J Neuromuscul Dis. 2025 Jun 10:22143602251339369. doi: 10.1177/22143602251339369. Online ahead of print.

ABSTRACT

BACKGROUND: Congenital myopathies are a group of neuromuscular disorders that typically present at birth or early childhood with hypotonia and non-progressive or slowly progressive muscle weakness. They are classically subclassified by characteristic structural changes and histopathological findings in skeletal muscle. Variants in over 40 genes have been described to date in patients with various forms of congenital myopathy with overlapping phenotypic and histological features, which poses a challenge for laboratories and clinicians in interpreting genetic findings.

OBJECTIVE: The purpose of this study was to evaluate the evidence supporting each gene-disease relationship and provide an expert-reviewed classification for the clinical validity of genes involved in congenital myopathies.

METHODS: The ClinGen Neurological Disorders Clinical Domain Working Group assembled the Congenital Myopathies Gene Curation Expert Panel (CongenMyopathy-GCEP), a group of clinicians and geneticists with expertise in congenital myopathies tasked to perform evidence-based curation of 50 gene-disease relationships using the ClinGen semiquantitative framework to assign clinical validity.

RESULTS: Our curation effort resulted in 35 (70%) Definitive, eight (16%) Moderate, six (12%) Limited, and one (2%) Disputed disease relationship classifications. The summary of each curation is made publicly available on the ClinGen website.

CONCLUSIONS: Expert-reviewed assignment of gene-disease relationships by the CongenMyopathy-GCEP facilitates accurate molecular diagnoses for congenital myopathies and can allow genetic testing to focus on genes with a validated role in disease.

PMID:40491337 | DOI:10.1177/22143602251339369

Medicine (Baltimore). 2025 Jun 6;104(23):e42807. doi: 10.1097/MD.0000000000042807.

ABSTRACT

RATIONALE: This study investigates the clinical, imaging, and pathological features of fibroblastic reticular cell tumors (FRCTs) through a retrospective analysis of a patient with FRCT, along with a review of relevant literature.

PATIENT CONCERNS: A 49-year-old male was admitted to our hospital because of swelling and discomfort in the right eye, occasionally accompanied by double vision, for more than 3 months. Physical examination revealed an obliquely downward right eye, ptosis, and a palpable medium-hard tumor at the supraorbital rim of the orbit.

DIAGNOSES: An orbital B-type ultrasound, orbital computed tomography, and orbital contrast-enhanced magnetic resonance imaging were performed, and the findings suggested a diagnosis of right orbital hemangioma.

INTERVENTIONS: Following imaging studies, the tumor was surgically excised. Microscopic pathological examination revealed that the lesion was composed of lymphatic follicles and spindle cells. Immunohistochemistry revealed that: the tumor is mainly composed of spindle fibroblastic cells, accompanied by the formation of lymphoid follicles. Immunohistochemical staining shows that the lymphoid follicles express CD20 positively, while the Ki67 positive index of the spindle tumor cells is lower. Based on these findings, the pathologists believed that the lesion was consistent with an FRCT.

OUTCOMES: The patient refused subsequent treatment and was discharged. Postoperative imaging (computed tomography and magnetic resonance imaging) conducted at 4 and 24 weeks revealed no recurrence of the tumor.

LESSONS: FRCTs are exceedingly rare in clinical practice, This is the first case report of an orbital FRCT. The main clinical manifestation is a painless orbital mass, and the imaging findings are nonspecific; therefore, the diagnosis mainly depends on the pathology and immune phenotype of the tumor. Currently, there are no detailed data regarding the effects of postoperative adjuvant therapy. With more reports and studies on patients with FRCT, the diagnostic accuracy for this disease can be increased, and more accurate and personalized treatment plans can be developed.

PMID:40489805 | DOI:10.1097/MD.0000000000042807

Hepatol Commun. 2025 Jun 9;9(7):e0746. doi: 10.1097/HC9.0000000000000746. eCollection 2025 Jul 1.

NO ABSTRACT

PMID:40489760 | DOI:10.1097/HC9.0000000000000746

Mol Ther Methods Clin Dev. 2025 Apr 24;33(2):101479. doi: 10.1016/j.omtm.2025.101479. eCollection 2025 Jun 12.

