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ABSTRACT Background Congenital insensitivity to pain with anhidrosis (CIPA) (OMIM 256800) is a rare autosomal‐recessive condition, also known as hereditary sensory and autonomic neuropathy type IV (HSAN‐IV). The most commonly reported features include anhidrosis, intellectual disability, self‐mutilation, febrile episodes, impaired temperature perception, recurrent infections and/or autonomic nervous system impairment. Major joint destruction and joint deformity known as Charcot (neuropathic) joints are also seen in CIPA patients attributed to insensitivity to joint pain. Methods We present a case of a 46‐year‐old female affected with CIPA with a known NTRK1 variant and previously unidentified variant. Minigene reporter constructs were generated encompassing the exon 8 to exon 13 of the NTRK1 gene using the reference sequence and one harboring c.1483 + 5G > A variant identified in our proband. Minigene constructs were transfected into HEK293T cells, and the transcript was analysed for splicing to evaluate the effect of this variant in splicing. Results The patient (46‐year‐old female) exhibited right ankle joint deformity around 5 years of age. Patient also experienced lumbar compression and knee damage in adulthood. She had undergone a significant number of evaluations without clear diagnosis. Her presentation lacked many of the common clinical presentations of CIPA, and therefore, the focus of her evaluation was directed towards her unexplained joint deformities. Exome sequencing revealed a known pathogenic variant in NTRK1 (c.851 ‐ 33T > A:p.? [Intron 7]) and a novel NTRK1 variant (c.1483 + 5G > A:p.? [Intron 11]), which was later re‐classified as likely pathogenic. The patient was started on a biologic disease‐modifying anti‐rheumatic medication (bDMARD) due to a possible inflammatory etiology of her joint deformity. Molecular diagnosis allowed for modification of her treatment and surveillance strategies. Our minigene splicing assay demonstrated that the presence of the c.1483 + 5G > A variant has a negative effect on splicing, supporting the pathogenicity of this novel variant.

Abstract Background Aromatic ʟ‐amino acid decarboxylase (AADC) deficiency is a rare, severe neurological disorder caused by pathogenic variants in the dopa decarboxylase (DDC) gene, resulting in a combined deficiency of monoamine neurotransmitters. Clinically, patients present with a range of dysfunctions that impact motor, autonomic, and cognitive development. The constellation of symptoms of AADC deficiency varies among patients, and clinical presentation falls across a wide spectrum. However, most patients with AADC deficiency experience significant impairments when compared with children with normal development, irrespective of genotype, phenotype, or disease severity. Further, AADC deficiency is associated with increased mortality. Methods In response to the recent approval of a disease‐modifying gene therapy for AADC deficiency, this review presents considerations for the selection of patients for treatment. Conclusion Suggested clinical criteria to determine whether a patient is a candidate for gene therapy are: (1) genetically and biochemically confirmed AADC deficiency; (2) lack of achievement of gross motor milestones and/or persistence of clinically significant movement disorders; (3) persistent neurocognitive or systemic symptoms secondary to AADC deficiency despite standard medical therapy; and (4) informed parental/guardian decision and consent to treatment.

ABSTRACT Importance Pediatric medication is a challenging issue globally. Promoting trials of medications for children and implementing measures to encourage innovation for addressing unmet medical and health needs are important. Objective To explore the recent landscape of pediatric clinical trials of new investigational drugs conducted by pharmaceutical enterprises in China from 2013 to 2022 to provide insight into pediatric drug development in the pharmaceutical industry and regulatory policy formulation. Methods We performed a cross‐sectional observational investigation of pediatric clinical trials registered from January 1, 2013, to December 31, 2022, on the Registration and Information Disclosure Platform for Drug Clinical Trials, the official registration platform established in 2013 for trials of new investigational drugs initiated by biopharmaceutical enterprises. Trials that included pediatric participants (under 18 years old) were retrieved, and their relevant characteristics were extracted and analyzed. Results In total, 895 pediatric clinical trials were collected, accounting for 5.1% of the total registered clinical trials initiated prior to January 1, 2023. The overall average annual growth rate for the number of pediatric clinical trials was 12% (P < 0.001). Phase III trials accounted for the highest proportion (49.1%, 439). Of the 895 trials included, 736 (82.2%) were domestic trials, and 159 (17.8%) were international multicenter trials. In terms of tested drugs, investigations of biological products accounted for the largest proportion of trials (67.4%, 603). Among pediatric clinical trials, studies of vaccines accounted for the largest proportion of trials (41.0%, 367), followed by trials for rare diseases (17.2%, 154). Furthermore, geographical distribution analysis revealed that the largest and smallest numbers of trials were conducted in North China (35.7%, 320) and Northeast China (0.8%, 7), respectively. Interpretation The growth trends for industry‐sponsored clinical trials involving children illustrate the progress and increasing capability of pediatric drug development achieved in China since 2013. Current challenges and potential areas of focus for policymakers and stakeholders include investigating orphan drugs for rare diseases according to the unique epidemiological characteristics of Chinese children, expanding the scope of pediatric clinical trials, and improving the uneven geographical distribution of leading research centers.

Abstract X‐linked muscular dystrophy in cats (FXMD) is an uncommon disease, with few reports describing its pathogenic genetic variants. A 9‐year‐old castrated male domestic shorthair cat was presented with persistent muscle swelling and breathing difficulty from 3 years of age. Serum activity of alanine aminotransferase, aspartate transaminase, and creatine kinase were abnormally high. Physical and neurological examinations showed muscle swelling in the neck and proximal limb, slow gait, and occasional breathing difficulties. Electromyography showed pseudomyotonic discharges and complex repetitive discharges with a “dive‐bomber” sound. Histopathology revealed muscle necrosis and regeneration. Whole‐genome sequencing identified a novel and unique hemizygous nonsense genetic variant, c.8333G > A in dystrophin (DMD), potentially causing a premature termination codon (p.Trp2778Ter). Based on a combination of clinical and histological findings and the presence of the DMD nonsense genetic variant, this case was considered FXMD, which showed mild clinical signs and long‐term survival, even though immunohistochemical characterization was lacking.

