is needed to better understand how pathogenic variation type affects phenotype.

PMID:39032379 | DOI:10.1016/j.pediatrneurol.2024.06.009

Med. 2024 Jul 16:S2666-6340(24)00253-8. doi: 10.1016/j.medj.2024.06.007. Online ahead of print.

ABSTRACT

BACKGROUND: Trofinetide was approved for the treatment of Rett syndrome (RTT) in patients aged ≥2 years based on the results of the 12-week, randomized, phase 3 LAVENDER study. In LILAC, a 40-week, open-label extension study of LAVENDER, trofinetide continued to improve the symptoms of RTT, with a similar safety profile as LAVENDER. Here, we report long-term safety and efficacy results of LILAC-2, a 32-month, open-label extension study.

METHODS: Females aged 5-22 years who completed LILAC were eligible to enter LILAC-2. Safety and tolerability were assessed with the incidence of adverse events (AEs). Efficacy was assessed with Rett Syndrome Behaviour Questionnaire (RSBQ) and Clinical Global Impression-Improvement (CGI-I) scores. Caregiver interviews explored the patient's experience with RTT and the efficacy of trofinetide during study participation.

FINDINGS: In total, 77 participants were enrolled in LILAC-2. The most common AEs were diarrhea (53.2%), COVID-19 (27.3%), and vomiting (19.5%). The mean (standard error [SE]) change in RSBQ score from LAVENDER baseline to week 104 of LILAC-2 was -11.8 (2.45). The mean (SE) CGI-I score from LILAC baseline to week 12 of LILAC-2 was 3.1 (0.10). Most caregivers (96%; n = 24/25) were satisfied or very satisfied with the benefits of trofinetide.

CONCLUSIONS: Long-term treatment with trofinetide continued to improve RTT symptoms, without new safety concerns. Caregivers reported satisfaction with trofinetide related to improvements that were meaningful for their child and themselves.

FUNDING: The study was supported by Acadia Pharmaceuticals (San Diego, CA, USA). This study was registered at ClinicalTrials.gov: NCT04776746.

PMID:39025065 | DOI:10.1016/j.medj.2024.06.007

PLoS One. 2024 Jul 18;19(7):e0307454. doi: 10.1371/journal.pone.0307454. eCollection 2024.

ABSTRACT

BACKGROUND: With the advancement of next-generation sequencing, clinicians are now able to detect ultra-rare mutations that are barely encountered by the majority of physicians. Ultra-rare and rare diseases cumulatively acquire a prevalence equivalent to type 2 diabetes with 80% being genetic in origin and more prevalent among high consanguinity communities including Saudi Arabia. The challenge of these diseases is the ability to predict their prevalence and define clear phenotypic features.

METHODS: This is a non-interventional retrospective multicenter study. We included pediatric patients with a pathogenic variant designated as ultra-rare according to the National Institute for Clinical Excellence's criteria. Demographic, clinical, laboratory, and radiological data of all patients were collected and analyzed using multinomial regression models.

RESULTS: We included 30 patients. Their mean age of diagnosis was 16.77 months (range 3-96 months) and their current age was 8.83 years (range = 2-15 years). Eleven patients were females and 19 were males. The majority were of Arab ethnicity (96.77%). Twelve patients were West-Saudis and 8 patients were South-Saudis. SCN1A mutation was reported among 19 patients. Other mutations included SZT2, ROGDI, PRF1, ATP1A3, and SHANK3. The heterozygous mutation was reported among 67.86%. Twenty-nine patients experienced seizures with GTC being the most frequently reported semiology. The mean response to ASMs was 45.50% (range 0-100%).

CONCLUSION: The results suggest that ultra-rare diseases must be viewed as a distinct category from rare diseases with potential demographic and clinical hallmarks. Additional objective and descriptive criteria to detect such cases are needed.

PMID:39024300 | DOI:10.1371/journal.pone.0307454

Cell Rep Med. 2024 Jul 16;5(7):101647. doi: 10.1016/j.xcrm.2024.101647.

ABSTRACT

Congenital hydrocephalus (CH), occurring in approximately 1/1,000 live births, represents an important clinical challenge due to the limited knowledge of underlying molecular mechanisms. The discovery of novel CH genes is thus essential to shed light on the intricate processes responsible for ventricular dilatation in CH. Here, we identify FLVCR1 (feline leukemia virus subgroup C receptor 1) as a gene responsible for a severe form of CH in humans and mice. Mechanistically, our data reveal that the full-length isoform encoded by the FLVCR1 gene, FLVCR1a, interacts with the IP3R3-VDAC complex located on mitochondria-associated membranes (MAMs) that controls mitochondrial calcium handling. Loss of Flvcr1a in mouse neural progenitor cells (NPCs) affects mitochondrial calcium levels and energy metabolism, leading to defective cortical neurogenesis and brain ventricle enlargement. These data point to defective NPCs calcium handling and metabolic activity as one of the pathogenetic mechanisms driving CH.

PMID:39019006 | DOI:10.1016/j.xcrm.2024.101647

Orphanet J Rare Dis. 2024 Jul 15;19(1):265. doi: 10.1186/s13023-024-03254-2.