ABSTRACT

Mucolipidosis IV (MLIV) is an autosomal-recessive pediatric disease that leads to motor and cognitive deficits and loss of vision. It is caused by loss of function of the lysosomal channel transient receptor potential mucolipin-1, TRPML1, and is associated with an early brain phenotype consisting of glial reactivity, hypomyelination, and lysosomal abnormalities. Although the field is approaching the first translationally relevant therapy, we currently lack a molecular signature of disease that can be used to detect therapeutic efficacy. Here, we analyzed 7,322 proteins in the plasma proteome from 17 MLIV patients and 37 controls and compared protein profiles with clinical measures of disease severity (motor function, muscle tone, and age). We found a decrease in neuronal proteins and an increase in muscle proteins in MLIV, consistent with neuronal dysfunction and muscle pathology observed in patients. Reduced synaptic proteins (e.g., GABARAP) best correlated with disease severity. Comparing the MLIV plasma proteome to the brain proteome from the MLIV mouse model identified shared alterations in 45 proteins, including upregulated proteins related to lysosomal function (e.g., ACTN2, GLB1) and downregulated proteins related to myelination (e.g., TPPP3, CNTN2). These data indicate that peripheral blood plasma protein signatures mirror changes found in the MLIV brain.

PMID:40486934 | PMC:PMC12141561 | DOI:10.1016/j.omtm.2025.101479

Orphanet J Rare Dis. 2025 Jun 6;20(1):282. doi: 10.1186/s13023-025-03796-z.

ABSTRACT

BACKGROUND: Rare diseases present a substantial patient burden, but the impact on non-professional caregivers is poorly understood. We explored the health-related quality of life (HRQoL) and productivity burden on caregivers of adults with rare diseases.

METHODS: We analysed physician- and caregiver-reported real-world data from France, Germany, Italy, Spain, the United Kingdom, and the United States of America collected July 2017-March 2021 via Adelphi Disease Specific Programmes™ in amyotrophic lateral sclerosis (ALS), eosinophilic esophagitis (EoE), graft versus host disease (GvHD), Huntington's disease (HD), myasthenia gravis (MG), and progressive supranuclear palsy (PSP). Non-professional caregivers completed the EQ-5D-5L and Work Productivity and Activity Impairment questionnaire. Multivariate regression analysis modelled the relationship of care recipient/caregiver characteristics with caregiver HRQoL and productivity.

RESULTS: Data were provided by 365 caregivers; 114, 89, 75, 32, 29 and 26 in GvHD, PSP, ALS, MG, EoE and HD, respectively. Care recipients' mean (standard deviation [SD]) age was 58.7 (15.6) years, 59% were male and 23% had both professional and non-professional caregivers. Patients' mean (SD) EuroQol visual analogue scale (EQ VAS) score was 50.9 (23.3) and mean EQ-5D utility was 0.460 (0.350). Caregivers' mean age was 55.8 (13.8) years, 66% were female. Caregivers' EQ-5D-5L indicated their greatest problems in anxiety/depression. Overall, 45% of caregivers were employed, mostly part-time. In the past 7 days, mean (SD) caregiver absenteeism was 5.2% (13.1%), presenteeism was 28.0% (23.7%), and activity impairment was 43.1% (27.2%). Regressions identified multiple significant associations with caregivers' HRQoL and productivity. Caregivers' HRQoL (EQ-5D utility and EQ VAS) was associated with care recipients' EQ-5D utility and caregivers' age. Outcomes relating to caregivers' employment and productivity (hours spent caring, employment status, hours in employment, hours of employment missed, absenteeism, presenteeism, work impairment and activity impairment) were most frequently associated with care recipients' EQ-5D utility, caregivers' age and sex, caregiver living with the care recipient, the presence of a professional caregiver, and the care recipient having HD.

CONCLUSIONS: The substantial burden of providing non-professional caregiving to adults with rare diseases is associated with multiple factors. Interventions improving care recipient HRQoL could enhance caregiver HRQoL and productivity.

PMID:40481583 | DOI:10.1186/s13023-025-03796-z

IUBMB Life. 2025 Jun;77(6):e70031. doi: 10.1002/iub.70031.

