With over 8000 rare diseases identified and treatments available for only a fraction, the urgency for accelerating therapeutic development is paramount. Drug repurposing – the process of identifying new uses for existing drugs – may offer a faster, more cost-effective approach than de novo drug development. Thus, the concept of drug repurposing for rare diseases was a hot topic during the RE(ACT) Congress and IRDiRC Conference held in Brussels on March 5–7, 2025. This article draws from the expert panel presentations and discussions, exploring the landscape of drug repurposing in rare diseases, including the opportunities, challenges, and examples of success. Key themes include collaborative infrastructure, data-driven innovation, patient-centricity, and the need for tailored regulatory and commercial strategies.
The 2025 Connect & Collaborate Okur–Chung Neurodevelopmental Syndrome (OCNDS) Scientific and Family Conference convened researchers, clinicians, and families to accelerate discovery and translation of research for OCNDS. OCNDS is an ultra-rare disorder caused by pathogenic variants in the CSNK2A1 gene. Nearly 200 participants joined the 4-day event featuring 17 scientific talks, 15 family sessions, and multiple roundtables integrating patient and researcher perspectives. Scientific sessions covered CK2 biology, variant functional studies, model organism pipelines, and early therapeutic exploration. Family sessions emphasized speech and language outcomes, sleep and behavioral challenges, and barriers to clinical care. Crowdsourced researcher-family dialogues identified shared priorities for the next research phase, including developing measurable clinical endpoints, expanding biobanking and variant data infrastructure, and focusing on translational models to enable preclinical testing. These priorities will steer the next several years of OCNDS research and collaboration, driving coordinated advances toward clinical translation.
With increasing use of prenatal screening, sex chromosome aneuploidies (SCAs) are more frequently detected. Individuals with SCAs have variable physical and medical findings, and developmental and behavioural outcomes. This retrospective study describes the growth, development and clinical features of individuals with SCAs seen at the Genetics clinic in KK Women’s and Children’s Hospital, Singapore, between January 2011 and July 2014. Forty-seven patients were included in this study, comprising six groups: 47, XXY (Klinefelter syndrome); 47, XXY/46, XY; 47, XYY; 47, XYY/46, XY; 47, XXX; and other rare SCAs. The majority (39 patients, 82.9%) were detected prenatally. A developmental assessment was available for 44/47 (93.6%). Of these, 28 (63.6%) were delayed in at least one domain, though the delay was mild in the majority (17 patients) with improvement documented on follow-up. Among eight individuals diagnosed postnatally, global developmental delay was reported in 4 (50%), compared to none among those diagnosed prenatally. Growth appeared unaffected in most, with 11.9% (5 patients) having tall stature. While 63.6% of our patients had developmental delay in at least one domain, commonly affecting speech and language, the delay was mild in the majority. No prenatally diagnosed patient had global developmental delay. This information is valuable in genetic counselling, especially prenatally. (201 words).
Trisomy 18 (Edwards syndrome) and trisomy 13 (Patau syndrome) have historically been regarded as “uniformly lethal” or “incompatible with life,” leading to the longstanding practice of withholding resuscitation and surgical intervention. However, accumulating evidence indicates that survival is more heterogeneous than previously recognized, and advances in neonatal and surgical care have improved outcomes. Among long-term survivors, gradual yet meaningful developmental progress has been observed, and parental reports describe affected children as happy and deeply valued members of their families. These findings have reshaped clinical and ethical perspectives, fostering a paradigm shift from uniform non-intervention toward individualized, family-centered decision-making. In parallel, the widespread adoption of noninvasive prenatal screening (NIPS) has markedly increased prenatal detection, further complicating perinatal counseling and underscoring the need for ethically consistent care. This narrative review summarizes current and evolving evidence on survival and treatment outcomes for trisomy 18 and trisomy 13 and synthesizes contemporary approaches to comprehensive care from the neonatal period through childhood. Within this evolving landscape, we propose a practical framework for counseling and iterative shared decision-making with families. Integrating accurate and up-to-date medical information with family perspectives is essential to provide compassionate, balanced, and equitable care for infants with these syndromes and their families.
Urea cycle disorders (UCD) result from either direct deficiency of a urea cycle enzyme or improper transport of urea cycle intermediates between cellular compartments. The urea cycle is the primary metabolic mechanism by which the body detoxifies waste nitrogen that otherwise accumulates as ammonia. Given this critical role, individuals with a UCD can present with severe hyperammonemia that may prove fatal. Furthermore, the care and management of those with a UCD is challenging and is hampered by our limited ability to prospectively predict the severity of disease in individuals based upon biochemical or molecular results. Similarly, treatment paradigms for UCD, while resulting in improvement in symptomatology are far from curative. Recent preclinical and clinical research has focused on both developing reliable predictors of severity and at advancing therapies and treatments that move closer to a cure. We present here an overview of this emerging work, targeting both areas of research, to provide a review of the state of investigation with regard to UCD.
