Orphanet Journal of Rare Diseases最新文献

Background: Clinical research has offered many definitions and fragmented perspectives of joint morbidity in haemophilia. As joint damage, pain and mobility impairment can be present without clinical record of persistent bleeding, a person-centric joint morbidity characterisation remained a priority for the haemophilia community, giving rise to the 'problem joint' concept. As diagnosing and managing joint morbidity is critical, the aim of this study was to analyse the holistic burden of problem joints in people with moderate or severe haemophilia A (HA). Data from the 'Cost of Haemophilia in Europe: a Socioeconomic Survey' (CHESS) cross-sectional studies were used. CHESS-Paediatrics included male paediatric patients (≤ 17 years) with congenital moderate or severe haemophilia, while CHESS II included adult males (≥ 18 years) of any severity. Both studies sought to collect detailed information on the clinical, economic and humanistic burden of haemophilia. Demographics, clinical outcomes, treatment regimen, adherence, physical activity, healthcare resource use and number of problem joints were evaluated and described by HA severity and number of problem joints (none, 1, ≥ 2).

Results: In total, 1171 people with non-inhibitor moderate or severe HA from CHESS-Paediatrics (n = 703) and CHESS II (n = 468) were included in this analysis. Presence of problem joints was more prevalent among CHESS II participants (44%) than in CHESS-Paediatrics (14%). Around two-thirds (67%) of CHESS-Paediatrics and 39% of CHESS II participants received prophylactic factor VIII replacement therapy. The presence of chronic pain was greater in severe HA with ' ≥ 2' problem joints in both cohorts. Clinical symptoms and bleed-related hospitalizations were more prevalent in the presence of problem joints regardless of HA severity in both cohorts.

Conclusions: This analysis of the CHESS population studies has expanded on previous work by examining the relevance of the problem joint measure of haemophilic morbidity and its associated burden. Adverse clinical symptoms and increased bleed-related hospitalizations were observed in the presence of problem joints in both children/adolescents and adults across HA severities. Use of person-centric characterizations of joint morbidity may improve analysis of long-term outcomes and lead to improvements in future haemophilia care.

Purpose: To enhance the detection rate of Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency (NICCD) through newborn screening (NBS), we analyzed the metabolic profiles of missed patients and proposed a more reliable method for early diagnosis.

Methods: In this retrospective study, NICCD patients were classified into "Newborn Screening" (64 individuals) and "Missed Screening" (52 individuals) groups. Metabolic profiles were analyzed using the non-derivatized MS/MS Kit, and genetic mutations were identified via next-generation sequencing and confirmed by Sanger sequencing. Receiver Operating Characteristic (ROC) analysis evaluated the predictive value of amino acids and acylcarnitines in dried blood spots (DBS) for identifying missed patients including 40 missed patients and 17,269 healthy individuals, with additional validation using 12 missed patients and 454 healthy controls.

Results: The age of diagnosis was significantly higher in the "Missed Screening" group compared to the "Newborn Screening" group (74.50 vs. 18.00 days, P < 0.001). ROC analysis revealed that citrulline had excellent diagnostic accuracy for missed patients, with an AUC of 0.970 and a cut-off value of 17.57 µmol/L. Additionally, glycine, phenylalanine, ornithine, and C8 were significant markers, each with an AUC greater than 0.70. A combination of these markers achieved an AUC of 0.996 with a cut-off value of 0.00195. Validation demonstrated a true positive rate of 91.67% and a true negative rate of 96.48%. Common SLC25A13 mutations in both groups were c.852_855del, IVS16ins3kb, and c.615 + 5G > A.

Conclusions: Combining multiple metabolic markers during NBS significantly improves sensitivity and specificity for detecting missed NICCD cases. However, the relationship between genetic mutations and missed cases remains unclear.

Background: Hereditary angioedema (HAE) is a rare, autosomal dominant disorder causing swelling attacks in various parts of the body, resulting in impacts on health-related quality of life (HRQoL). The symptoms of HAE and its impacts on HRQoL have been well-documented in adults; however, relatively little is known about the experiences of adolescents with HAE. The objective of this study was to use qualitative interviews to investigate how adolescents experience HAE symptoms and how HAE impacts their HRQoL.

