Ann Acad Med Singap. 2023 Nov 29;52(11):625-634. doi: 10.47102/annals-acadmedsg.202323.

ABSTRACT

INTRODUCTION: Rare paediatric eye diseases (RPEDs) threaten both vision and life. Recently, rare diseases were recognised as a global public health agenda, with children specified as a priority in the World Health Organization's VISION 2020 against avoidable visual loss.

METHOD: We conducted a review through a query of online databases (PubMed, Embase and Cochrane Library). Articles related to RPEDs were selected based on relevance by 2 authors, with any disagreements adjudicated by the third author.

RESULTS: We synthesise the current state of knowledge regarding RPEDs, barriers to their care, and recommendations for the future. RPEDs often result in significant visual loss, profoundly impacting the way children comprehend and participate in the world. These diseases may also reduce life expectancy and even be life-threatening. Barriers to the care of RPEDs include an unclear definition of "rare diseases", missed or delayed diagnosis, inadequate knowledge and expertise in management, and challenging research environments.

CONCLUSION: Our findings provide an update on the diagnosis and management of RPEDs, which is of relevance to ophthalmologists, paediatricians, healthcare policymakers and social workers. We propose supportive policies and adequate resource allocation to these diseases, comprehensive and patient-centred care, alongside improved education and training, enhanced research capabilities and continued collaboration across institutions.

PMID:38920150 | DOI:10.47102/annals-acadmedsg.202323

Nat Rev Drug Discov. 2024 Aug;23(8):574-576. doi: 10.1038/d41573-024-00109-0.

NO ABSTRACT

PMID:38918582 | DOI:10.1038/d41573-024-00109-0

Eur J Paediatr Neurol. 2024 Jul;51:110-117. doi: 10.1016/j.ejpn.2024.06.007. Epub 2024 Jun 19.

ABSTRACT

BACKGROUND: NKX2-1-related disorder (NKX2-1-RD) is a rare disease characterized by a triad of primary hypothyroidism, neonatal respiratory distress, and neurological features, including chorea.

OBJECTIVE: This study aimed to identify discrepancies in the management of NKX2-1-RD among European Union (EU) specialists.

METHODS: The ERN-RND Chorea & Huntington disease group designed a survey to conduct a cross-sectional multicenter study on the management of NKX2-1-RD. Descriptive analysis was performed, and total responses are presented for each item.

RESULTS: The study involved 23 experts from 13 EU countries with experience in evaluating hyperkinetic patients with NKX2-1-RD: 11 were adult specialists, and 12 were pediatric specialists. NKX2-1-RD diagnosis was made at different ages, with the most common initial symptoms being hypotonia and/or motor developmental delay (reported by 11 experts) and chorea (reported by 8 experts). Chorea involved various body parts and showed improvement as reported by 9 experts, stabilization by 12 experts, and worsening by 2 experts with age. The pharmacological treatment of chorea varied widely among the experts. Misdiagnosis was reported by 14 experts. NKX2-1 pathogenic variants or deletions were confirmed in >75 % of patients (reported by 12 experts). Pulmonary and endocrinology evaluations were requested by 7 and 12 experts, respectively. The management of psychiatric comorbidities also varied among the different experts.

CONCLUSIONS: This study highlights the need for a clinical practice guideline for the management of NKX2-1-RD to ensure that patients across the EU receive consistent and appropriate care. Such a guideline would benefit both doctors and healthcare practitioners.

PMID:38917695 | DOI:10.1016/j.ejpn.2024.06.007

Med. 2024 Jun 14:S2666-6340(24)00222-8. doi: 10.1016/j.medj.2024.05.018. Online ahead of print.

ABSTRACT

BACKGROUND: Trofinetide was approved for the treatment of Rett syndrome based on the results of the phase 3, randomized, placebo-controlled, 12-week LAVENDER study. Rett syndrome is a chronic disorder requiring long-term treatment. We report the efficacy and safety results of LILAC, a 40-week, open-label extension study of LAVENDER.

METHODS: Females with Rett syndrome aged 5-21 years received open-label treatment with trofinetide for 40 weeks. The primary endpoint was long-term safety of trofinetide; secondary endpoints included the change from baseline at week 40 in the Rett Syndrome Behaviour Questionnaire score and the Clinical Global Impression-Improvement score at week 40.