Danon disease is a rare, X-linked genetic disorder. We report a case of a 17-year-old male with learning difficulties who presented due to advanced heart failure and the subsequent discovery of this highly penetrant but variable disease among a family unit. Cascade screening was offered to all siblings and parents that demonstrated great phenotypic heterogeneity among family members, most pronounced among female siblings. We highlight the importance of genetic testing to ultimately clinch the diagnosis of Danon disease, but how cost and reimbursement remain a major barrier in ensuring genetic testing is performed more routinely in South-East Asia, and more efforts are needed to improve this. Our case also highlights the utility of echocardiographic strain imaging in detecting subclinical disease as part of the cascade screening process. In view of the myriads of presentations, a high index of suspicion, thorough multi-systemic evaluation at baseline and robust follow-up care following genetic testing and cascade screening are all pivotal in the diagnosis and care of the condition.
Congenital infections significantly impact neurodevelopment, often leading to long-term neurological deficits. This review explores four major congenital and perinatal infections: congenital cytomegalovirus (CMV), neonatal herpes simplex virus (HSV), neonatal enterovirus syndrome, and congenital syphilis. We focus on their epidemiology, clinical presentation, sequelae, diagnosis, treatment, and future directions. Advances in early detection, antiviral and antimicrobial therapies, and vaccine development offer promise for improving outcomes. Future research should focus on enhanced screening, novel therapeutics, and public health interventions to mitigate the lifelong impact of these infections on neurodevelopment.
Children with severe genetic conditions often need long-term care and rehabilitation. The purpose of this study was to characterize the medical and rehabilitation needs of children with severe genetic conditions living in a long-term care (LTC) facility in Abu Dhabi, United Arab Emirates (UAE). A cross-sectional, retrospective chart review of all children with severe genetic conditions admitted to an LTC facility between September and November 2024 was conducted. Data were extracted from medical records, including age, primary diagnosis, comorbidities, respiratory support needs, level of consciousness, medication list, and rehabilitation services. A total of 10 children were included in the study. The diagnoses varied from common to very rare genetic conditions. All children exhibited global developmental delay, abnormal muscle tone, and complete functional dependence. All children had chronic respiratory failure requiring long-term mechanical ventilation, highlighting the severity of their conditions. Seven children had scoliosis with multiple contractures. Routine and as-needed medications with nursing, dietary, physical, occupational, and respiratory therapies were offered for all children. Children with severe genetic conditions in an LTC are medically complex and require multidisciplinary care and rehabilitation. This study highlights the need for interventions to improve the quality of life of these vulnerable children.
One of male factor related to infertility is asthenozoospermia which is a condition associated with low sperm motility in fresh ejaculate. The present study was designed to assess the efficacy of a Maca culture medium to improving certain sperm function parameters in vitro using discontinuous density gradient technique (DGT) for men with asthenozoospermia. Fifty semen samples of infertile men were involved in this study. The volume of each semen sample was not less than 2 mL. Seminal fluid analysis was done after 2–7 days of abstinence as a control group before activation. Each asthenozoospermic semen sample was divided equally into two portions, subjected to DGT with and without Maca medium (1 mg maca /10 mL phosphate buffer solution) as treated groups after activation. Certain sperm function parameters were measured guidelines pre- and post-activation. Sperm concentration revealed highly significant ( p < 0.001) differences between post-activation DGT with and without Maca medium. Significant ( p < 0.001) improvement in progressive sperm motility, total sperm motility, and morphologically normal sperm (MNS) percentage were observed post-activation by using DGT and Maca medium compared to medium without Maca and pre-activation. The present study concluded that combining of DGT with Maca medium may reveal a novel method to improve certain sperm function parameters in men dealing with asthenozoospermia.
Background and aim Lung cancer, particularly NSCLC, is the foremost reason behind deaths associated with cancer globally and the second most prevalent malignancy among males in Iraq. Mutations in the EGFR gene are significant druggable targets in NSCLC, linked to sensitivity to tyrosine kinase inhibitors. This study aims to analyse the incidence and kinds of EGFR mutations in Iraqi NSCLC patients and their correlation with gender and smoking status, despite global data indicating that EGFR mutations are more prevalent in females and non-smokers. Materials and methods A retrospective analysis was conducted on 214 FFPET samples. Information regarding the patients’ gender and smoking history was documented. DNA was extracted use the NucleoSpin tissue kit, and EGFR mutations were identified employing the Cobas z 480 analyser. The prevalence and types of mutations were associated with gender and smoking status; a p-value below 0.05 was regarded as statistically significant. Results Among 214 NSCLC cases, 51 (23.8%) exhibited EGFR mutations, with 58.8% being male and 41.2% female. The exon 19 deletion, Exdel19, represented the highest prevalence in both males and females, constituting 70% and 71.4%, respectively. The smoking status exhibited a significant correlation with Exdel19 mutation status ( p = 0.048), indicating a considerably greater mutation rate among nonsmokers. Conclusion The results of this study demonstrated the influence of smoking on the occurrence of EGFR mutations, particularly Exdel19, in Iraqi lung cancer patients. Systematic evaluation of EGFR mutations, in conjunction with smoking reduction initiatives, will enhance results with targeted therapy and diminish the burden of lung cancer both locally and globally.
