Am J Ophthalmol. 2025 Mar 31:S0002-9394(25)00162-X. doi: 10.1016/j.ajo.2025.03.043. Online ahead of print.

ABSTRACT

OBJECTIVE: Neurotrophic keratopathy (NK) is a rare disease characterized by the loss of corneal innervation and increased vulnerability to injury. The diagnosis and treatment of NK can be challenging for pediatric patients and their caregivers. This study explores the experiences of caregivers navigating the diagnostic and treatment journey of pediatric patients with neurotrophic keratopathy.

DESIGN: This study is a qualitative study using semi-structured interviews.

SUBJECTS: Ten caregivers of pediatric patients with NK who had undergone corneal neurotization (CN) surgery.

METHODS: Caregivers were interviewed about their experiences related to the diagnostic process, treatment challenges, lifestyle changes, and the impact of CN surgery. Interviews were recorded, transcribed, and analyzed using an inductive-deductive approach to identify recurring themes.

MAIN OUTCOMES: Caregiver experiences and perceptions of diagnostic delays, information-seeking behaviors, lifestyle changes, and the effects of CN surgery on corneal health and quality of life.

RESULTS: Five key themes emerged from the analysis: (1) Delays in diagnosis due to insufficient specialist knowledge; (2) Caregivers' proactive efforts in seeking information; (3) Substantial lifestyle changes required by NK; (4) The impact of CN surgery on corneal health and quality of life; and (5) Variability in healthcare experiences, highlighting the need for effective communication. Caregivers expressed frustration with diagnostic delays and highlighted their reliance on external support networks.

CONCLUSIONS: This study illustrates the need for enhanced awareness among clinicians about NK and the benefits of narrative medicine in fostering caregiver-provider relationships. The challenges reported by families navigating NK inform strategies that may improve diagnosis and treatment of NK.

PMID:40174715 | DOI:10.1016/j.ajo.2025.03.043

Pediatr Blood Cancer. 2025 Apr 2:e31697. doi: 10.1002/pbc.31697. Online ahead of print.

ABSTRACT

Parents of children with complex vascular anomalies (VAs) struggle to locate credible information. We explored whether their perceptions of the adequacy of VA-related information were associated with caregiver burden, anxiety, child health, and their ability to navigate the healthcare system and seek information. We also examined how their perceptions of clinician knowledge and communication affect their perceptions of information adequacy. A total of 86 parents completed our online survey. Perceived information adequacy was associated with lower anxiety, greater ability to navigate the healthcare system, greater clinician knowledge, and better clinician communication. These data identify important communication barriers that future research studies should address.

PMID:40172173 | DOI:10.1002/pbc.31697

Biochemistry. 2025 Apr 15;64(8):1698-1719. doi: 10.1021/acs.biochem.4c00722. Epub 2025 Apr 1.

ABSTRACT

Rare diseases are a diverse group of disorders that, despite each individual condition's rarity, collectively affect a significant portion of the global population. Currently approximately 10,000 rare diseases exist globally, with 80% of these diseases being identified as having genetic origins. In this Review, we examine data from the CAS Content Collection to summarize scientific progress in the area of rare diseases. We examine the publication landscape in the area in an effort to provide insights into current advances and developments. We then discuss the evolution of key concepts in the field, genetic associations, as well as the major technologies and development pipelines of rare disease treatments. We focus our attention on three specific rare diseases: (i) amyotrophic lateral sclerosis, a terminal neurodegenerative disease affecting the central nervous system resulting in progressive loss of motor neurons that control voluntary muscles; (ii) Huntington's disease, another terminal neurodegenerative disease that causes progressive degeneration of nerve cells in the brain, with a wide impact on a person's functional abilities; and (iii) myasthenia gravis, a chronic autoimmune synaptopathy leading to skeletal muscle weakness. While the pathogenesis of these rare diseases is being elucidated, there is neither a cure nor preventative treatment available, only symptomatic treatment. The objective of the paper is to provide a broad overview of the evolving landscape of current knowledge on rare diseases and specifically on the biology and genetics of the three spotlighted diseases, to outline challenges and evaluate growth opportunities, an aim to further efforts in solving the remaining challenges.

PMID:40169538 | DOI:10.1021/acs.biochem.4c00722

Res Sq [Preprint]. 2025 Mar 20:rs.3.rs-5968078. doi: 10.21203/rs.3.rs-5968078/v1.