FINDINGS: Overall, 154 participants were enrolled and treated with trofinetide in LILAC. The most common adverse events in LILAC were diarrhea (74.7%), vomiting (28.6%), and COVID-19 (11.0%). Diarrhea was the most common adverse event leading to treatment withdrawal (21.4%). The Rett Syndrome Behaviour Questionnaire mean score (standard error) improvement from the LAVENDER baseline to week 40 in LILAC was -7.3 (1.62) and -7.0 (1.61) for participants treated with trofinetide and placebo in LAVENDER, respectively. Mean Clinical Global Impression-Improvement scores (standard error) at week 40 rated from the LILAC baseline were 3.1 (0.11) and 3.2 (0.14) for participants treated with trofinetide and placebo in LAVENDER, respectively.

CONCLUSIONS: Treatment with trofinetide for ≤40 weeks continued to improve symptoms of Rett syndrome. Trofinetide had a similar safety profile in LILAC as in LAVENDER.

FUNDING: The study was supported by Acadia Pharmaceuticals Inc. (San Diego, CA, USA). This trial was registered at ClinicalTrials.gov (NCT04279314).

PMID:38917793 | DOI:10.1016/j.medj.2024.05.018

Lab Anim (NY). 2024 Jul;53(7):161-165. doi: 10.1038/s41684-024-01395-2.

NO ABSTRACT

PMID:38914824 | DOI:10.1038/s41684-024-01395-2

Ital J Pediatr. 2024 Jun 24;50(1):121. doi: 10.1186/s13052-024-01691-0.

ABSTRACT

BACKGROUND: Townes-Brocks syndrome (TBS) is a rare genetic disorder characterized by imperforate anus, dysplastic ears, thumb malformations, and other abnormalities. Previous studies have revealed that mutations in the SALL1 gene can disrupt normal development, resulting in the characteristic features of Townes-Brocks syndrome. Spalt-like transcription factors (SALLs) are highly conserved proteins that play important roles in various cellular processes, including embryonic development, cell differentiation, and cell survival. Over 400 different variants or mutations have been reported in the SALL1 gene in individuals with TBS. Most of these variants lead to the formation of premature termination codons (PTCs), also known as nonsense mutations. The majority of these PTCs occur in a specific region of the SALL1 gene called the "hotspot region", which is particularly susceptible to mutation.

METHODS: In this study, we conducted whole-exome sequencing on a three-generation Chinese family with anorectal malformations.

RESULTS: We identified a novel heterozygous mutation (chr16:51175376:c.757 C > T p.Gln253*) in the SALL1 gene. Molecular analysis revealed a heterozygous C to T transition at nucleotide position 757 in exon 2 of the SALL1 (NM_002968) gene. This mutation is predicted to result in the substitution of the Gln253 codon with a premature stop codon (p.Gln253*). The glutamine-rich domain forms a long alpha helix, enabling the mutant protein to interact with the wild-type SALL1 protein. This interaction may result in steric hindrance effects on the wild-type SALL1 protein.

CONCLUSIONS: Our findings have expanded the mutation database of the SALL1 gene, which is significant for genetic counseling and clinical surveillance in the affected family. Furthermore, our study enhances the understanding of Townes-Brocks syndrome and has the potential to improve its diagnosis and treatment.

PMID:38915054 | DOI:10.1186/s13052-024-01691-0

Dev Med Child Neurol. 2024 Aug;66(8):e163. doi: 10.1111/dmcn.16008. Epub 2024 Jun 19.

NO ABSTRACT

PMID:38898751 | DOI:10.1111/dmcn.16008

Br J Gen Pract. 2024 Jun 20;74(suppl 1):bjgp24X738105. doi: 10.3399/bjgp24X738105.

ABSTRACT

BACKGROUND: Rare diseases affect millions of people globally, with a lifetime incidence of 1 in 17. They are complex, multisystem, severe disease, and patients experience a diagnostic delay averaging 5.6 years with associated misdiagnoses, inappropriate treatments, and anxiety. MendelScan is a digital case-finding tool that uses structured primary care data to identify patients at risk of being affected by one of a series of rare diseases. This qualitative study explored primary healthcare professionals' experiences of implementing this technology.