ABSTRACT

Over 7000 rare diseases have been described, collectively affecting 350 million people worldwide. Most of these conditions result from nonsense mutations, representing approximately 10% of all genetic mutations associated with human inherited diseases. Nonsense mutations convert a sense codon into a premature termination codon (PTC), leading to premature translation termination and the production of truncated, nonfunctional proteins. This results in a loss-of-function phenotype in many genetic disorders, contributing to the disease's severity and progression. The molecular mechanisms of PTC formation involve various genetic alterations, including single-nucleotide changes, frameshifts, and splicing mutations. The nonsense-mediated mRNA decay (NMD) pathway degrades mRNAs containing premature termination codons (PTCs). In contrast, 25% of PTC mRNAs, depending on the PTC position and cellular context, can evade NMD, resulting in the synthesis of truncated proteins. A termination codon during translation is essential for proper protein synthesis, and translational readthrough-a process in which the ribosome bypasses the PTC and reaches the natural stop codon-may restore some level of protein function. The effectiveness of readthrough depends on the surrounding genetic context and the type of amino acid incorporated at the PTC position. This review aims to explore the molecular characteristics of nonsense-related diseases (NRDs), including cystic fibrosis, hemophilia, Fabry disease, choroideremia, Usher syndrome, Shwachman-Diamond syndrome, and certain hereditary neuropathies and cancers.

PMID:40474765 | DOI:10.1002/iub.70031

Orphanet J Rare Dis. 2025 Jun 5;20(1):277. doi: 10.1186/s13023-025-03805-1.

ABSTRACT

Rare diseases present critical challenges to healthcare systems, patients, and caregivers due to their low prevalence and unique characteristics. Designing clinical trials and developing statistical methodologies for evaluating interventions in rare diseases face several challenges. The "EBStatMax" project, part of the European Joint Programme on Rare Diseases' Demonstration Projects, aimed to address one of these challenges, namely: designing and analyzing longitudinal cross-over data in rare diseases, like Epidermolysis bullosa simplex (EBS). Although the main findings of the project have been published elsewhere, this manuscript reflects on additional hurdles encountered during the project, particularly regarding outcomes and methodological considerations. It explores issues surrounding outcome measurement, statistical methodology, and clinical considerations, emphasizing their broader relevance to methodological advancements in rare disease research beyond this specific case. This manuscript highlights the critical role of international collaboration in rare disease research to enhance evidence quality and aims to inspire further advancements in the field.

PMID:40474287 | DOI:10.1186/s13023-025-03805-1

Orphanet J Rare Dis. 2025 Jun 5;20(1):279. doi: 10.1186/s13023-025-03828-8.

ABSTRACT

Gene therapy has transitioned from a long-awaited promise to a clinical reality, offering transformative treatments for rare congenital diseases and certain cancers, which have a significant impact on patients' lives. Current approaches focus on gene replacement therapy, either in vivo or ex vivo, mostly utilizing viral vectors to deliver therapeutic genes into target cells. However, refining these techniques is essential to overcome challenges and complications associated with gene therapy to ensure long-term safety and efficacy. Slovenia has witnessed significant advancements in this field since 2018, marked by successful gene therapy trials and treatments for various rare diseases. Significant strides have been made in the field of gene therapy in Slovenia, treating patients with spinal muscular atrophy and rare metabolic disorders, including the pioneering work on CTNNB1 syndrome. Additionally, immune gene therapy, exemplified by IL-12 adjuvant therapy for cancer, has been a focus of research in Slovenia. Through patient-centred initiatives and international collaborations, researchers in Slovenia are advancing preclinical research and clinical trials, paving the way for accessible gene therapies. Establishing clinical infrastructure and genomic diagnostics for rare diseases is crucial for gene therapy implementation. Efforts in this regard in Slovenia, including the establishment of a Centre for Rare Diseases, Centre for the Technologies of Gene and Cell Therapy, and rapid genomic diagnostics, demonstrate a commitment to comprehensive patient care. Despite the promises of gene therapy, challenges remain, including cost, distribution, efficacy, and long-term safety. Collaborative efforts are essential to address these challenges and ensure equitable access to innovative therapies for patients with rare diseases.

PMID:40474241 | DOI:10.1186/s13023-025-03828-8

Orphanet J Rare Dis. 2025 Jun 5;20(1):280. doi: 10.1186/s13023-025-03762-9.

