Orphanet Journal of Rare Diseases最新文献

Background: Patients with cystic fibrosis (CF) are rare in China and differ significantly from the Caucasian populations in terms of clinical and genetic characteristics. However, the progression and mortality of Chinese patients with CF have not been well described.

Results: This study included all 67 patients from the Peking Union Medical College Hospital CF cohort, with a median followed up time of 5.2 years. Compared to patients diagnosed with CF in childhood, adult-diagnosed patients exhibit a lower proportion of pancreatic exocrine insufficiency (25.0% vs. 77.8%, P = 0.001) and a higher body mass index (19.6 vs. 17.7 kg/m², P = 0.045). According to the mixed-effects model, for patients ≤ 30 years of age at diagnosis, FEV₁% predicted decreased 1.17% per year. The generalized linear regression model showed that higher baseline FEV₁% predicted and occurrence of pulmonary exacerbations were associated with the progression of patients with CF. The survival rates at 5 years and 10 years after the diagnosis were 96.7% and 80.6%, respectively. The log-rank test showed baseline FEV₁% predicted < 50%, and high CF-ABLE and 3-year prognostic scores were associated with mortality in patients with CF in China.

Conclusions: We reported the progression and mortality of patients with CF in China, which was a rare and relatively unknown population in the past. Baseline FEV₁% predicted is associated with progression and mortality. Pulmonary exacerbations can accelerate the decline in lung function. The CF-ABLE and 3-year prognostic scores are applicable for predicting poor prognosis in patients with CF in China.

Fabry disease is an X-linked lysosomal storage disorder that causes accumulation of glycosphingolipids in body tissues and fluids, leading to progressive organ damage and life-threatening complications. It can affect both males and females and can be classified into classic or later-onset phenotypes. The disease severity in females ranges from asymptomatic to the more severe, classic phenotype. Most females are hemizygous and the X-linked inheritance is associated with variable X-activation pattern and residual enzymatic activity. The heterogeneity of clinical presentation in females requires different approaches to diagnosis and management than males. A European group of 7 physicians, experienced in the management of Fabry disease, convened to discuss patient perspectives and published guidelines. The experts discussed the need to focus on psychological treatment in relation to individual coping styles when monitoring targets, and the lack of data supporting the use of plasma globotriaosylsphingosine over enzyme activity in the diagnosis of these patients. It was suggested that the high phenotypic variability in female patients may be related to the dynamic nature of the X-chromosome inactivation process and further understanding of this process could help predict the progression of Fabry disease in females and facilitate timely intervention. Due to the range of disease severity they exhibit, female patients with Fabry disease may require a more individualized treatment approach than males. Despite current recommendations, the experts agreed that early disease-specific treatment initiation in high-risk females could improve clinical outcome.

Background: Alström syndrome (AS) is a recessively inherited genetic condition which is ultra-rare and extremely complex. Symptoms include retinal dystrophy, nystagmus, photophobia, hearing loss, obesity, insulin resistance, diabetes and cardiomyopathy. The condition is progressive, but it is important to note that not all the complications associated with AS occur in everyone affected. Symptoms can also present at different stages, making diagnosis difficult. There are currently 88 people diagnosed with AS in the UK.

Objectives: The aim of this report is to raise awareness of the key symptoms of AS, in order to promote a faster and more effective diagnosis. This involves identification of individual or a combination of 'red flag' symptoms. Overall the findings should improve the patient experience, and their long-term health outcomes.

Methods: Between August-October 2022 we conducted research into a sample of patients from the ASUK database. The process involved a combination of interviews with families, social care and education reviews. Interviews were semi-structured using open questions and a patient-centred approach.

Results: Seventeen newly diagnosed patients were included in our sample. Only 24% of patients were diagnosed within one year following the onset of AS symptoms. Patients with visual impairment and cardiomyopathy were diagnosed much more quickly, either in infancy or early childhood. 41% of our research participants waited over 5 years for a diagnosis. Insufficient research and treatment advances can further impede the diagnostic process and limit access to therapies or clinical trials, ultimately impacting patient outcomes.

Conclusion: While we welcome these developments, our findings, and the evidence we have gathered in this report suggests that more needs to be done to improve the experiences of people receiving a diagnosis of AS. Obesity rapidly developing in infancy should be flagged as a key symptom to be aware of where AS is a possible diagnosis. Visual impairment (88%) in combination with cardiomyopathy (59%) is a frequent first presentation for patients with AS. Most patients (7/17) are diagnosed many years after symptom onset (5-20 years).

Background: Epidermolysis bullosa (EB) is a serious, painful, hereditary and still incurable genetic condition. Due to blistering or wounds on the skin caused by the slightest touch, a person suffering from epidermolysis bullosa is prevented from achieving the same quality of life as a healthy person. Until now, psychosocial research has focused on the description of the problems of people living with the disease.