Key Clinical Message This case highlights the challenges in diagnosing Bethlem myopathy, the need for a high index of suspicion, and the importance of recognizing the diverse clinical presentations of this rare condition. Enhanced understanding can aid in early diagnosis and tailored management. Abstract Bethlem myopathy (BM), a rare collagen VI‐related myopathy, is characterized by progressive muscle weakness and contractures, typically affecting the proximal muscles and joints. This case report presents a 15‐year‐old girl from Tehran, Iran, with a 5‐year history of severe limb pain and progressive weakness. Born to consanguineous parents, the patient displayed delayed walking milestones and significant hypotonia, leading to a waddling gait and lumbar hyperlordosis. Neurological examination revealed marked proximal lower limb weakness, a positive Gowers' sign, and absent myotatic reflexes. Elevated creatine phosphokinase (CPK) levels and electromyography (EMG) results indicated myopathy, while nerve conduction studies showed no neuropathy. Genetic testing revealed a novel homozygous variant of c.385C>T (p.Arg129Cys) in the COL6A2 gene, classified as a variant of uncertain significance (VUS) per American College of Medical Genetics and Genomics (ACMG) guidelines due to its rarity and specific phenotype association. Differential diagnosis is essential to distinguish it from other neuromuscular conditions. Management primarily focuses on symptom relief and enhancing patients' quality of life. This case highlights the challenges in diagnosing BM, the need for a high index of suspicion, and the importance of recognizing the diverse clinical presentations of this rare condition. Enhanced understanding can aid in early diagnosis and tailored management.

Key Clinical Message Treatment of patients with amelogenesis imperfecta extends over many years, from childhood to early adulthood. Their management at any age is complex and has to be adapted in relation to therapies validated in the general population.

Abstract Hepatic fibrinogen storage disease (HFSD) was diagnosed in a 5‐month‐old Wagyu calf with a history of recurrent respiratory disease. It was characterized by lethargy, dehydration, acidemia, and increased liver enzyme activities. Histologically, disseminated hepatocytes were swollen and showed a single, sharply demarcated, faintly eosinophilic cytoplasmic inclusion with a ground‐glass appearance, with the nucleus in an eccentric position. Cytoplasmic inclusions did not stain with the periodic acid‐Schiff (PAS) reaction. Using a rabbit polyclonal antibody against fibrinogen, the cytoplasmic vacuoles in the hepatocytes stained intensely. Electron microscopy disclosed hepatocytes with membrane‐bound cytoplasmic inclusions filled with fine granular material interspersed with a few coarse‐grained electron‐dense granules. A trio whole‐genome sequencing approach identified a deleterious homozygous missense variant in DGKG (p.Thr721Ile). The allele frequency in 209 genotyped Wagyu was 7.2%. This is a report of a DGKG‐related recessive inherited disorder in cattle and adds DGKG to the list of candidate genes for HFSD in other species.

Abstract Background A recessive form of MOCOS‐associated xanthinuria type II is described in Tyrolean grey cattle. A similar case was identified in a 5‐month‐old Brown Swiss calf with hoof overgrowth, rough coat, urine sediment, and pneumonia. Hypothesis/Objectives To characterize the disease phenotype, to evaluate its genetic etiology, and to determine the prevalence of the deleterious allele in the Brown Swiss population. Animals An affected calf, its parents, and 65 441 Swiss dairy cattle. Methods The affected animal was clinically examined and necropsied. Microarray genotyping was used to determine the genotypes and to assess the frequency of the MOCOS allele in a Brown Swiss control cohort. Results Ultrasonography revealed hyperechoic renal pyramids with multifocal distal shadowing and echogenic sediment in the urinary bladder. Necropsy revealed suppurative bronchopneumonia and urolithiasis. Histology revealed numerous nephroliths with multifocal chronic lymphohistiocytic interstitial infiltrates, fibrosis, tubular degeneration, chronic multifocal glomerulonephritis with sclerosis, and bilateral hydronephrosis. Dysplastic changes were observed in the corium of the claw and the cornea. Genetic testing identified the homozygous presence of a known MOCOS frameshift variant in the case. Both parents were heterozygous and the prevalence of carriers in genotyped Brown Swiss cattle was 1.4% (342/24337). Conclusions and Clinical Importance The findings were consistent with the diagnosis of a recessive renal syndrome similar to xanthinuria type II described in Tyrolean grey cattle. The prevalence of the deleterious MOCOS allele is low in the Brown Swiss breed. However, mating of carriers should be avoided to prevent further losses.

Abstract Objectives We describe the Residras registry, dedicated to Dravet syndrome (DS) and to other phenotypes related to SCN1A mutations, as a paradigm of registry for rare and complex epilepsies. Our primary objectives are to present the tools and framework of the integrative platform, the main characteristics emerging from the patient cohort included in the registry, with emphasis on demographic, clinical outcome, and mortality. Methods Standardized data of enrolled pediatric and adult patients were collected in 24 Italian expert centers and regularly updated at least on a yearly basis. Patients were prospectively enrolled, at registry starting, but historical retrospective data were also included. Results At present, 281 individuals with DS and a confirmed SCN1A mutation are included. Most patients have data available on epilepsy (n = 263) and their overall neurological condition (n = 255), based on at least one follow‐up update. Median age at first clinical assessment was 2 years (IQR 0–9) while at last follow‐up was 11 years (IQR 5–18.5). During the 7‐year activity of the registry, five patients died resulting in a mortality rate of 1.84 per 1000‐person‐years. When analyzing clinical changes over the first 5‐year follow‐up, we observed a significant difference in cognitive function (P

Abstract Hereditary angioedema (HAE) is a rare autosomal dominant disease, with patients often suffering with associated symptoms for many years before receiving a correct diagnosis. The symptoms greatly impact a patient's quality of life (QoL) and include excruciating abdominal pain and angioedema of the skin and submucosa. Angioedema of the larynx represents a significant mortality risk in undiagnosed patients, and a large proportion of patients with HAE receive incorrect diagnoses and undergo unnecessary surgery. HAE‐specific treatments can control and prevent acute life‐threatening episodes, in addition to improving QoL, emphasizing the value of early diagnosis for patients. Diagnostic delay may be due to a lack of HAE awareness by healthcare professionals and the similarity of HAE symptoms with those of more common conditions, complicating differential diagnosis. The multifaceted nature of the condition may result in visits to one of many different medical settings, for example: the Emergency Room, pediatrics, general practice, otolaryngology, gastroenterology, and dermatology. Therefore, it is crucial that physicians in multiple healthcare specialties are aware of the disease to ensure that patients with HAE receive a timely diagnosis. Using patient cases from various medical specialties, this review highlights the necessity for cross‐specialty awareness of HAE and outlines the essential information for the various healthcare professionals that may encounter a patient with HAE symptoms, in order to effectively treat and/or diagnose HAE.