AIM: To develop an understanding of primary healthcare professionals' experiences of implementing MendelScan with a focus on their perception of the technology and its implementation, challenges and opportunities.

METHOD: A qualitative appraisal of implementing MendelScan using descriptive analysis of surveys and semi-structured interviews with professionals.

RESULTS: A total of 11 professionals from the two project areas participated. Participants included GPs, nurses, a genetic counsellor, and healthcare managers.Participants reported that they received adequate support, the project increased confidence in integrating genetics in primary care, and that it may improve inequity in rare disease diagnosis. Professionals' reservations were related to knowledge, time commitments, primary care pressures, contacting patients, data sharing and confidentiality, and overcoming clinical resistance in sharing data with a non-NHS external body.

CONCLUSION: This study provides a valuable insight into the experiences of primary care professionals using a novel tool to identify rare diseases. The potential of this tool is promising with benefits for skill development. Large-scale implementation faces challenges related to primary care capacity, data, and funding.

PMID:38902040 | DOI:10.3399/bjgp24X738105

Nat Med. 2024 Jul;30(7):1823-1825. doi: 10.1038/s41591-024-03055-x.

NO ABSTRACT

PMID:38898121 | DOI:10.1038/s41591-024-03055-x

Dig Dis Sci. 2024 Jun 19. doi: 10.1007/s10620-024-08497-4. Online ahead of print.

ABSTRACT

Decision-making in clinical medicine ideally is based upon evidence from randomized, placebo-controlled trials (RCTs) and subsequent systematic reviews and meta-analyses. However, for orphan diseases, the expectation of having one or multiple RCTs that inform clinical guidelines or justify specific treatments can be unrealistic and subsequent therapeutic nihilism can be detrimental to patients. This article discusses the benefits of therapeutic decision-making in the context of orphan diseases, focusing on primary sclerosing cholangitis (PSC) as an example of an orphan disease with poor clinical outcomes. PSC is a rare disorder characterized by inflammation and progressive fibrosis of the bile ducts. It carries a high risk of liver failure, malignancies, and debilitating symptoms that impair quality of life. Liver transplantation is currently the only life-prolonging intervention for PSC, but it is not a curative option. The article highlights the potential benefits of treating PSC patients with oral vancomycin (OV), which has shown significant clinical responses and improved quality of life in some cases. However, access to OV therapy is limited due to the lack of RCTs supporting its use. The standard requirement of having evidence from RCTs may result in withholding potentially life-altering and/or life-saving treatments for patients with orphan diseases. Conducting RCTs is challenging in these patient populations due to difficulties in recruiting the required patient cohorts and limited commercial returns. A standardized 'adaptive treatment strategy' is proposed to address this. This approach leverages the best available evidence for specific treatments, considers individual clinical responses, and adjusts treatment over time.

PMID:38896361 | DOI:10.1007/s10620-024-08497-4

Sensors (Basel). 2024 Jun 3;24(11):3613. doi: 10.3390/s24113613.

ABSTRACT

The interpretability of gait analysis studies in people with rare diseases, such as those with primary hereditary cerebellar ataxia (pwCA), is frequently limited by the small sample sizes and unbalanced datasets. The purpose of this study was to assess the effectiveness of data balancing and generative artificial intelligence (AI) algorithms in generating synthetic data reflecting the actual gait abnormalities of pwCA. Gait data of 30 pwCA (age: 51.6 ± 12.2 years; 13 females, 17 males) and 100 healthy subjects (age: 57.1 ± 10.4; 60 females, 40 males) were collected at the lumbar level with an inertial measurement unit. Subsampling, oversampling, synthetic minority oversampling, generative adversarial networks, and conditional tabular generative adversarial networks (ctGAN) were applied to generate datasets to be input to a random forest classifier. Consistency and explainability metrics were also calculated to assess the coherence of the generated dataset with known gait abnormalities of pwCA. ctGAN significantly improved the classification performance compared with the original dataset and traditional data augmentation methods. ctGAN are effective methods for balancing tabular datasets from populations with rare diseases, owing to their ability to improve diagnostic models with consistent explainability.

PMID:38894404 | DOI:10.3390/s24113613

Sensors (Basel). 2024 May 22;24(11):3294. doi: 10.3390/s24113294.