Methods: This was a non-interventional, qualitative study of adolescents with HAE. Participants were recruited via a patient advocacy organization and were eligible to take part in this study if they had a confirmed diagnosis of type I or type II HAE and were currently on prophylactic treatment to prevent HAE attacks. All participants completed a one-to-one, 60-minute, remote interview designed to elicit their experiences of HAE. Interview data were coded and analyzed using NVivo qualitative software.

Results: Twelve adolescents took part in this study. HAE attacks were described as painful and uncomfortable. Attacks varied by trigger, frequency, severity, location, and duration. Participants described ways in which HAE impacted their daily lives, including impacts on physical, social, emotional, and cognitive functioning, in addition to sleep disturbance, school-related impacts, and a need to avoid attack triggers. Impacts on emotional and social functioning were particularly noteworthy, as participants reported having to miss or skip social events, and sometimes withdrawing socially. Since initiating prophylaxis, participants reported the frequency, severity, and duration of attacks had been reduced and their HAE-related impacts had been minimized. Participants were satisfied with their current prophylactic and acute treatments, and expressed a preference for treatments that were effective, convenient, self-administered, and had minimal side effects.

Conclusion: Adolescents with HAE reported experiencing a range of symptoms that, when untreated, impacted their HRQoL in ways that are unique from adults. Further, participants reported that effective treatments (prophylactic and acute) inhibited symptoms and HRQoL impacts with minimal treatment burden. Findings from this study suggest that health care providers and clinical investigators should consider the unique HRQoL impacts experienced by adolescents when evaluating treatment benefit.

Background: Transient receptor potential cation channel subfamily V member 2 (TRPV2) functions as a stretch-sensitive calcium channel, with overexpression in the sarcolemma of skeletal and cardiac myocytes leading to detrimental calcium influx and triggering muscle degeneration. In our previous pilot study, we showed that tranilast, a TRPV2 inhibitor, reduced brain natriuretic peptide levels in two patients with muscular dystrophy and advanced heart failure. Building on this, we performed a single-arm, open-label, multicenter study herein to evaluate the safety and efficacy of tranilast in the treatment of advanced heart failure in patients with muscular dystrophy.

Results: This study involved 18 patients with muscular dystrophy who had brain natriuretic peptide levels > 100 pg/mL, despite receiving standard cardioprotective therapy. Tranilast was administered orally at a dose of 100 mg three times daily. Over the short-term period (28 weeks), the primary endpoint of change ratio in the logarithm of brain natriuretic peptide level from baseline to 28 weeks was not significant in the full analysis set but was lower in the per set protocol compared with data from a previous beta-blocker treatment study. All 15 patients who completed the short-term treatment consented to be enrolled in long-term therapy for an additional 116 weeks. After all participants completed the long-term treatment, we analyzed all data. TRPV2 expression on the peripheral blood mononuclear cell surfaces decreased throughout the study period, confirming that the TRPV2 inhibitory effect of tranilast was maintained over time. Despite the presence of progressive disease, cardiac indices such as brain natriuretic peptide level, human atrial natriuretic peptide level, and fractional shortening, remained stable, and only brain natriuretic peptide levels at 144 weeks showed significant changes. The survival rate was 80.7%, and no cardiac deaths were reported. Regarding safety, no serious adverse events associated with tranilast were noted, except for recurrent diarrhea during the short-term period in one case.

Conclusions: The findings suggest that tranilast can inhibit TRPV2 expression for an extended period and is effective in preventing the worsening of cardiac function and subsequent death from heart failure.

Clinical trial registration details: The study was registered in the UMIN Clinical Trials Registry (UMIN-CTR: UMIN000031965, URL: http://www.umin.ac.jp/ctr/ ) [March 30, 2018] and the Japan Registry of Clinical Trials (jRCT, registration number: jRCTs031180038, URL: https://jrct.niph.go.jp/ ) [November 12, 2021]. Patient registration was initiated on December 19, 2018.