Abstract Introduction COVID‐19 changed the way we lived with uncertainty from the outset as the pandemic impacted every aspect of our lives from well‐being, socializing to accessing healthcare. For people in vulnerable populations, such as those with genetic, undiagnosed and rare disorders, the experience was heightened. Aim The aim of this study was to identify how the rapidly changing COVID‐19 environment impacted the lives of the Genetic, Undiagnosed and Rare Disease community. Methods From June 2020 to May 2021, we collected monthly open‐ended journals from people living in Australia with genetic, undiagnosed and rare disorders. Data analysis was deductive, using the Resilience Scale for Adults, and inductive using thematic analysis. Results We recruited 29 people (average of n = 9.7 submissions each month). Responses changed over the year, with initial journals focusing on the importance of developing new structures for day‐to‐day lives, while later journals started to focus on mental well‐being. Throughout the project, participants reported challenges in accessing health and social care that was compounded by fear and concern over being exposed to the virus. Later journals highlight inconsistent messaging for vaccinations for this vulnerable community. Discussion/Conclusion In parallel with the waves of the COVID‐19 pandemic, there need to be waves of targeted support for vulnerable communities. The first support wave needs to focus on facilitating the identification of new frameworks to structure day‐to‐day lives. A later second wave needs to focus on mental well‐being and coping with isolation, while consistent communication relating to health and social care throughout was essential. Patient/Public Contribution This study was co‐designed, co‐led and analysed with a patient support network.

Abstract We reviewed 11 patients with systemic sclerosis‐related ILD who were referred to our Scleroderma Unit from January 2020 to January 2021 and started Nintedanib. Non‐specific interstitial pneumonia (NSIP) was prevalent (45%), usual interstitial pneumonia (UIP) and UIP/NSIP pattern were both 27%. Only one patient had a history of smoking. Eight patients were on mycophenolate mofetil (MMF), eight were treated with corticosteroids (mean dose 5 mg/day of Prednisone or equivalent), and three were on Rituximab. The mean modified British Council Medical Questionnaire (mmRC) decreased from 3 to 2.5. Two patients had to reduce their daily dose to 200 mg/day for severe diarrhoea. Nintedanib was generally well tolerated.

Abstract Many patients with pulmonary arterial hypertension (PAH) experience substantial delays in diagnosis, which is associated with worse outcomes and higher costs. Tools for diagnosing PAH sooner may lead to earlier treatment, which may delay disease progression and adverse outcomes including hospitalization and death. We developed a machine‐learning (ML) algorithm to identify patients at risk for PAH earlier in their symptom journey and distinguish them from patients with similar early symptoms not at risk for developing PAH. Our supervised ML model analyzed retrospective, de‐identified data from the US‐based Optum® Clinformatics® Data Mart claims database (January 2015 to December 2019). Propensity score matched PAH and non‐PAH (control) cohorts were established based on observed differences. Random forest models were used to classify patients as PAH or non‐PAH at diagnosis and at 6 months prediagnosis. The PAH and non‐PAH cohorts included 1339 and 4222 patients, respectively. At 6 months prediagnosis, the model performed well in distinguishing PAH and non‐PAH patients, with area under the curve of the receiver operating characteristic of 0.84, recall (sensitivity) of 0.73, and precision of 0.50. Key features distinguishing PAH from non‐PAH cohorts were a longer time between first symptom and the prediagnosis model date (i.e., 6 months before diagnosis); more diagnostic and prescription claims, circulatory claims, and imaging procedures, leading to higher overall healthcare resource utilization; and more hospitalizations. Our model distinguishes between patients with and without PAH at 6 months before diagnosis and illustrates the feasibility of using routine claims data to identify patients at a population level who might benefit from PAH‐specific screening and/or earlier specialist referral.

Abstract Background Neurofibromatosis type I (NF1) is a rare genetic disorder, associated with some physical symptoms including spots and tiny bumps on the skin, and internal organ involvement. People suffering from neurofibromatosis face various challenges in their daily lives. However, there is little understanding on how patients deal with neurofibromatosis. This study aimed to investigate the life challenges of patients with NF1. Methods This qualitative study was performed by implementing a grounded theory with the cooperation of the Society for Neurofibromatosis Patients over the course of 15 months in 2019 across 4 provinces in Iran. Twenty‐four patients with NF1 were interviewed. An analysis was performed using the constant comparative method. Findings The results of the analyses indicated that the major concern of the NF1 patients was feelings of failure and falling behind in life. In the face of failure in life in such a context, patients used the main strategy of “unsuccessful struggle to escape” the disease and its complications, which was represented itself in the forms of ‘hopelessness and impatience’, ‘suicidal thoughts and unsuccessful suicide attempts’, ‘isolation and seclusion’, ‘expressing complaints and grievances to God’, ‘hiding the disease’ and ‘hopelessness and refusing to receive care’. The implementation of such strategies helped patients reduce tension and achieve a temporary, though vulnerable and fragile, sense of relief and peace. Conclusion Given an unfavourable life condition, NF1 patients turned to a harmful passive strategy in the face of the challenges posed by the disease. Patient or Public Contribution Public contributors were active partners throughout, and co‐authored the paper.