ABSTRACT

BACKGROUND: Duchenne muscular dystrophy (DMD) is a progressive genetic disease that leads to degeneration of muscles, including respiratory muscles, and requires early introduction of non-invasive ventilation (NIV). Parental knowledge and management strategies for pulmonary care are essential when respiratory function is compromised, particularly in conditions involving sleep apnea and the progression of chronic respiratory failure. The aim of this study was to assess parental knowledge of key aspects of pulmonary care in DMD and to identify knowledge gaps that may influence therapeutic decisions.

METHODS: A cross-sectional survey was conducted as part of the multidisciplinary care program for DMD at the Center for Rare Diseases in Gdańsk, accredited by the World Duchenne Organization. The questionnaire assessed (1) demographic and clinical details, (2) pulmonary healthcare practices, (3) understanding of pulmonary rehabilitation, (4) knowledge about NIV, and (5) sources of information on respiratory care.

RESULTS: The study included 111 parents (F/M 83/28, mean age 45.5 ± 6.75 years) of 111 children with DMD (all male, mean age 11.5 ± 5.45 years; 38% non-ambulatory). The majority of individuals (77.5%) regularly visited a pulmonary specialist with spirometry performed. Most parents reported satisfactory knowledge about respiratory issues in DMD but 77% of them reported insufficient knowledge about NIV (Chi2 = 53.4, df = 12, p = 0.00). Only 11% weren't afraid to use NIV in the future, while 73% were afraid because of a lack of or inaccurate information. Physicians were the primary source of knowledge for pulmonary care, while the internet and peer experiences were rarely used.

CONCLUSION: The majority of parents of children with DMD understand the basics of pulmonary problems. A significant information gap exists concerning advanced respiratory interventions such as non-invasive ventilation (NIV). This leads to anxiety among parents and impairs therapeutic decision-making, delaying appropriate treatment including respiratory support. There is a need for respiratory education programmes for parents and patients, especially as the estimated longer survival time for patients with DMD will make respiratory challenges even more significant.

PMID:40474208 | DOI:10.1186/s13023-025-03762-9

Genome Res. 2025 Jul 1;35(7):1473-1484. doi: 10.1101/gr.278291.123.

ABSTRACT

Individuals living with rare diseases often undergo a frustrating and expensive diagnostic odyssey. Clinical geneticists who analyze exome or genome sequencing data from rare disease patients often encounter a list of variants of uncertain significance (VUS) in known disease-causing genes or rare variants in genes of uncertain significance (GUS) that are difficult to interpret, even with the integration of the latest bioinformatic tools. In this Perspective, we review how studies using the fruit fly Drosophila melanogaster have facilitated rare disease diagnosis by uncovering the clinical relevance of GUS and classifying rare variants into specific allelic categories (loss-of-function or gain-of-function, Muller's morphs). We showcase how fly researchers have been collaboratively studying the loss-of-function of orthologous fly genes, assessing the ability of the human genes to rescue the fly mutant phenotypes, determining the effect of overexpressing human proteins, and testing functional consequences of rare variants of interest by generating analogous fly mutants to contribute to rare disease diagnosis. We argue that data obtained using Drosophila can be leveraged to design effective multiplexed assays for variant effects (MAVEs) to decipher the vast human variome.

PMID:40467338 | DOI:10.1101/gr.278291.123

BMC Health Serv Res. 2025 Jun 4;25(1):799. doi: 10.1186/s12913-025-12784-9.

ABSTRACT

BACKGROUND AND METHODS: The organization of care profoundly impacts the variability in the quality of care provided to patients and the equity of access to care. The lack of coordination of care, of communication among healthcare providers, healthcare professionals, and patients, and the duplication of services provided to the patients represent some paradigmatic examples of organizational barriers to deliver high-quality patient-centered care and to promote equitable access to healthcare services. Patient care pathways (PCPs) are valuable tools for the (re)design and the (re)definition of the provision of healthcare services to patients. This work represents the first application of the RarERN Path© methodology for the (re)design of Patient Care Pathways (PCPs) to Ataxias, Dystonia, and Phenylketonuria (PKU). The study was conducted with the support of Academic Partners and in collaboration with experts from two of the 24 European Reference Networks for rare diseases (ERN RND and MetabERN).

RESULTS: The application of some of the phases of RarERN Path© methodology enabled the translation of the good practices already in place in the centers of expertise into a common optimized PCP, one for each of the three diseases, integrating the expertise of some reference centers of excellence with the patients' perspectives, and principally focusing on the organization of care.