ABSTRACT

Cerebrospinal fluid (CSF) is a body fluid that can be used for the diagnosis of various diseases. However, CSF collection requires an invasive and painful procedure called a lumbar puncture (LP). This procedure is applied to any patient with a known risk of central nervous system (CNS) damage or neurodegenerative disease, regardless of their age range. Hence, this can be a very painful procedure, especially in infants and elderly patients. On the other hand, the detection of disease biomarkers in CSF makes diagnoses as accurate as possible. This review aims to explore novel electrochemical biosensing platforms that have impacted biomedical science. Biosensors have emerged as techniques to accelerate the detection of known biomarkers in body fluids such as CSF. Biosensors can be designed and modified in various ways and shapes according to their ultimate applications to detect and quantify biomarkers of interest. This process can also significantly influence the detection and diagnosis of CSF. Hence, it is important to understand the role of this technology in the rapidly progressing field of biomedical science.

PMID:38894085 | DOI:10.3390/s24113294

Cells. 2024 May 29;13(11):934. doi: 10.3390/cells13110934.

ABSTRACT

Sickle cell disease is an orphan disease affecting ethnic minorities and characterized by profound systemic manifestations. Although around 100,000 individuals with SCD are living in the US, the exact number of individuals is unknown, and it is considered an orphan disease. This single-gene disorder leads to red blood cell sickling and the deoxygenation of hemoglobin, resulting in hemolysis. SCD is associated with acute complications such as vaso-occlusive crisis, infections, and chronic target organ complications such as pulmonary disease and renal failure. While genetic therapy holds promise to alter the fundamental disease process, the major challenge in the field remains the target end organ damage and ways to mitigate or reverse it. Here, we provide an overview of the clinical manifestations and pathogenesis with a focus on end-organ damage and current therapeutic options, including recent FDA-approved stem cell and gene editing therapies.

PMID:38891066 | DOI:10.3390/cells13110934

Sci Rep. 2024 Jun 18;14(1):14016. doi: 10.1038/s41598-024-63962-4.

ABSTRACT

This study explores the experiences of Polish caregivers of children with rare disease (CRD) with health care and social services for CRD. A mixed-methods approach was employed, using an open-ended questionnaire with a convenience sample. Quantitative data presented through descriptive statistics, were complemented by thematic analysis applied to qualitative responses. Responses from 925 caregivers of 1002 children with CRD revealed that the duration of the diagnostic journey varied, spanning from 0 to 18 years, with an average time of 1.7 years. Similarly, the average number of physicians consulted before receiving the correct diagnosis was 4.8. The Internet was basic source of information about children's disease. Although caregivers were to some extent satisfied with the quality of health care for CRD, they complained at the accessibility of health care and social services, physicians' ignorance regarding RDs, the lack of co-ordinated care and financial and psychological support. To break the cycle of the diagnostic and therapeutic odyssey that may aggravate the condition of CRD, cause parental stress and financial burden there is a need to change our view on CRD from cure to family-oriented care. Multifaceted challenges and needs of CRD families should be prioritized.

PMID:38890437 | DOI:10.1038/s41598-024-63962-4

Sud Med Ekspert. 2024;67(3):45-49. doi: 10.17116/sudmed20246703145.

ABSTRACT

The article is devoted to the problem of diagnosis and treatment strategy of Buerger's disease rarely found in the expert and clinical practice, that is inflammatory disease of unknown etiology, affecting mainly small and medium arteries and veins of limbs. Vascular surgeons around the world have been solving this problem for many years, both in terms of timely diagnosis of this disease and its proper pathogenic treatment. The authors of the article described an expert case of Buerger's disease larvated course in 15-years-old girl, which primarily was mistakenly assessed by specialists as iatrogenic pathology of right forearm vessels in injecting aminazin solution that, according to the clinicians' opinion, led to dry gangrene formation of right wrist and its subsequent amputation. The results of the forensic histological study and retrospective analysis of all child's medical documents allowed to correctly diagnose this rare pathology but only on the stage of commission forensic medical examination in the framework of the initiated criminal proceeding against several leading medical organizations in Saint-Petersburg with a pediatric profile. The authors noted the role of routine medical manipulation in manifestation of larvated pathologic process in a teenage girl in addition to full health and well-being. The objective of present article is devoted to understanding this problem.