ABSTRACT

A time-release ion matrix (TRIM) restores damaged tissue following injury through local ion release to stimulate regenerative gene expression. Here we report the use of CoO-TRIM, an FDA-designated Rare Pediatric Disease Drug, to restore muscle function and structure in the context of debilitating muscle disease. We demonstrate in an established animal model of Duchenne Muscular Dystrophy (DMD), the D2.mdx mouse, that tibialis anterior (TA) muscles receiving a single injection of CoO-TRIM exhibit greater active force, myofiber size and regeneration through 70 days post-treatment compared to D2.mdx receiving vehicle alone. TRIM promoted upregulation of pro-angiogenic growth factor (vascular endothelial growth factor) and increased muscle microvasculature. These findings indicate that CoO-TRIM stimulates growth factors to promote the restoration of muscle structure and function of severely dystrophic mice in vivo without toxicity. We conclude that CoO-TRIM is a first-in-class therapeutic compound to combat soft tissue disease by restoring tissue integrity. Moreover, this novel treatment strategy could benefit both early and late-stage DMD patients.

PMID:40166018 | PMC:PMC11957216 | DOI:10.21203/rs.3.rs-5968078/v1

Orphanet J Rare Dis. 2025 Apr 1;20(1):150. doi: 10.1186/s13023-025-03656-w.

ABSTRACT

Diagnosing rare diseases is challenging due to their low prevalence, diverse presentations, and limited recognition, often leading to diagnostic delays and errors. This study evaluates the effectiveness of multiple large language models (LLMs) in identifying rare diseases, comparing their performance with that of human physicians using real clinical cases. We analyzed 152 rare disease cases from the Chinese Medical Case Repository using four LLMs: ChatGPT-4o, Claude 3.5 Sonnet, Gemini Advanced, and Llama 3.1 405B. Overall, the LLMs performed better than human physicians, and Claude 3.5 Sonnet achieved the highest accuracy at 78.9%, significantly surpassing the accuracy of human physicians, which was 26.3%. These findings suggest that LLMs can improve rare disease diagnosis and serve as valuable tools in clinical settings, particularly in regions with limited resources. However, further validation and careful consideration of ethical and privacy issues are necessary for their effective integration into medical practice.

PMID:40165285 | DOI:10.1186/s13023-025-03656-w

bioRxiv [Preprint]. 2025 Mar 10:2025.03.07.642063. doi: 10.1101/2025.03.07.642063.

ABSTRACT

BACKGROUND: Changes in RNA splicing over the course of evolution have profoundly diversified the functional landscape of the human genome. While DNA sequences proximal to intron-exon junctions are known to be critical for RNA splicing, the impact of distal intronic sequences remains underexplored. Emerging evidence suggests that inverted pairs of intronic Alu elements can promote exon skipping by forming RNA stem-loop structures. However, their prevalence and influence throughout evolution remain unknown.

RESULTS: Here, we present a systematic analysis of inverted Alu pairs across the human genome to assess their impact on exon skipping through predicted RNA stem-loop formation and their relevance to hominoid evolution. We found that inverted Alu pairs, particularly pairs of AluY-AluSx1 and AluSz-AluSx, are enriched in the flanking regions of skippable exons genome-wide and are predicted to form stable stem-loop structures. Exons defined by weak 3' acceptor and strong 5' donor splice sites appear especially prone to this skipping mechanism. Through comparative genome analysis across nine primate species, we identified 67,126 hominoid-specific Alu insertions, primarily from AluY and AluS subfamilies, which form inverted pairs enriched across skippable exons in genes of ubiquitination-related pathways. Experimental validation of exon skipping among several hominoid-specific inverted Alu pairs further reinforced their potential evolutionary significance.

CONCLUSION: This work extends our current knowledge of the roles of RNA secondary structure formed by inverted Alu pairs and details a newly emerging mechanism through which transposable elements have contributed to genomic innovation across hominoid evolution at the transcriptomic level.

PMID:40161837 | PMC:PMC11952303 | DOI:10.1101/2025.03.07.642063

bioRxiv [Preprint]. 2025 Mar 14:2025.03.12.642857. doi: 10.1101/2025.03.12.642857.