Abstract Hemifacial microsomia (HFM) was diagnosed in a 9‐day‐old Romagnola calf. The condition was characterized by microtia of the left ear, anotia of the right ear, asymmetry of the face, and deafness. Magnetic resonance imaging revealed agenesis of the right pinna and both tympanic bullae, asymmetry of the temporal bones and temporomandibular joints, and right pontine meningocele. Brainstem auditory evoked responses confirmed the impaired auditory capacity. At gross post mortem examination, there was agenesis and hypoplasia of the right and the left external ear, respectively. No histological abnormalities were detected in the inner ears. A trio whole‐genome sequencing approach was carried out and identified a private homozygous missense variant in LAMB1 affecting a conserved residue (p.Arg668Cys). Genotyping of 221 Romagnola bulls revealed a carrier prevalence

Vatiquinone, a 15-lipoxygenase inhibitor, is in development for patients with Friedreich ataxia. The study determined the effect of vatiquinone on electrocardiogram parameters. This was a 2-part, single-center, randomized, double-blinded, and placebo-controlled study. Part 1 used an adaptive approach to identify a supratherapeutic dose, while Part 2 evaluated the effect of vatiquinone on Fridericia corrected QT interval (QTcF). A safe and tolerated supratherapeutic dose of 1400 mg was identified. Concentration-QTcF analysis confirmed there was no statistically significant relationship between vatiquinone concentration and QTcF. QTcF effect (ie, ΔΔQTcF) exceeding 10 milliseconds was excluded for concentrations up to approximately 11,500 ng/mL. By-time-point analysis confirmed that least-squares mean ΔΔQTcF was below 10 milliseconds. Largest least-squares mean ΔΔQTcF of 1.5 milliseconds was observed at 2 hours after dosing. Vatiquinone did not have a clinically relevant effect on heart rate nor on cardiac conduction (PR interval and QRS interval). No new safety signals were found, as safety data are consistent with the known safety profile of vatiquinone. These findings altogether demonstrated that there is a minimal cardiac risk for vatiquinone concentrations up to the supratherapeutic dose level., (© 2024 The Author(s). Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Rare diseases (RDs), important for children and families, have been poorly studied in Turkey. This study aimed to describe the experiences and needs of mothers whose children have RDs from the perspectives of their mothers. In-depth interviews were held with the mothers of 16 children followed up in the Pediatric Nutrition and Metabolism Outpatient Clinic of a University Hospital. The data were analyzed using thematic analysis procedures. The experiences of mothers caring for children with RDs were categorized into three main themes: (1) challenges with treatment, (2) burden of care, and (3) expectations. This study demonstrated that mothers of children with RDs experienced many common challenges in caregiving., (© 2024 National Society of Genetic Counselors.)

Vatiquinone, a 15-lipoxygenase inhibitor, is in development for patients with Friedreich's ataxia. Physiologically based pharmacokinetic (PBPK) modeling addressed drug-drug interaction gaps without additional studies. A PBPK model (Simcyp Simulator version 21, full model) was developed using parameters obtained from in vitro studies, in silico estimation and optimization, and two clinical studies. A venous blood dosing model best characterized vatiquinone lymphatic absorption. Apparent oral clearance (CL/F) was used to optimize intrinsic clearance (CL int ). Intestinal availability (F g ) was estimated using the hybrid flow term (Q gut ), unbound fraction in the enterocytes (fu gut ), and gut intrinsic metabolic clearance (CLu G,int ). Renal clearance (CL R ) was set to zero. Assuming an F a of 1, CYP3A4 contribution (fm CYP3A4 ) was further optimized. The PBPK model was verified with two clinical studies and demonstrated that it adequately characterized vatiquinone PK. As a perpetrator, the model predicted no risk for vatiquinone to significantly alter the drug exposures of CYP3A4 and CYP1A2 substrates as evident bynegligible reduction in both midazolam and caffeine area under the curve (AUC) inf and C max . As a victim, the model predicted that vatiquinone exposures are weakly influenced by moderate CYP3A4 inhibitors and inducers. With fluconazole coadministration, vatiquinone AUC inf and C max increased by nearly 50% and 25%, respectively. With efavirenz coadministration, vatiquinone AUC inf and C max decreased by approximately 20% and 10%, respectively. Results suggested that vatiquinone does not significantly impact CYP3A4 and CYP1A2 substrates and that moderate CYP3A4 inhibitors and inducers weakly impact vatiquinone AUC., (© 2024, The American College of Clinical Pharmacology.)

Among clinical trialists, there has been a growing interest in using external data to improve decision-making and accelerate drug development in randomized clinical trials (RCTs). Here we propose a novel approach that combines the propensity score weighting (PW) and the multi-source exchangeability modelling (MEM) approaches to augment the control arm of a RCT in the rare disease setting. First, propensity score weighting is used to construct weighted external controls that have similar observed pre-treatment characteristics as the current trial population. Next, the MEM approach evaluates the similarity in outcome distributions between the weighted external controls and the concurrent control arm. The amount of external data we borrow is determined by the similarities in pretreatment characteristics and outcome distributions. The proposed approach can be applied to binary, continuous and count data. We evaluate the performance of the proposed PW-MEM method and several competing approaches based on simulation and re-sampling studies. Our results show that the PW-MEM approach improves the precision of treatment effect estimates while reducing the biases associated with borrowing data from external sources., (© 2024 John Wiley & Sons Ltd.)

Inborn errors of metabolism (IEM) such as lysosomal storage disorders (LSDs) are conditions caused by deficiency of one or more key enzymes, cofactors, or transporters involved in a specific metabolic pathway. Enzyme replacement therapy (ERT) provides an exogenous source of the affected enzyme and is one of the most effective treatment options for IEMs. In this paper, we review the first-in-human (FIH) protocols for ERT drug development programs supporting 20 Biologic License Applications (BLA) approved by the Center for Drug Evaluation and Research (CDER) at the US Food and Drug Administration (FDA) in the period of May 1994 to September 2023. We surveyed study design elements across these FIH protocols including study population, dosage form, dose selection, treatment duration, immunogenicity, biomarkers, and study follow-up. A total of 18 FIH trials from 20 BLAs were identified and of those, 72% (13/18) used single ascending dose (SAD) and/or multiple ascending dose (MAD) study design, 83% (15/18) had a primary objective of assessing the safety and tolerability, 72% (13/18) included clinical endpoint assessments, and 94% (17/18) included biomarker assessments as secondary or exploratory endpoints. Notably, the majority of ERT products tested the approved route of administration and the approved dose was tested in 83% (15/18) of FIH trials. At last, we offer considerations for the design of FIH studies., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA.)