CONCLUSIONS: The PCPs proposed for progressive ataxias, dystonia, and PKU provide insight into the value of specialized centers in diagnosing and managing patients with rare and complex conditions and are the results of a co-designed optimized process integrating the good practices of the centers of excellence and expertise with the perspectives of the patients' representatives. This integrated approach allowed for the re-design and optimization of the organizational dimensions of the patient's care pathways.

PMID:40468287 | DOI:10.1186/s12913-025-12784-9

Sci Transl Med. 2025 Jun 4;17(801):eadq1810. doi: 10.1126/scitranslmed.adq1810. Epub 2025 Jun 4.

ABSTRACT

Hydrocephalus (HC) is a failure of brain and cerebrospinal fluid (CSF) homeostasis often associated with dilation of the CSF-filled ventricles (ventriculomegaly). Hallmarks of HC include aberrant CSF dynamics, neural stem cell dysfunction resulting in impaired neurogenesis and corticogenesis, biomechanical instability at the brain-CSF interface, and disrupted synaptogenesis and neural circuitry. Pleiotropic mechanisms, including genetic and environmental insults to the brain, contribute to neurodevelopmental comorbidities. Hypothesis generation from genome-wide, single-cell multi-omic analyses coupled to experimental validation using induced pluripotent stem cell-derived cerebral organoids will refine molecular classification of HC subtypes and may lead to precision-based surgical and pharmacologic treatments.

PMID:40465691 | DOI:10.1126/scitranslmed.adq1810

Orphanet J Rare Dis. 2025 Jun 2;20(1):266. doi: 10.1186/s13023-025-03756-7.

ABSTRACT

BACKGROUND: In the European Union (EU), the orphan legislation, aiming to increase the number of pharmacotherapies available for rare diseases, came into force in April 2000. This study examined the development of the selection of orphan medicines granted marketing authorisation, their approved indications, and the number of orphan medicines developed for paediatric use in EU during 2000-2022. This study also examined the availability of the orphan medicines with a marketing authorisation in the Finnish market in order to demonstrate their country level uptake in a single member state.

METHODS: The material on orphan medicines' marketing authorisations and their introduction were collected from the European Commission's Community Registers in June 2022 and analysed with a qualitative document analysis. This study covered the period 2000-2022 since the introduction of the orphan legislation, and comparisons were made in 10-year periods of, 2001-2010 and 2011-2020.

RESULTS: By May 2022, there were 213 novel orphan medicines approved in Europe during the observation period. Of them, 67% (n = 142) were on the market in Finland in May 2024. The number of new orphan medicines approved in Europe doubled from 63 products in 2001-2010 to 127 products in 2011-2020. Several orphan medicines were developed for certain type of rare diseases, such as haematological cancers. The proportion of orphan medicines approved for paediatric use decreased from 55% in 2001-2010 to 42% in 2011-2020.

CONCLUSION: The number of orphan medicines available within EU increased significantly after the orphan legislation came into force. The development of orphan medicines seemed to often focus on diseases or disease groups that already have available treatment options, while several rare diseases remain without available treatment. Even though rare diseases are more common in children, orphan medicines have not been developed for paediatric use in the same proportion.

PMID:40457478 | DOI:10.1186/s13023-025-03756-7

PLoS One. 2025 Jun 2;20(6):e0321864. doi: 10.1371/journal.pone.0321864. eCollection 2025.

ABSTRACT

Factor V deficiency is a congenital coagulation disorder characterized by the absence or malfunction of factor V (FV). The purpose of this study was to develop a viable FV-deficient mouse model using CRISPR/Cas9 technology. A viable pathological model of the disease was not available to develop new therapies. A previous in silico study was performed to select a mutation causing a mild disease phenotype in humans (Thr1898Met missense). Such mutation was replicated in mice by CRISPR-mediated homology directed repair. Following crossing, homozygous individuals were subjected to coagulometry assays, including FV levels, prothrombin time (PT), and activated partial thromboplastin time (aPTT). The in silico study suggested that the mutation destabilizes FV structure of both mouse and human variants, putatively producing a mild phenotype of the disease in mice. Mendelian inheritance was observed in the offspring. No spontaneous signs of blood clotting disturbances, premature deaths or gestational dysfunctions were observed. FV levels in homozygous animals were 24.5% ± 5.1; 39.7 sec ± 2.8; PT was 61.8% ± 6.3; 23.4 sec ± 1.6 (INR = 1.47 ± 0.12); and aPTT was 46.9 sec ± 3.2. A viable FV-deficient mouse model was generated by introducing a missense mutation in FV. The model exhibits a mild phenotype of the disease, akin to that observed in humans.