ABSTRACT

Therapeutic strategies for Duchenne Muscular Dystrophy (DMD) will likely require complementary approaches. One possibility is to explore genetic modifiers that improve muscle regeneration and function. The beneficial effects of the overexpression of Jagged-1 were described in escaper golden retriever muscular dystrophy (GRMD) dogs that had a near-normal life and validated in dystrophin-deficient zebrafish (1). To clarify the underlying biology of JAG1 overexpression in dystrophic muscles, we generated a transgenic mouse (mdx5cv-JAG1) model that lacks dystrophin and overexpresses human JAG1 in striated muscles. Skeletal muscles from mdx5cv-JAG1 and mdx5cv mice were studied at one, four, and twelve-month time points. JAG1 expression in mdx5cv-JAG1 increased by three to five times compared to mdx5cv. Consequently, mdx5cv-JAG1 muscles were significantly bigger and stronger than dystrophic controls, along with an increased number of myofibers. Proteomics data show increased dysferlin in mdx5cv-JAG1 muscles and an association of Nsd1 with the phenotype. Our data supports the positive effect of JAG1 overexpression in dystrophic muscles.

PMID:40161820 | PMC:PMC11952387 | DOI:10.1101/2025.03.12.642857

Drug Discov Today. 2025 Apr;30(4):104346. doi: 10.1016/j.drudis.2025.104346. Epub 2025 Mar 28.

ABSTRACT

Ultra-rare diseases, particularly those that affect a few hundred patients worldwide, are of little commercial interest to the pharmaceutical industry. Patient-led organizations have made remarkable progress in funding the early-stage, academic development of therapies for such neglected ultra-rare conditions. But the long and difficult path to translate most academic proof-of-concept studies into approved medicines means that very few therapies ever reach patients. Here, we discuss some of the roadblocks to the development of therapeutics for conditions of limited commercial interest and propose ways to overcome these obstacles.

PMID:40158837 | DOI:10.1016/j.drudis.2025.104346

Echocardiography. 2025 Apr;42(4):e70142. doi: 10.1111/echo.70142.

ABSTRACT

Left main coronary artery atresia (LMCAA) is a rare congenital coronary anomaly and sometimes presents with non-specific clinical symptoms that make the diagnosis challenging. We are presenting an interesting case that required multimodality imaging to establish the diagnosis.

PMID:40159450 | DOI:10.1111/echo.70142

Bull Cancer. 2025 Mar;112(3S1):3S107-3S116. doi: 10.1016/S0007-4551(25)00164-X.

ABSTRACT

In Europe, a rare cancer is defined as having an incidence rate of less than 6/100,000. Rare lung cancers encompass many entities defined by the 2021 WHO classification of thoracic tumors, and represent around 10% of all lung cancers. Rare lung cancers involve several histological types (carcinoma, sarcoma and lymphoma), each of which comprises several entities. The management of these patients with rare cancers requires specific medical expertise at every level (diagnosis, treatment and follow-up). These patients should therefore be referred to expert centers affiliated with national networks, giving them appropriate care and better access to innovative treatments. The deployment of systematic molecular characterization of these tumors has allowed for the identification and better characterization of specific entities. Some entities are specific to the lung, while others are more commonly found in other organs. In this review, we will only consider malignant lung tumors with an incidence of less than 1%.

PMID:40155070 | DOI:10.1016/S0007-4551(25)00164-X

PLoS One. 2025 Mar 28;20(3):e0304540. doi: 10.1371/journal.pone.0304540. eCollection 2025.

ABSTRACT

The primary objective is to identify which observational research methods have been used in the last 5 years in rare disease drug evaluation and how they are applied to generate adequate evidence regarding the real-world effectiveness or safety of rare disease drugs. Rare disease is an umbrella term for a condition which affects < 200,000 people each year and despite the rarity of these conditions, collectively they encompass approximately 7000 different conditions. With the striking number of rare conditions, many pharmaceutical manufacturers are introducing an increased number of drugs to treat them. However, due to small patient populations, heterogeneity and other factors related to rare diseases, there are feasibility concerns regarding the generation of adequate efficacy and safety evidence using conventional randomized controlled trials (RCTs). Recently, real-world evidence generated through observational (or real-world) studies has been proposed to address some of the feasibility concerns with RCTs by measuring drug effectiveness or safety in the real-world setting. However, there remain methodological concerns due to a lack of randomization/masking. This proposed scoping review aims to identify which observational research methods in the last 5 years are used in rare disease drug evaluation to address methodological concerns and how they are applied to generate evidence on drug effectiveness or safety. Articles must be primary observational or real-world studies reporting rare disease drug effectiveness or safety published within the five years preceding this review. Literature reviews, meta-analyses, randomized control trials, case series, case reports, opinion pieces, conference abstracts, and studies with unavailable full-text articles will be excluded. The search strategy will combine the following key search concepts: rare disease, drugs for rare disease and observational/real-world studies. The search will be conducted in MEDLINE and EMBASE. Review registration number: Open Science Framework, https://osf.io/f3wpv.