Abstract Cystic pulmonary tuberculosis is a unique form of pulmonary tuberculosis (PTB) presenting with multiple reversible cysts of the lung. Unlike the other forms, this cystic lung disease can improve with prompt tuberculosis treatments. Here we report the case of a 15‐year‐old girl who presented with respiratory failure and severe lung damage at hospital admission. We diagnosed her with PTB based on her positive GeneXpert result test. The patient was treated with a standard tuberculosis regimen for 6 months and recovered completely.

Abstract Social determinants of health (SDoH) can impact the vulnerable pulmonary arterial hypertension (PAH) population, especially during the COVID‐19 pandemic. Providers' understanding of SDoH at the point of care and their impact is unknown. We conducted semi‐structured virtual interviews with US clinicians at 17 pulmonary hypertension (PH) centers and one patient advocate from the Pulmonary Hypertension Association. We sought participants' perspective on SDoH in PAH and their impact. Transcripts were developed and analyzed for key themes to assess potential policy implications. Participants served a large PAH population and demonstrated high awareness of SDoH and its impact on treatment and outcomes. They reported that patients' SDoH, including socioeconomic status, health insurance, access to health care, education levels, health literacy, employment status, and insecurities associated with housing, food, transportation, and family support, impacted health and well‐being. COVID‐19‐related social isolation, mental health, and substance abuse contributed to significant inequities in care provision and outcomes. While telemedicine helped clinicians manage patients remotely during the pandemic, there was a concern for patients with limited access to this medium. Participants reported no formal screening for SDoH at the point of care. With the recognition and the desire to act upon health inequities associated with SDoH, participants felt that it was vital for their centers to have a dedicated PH social worker and support staff to optimize care and outcomes. An approach that integrates SDoH in PAH care management, streamlined through institutional policy, could address health disparities leading to improved healthcare access, outcomes, and quality of care.

Abstract Inherited metabolic disorders (IMDs) can present with psychiatric signs that vary widely from one disease to another. This picture is further complicated by the fact that these features occur at very different illness time points, which may further delay appropriate diagnosis and treatment. In this case series of 62 children and adolescents suffering from IMDs, we clustered psychiatric signs (on the basis of the fifth edition of the Diagnostic and Statistical Manual for Mental Disorders classification) as well as impaired cognitive domains (on the basis of the Research Domain Criteriamatrix) according to their mean age of onset (5.7 ± 4 years). We observed consistent patterns of occurrence across disorders. Externalizing symptoms, sleep problems, and cross‐domain self‐regulation deficits were found to precede the IMD diagnosis. Repetitive thoughts and behaviors as well as emotional dysregulation were found to occur around the disease onset. Finally, late‐onset features included dissociative or eating disorders, together with impaired emotion knowledge. Clinicians should specifically look for the co‐occurrence of age‐specific atypical signs, such as treatment resistance or worsening with psychotropic medication in the earliest stages and symptom fluctuation, confusion, catatonia, or isolated visual hallucinations. We believe that the combined characterizations of psychiatric signs and impaired neurocognitive domains may enable the earliest detection of IMDs and the appropriate care of these particular manifestations. Key Points Psychiatric signs are common in inherited metabolic disorders (IMDs) and may occur in the same age‐range as other clinical manifestations. Three clusters of psychiatric signs and two clusters of neurocognitive domains can be defined according to their mean age of onset. Warning signs to be used in liaison psychiatry should include age‐specific cognitive impairments

Abstract Amelogenesis imperfecta, a rare disease, represents inherited, congenital defects that primarily affect enamel with esthetic and functional impairment affecting everyday life. We present oral rehabilitation of a mother and her son, respectively, suffering from an hypoplastic and an hypocalcified form of AI.

Introduction There have been few reported cases of villous adenoma of the bladder. It commonly occurs in the superior area of the bladder with hematuria as the most common symptom. Here, we have presented a case of villous adenoma of the bladder neck and reviewed the existing literature. Case presentation A 90‐year‐old man presented with voiding difficulty. Although urine analysis revealed microscopic hematuria and pyuria, the patient never complained about gross hematuria. Ultrasonography and cystoscopic examination revealed a bladder tumor located at the bladder neck. Transurethral resection was performed and villous adenoma was diagnosed by histopathologic examination. Conclusion Villous adenoma of the bladder is a rare disease, which is difficult to diagnose when the patient presents with uncommon clinical features. Although villous adenoma is known as a benign tumor, some reports suggest its association with malignancy. Therefore, careful management and follow‐up are necessary.

Abstract Background Alkaptonuria (AKU) is an ultrarare and multifaceted disease characterized by the absence of functional homogentisate 1,2‐dioxygenase activity, the enzyme responsible for breakdown of homogentisic acid—a tyrosine‐degradation product. The presymptomatic phase of the disease makes diagnosis difficult, with many patients unidentified or diagnosed late in life. Objective To date, no study has analyzed the perceived impact of different symptoms or the experiences of individuals through the patient journey in the context of AKU. This study aimed to examine patients' perceptions of AKU symptoms and their impact on quality of life as well as patients' experiences of being diagnosed and living with the disease. Methods Data for this study were collected using a quantitative self‐report questionnaire administered online to people with AKU. Results Data from 45 participants indicate that symptoms with the highest impact for patients are those related to pain and ruptures, disability and inability to perform normal routines, emotional/mental health issues, and heart complications. Findings also revealed significant delays in contact with healthcare services and time to diagnosis. Furthermore, patients reported difficulty in receiving information about AKU, treatment and care, and long‐term disease management support. Conclusions Time to diagnosis and care of AKU is significantly delayed. Symptoms of AKU with the highest impact on quality of life for patients are those related to pain and disability and the inability to perform normal routines. Bridging any gaps between patients with AKU and healthcare professionals through education could help improve patients' experiences with AKU through the patient journey.