PMID:38887071 | DOI:10.17116/sudmed20246703145

Clin Chim Acta. 2024 Jul 15;561:119811. doi: 10.1016/j.cca.2024.119811. Epub 2024 Jun 13.

ABSTRACT

BACKGROUND: Patient registries are crucial for rare disease management. However, manual registry construction is labor-intensive and often not user-friendly. Our goal is to establish Hong Kong's first computer-assisted patient identification tool for rare diseases, starting with inborn errors of metabolism (IEM).

METHODS: Patient data from 2010 to 2019 was retrieved from electronic databases. Through big data analytics, patient data were filtered based on specific IEM-related biochemical and genetic tests. Clinical notes were analyzed using a rule-based natural language processing technique called regular expression. The algorithm classified each extracted paragraph as "IEM-related" or "not IEM-related." Pathologists reviewed the paragraphs for curation, and the algorithm's performance was evaluated.

RESULTS: Out of 46,419 patients with IEM-related tests, the algorithm identified 100 as "IEM-related." After pathologists' validation, 96 cases were confirmed as true IEM, with 1 uncertain case and 3 false positives. A secondary ascertainment yielded a sensitivity of 92.3% compared to our previously published IEM cohort.

CONCLUSIONS: Our artificial intelligence approach provides a novel method to identify IEM patients, facilitating the creation of a centralized, computer-assisted rare disease patient registry at the local and national levels. This data can potentially be accessed by multiple stakeholders for collaborative research and to enhance healthcare management for rare diseases.

PMID:38879064 | DOI:10.1016/j.cca.2024.119811

Lancet Haematol. 2024 Jun 12:S2352-3026(24)00138-8. doi: 10.1016/S2352-3026(24)00138-8. Online ahead of print.

ABSTRACT

BACKGROUND: Inferior vena cava agenesis (IVCA) is a rare anomaly predisposing affected people to lower-limb venous thrombosis with low frequency of pulmonary embolism. Antenatal thrombosis and inherited thrombophilia have been suggested as causes of IVCA. However, there is little evidence on the clinical course and management of this condition. We designed a patient registry to assess the thrombotic risk and features of IVCA.

METHODS: In this this multicentre, retrospective, observational study, we included patients with IVCA diagnosed by routine imaging from 20 hospitals in Spain (n=18), Portugal (n=1), and Italy (n=1). Patients were identified from a systematic search in radiology databases using data extraction software (cohort A) and alternative searches in medical records for confirmed IVCA (cohort B; option allowed when systematic approaches were unapplicable). Primary outcomes were clinical and imaging features, thrombotic risk, phenotype of IVCA-associated thrombosis, anticoagulant treatment, and the results of thrombophilia testing.

FINDINGS: We included patients with IVCA diagnosed by routine imaging studies done between Jan 1, 2010, and Dec 31, 2022. In the systematic search, 4 341 333 imaging exams were screened from the radiology databases of eight centres. 122 eligible patients were enrolled in cohort A. A further 95 patients were identified by screening medical records at 12 centres, of whom 88 were eligible and included in cohort B, making a combined cohort of 210 patients. 96 (46%) of 210 patients were female and 200 (95%) were European or Hispanic. 60 (29%) of 210 patients had hepatic IVC interruption, whereas 150 (71%) had extrahepatic IVCA. In cohort A, 65 (53%) of 122 patients had venous thrombosis, with an estimated annual risk of 1·15% (95% CI 0·89-1·46). Extrahepatic IVCA was associated with a greater risk of venous thrombosis than hepatic IVCA (56 [67%] of 84 patients vs nine [24%] of 38 patients, odds ratio 5·31, 95% CI 2·27-12·43; p<0·0001). Analysis of 126 patients with venous thrombosis pooled from cohorts A and B showed early-onset (median age 34·6 years, IQR 23·3-54·3) and recurrent events (50 [40%] of 126 patients). Patients with extrahepatic IVCA had greater proportions of lower-limb venous thrombosis (95 [87%] of 109 vs nine [53%] of 17, p=0·0010) and recurrence (48 [44%] of 109 vs two [12%] of 17, p=0·015), but lower rates of pulmonary embolism (10 [10%] of 99 vs four [33%] of 12, p=0·044) than did patients with hepatic IVCA. 77 (63%) of 122 patients with thrombosis underwent indefinite anticoagulation. 32 (29%) of 111 patients (29 [34%] of 86 with thrombosis) had coexisting thrombophilias. The recurrence risk was lower for patients receiving indefinite anticoagulation (adjusted odds ratio 0·24, 95% CI 0·08-0·61; p=0·010), and greater for thrombophilias (3·19, 1·09-9·32; p=0·034).