PMID:40153394 | DOI:10.1371/journal.pone.0304540

BMC Cancer. 2025 Mar 28;25(1):558. doi: 10.1186/s12885-025-13934-2.

ABSTRACT

BACKGROUND: Cancers affecting < 6/100,000/year are classified as rare, but they account for up to 25% of all cancers and are associated with worse 5-year survival than common cancers. Early-phase clinical trials (EPCTs) may represent a viable treatment option for patients with rare cancers as they have evolved significantly with novel designs and the increasing use of precision medicine.

METHODS: A retrospective study of patients with rare cancers referred to a large EPCT team at a UK specialist centre over 5 years (2016-2020) was conducted. Patient demographics, medical and oncological history, genomic variants, EPCT participation, responses and survival outcomes were analysed.

RESULTS: In total, 240 patients with rare cancers were included. The mean age at diagnosis was 51.7 years (range 16-84), 54.2% of the patients were female. The most frequent rare cancers originated from the digestive system (27.1%), female genital tract (20%) and head and neck (H + N) (18.3%). Molecular profiling was offered to 45.5% of the population, median number of gene alterations was 3 per patient (range 1-20) while actionable gene alterations were reported in 60.2% (n = 50) of those with identified gene aberrations. Fifty-one patients participated in EPCTs, with 39.2% achieving SD and 11.8% PR. Median PFS for trial participants was three months (95% CI 1.12 - 4.88) while median OS in the trial patients was 16 months (95% CI 9.10 - 22.90) compared to 7 months for non-trial participants (95% CI 5.50 - 8.51). Finally, poor Royal Marsden Hospital (RMH) prognostic score (2-3) was correlated with worse survival when controlling for age and sex (HR 1.714, 95% CI 1.19 - 2.46, p = 0.004).

CONCLUSIONS: Participation of patients with rare cancers in EPCTs may be associated with a survival benefit and lead to the development of new treatments for these patients. Moreover, expanded use of precision medicine is paramount as it can inform targeted treatment selection in this heterogenous group.

PMID:40148757 | DOI:10.1186/s12885-025-13934-2

Genome Res. 2025 Apr 14;35(4):755-768. doi: 10.1101/gr.279414.124.

ABSTRACT

Solve-RD is a pan-European rare disease (RD) research program that aims to identify disease-causing genetic variants in previously undiagnosed RD families. We utilized 10-fold coverage HiFi long-read sequencing (LRS) for detecting causative structural variants (SVs), single-nucleotide variants (SNVs), insertion-deletions (indels), and short tandem repeat (STR) expansions in previously studied RD families without a clear molecular diagnosis. Our cohort includes 293 individuals from 114 genetically undiagnosed RD families selected by European Reference Network (ERN) experts. Of these, 21 families were affected by so-called "unsolvable" syndromes for which genetic causes remain unknown and for which prior testing was not a prerequisite. The remaining 93 families had at least one individual affected by a rare neurological, neuromuscular, or epilepsy disorder without a genetic diagnosis despite extensive prior testing. Clinical interpretation and orthogonal validation of variants in known disease genes yielded 12 novel genetic diagnoses due to de novo and rare inherited SNVs, indels, SVs, and STR expansions. In an additional five families, we identified a candidate disease-causing variant, including an MCF2/FGF13 fusion and a PSMA3 deletion. However, no common genetic cause was identified in any of the "unsolvable" syndromes. Taken together, we found (likely) disease-causing genetic variants in 11.8% of previously unsolved families and additional candidate disease-causing SVs in another 5.4% of these families. In conclusion, our results demonstrate the potential added value of HiFi long-read genome sequencing in undiagnosed rare diseases.

PMID:40138663 | DOI:10.1101/gr.279414.124

Soc Sci Med. 2025 May;372:117958. doi: 10.1016/j.socscimed.2025.117958. Epub 2025 Mar 14.