Abstract Propionic Acidemia (PA) is characterized by the accumulation of propionic acid (PPA), its toxic derivatives, and ammonia. The disease causes multiorgan damage, especially in heart, pancreas, and brain; seizures and intellectual disability are often described. Some PA children also show autism spectrum disorders (ASD). In this study, we have compiled data from 62 individuals from the Propionic Acidemia International Patient Registry and compared it to the published literature on the prevalence of autism in PA. The PA registry shows a significant proportion of ASD diagnoses that is consistent with the combined prevalence reported in the literature. It also shows that ASD in PA is gender balanced and it is diagnosed at older ages (median age 8 years) than in the national registry for autism (median age 4.3 years), which raises the possibility, among others, of PA specific risk factors affecting the natural history of ASD. Data from patient registries provide valuable information on studying the mechanisms involved in a rare disease, although more outreach effort must be done to increase participation and consistency in data entry.

Abstract Cleidocranial dysplasia is a rare disease with an autosomal‐dominant inheritance that mainly affects the bones of the axial skeleton. In this report, we discuss the clinical and radiological signs of a case series comprising three sisters and the son of one of the sisters, all with suspected bone dysplasia.

The goal of this study was to assess the feasibility of using exome (ES) and genome sequencing (GS) in guiding preconception genetic screening (PCGS) for couples who are planning to conceive by creating a workflow for identifying risk alleles for autosomal recessive (AR) and X-linked (XL) disorders without the constraints of a predetermined, targeted gene panel. There were several limitations and challenges related to reporting and the technical aspects of ES and GS, which are listed in the discussion. We selected 150 couples from a cohort of families (trios) enrolled in a research protocol where the goal was to define the genetic etiology of disease in an affected child. Pre-existing, de-identified parental sequencing data were analyzed to define variants that would place the couple at risk of having a child affected by an AR or XL disorder. We identified 17 families who would be selected for counseling about risk alleles. We noted that only 3 of these at-risk couples would be identified if we limited ourselves to the current ACMG-recommended expanded carrier screening gene panel. ES and GS successfully identified couples who are at risk of having a child with a rare AR or XL disorder that would have been missed by the current recommended guidelines. Current limitations of this approach include ethical concerns, difficulties in reporting results including variant calling due to the rare nature of some of the variants, determining which disorders to report, as well as technical difficulties in detecting certain variants such as repeat expansions., (© 2024 The Author(s). Journal of Genetic Counseling published by Wiley Periodicals LLC on behalf of National Society of Genetic Counselors.)

Vatiquinone is a small molecule inhibitor of 15-lipoxygenase in development for patients with Friedreich's ataxia. The objective of this analysis was to determine the effect of a cytochrome P450 isoform 3A4 (CYP3A4) inhibitor and inducer on vatiquinone pharmacokinetics (PKs). The coadministration of 400 mg of vatiquinone with 200 mg of itraconazole (a CYP3A4 inhibitor) resulted in increased maximum observed concentration (C max ) of vatiquinone and systemic exposure (AUC 0-inf ) by approximately 3.5- and 2.9-fold, respectively. The coadministration of 400 mg of vatiquinone with 600 mg of rifampin (a CYP3A4 inducer) resulted in decreased vatiquinone C max and AUC 0-inf by approximately 0.64- and 0.54-fold, respectively. The terminal half-life of vatiquinone was not affected by itraconazole or rifampin. These clinical study results confirm the in vitro reaction phenotyping data that shows that CYP3A4 plays an important role in vatiquinone metabolism. The result of this analysis together with phase 3 efficacy and safety data, population PK analysis, and the exposure-response relationship will determine if the extent of vatiquinone changes in the presence of CYP3A4 inhibitors and inducers are considered clinically relevant., (© 2024 PTC Therapeutics, Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Abstract Background Primary microcephaly (PM) is defined as a significant reduction in occipitofrontal circumference (OFC) of prenatal onset. Clinical and genetic heterogeneity of PM represents a diagnostic challenge. Methods We performed detailed phenotypic and genomic analyses in a large cohort (n = 169) of patients referred for PM and could establish a molecular diagnosis in 38 patients. Results Pathogenic variants in ASPM and WDR62 were the most frequent causes in non‐consanguineous patients in our cohort. In consanguineous patients, microarray and targeted gene panel analyses reached a diagnostic yield of 67%, which contrasts with a much lower rate in non‐consanguineous patients (9%). Our series includes 11 novel pathogenic variants and we identify novel candidate genes including IGF2BP3 and DNAH2. We confirm the progression of microcephaly over time in affected children. Epilepsy was an important associated feature in our PM cohort, affecting 34% of patients with a molecular confirmation of the PM diagnosis, with various degrees of severity and seizure types. Conclusion Our findings will help to prioritize genomic investigations, accelerate molecular diagnoses, and improve the management of PM patients.

Abstract Although pregnant neurofibromatosis or HIV patient established a high‐risk group, this report demonstrated that a careful planning and widespread valuations should be associated with a favorable prognosis for both mother and newborn.

Abstract Hermansky–Pudlak syndrome (HPS) is a rare genetic disorder which, in its most common and severe form, HPS‐1, leads to fatal adult‐onset pulmonary fibrosis (PF) with no effective treatment. We evaluated the role of the endocannabinoid/CB1R system and inducible nitric oxide synthase (iNOS) for dual‐target therapeutic strategy using human bronchoalveolar lavage fluid (BALF), lung samples from patients with HPS and controls, HPS‐PF patient‐derived lung fibroblasts, and bleomycin‐induced PF in pale ear mice (HPS1ep/ep). We found overexpression of CB1R and iNOS in fibrotic lungs of HPSPF patients and bleomycin‐infused pale ear mice. The endocannabinoid anandamide was elevated in BALF and negatively correlated with pulmonary function parameters in HPSPF patients and pale ear mice with bleomycin‐induced PF. Simultaneous targeting of CB1R and iNOS by MRI‐1867 yielded greater antifibrotic efficacy than inhibiting either target alone by attenuating critical pathologic pathways. Moreover, MRI‐1867 treatment abrogated bleomycin‐induced increases in lung levels of the profibrotic interleukin‐11 via iNOS inhibition and reversed mitochondrial dysfunction via CB1R inhibition. Dual inhibition of CB1R and iNOS is an effective antifibrotic strategy for HPSPF.