We discuss a previously healthy adolescent male presenting with subacute neuropsychiatric issues, tremors, hyperreflexia, and hypertension. Laboratory studies revealed acute on chronic kidney disease. Additional investigations yielded a treatable late-onset inborn error of metabolism (IEM). Late-onset forms of IEMs may present very differently than early-onset disease manifestations (e.g., neuropsychiatric issues may be the predominant symptom), thus leading to the underrecognition of a treatable underlying etiology.
Background:Pitt-Hopkins syndrome (PTHS) is a rare genetic disorder caused by mutations in the TCF4 gene. The majority of individuals with PTHS have severe intellectual disability, language impairments, and gross motor impairments (e.g., ambulation and limb coordination difficulties). Objective:To demonstrate that PTHS may have a wider functional spectrum than previously understood. Methods:A child that previously participated in a PTHS research study was identified as having a milder clinical presentation than other children in the study. A follow-up interview was conducted with the child's mother to follow the child's developmental course since the initial study. Results:The child's clinical presentation consisted of mild academic delays, speech consisting of full sentences, and full ambulatory function. Additionally, the child's musical abilities (e.g., perfect pitch, the ability to transpose music, plays several instruments) has allowed him to enroll in a performing arts charter school. Conclusions:Such PTHS case presentations further emphasize that individuals with mild medical and neurocognitive impairments could benefit from comprehensive genetics-informed care.
Rett syndrome (RTT) was first recognized in the late 1950s by Andreas Rett in Vienna and Bengt Hagberg in Uppsala. Hagberg, following a meeting with Rett, decided to call the disorder Rett syndrome in the landmark paper which appeared in the Annals of Neurology in 1983. That report led to the worldwide recognition of this relatively young and unique neurodevelopmental disorder, the concerted effort to establish its epidemiology, etiology, and natural history, and the establishment of clinical criteria for its diagnosis. Our understanding of RTT progressed rapidly, in part due to the remarkable diagnostic advances in genetics linking RTT with variations in the methyl-CpG-binding protein 2 (MECP2) gene at Xq28. In 2003, the NIH funded a Natural History study of RTT and related disorders which provided critical cross-sectional and longitudinal data that resulted in the increased understanding of RTT, the development of better management strategies, and an increase in pharmaceutical and gene-based products designed to provide specific therapies. The FDA-approved oral agent trofinetide has been shown to provide incremental improvements in the core features of RTT. Two gene-based therapies are currently being assessed in clinical trials in Canada and the US. Additional treatment strategies are being assessed at the clinical and translational levels.
BACKGROUND: Circulating β-casomorphins (BCM) and gluten exorphins (GE), which are exogenous opioid peptides originating from bovine milk protein casein and cereal protein gluten, respectively, have been proposed as potential trigger factor to symptoms observed in children with autism. OBJECTIVE: Given the debate surrounding the detectability of these opioid peptides in body fluids, particularly using highly sensitive and specific mass spectrometry (HPLC-MS) techniques, we aimed to investigate their presence in urine samples of autistic subjects. METHODS: We employed an HPLC-MS method for peptide detection. RESULTS: The presence of several BCMs and GEs in the urine of both autistic children (ASD) and healthy controls (HC) was documented. The detection of dietary opioid peptides even at very low concentrations underscores the sensitivity of this novel HPLC-MS method. BCM-8 was more often detected in the ASD group compared to the HC group. A higher prevalence of gastrointestinal (GI) symptoms were also observed in the ASD group. CONCLUSIONS: This pilot study supports the presence of BCMs and GEs in urine samples in subjects with autism as well as healthy controls which was the main goal of this pilot study. Prolonged exposure to bovine BCMs and GEs may play a role in the manifestation of core and GI symptoms in subgroups of autism. Further research is warranted to investigate this phenomenon thoroughly.