PMID:40455764 | DOI:10.1371/journal.pone.0321864

HGG Adv. 2025 Jul 10;6(3):100462. doi: 10.1016/j.xhgg.2025.100462. Epub 2025 May 30.

ABSTRACT

Trzupek et al. describe a rare disease Open Science Data Challenge, using data collected systematically on RARE-X across 27 neurodevelopmental disorders. Clinical diagnoses, symptoms, genetic data, and PROs were included. Researchers and statisticians generated solutions that identified previously underappreciated symptoms and used machine learning to test predictive models for diagnosis.

PMID:40450527 | PMC:PMC12210303 | DOI:10.1016/j.xhgg.2025.100462

Soc Sci Med. 2025 Sep;380:118175. doi: 10.1016/j.socscimed.2025.118175. Epub 2025 May 15.

ABSTRACT

Individuals living with rare diseases have conventionally been understood as being particularly vulnerable, which often promotes a negative and stigmatising interpretation of vulnerability. In this article, we embrace the framework of structural (health) vulnerability to gain a deeper understanding of the circumstances and factors contributing to adverse outcomes in the specific context of a Global South country, India, and a particular rare disease, Cystic Fibrosis (CF). By drawing on published materials and preliminary data from an evolving ethnographic research project, we contend that it is crucial to examine global power dynamics and the unequal distribution of resources to contextualize the precarious conditions experienced by Indians living with CF. Epistemologically, this stems from pervasive racialised assumptions ingrained in CF knowledge production, constituting a form of hermeneutic injustice, while economically, India's position in the global bioeconomy restricts access to potentially beneficial treatments derived from advanced clinical research. Moreover, reduced investment in healthcare by the Indian Central Government, notably evident in its rare disease policy, leaves CF patients reliant on philanthropy, which is susceptible to shifting interests and priorities. Therefore, we argue that focusing on structural (health) vulnerability is essential for shedding light on the distinct challenges faced by individuals living with CF in India, as well as in other locations in the Global South.

PMID:40449408 | DOI:10.1016/j.socscimed.2025.118175

Depress Anxiety. 2025 May 22;2025:9002779. doi: 10.1155/da/9002779. eCollection 2025.

ABSTRACT

Background: People living with a rare disease are a vulnerable patient group and experience challenges in participation and healthcare. Due to changes in healthcare and threat of the infection during coronavirus disease 2019 (COVID-19) pandemic, people living with rare diseases have been particularly affected. Therefore, this study aimed to investigate depressive symptoms and symptoms of anxiety during the COVID-19 pandemic and identify factors associated with symptom levels. Methods: One-hundred and seventy-two people living with a rare disease were recruited from centers for rare diseases and patient organizations in Germany from January 2021 to January 2022. In addition to descriptive analyses and group comparisons, we applied multiple linear regression models to identify factors associated with outcome variables of interest (depressive and anxiety symptoms, assessed by the Hospital Anxiety and Depression Scale [HADS]). Results: For the depressive symptoms, 14% of the participants reached the cutoff for moderate and 14.5% for a high level of depressive symptoms. Concerning anxiety symptoms, 22% reported moderate levels of anxiety and 13.4% reported high levels of anxiety. Higher depressive symptoms were significantly associated with older age, lower socioeconomic status, having severe or varying symptoms compared to low symptom severity, lower treatment satisfaction, lower social support, and more unmet needs. Higher anxiety levels were associated with more unmet needs and more intense COVID-19-related concerns. Conclusions: The findings indicate red flags of high symptoms that should be considered during routine care of patients with rare diseases. Healthcare providers should be sensitized for the need for psychosocial support and use a quick assessment to assign patients in need to specific support programs. Trial Registration: German Clinical Trials Registry: DRKS00020488.

PMID:40444181 | PMC:PMC12122157 | DOI:10.1155/da/9002779

PLoS One. 2025 May 29;20(5):e0323043. doi: 10.1371/journal.pone.0323043. eCollection 2025.