Enrolling patients to the standard of care (SOC) arm in randomized clinical trials, especially for rare diseases, can be very challenging due to the lack of resources, restricted patient population availability, and ethical considerations. As the therapeutic effect for the SOC is often well documented in historical trials, we propose a Bayesian platform trial design with hybrid control based on the multisource exchangeability modelling (MEM) framework to harness historical control data. The MEM approach provides a computationally efficient method to formally evaluate the exchangeability of study outcomes between different data sources and allows us to make better informed data borrowing decisions based on the exchangeability between historical and concurrent data. We conduct extensive simulation studies to evaluate the proposed hybrid design. We demonstrate the proposed design leads to significant sample size reduction for the internal control arm and borrows more information compared to competing Bayesian approaches when historical and internal data are compatible., (© 2024 John Wiley & Sons Ltd.)

While digital tools, such as the Internet, smartphones, and social media, are an important part of modern society, little is known about the specific role they play in the healthcare management of individuals and caregivers affected by rare disease. Collectively, rare diseases directly affect up to 10% of the global population, suggesting that a significant number of individuals might benefit from the use of digital tools. The purpose of this qualitative interview-based study was to explore: (a) the ways in which digital tools help the rare disease community; (b) the healthcare gaps not addressed by current digital tools; and (c) recommended digital tool features. Individuals and caregivers affected by rare disease who were comfortable using a smartphone and at least 18 years old were eligible to participate. We recruited from rare disease organizations using purposive sampling in order to achieve a diverse and information rich sample. Interviews took place over Zoom and reflexive thematic analysis was utilized to conceptualize themes. Eight semistructured interviews took place with four individuals and four caregivers. Three themes were conceptualized which elucidated key aspects of how digital tools were utilized in disease management: (1) digital tools should lessen the burden of managing a rare disease condition; (2) digital tools should foster community building and promote trust; and (3) digital tools should provide trusted and personalized information to understand the condition and what the future may hold. These results suggest that digital tools play a central role in the lives of individuals with rare disease and their caregivers. Digital tools that centralize trustworthy information, and that bring the relevant community together to interact and promote trust are needed. Genetic counselors can consider these ideal attributes of digital tools when providing resources to individuals and caretakers of rare disease., (© 2024 The Authors. Journal of Genetic Counseling published by Wiley Periodicals LLC on behalf of National Society of Genetic Counselors.)

Background: The Pediatric Eating Assessment Tool (PEDI-EAT-10) is a reliable and valid tool for rapid identification of dysphagia in patients aged 18 months to 18 years., Aims: To translate and adapt the PEDI-EAT-10 into the Italian language and evaluate its validity and reliability., Methods & Procedures: The translation and cross-cultural adaptation of the tool consisted of five stages: initial translation, synthesis of the translations, back translation, expert committee evaluation and test of the prefinal version. The internal consistency of the translated tool was analysed in a clinical group composed of 200 patients with special healthcare needs aged between 18 months and 18 years. They were consecutively enrolled at the Rare Disease Unit, Paediatrics Department, Fondazione Policlinico Agostino Gemelli-IRCCS, Rome. For test-retest reliability, 50 caregivers filled in the PEDI-EAT-10 questionnaire for a second time after a 2-week period. Construct validity was established by comparing data obtained from patients with data from healthy participants (n = 200). The study was approved by the local ethics committee., Outcomes & Results: Psychometric data obtained from patients (104 M; mean age = 8.08 ± 4.85 years; median age = 7 years) showed satisfactory internal consistency (Cronbach's α = 0.89) and test-retest reliability (Pearson r = 0.99; Spearman r = 0.96). A total of 30% of children were classified as having a high risk of penetration/aspiration. The Italian PEDI-EAT-10 mean total score of the clinical group was significantly different from that resulting from healthy participants., Conclusions & Implications: The PEDI-EAT-10 was successfully translated into Italian, validated and found to be a reliable one-page rapid screening tool to identify dysphagia in children and adolescents with special needs., What This Paper Adds: What is already known on the subject The PEDI-EAT-10 is a valid and reliable quick discriminative paediatric tool for identifying penetration/aspiration risks. What this paper adds to the existing knowledge In the present study we successfully translated and adapted the PEDI-EAT-10 into the Italian language. What are the potential or actual clinical implications of this work? This translation and adaptation increase access to valid feeding and swallowing assessment for children of Italian-speaking families. In addition, the I-PEDI-EAT-10 can suggest further assessment of patients' swallowing abilities., (© 2023 The Authors. International Journal of Language & Communication Disorders published by John Wiley & Sons Ltd on behalf of Royal College of Speech and Language Therapists.)

Ataxia-telangiectasia (A-T) is a rare, childhood-onset, multi-systemic, progressive condition. Parents of children with rare diseases like A-T are emotionally, socially, and psychologically impacted by the diagnosis. To examine the parental perspective of having a child with A-T, and to better understand how parents cope with an A-T diagnosis, we conducted 10 semistructured interviews. Thematic analysis using a phenomenological approach resulted in five themes: (1) Parental responsibilities change as the result of an A-T diagnosis, (2) An A-T diagnosis brings about shifts in identity for all family members, (3) Parental coping changes over time, (4) A-T parents experience continuous uncertainty and a lack of stability, and (5) A-T parents receive support from various people, places, and resources. Many parents fostered resilience by adopting a present-centered and positive mindset about the impacts of the diagnosis. Parents also became A-T experts and used their knowledge to advocate for their children and help mentor other parents. Responses from parents indicated a need for providers to incorporate parental mental well-being check-ins to pediatric rare disease appointments and welcome parents as respected members of their children's care team. Genetic counselors are in a unique position to help coordinate complex care for children with A-T (and other rare diseases) and provide support to family members using the framework of family-centered care. This paper offers suggestions for expanding support and learning to cope with a difficult diagnosis for parents of children with rare diseases, specifically A-T, based on stories from parents of children with A-T., (© 2023 National Society of Genetic Counselors.)