The 2024 International Rett Syndrome Foundation (IRSF) Rett Syndrome Scientific Meeting, held in Westminster, Colorado, gathered over 200 researchers and clinicians to discuss advancements in understanding and treating Rett syndrome (RTT). Key topics included MeCP2 biology, neuronal circuitry, therapeutic development, and clinical trial outcomes. The meeting reinforced the importance of collaborative research in unraveling RTT’s complex pathology and advancing treatment approaches. With promising therapeutic candidates in development, the conference underscored a growing hope for effective treatments, offering a path toward improving the quality of life for individuals with Rett syndrome and their families.
BACKGROUND: Multiple sclerosis (MS) is a long-term condition characterized by chronic inflammation, damage to the myelin sheath, and progressive nerve cell degeneration. It is a heterogeneous and multifactorial disease. The aim of the present investigation was to analyze the connection between variations in the vitamin D receptor gene. (APAI rs7975232) and vitamin D serum levels among MS patients. METHODS: Blood samples were collected from 75 Iraqi patients with MS (33 male, 42 female), and 75 control group volunteers who appeared to be in good health with an age range of 20–50 years. Vitamin D receptor (VDR) gene polymorphism was detected by HRM RT-PCR and vitamin D serum levels were assessed by ELISA. RESULTS: Detection of VDR gene polymorphism in MS patients discovered that the wild genotype was C/C 15 (20%), the heterozygous genotype CA was 27(36%), and the homozygous genotype AA was 33(44%), whilst allele C occurrence was 57(38%) and allele A was 93(62%), compared per control genotype C/C was 40(53.3%), CA genotype was 20(26.6%), AA genotype was 15(20%), C allele frequency was 100(66.6%) and A allele was 50(33.3%) with highly significant difference (P≤0.001). Analysis of vitamin D serum levels showed much higher levels in the control group (43.40±0.85 pg/ml) than in the MS patients group (15.46±0.93 pg/ml; P≤0.001). Result of relationship between Vitamin D serum level with genotype of VDR among individuals with MS was found to be significant decrease (5.3±0.52) at AA genotype of MS patients, followed by (11.79±0.68) in CA genotype and finally (15.52±0.93) in CC genotype, all highly significant (P≤0.01). CONCLUSION: There was a notable correlation observed with VDR (APAI rs7975232) genotypes and Vitamin D serum level in MS Iraqi patients.
BACKGROUND: Wiedemann-Rautenstrauch Syndrome (WRS) is a neonatal progeroid syndrome for which biallelic pathogenic variants in RNA polymerase III subunit A (POLR3A) have recently been described. POLR3 is a 17 subunits protein complex responsible for the transcription of short RNAs including all the transfer RNAs (tRNAs), the 5 S subunit of ribosomal RNA, the short nuclear RNA U6, among other regulatory RNAs. OBJECTIVE: We aim to evaluate the impact of POLR3A pathogenic variants on the relative expression of the short nuclear RNA U6 and on the differential profile of intron retention RNA U6, p53 isoforms and in fibroblasts derived from patients with WRS and control fibroblasts. METHODS: RNA was extracted by the TRIzol method; intron retention analysis was performed by using IRFinder from an mRNA sequencing (RNA-Seq) platform; P53 isoforms, short nuclear RNA U6 and additional genes related to cell senescence were measured by RT-PCR. RESULTS: No significant differences were found in the percentage of intron retention (control: 7.8%, WRS1 : 6.3%and WRS2 : 8.14%). Genes showing higher intron retention profile in both groups were mainly related to RNA binding pathways, cell cycle regulation, positive regulation of transcription, positive regulation of inflammatory pathways, negative regulation of apoptosis, RNA transcription, mitochondria, and regulation of translation initiation. However, in WRS fibroblasts the genes with more intron retention were those related to the immune response and mitochondrial function; while in control those related to the response to oxidative stress had the most introns retained. WRS1 showed higher expression of short nuclear RNA U6 compared to control and WRS2; while both WRS cells showed higher expression of p53β and lower percentage of Δ133p63α, consistent with a higher expression of the cellular senescence markers p16 and p21. CONCLUSIONS: These results demonstrated the important role of POLR3A in the maintenance of cellular homeostasis and highlight its potential role in cell senescence in WRS.
Autism is a group of neurodevelopmental disorders that involve definite impairments in social interactions, disturbance in language, and a stereotyped pattern of behaviour. These clinical features are described as the core symptoms. The condition represents a very large number of diseases and syndromes that are individually rare. Therefore, most people will refer to autism in the plural – autisms. The prevalence of autism has increased incredibly in the last three decades. However, although the number of people diagnosed with autism has increased, this is not the same as saying that there is an increase in the number of cases of autism. Most likely, many children and adults 40–50 years ago had autistic behaviour that went under other diagnoses. The cause of the autistic features has been thoroughly discussed for many years and has been the subject of many research activities. The dominant view today is that genetic and environmental factors mainly cause autism. In this article we want to give a brief status quo of the clinic, epidemiology and causes of autism.