ABSTRACT

Rare disease organisations can play a crucial role in shaping the medical and scientific landscape. This article draws from interviews with sixteen founders of UK-based, rare disease organisations, all of whom were patients, parents or family members, to understand their experiences and commitment to the organisation and its community. First, we explore the work involved in creating a professional community and addressing the challenge of expert capacity-building for rare diseases. We then utilise the concept of 'translation' to emphasise the efforts of founders at an intermediate stage, for example encouraging health professionals to collaborate and realise that a project is achievable. Third, we consider the personal implications for the founders in their efforts to develop and sustain the organisation. Founders' biographies are intimately entwined with the establishment and development of their organisation, and we highlight how they are fundamentally shaped by the necessity of their hard work, skills and passion. Finally, we recognise that although some of the efforts of founders are undervalued both socially and economically, the founders themselves understand their work and role as crucial to the organisation's long-term success.

PMID:40138978 | DOI:10.1016/j.socscimed.2025.117958

Pediatr Blood Cancer. 2025 Jun;72(6):e31667. doi: 10.1002/pbc.31667. Epub 2025 Mar 25.

ABSTRACT

BACKGROUND: Although research has improved the prognosis of childhood cancer, many challenges remain, especially for high-risk, recurrent, and rare cancers. The recognition that diverse cancer types may share molecular alterations that can be therapeutically targeted has stimulated "precision medicine" approaches in research. Understanding parent and patient interest in genomic-derived therapeutic options in the clinical setting is limited and offers a potential for improved care.

METHODS: A qualitative study was conducted to explore how young adult (YA) patients and parents of children and adolescent patients regard targeted therapy options. These patients had high-risk, recurrent, or rare cancer for which there was no known curative therapy and were enrolled in a study evaluating investigational genomic tumor profiling. Clinical data were retrieved from medical records, and interviews were conducted.

RESULTS: Seventeen participants were interviewed (11 parents and six YA patients). Six themes emerged: (i) Genomic Understanding, (ii) Partnerships in Decision-Making, (iii) Connection with and Trust in Providers, (iv) Quality-of-Life (QOL) Considerations, (v) Understanding of Prognosis, and (vi) Nurturing Hope. Treatment decision-making is complex and depends on the connection (with providers and others), understanding (of prognosis, genomic literacy), care goals (QOL considerations), and planning for the future (hope).

CONCLUSIONS: Participants favored partnership in decision-making, expressed trust in their providers, and recognized the value of research. Engaging parents and YA patients in the planning of precision medicine translational research may be a path to designing an integrated research and care model that maximizes translational research implemented in real time, leading to improved outcomes.

PMID:40130678 | DOI:10.1002/pbc.31667

Proc Natl Acad Sci U S A. 2025 Apr;122(13):e2420343122. doi: 10.1073/pnas.2420343122. Epub 2025 Mar 24.

ABSTRACT

Congenital heart disease (CHD) is a leading cause of infant mortality. We analyzed de novo mutations (DNMs) and very rare transmitted/unphased damaging variants in 248 prespecified genes in 11,555 CHD probands. The results identified 60 genes with a significant burden of heterozygous damaging variants. Variants in these genes accounted for CHD in 10.1% of probands with similar contributions from de novo and transmitted variants in parent-offspring trios that showed incomplete penetrance. DNMs in these genes accounted for 58% of the signal from DNMs. Thirty-three genes were linked to a single CHD subtype while 12 genes were associated with 2 to 4 subtypes. Seven genes were only associated with isolated CHD, while 37 were associated with 1 or more extracardiac abnormalities. Genes selectively expressed in the cardiomyocyte lineage were associated with isolated CHD, while those widely expressed in the brain were also associated with neurodevelopmental delay (NDD). Missense variants introducing or removing cysteines in epidermal growth factor (EGF)-like domains of NOTCH1 were enriched in tetralogy of Fallot and conotruncal defects, unlike the broader CHD spectrum seen with loss of function variants. Transmitted damaging missense variants in MYH6 were enriched in multiple CHD phenotypes and account for ~1% of all probands. Probands with characteristic mutations causing syndromic CHD were frequently not diagnosed clinically, often due to missing cardinal phenotypes. CHD genes that were positively or negatively associated with development of NDD suggest clinical value of genetic testing. These findings expand the understanding of CHD genetics and support the use of molecular diagnostics in CHD.