Purpose: In rare diseases, real-world evidence (RWE) generation is often restricted due to small patient numbers and global geographic distribution. A federated data network (FDN) approach brings together multiple data sources harmonized for collaboration to increase the power of observational research. In this paper, we review how to increase reproducibility and transparency of RWE studies in rare diseases through disease-specific FDNs., Method: To be successful, a multiple stakeholder scientific FDN collaboration requires a strong governance model in place. In such a model, each database owner remains in full control regarding the use of and access to patient-level data and is responsible for data privacy, ethical, and legal compliance. Provided that all this is well documented and good database descriptions are in place, such a governance model results in increased transparency, while reproducibility is achieved through data curation and harmonization, and distributed analytical methods., Results: Leveraging the OHDSI community set of methods and tools, two rare disease-specific FDNs are discussed in more detail. For multiple myeloma, HONEUR-the Haematology Outcomes Network in Europe-has built a strong community among the data partners dedicated to scientific exchange and research. To advance scientific knowledge in pulmonary hypertension (PH) an FDN, called PHederation, was established to form a partnership of research institutions with PH databases coming from diverse origins., (© 2024 Actelion Pharmaceuticals Ltd. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Incontinentia pigmenti (IP) is a rare X-linked dominant genodermatosis that affects skin, hair, teeth, eyes and central nervous system. We present the case of a female patient with mild IP caused by a hypomorphic pathogenic variant of the inhibitor of the kappa light polypeptide gene enhancer in B cells, kinase gamma (IKBKG) gene. This is the first report of a female IP patient with the hypomorphic variant, NM&#95;001099856.6: c.1423dup, which is causative of anhidrotic ectodermal dysplasia with immune deficiency in males., (© 2023 Wiley Periodicals LLC.)

Abstract Background Our primary aim was to evaluate the systematic reanalysis of singleton exome sequencing (ES) data for unsolved cases referred for any indication. A secondary objective was to undertake a literature review of studies examining the reanalysis of genomic data from unsolved cases. Methods We examined data from 58 unsolved cases referred between June 2016 and March 2017. First reanalysis at 4–13 months after the initial report considered genes newly associated with disease since the original analysis; second reanalysis at 9–18 months considered all disease‐associated genes. At 25–34 months we reviewed all cases and the strategies which solved them. Results Reanalysis of existing ES data alone at two timepoints did not yield new diagnoses. Over the same timeframe, 10 new diagnoses were obtained (17%) from additional strategies, such as microarray detection of copy number variation, repeat sequencing to improve coverage, and trio sequencing. Twenty‐seven peer‐reviewed articles were identified on the literature review, with a median new diagnosis rate via reanalysis of 15% and median reanalysis timeframe of 22 months. Conclusion Our findings suggest that an interval of greater than 18 months from the original report may be optimal for reanalysis. We also recommend a multi‐faceted strategy for cases remaining unsolved after singleton ES.

Abstract Background Whole‐exome sequencing (WES) has emerged as a successful diagnostic tool in molecular genetics laboratories worldwide. In this study, we aimed to find the potential genetic cause of skeletal disease, a heterogeneous disease, revealing the obvious short stature phenotype. In an Iranian family, we used solo‐WES in a suspected patient to decipher the potential genetic cause(s). Methods A comprehensive clinical and genotyping examination was applied to suspect the disease of the patient. The solo clinical WES was exploited, and the derived data were filtered according to the standard pipelines. In order to validate the WES finding, the region harboring the candidate variant in the CTSK gene was amplified from genomic DNA and sequenced directly by Sanger sequencing. Results Sequence analysis revealed a rare novel nonsense variant, p.(Trp320*); c.905G>A, in the CTSK gene (NM_000396.3). In silico analysis shed light on the contribution of the variant to the pathogenicity of pycnodysostosis. This variant was confirmed by Sanger sequencing and further clinical examinations of the patient confirmed the disease. Conclusion The present study shows a rare variant of the CTSK gene, which inherited as autosomal recessive, in an Iranian male patient with pycnodysostosis. Taken together, the novel nonsense CTSK variant meets the criteria of being likely pathogenic according to the American College of Medical Genetics and Genomics‐the Association for Molecular Pathology (ACMG‐AMP) variant interpretation guidelines.

Abstract Introduction In Japan, there are approximately 300 projects conducting research on rare diseases supported by the Ministry of Health, Labour and Welfare of Japan (MHLW) and the Japan Agency for Medical Research and Development (AMED). Diverse data, including clinical, genomic, and sample‐related data, are generated by these projects. However, at present, such data are managed individually by each project. This makes it difficult for third parties to ascertain the data generated by projects. Methods Again this background, at the beginning of 2017, the AMED started the National Platform for Rare Diseases Data Registry of Japan (RADDAR‐J), whose mission is to construct a cross‐sectional data integration platform incorporating projects supported by the AMED and MHLW. RADDAR‐J promotes data sharing by the projects in accordance with the data‐sharing policy established by the AMED, which classifies data sharing into three categories based on the strategies used to protect the rights of researchers while promoting data sharing. RADDAR‐J integrates and analyzes data shared by each project to add value to the resources and promote secondary use by third parties while protecting the rights of the researchers who shared their data. The platform is designed to provide incentives to projects that shared their data by supporting registry construction or genomic analysis to promote data sharing. RADDAR‐J also has the function of data identification to securely integrate data originating from the same person. RADDAR‐J accelerates clinical research by encouraging each project to utilize a central ethics committee. Results/Conclusion The use of the platform by projects is expected to lead to streamlined data collection, improved quality assurance, improved access to data, and promotion of joint research and the secondary use of shared data. These benefits will accelerate research into diagnosis and treatment technologies and will hopefully lead to improved quality of life for patients with rare diseases.