Background: Glycogen storage disease (GSD) Ia is an ultra-rare inherited disorder of carbohydrate metabolism. Patients often present in the first months of life with fasting hypoketotic hypoglycemia and hepatomegaly. The diagnosis of GSD Ia relies on a combination of different biomarkers, mostly routine clinical chemical markers and subsequent genetic confirmation. However, a specific and reliable biomarker is lacking. As GSD Ia patients demonstrate altered lipid metabolism and mitochondrial fatty acid oxidation, we built a machine learning model to identify GSD Ia patients based on plasma acylcarnitine profiles.

Methods: We collected plasma acylcarnitine profiles from 3958 patients, of whom 31 have GSD Ia. Synthetic samples were generated to address the problem of class imbalance in the dataset. We built several machine learning models based on gradient-boosted trees. Our approach included hyperparameter tuning and feature selection and generalization was checked using both nested cross-validation and a held-out test set.

Results: The binary classifier was able to correctly identify 5/6 GSD Ia patients in a held-out test set without generating significant amounts of false positive results. The best model showed excellent performance with a mean received operator curve (ROC) AUC of 0.955 and precision-recall (PR) curve AUC of 0.674 in nested CV.

Conclusions: This study demonstrates an innovative approach to applying machine learning to ultra-rare diseases by accurately identifying GSD Ia patients based on plasma free carnitine and acylcarnitine concentrations, leveraging subtle acylcarnitine abnormalities. Acylcarnitine features that were strong predictors for GSD Ia include C16-carnitine, C14OH-carnitine, total carnitine and acetylcarnitine. The model demonstrated high sensitivity and specificity, with selected parameters that were not only robust but also highly interpretable. Our approach offers potential prospect for the inclusion of GSD Ia in newborn screening. Rare diseases are underrepresented in machine learning studies and this work highlights the potential for these techniques, even in ultra-rare diseases such as GSD Ia.

Introduction: The purpose of this study was to investigate perceptions and opinions on what constitutes determinants for quality of life (QoL) in individuals with syndromic Heritable Aortic Disease (sHTAD), utilizing a qualitative study approach. Further to discuss clinical implications and direction for research.

Method: A qualitative focus group interview study was conducted of 47 adults (Marfan syndrome (MFS) = 14, Loeys-Dietz syndrome (LDS) = 11, vascular Ehlers Danlos syndrome (EDS) = 11, relatives = 11). The interviews were digitally recorded and transcribed verbatim. Significant themes were identified, extracted, and organised undergoing content analyses.

Results: The two main themes and 10 subthemes identified; I. Psychosocial well-being; (i) Social engagement and activity, (ii) Self-sufficient in daily living, (iii) Participation in education and work life, (iv) Coping with fear related to the disease, (v) Being able to control and accept fatigue and pain, (vi) Maintaining active engagement with family and friends (vii) Finding health-promoting physical activities. II. Monitoring and meetings with the health service: (viii) Feeling safe and receiving coordinated care, (ix) Being recognized, seen, and accepted, (x) Receiving factual and sober information and advice. The sub-themes seemed mutually interrelated in terms of barriers, strategies, and facilitators for improving quality of life. There was high degree of consensus regarding the factors emphasized as important for QoL among the various diagnostic groups and the relatives.

Conclusion: Based on our findings, to improve QoL in patients with sHTAD we should more effectively integrate the patient`s perspectives and voice on the elements crucial to QoL. In addition, it is vital for developing and customizing validated questionnaires to accurately reflect the factors deemed significant by this specific patient cohort. The research is limited on patients' perspectives on QoL, and more research is warranted. This might also be crucial for identifying relevant validated QoL instruments that reflect the patients` perceptions of what is vital for QoL.

Background: Ornithine transcarbamylase deficiency exhibits a high degree of clinical heterogeneity, making its screening and classification challenging in some instances. In this study, we first established a simple and stable method for testing ornithine transcarbamylase activity using micro blood from newborns, rather than relying on venous blood.