ABSTRACT

BACKGROUND: Globally, researchers are working on projects aiming to enhance the availability of data for rare disease research. While data sharing remains critical, developing suitable methods is challenging due to the specific sensitivity and uniqueness of rare disease data. This creates a dilemma, as there is a lack of both methods and necessary data to create appropriate approaches initially. This work contributes to bridging this gap by providing synthetic datasets that can form the foundation for such developments.

METHODS: Using a hierarchical data generation approach parameterised with publicly available statistics, we generated datasets reflecting a random sample of rare disease patients from the United States (US) population. General demographics were obtained from the US Census Bureau, while information on disease prevalence, initial diagnosis, survival rates as well as race and sex ratios were obtained from the information provided by the US Centers for Disease Control and Prevention as well as the scientific literature. The software, which we have named SynthMD, was implemented in Python as open source using libraries such as Faker for generating individual data points.

RESULTS: We generated three datasets focusing on three specific rare diseases with broad impact on US citizens, as well as differences in affected genders and racial groups: Sickle Cell Disease, Cystic Fibrosis, and Duchenne Muscular Dystrophy. We present the statistics used to generate the datasets and study the statistical properties of output data. The datasets, as well as the code used to generate them, are available as Open Data and Open Source Software.

CONCLUSION: The results of our work can serve as a starting point for researchers and developers working on methods and platforms that aim to improve the availability of rare disease data. Potential applications include using the datasets for testing purposes during the implementation of information systems or tailored privacy-enhancing technologies.

PMID:39010138 | DOI:10.1186/s13023-024-03254-2

Biol Aujourdhui. 2024;218(1-2):9-18. doi: 10.1051/jbio/2024005. Epub 2024 Jul 15.

ABSTRACT

Systemic lupus erythematosus (SLE) presents a complex clinical landscape with diverse manifestations, suggesting a multifactorial etiology. However, the identification of rare monogenic forms of the disease has shed light on specific genetic defects underlying SLE pathogenesis, offering valuable insights into its underlying mechanisms and clinical heterogeneity. By categorizing these monogenic forms based on the implicated signaling pathways, such as apoptotic body clearance, type I interferon signaling, JAK-STAT pathway dysregulation, innate immune receptor dysfunction and lymphocytic abnormalities, a more nuanced understanding of SLE's molecular basis emerges. Particularly in pediatric populations, where monogenic forms are more prevalent, routine genetic testing becomes increasingly important, with a diagnostic yield of approximately 10% depending on the demographic and methodological factors involved. This approach not only enhances diagnostic accuracy but also informs personalized treatment strategies tailored to the specific molecular defects driving the disease phenotype.

PMID:39007772 | DOI:10.1051/jbio/2024005

Cureus. 2024 Jun 12;16(6):e62267. doi: 10.7759/cureus.62267. eCollection 2024 Jun.

ABSTRACT

Objective Adult-onset Still's disease (AOSD) is a rare orphan disease, the diagnosis of which remains challenging. This study aimed to identify additional clues for establishing early diagnosis beyond the existing criteria. Methods A retrospective longitudinal cohort study was conducted at two community hospitals in Japan between March 2012 and December 2022. The clinical characteristics and medical histories of patients with AOSD were extracted from the clinical records. The primary outcome was to identify the key manifestations of AOSD for an early diagnosis beyond the existing criteria. Results Twenty-one patients (mean age, 58 years) were included in the study. Fever was the first symptom in 13 out of 21 patients (62%). Six out of 21 patients (29%) presented with a pruritic rash only, while two out of 21 (10%) initially presented with a sore throat. All patients visited more than one medical institution. The median time to reach a correct diagnosis was 41 days (IQR 19-138). Nineteen out of 20 patients (95%) exhibited a pruritic rash, identified as persistent pruritic linear streaks, with a median duration of 21 days (IQR 12-64) before the diagnosis of AOSD as a cutaneous manifestation. Conclusions Persistent pruritic linear streaks were a key feature in the context of an early diagnosis of AOSD, offering an option for reconsidering and revising the existing classification criteria.

PMID:39006577 | PMC:PMC11245378 | DOI:10.7759/cureus.62267

Int J Mol Sci. 2024 Jun 25;25(13):6953. doi: 10.3390/ijms25136953.

ABSTRACT

The study of rare diseases is important not only for the individuals affected but also for the advancement of medical knowledge and a deeper understanding of human biology and genetics. The wide repertoire of structural information now available from reliable and accurate prediction methods provides the opportunity to investigate the molecular origins of most of the rare diseases reviewed in the Orpha.net database. Thus, it has been possible to analyze the topology of the pathogenic missense variants found in the 2515 proteins involved in Mendelian rare diseases (MRDs), which form the database for our structural bioinformatics study. The amino acid substitutions responsible for MRDs showed different mutation site distributions at different three-dimensional protein depths. We then highlighted the depth-dependent effects of pathogenic variants for the 20,061 pathogenic variants that are present in our database. The results of this structural bioinformatics investigation are relevant, as they provide additional clues to mitigate the damage caused by MRD.

PMID:39000061 | DOI:10.3390/ijms25136953