ABSTRACT

OBJECTIVE: Isolated sulfite oxidase deficiency (ISOD; OMIM #272300) is a devastating rare neurometabolic disorder due to biallelic pathogenic variants in the SUOX gene, that typically results in neonatal refractory epilepsy and progressive severe encephalopathy. Knowledge on the quantitative natural history of ISOD is limited and clinical outcome parameters for future clinical trials remain to be defined.

MATERIAL AND METHODS: We performed a comprehensive analysis of published cases (N=74) with ISOD applying quantitative retrospective natural history modeling (QUARNAM). Main outcome parameters were age of disease onset, diagnostic delay and survival. Clinical characteristics and potential associations between biochemical parameters and clinical outcome (i.e. age of disease onset, survival) were explored.

RESULTS: The median survival period of the study cohort was 60 months. ISOD typically presented shortly after birth with a median age of onset of 3 days. Median age at diagnosis was 10 months, leading to a substantial median diagnostic delay of 5.7 months. Homocysteine concentrations in plasma correlated with age of disease onset. An association of biochemical parameters of cysteine metabolism and survival could not be identified.

CONCLUSION: The present analysis describes long-term outcome measures adding to the quantitative understanding of the natural history of ISOD, which might be helpful in the planning of prospective clinical trials and potentially stimulate development of targeted therapies in the future.

PMID:40440599 | DOI:10.1371/journal.pone.0323043

Public Health Genomics. 2025;28(1):217-228. doi: 10.1159/000546172. Epub 2025 May 28.

ABSTRACT

INTRODUCTION: Although it is generally agreed that the perspectives of patients should be included in decision-making about genomic data, patients rarely have a significant role in the governance of genomic data archives (GDAs). Guidance on the successful implementation of patient involvement (PI) in the governance of GDAs is lacking. This study explores the perspectives of German patients on PI in the governance of GDAs and how these perspectives can be implemented to have an impact on governance.

METHODS: We conducted 2 online deliberative forums with 26 members of the cancer and rare diseases (RD) communities in Germany. The forums were analyzed qualitatively. The findings were discussed in a follow-up dialogue event with 17 of the participants and 9 members of a GDA (The German Human Genome-Phenome Archive, GHGA) (n = 26). Two patient coresearchers were involved in all phases of the study.

RESULTS: Five themes were identified: (a) motivations for PI; (b) concerns about PI; (c) areas of governance in which PI is required; (d) resources necessary for implementation of PI; and (e) the form PI should take.

CONCLUSION: For PI in GDAs to be meaningful, patient perspectives on the specific contextual aspects of GDAs should be actively sought. Patients' views on representation affect what form of PI they prefer and whether they experience the representation as legitimate. We discuss how the suggestions from the participants of this study were taken up in the governance policy of the GHGA.

PMID:40435999 | DOI:10.1159/000546172

Medicina (Kaunas). 2025 May 12;61(5):881. doi: 10.3390/medicina61050881.

ABSTRACT

Background and Objectives: Poretti-Boltshauser syndrome (PBS) is a rare, autosomal recessive disorder caused by pathogenic variants in the LAMA1 gene, resulting in laminin dysfunction. This manifests as a cerebellar malformation with cysts, and patients present with developmental delay and ataxia; however, ocular features are not well-characterised. We aimed to summarise the ocular phenotypes of PBS based on cases reported in the literature. Materials and Methods: A literature search was conducted on Medline, Embase, and PubMed on PBS and its ocular associations. Genetically confirmed PBS cases were reviewed, and genotype-phenotype correlations were investigated. Results: Comprehensive reporting of genotypes and associated systemic and ocular phenotypes was available in 51 patients with PBS, who had 52 distinct variants in LAMA1. Most patients carried homozygous variants. The most common genotype was a c.2935delA homozygous mutation, followed by the c.768+1G>A; c.6701delC compound heterozygous mutation. High myopia was the most common ocular phenotype (n = 39), followed by strabismus (n = 27) and ocular motor apraxia (n = 26). A wide range of other ocular manifestations, including retinal dystrophy, retinal neovascularisation, retinal detachment, strabismus, nystagmus, optic disc and iris hypoplasia, were reported. Patients with the same genotype exhibited variable expressivity. Conclusions: PBS has a broad ocular phenotypic spectrum, and characterisation of this variability is important for making an accurate diagnosis and informing genetic counselling.

PMID:40428839 | PMC:PMC12113114 | DOI:10.3390/medicina61050881