PMID:40127276 | DOI:10.1073/pnas.2420343122

J Am Podiatr Med Assoc. 2025 Jan-Feb;115(1):23-182. doi: 10.7547/23-182.

ABSTRACT

Osteolipoma is a rare lipoma variant characterized by mature osseus metaplasia within mature adipose tissue, most commonly found in the head and neck, and seldom reported in the extremities. We present a case of a large osteolipoma of the posterior ankle associated with antecedent trauma. These tumors are typically slow growing and can be associated with pain and stiffness, depending on tumor size and location. Treatment is surgical excision, and recurrence is not reported. Interdisciplinary care involving radiology, pathology, and the surgical service is necessary for proper diagnosis and treatment of this rare benign neoplasm.

PMID:40126985 | DOI:10.7547/23-182

J Pediatr Hematol Oncol. 2025 Apr 1;47(3):109-114. doi: 10.1097/MPH.0000000000003008. Epub 2025 Mar 24.

ABSTRACT

BACKGROUND: Congenital CD59 deficiency is a rare genetic disorder marked by chronic hemolysis, recurrent cerebrovascular events, and chronic inflammatory demyelinating polyneuropathy (CIDP). In a specific clinic, 3 siblings from a consanguineously married family were diagnosed with this condition, suggesting a genetic predisposition in their village where endogamous marriages are common.

MATERIALS AND METHODS: Genetic screening was conducted on 71 individuals from the village, including relatives of the diagnosed siblings, to investigate the prevalence and genetic transmission of the disorder.

RESULTS: The screening identified 18 carriers of the genetic mutation and revealed 2 additional siblings of the index patient with the disease. A past case of a cousin with a similar clinical history was also uncovered.

CONCLUSION: The findings highlight the increased risk of genetic disorders like CD59 deficiency in populations with frequent consanguineous marriages. The study underscores the importance of genetic counseling and preventive measures in such communities to mitigate the risk of congenital disorders.

PMID:40126046 | DOI:10.1097/MPH.0000000000003008

Drug Discov Today. 2025 Apr;30(4):104343. doi: 10.1016/j.drudis.2025.104343. Epub 2025 Mar 22.

ABSTRACT

Drug-device combinations (DDCs) are therapeutic products that integrate drugs with medical devices to enhance treatment efficacy and/or safety. These combinations hold significant promise for rare diseases, which affect millions of patients globally, by improving drug delivery, targeting specific organs, and reducing side effects. However, the regulatory framework for DDCs remains complex and lacks specific incentives for rare diseases, unlike orphan drugs. This review examines regulatory approaches and case studies of DDCs in rare diseases, and highlights specific challenges and untapped opportunities. Moreover, the publication discusses recommendations to overcome these challenges through tailored policies and incentives to unlock the potential of DDCs in the context of rare diseases.

PMID:40122448 | DOI:10.1016/j.drudis.2025.104343

Orphanet J Rare Dis. 2025 Mar 22;20(1):141. doi: 10.1186/s13023-025-03619-1.

ABSTRACT

BACKGROUND: Chronic singultus lasting longer than one month is a rare disease. Due to its low prevalence, generating evidence about it is difficult. Patients with chronic diseases struggle with considerable restrictions in their quality of life. Chronic hiccups can lead to problems such as insomnia, anorexia, fatigue, exhaustion, weight loss, and depression. The aim of this study was to gain a better understanding of the quality of life of patients with chronic singultus and their experiences in contact with the healthcare system and with the general population.

METHODS: The data were collected using semi-structured interviews. The data analysis was carried out using qualitative structuring content analysis according to Kuckartz and Rädiker. Reliability was ensured by joint interprofessional evaluation of the interviews by experts, considering different perspectives.

RESULTS: Interviews from 20 patients with chronic singultus were analyzed. Analysis yielded 43 categories that could be assigned to five main topics. The disease burden of the patients was high. In addition to physical symptoms such as concomitant gastroenterological symptoms, shortness of breath, and fatigue, psychosocial consequences such as shame, social withdrawal, anxiety, depression, and even suicidality led to reduced quality of life.

CONCLUSIONS: Ignorance and helplessness among healthcare stakeholders in the case of chronic singultus could lead to a marginalization of the disease and patients. Referring patients to a center with the appropriate expertise can help to avoid underuse, overuse, or misuse of healthcare. Therefore, the awareness of the disease among stakeholders must raise.

PMID:40121512 | DOI:10.1186/s13023-025-03619-1