Methods: The activity of ornithine transcarbamylase was assessed by measuring the concentration of citrulline produced in the reaction with carbamoyl phosphate and ornithine, using serum, plasma or micro blood. Correlation analysis was evaluated using Sangerbox Tools. The Receiver Operating Characteristic curve was used in SPSS Statistics 17.0 to evaluate the diagnostic efficiency of Ornithine transcarbamylase deficiency.

Results: A strong linear relationship was observed between ornithine transcarbamylase activity and both micro blood volume and reaction time (R² = 0.9793, 0.9922 respectively). The intra-coefficient variation and inter-coefficient variation were 11% and 12.5% with a 1-h reaction time, and 6.77% and 9.58% with a 3-h reaction time, respectively. And the inter-coefficient variation was lower than the most widely used colorimetry method (5.1-21.1%). The Limit of Blank was 0.57 nmol/mL/h. The reference interval for normal newborn population is greater than or equal to 39.6 nmol/mL/h. Notably, the method exhibited a 100% sensitivity, surpassing the sensitivity of colorimetry method (94.3%), along with and a specificity of 96.9% for diagnosing ornithine transcarbamylase deficiency.

Conclusions: We pioneered a method for testing OTC activity that normally carried on venous blood can be effectively performed on microblood heel samples. Meanwhile, our method presents a simpler, more stable and reproducible approach compared to colorimetry.

Background: Non-isolated auditory neuropathy (AN), or syndromic AN, is marked by AN along with additional systemic manifestations. The diagnostic process is challenging due to its varied symptoms and overlap with other syndromes. This study focuses on two mitochondrial function-related genes which result in non-isolated AN, FDXR and TWNK, providing a summary and enrichment analysis of genes associated with non-isolated AN to elucidate the genotype-phenotype correlation and underlying mechanisms.

Methods: Seven independent Chinese Han patients with mutations in FDXR and TWNK underwent comprehensive clinical evaluations, genetic testing, and bioinformatics analyses. Diagnostic assessments included auditory brainstem response and distortion product otoacoustic emissions, supplemented by other examinations. Whole exome sequencing and Sanger sequencing validated genetic findings. Pathogenicity was assessed following American College of Medical Genetics and Genomics guidelines. Genes associated with non-isolated AN were summarized from prior reports, and functional enrichment analysis was conducted using Gene Ontology databases.

Results: A total of 11 variants linked to non-isolated AN were identified in this study, eight of which were novel. Patients' age of hearing loss onset ranged from 2 to 25 years, averaging 11 years. Hearing loss varied from mild to profound, with 57.1%(4/7) of patients having risk factors and 71.4%(5/7) exhibiting additional systemic symptoms such as muscle weakness, ataxia, and high arches. Functional enrichment analysis revealed that genes associated with non-isolated AN predominantly involve mitochondrial processes, affecting the central and peripheral nervous, musculoskeletal, and visual systems.

Conclusion: This study identifies novel mutations in FDXR and TWNK that contribute to non-isolated AN through mitochondrial dysfunction. The findings highlight the role of mitochondrial processes in non-isolated AN, suggesting potential relevance as biomarkers for neurodegenerative diseases. Further research is required to explore these mechanisms and potential therapies.

Maple Syrup Urine Disease (MSUD) disease is a defect in the function of the Branched-chain 2-ketoacid dehydrogenase complex (BCKDH). It is caused by pathogenic biallelic variants in BCKDHA, BCKA decarboxylase, or dihydrolipoamide dehydrogenase. The brain is the major organ involved in MSUD. MSUD happens in about 1 in 86,800 to 185,000 live births. According to some diversity in the management of Iranian patients with MSUD, the development of a national guideline is essential. This guideline is provided through a literature search on articles in PubMed, Scopus, Web of Sciences, Cochrane, and Embase databases from 2001 to 2022 accompanied by a consensus of physicians of different centers in Iran who are experts in the diagnosis and management of this disease. This article considers pathogenesis, epidemiology, clinical manifestations, diagnosis, treatment, and monitoring of MSUD patients with limited recourse.