INTERPRETATION: This evaluation of a large patient cohort demonstrates the high thrombotic burden of IVCA. We have identified two distinct forms of IVCA, hepatic and extrahepatic, suggesting different underlying mechanisms. Beyond clinical characterisation, we draw attention to this orphan disease and highlight the need for its study and improved care.

FUNDING: Spanish Society of Thrombosis and Haemostasis, Instituto de Salud Carlos III, FEDER, Fundación Séneca.

PMID:38878784 | DOI:10.1016/S2352-3026(24)00138-8

Int J Dermatol. 2024 Aug;63(8):e182-e184. doi: 10.1111/ijd.17315. Epub 2024 Jun 14.

NO ABSTRACT

PMID:38876478 | DOI:10.1111/ijd.17315

Orphanet J Rare Dis. 2024 Jun 14;19(1):235. doi: 10.1186/s13023-024-03224-8.

ABSTRACT

BACKGROUND: Arthrogryposis multiplex congenita (AMC) is a group of rare musculoskeletal conditions that is associated with complex healthcare needs and long-term follow up. The literature reports significant direct, indirect, and psychosocial costs for caregivers of children with neuromuscular conditions. Due to mobility limitations and frequent hospital visits, caring for a child with AMC is complex. Other challenges experienced by caregivers include financial strain, job changes, changes in interpersonal relationships and abandonment. This study was aimed at exploring the lived experience of caregivers of children with AMC.

METHODS: The present study is part of a larger global mixed methods study. In the initial quantitative aspect of the study, caregivers (n = 158) of children and youths with AMC (aged 0-21 years) responded to a cost of care survey on an electronic platform. Of the 158 participants, 13 caregivers then further consented to participate in the qualitative aspect of the study in which a 60-min semi-structured, individual interview was conducted remotely. Open-ended questions were developed to gain a deeper understanding of the direct and indirect costs of care, their impact on the caregivers' lives and the quality of the care-giving experience. Interviews were transcribed, and a coding scheme was developed drawing from both the existing literature and the content of the interviews. A deductive and inductive thematic analysis was used to analyze the qualitative data using the NVivo® qualitative data analysis software.

RESULTS AND CONCLUSION: Five themes describing the experiences of caregivers of children with AMC emerged from the analysis of the qualitative data: 1. Impact of the caregiving experience; 2. Cost of childcare; 3. Support system for care; 4. Managing and navigating care; 5. Supporting the child's growth and development. In addition to the results of the thematic analysis, specific recommendations shared by the caregivers included the need for support groups and provision of support to youths to prepare them for adolescence. These findings will inform resource allocation, policymaking, and support services for children with rare conditions, their caregivers and families.

PMID:38877508 | DOI:10.1186/s13023-024-03224-8

Lancet Glob Health. 2024 Jul;12(7):e1192-e1199. doi: 10.1016/S2214-109X(24)00134-7.

ABSTRACT

Rare diseases affect over 300 million people worldwide and are gaining recognition as a global health priority. Their inclusion in the UN Sustainable Development Goals, the UN Resolution on Addressing the Challenges of Persons Living with a Rare Disease, and the anticipated WHO Global Network for Rare Diseases and WHO Resolution on Rare Diseases, which is yet to be announced, emphasise their significance. People with rare diseases often face unmet health needs, including access to screening, diagnosis, therapy, and comprehensive health care. These challenges highlight the need for awareness and targeted interventions, including comprehensive education, especially in primary care. The majority of rare disease research, clinical services, and health systems are addressed with specialist care. WHO Member States have committed to focusing on primary health care in both universal health coverage and health-related Sustainable Development Goals. Recognising this opportunity, the International Rare Diseases Research Consortium (IRDiRC) assembled a global, multistakeholder task force to identify key barriers and opportunities for empowering primary health-care providers in addressing rare disease challenges.

PMID:38876765 | DOI:10.1016/S2214-109X(24)00134-7