Objectives: The aim of this paper is to provide a structured overview of potential psychosocial effects of epidermolysis bullosa on the everyday lives of people with the condition and to explore helpful aspects for coping with EB.

Methods: Semi-structured interviews with persons living with EB were conducted. Analyses were based on a combination of a reflexive grounded theory approach and a structured coding guide. By means of purposive sampling across three countries, a high diversity within the sample was achieved in order to obtain a wide range of possible effects.

Results: A total of 17 individuals living with EB across all EB types were interviewed, resulting in 36,315 words being analysed. Psychosocial aspects of EB comprise physical, emotional, social, and functional dimensions. Identified burdens and helpful aspects in dealing with EB are described along this structure.

Conclusions: Our results highlight the broad range of possible psychosocial effects caused by epidermolysis bullosa. It is particularly important to recognise those affected as individuals with their personal needs and to avoid unnecessary strains. Furthermore, emotional support is crucial in every respect.

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder affecting multiple organ systems, with a prevalence of 1:6,760-1:13,520 live births in Germany. On the molecular level, TSC is caused by heterozygous loss-of-function variants in either of the genes TSC1 or TSC2, encoding the Tuberin-Hamartin complex, which acts as a critical upstream suppressor of the mammalian target of rapamycin (mTOR), a key signaling pathway controlling cellular growth and metabolism. Despite the therapeutic success of mTOR inhibition in treating TSC-associated manifestations, studies with mTOR inhibitors in children with TSC above two years of age have failed to demonstrate beneficial effects on disease-related neuropsychological deficits. It has thus been hypothesized, that the critical time window for mTOR inhibitors may lie in early infancy, before TSC-related symptoms such as early-onset epilepsy and infantile spasms as sign of disruptive brain maturation occur. No controlled prospective clinical trials have evaluated the effect of pre-symptomatic mTOR inhibitor therapy on neuropsychological manifestations in TSC patients under two years of age.

Methods: This two-arm, randomized, observer-blind, phase IIb national multicenter clinical trial aims at investigating the long-term neuropsychologic outcomes of pre-emptive mTOR inhibitor treatment in children diagnosed with TSC under four months of age. Sixty participants will be allocated to the trial with a 1:1 randomization ratio. The primary endpoint will be the neuropsychological outcome assessed by the cognitive scale of the Bayley Scales of Infant and Toddler Development III at 24 months of age compared to Standard of Care. Secondary endpoints include neuropsychologic outcomes at 12 months of age, seizure frequency, cardiac and cerebral tumor load, and safety assessments. Inclusion criteria are a definite TSC diagnosis and an age below four months at enrolment. The investigational medicinal product is sirolimus (Rapamune®), administered orally based on body surface area and surveilled by pharmacokinetic measurements, starting within the first four months of life and continuing until the second birthday.

Conclusion: This study addresses a critical gap in understanding the impact of pre-emptive mTOR inhibitor therapy on neuropsychologic outcomes in young TSC patients, aiming to improve overall patient outcomes and quality of life. EUCT number: 2022-502332-39-00, Registered 22/06/2023, https://euclinicaltrials.eu/search-for-clinical-trials/?lang=en&EUCT=2022-502332-39-00.

Background: NF2-related schwannomatosis (NF2) is associated with various tumors of the central and peripheral nervous system. There is a wide range of disabilities these patients may suffer from and there is no validated clinical classification for disease severity. We propose a clinical classification consisting of three severity grades to assist in patient management.

Methods: Patient records from 168 patients were screened for most common diagnoses with severe impact on everyday tasks, social interactions and life expectancy. Eight main categories were identified. One point was assigned to each category. Three severity grades were differentiated as follows: grade 1 (mild NF2): 0 points; grade 2 (moderate NF2): < 3 points; grade 3 (severe NF2): ≥ 3 points. This grading system was then evaluated with respect to inter-rater reliability and clinical significance.

Results: The patients were grouped according to our new clinical grading system into grade 1 in 48% (n = 80), grade 2 in 43% (n = 72), and grade 3 in 10% of patients (n = 16). There was substantial inter-rater reliability between 3 raters with different levels of clinical experience (Fleiss' kappa = 0.62). The severity grades correlated significantly with hospitalization, number of operations and dependency on implants (such as cochlear implant, auditory brain-stem implants or ventriculoperitoneal shunts).

Conclusions: Clinical disease severity of NF2 patients is reflected in a simplified and rater-independent score with three grades. The score facilitates communication for medical personnel of varying experience and backgrounds, and adds a clinical tool to decision-making and research.

Background: Sarcoglycanopathies (SGPs) are limb-girdle muscular dystrophies (LGMDs) that can be classified into four types, LGMDR3, LGMDR4, LGMDR5, and LGMDR6, caused by mutations in the genes, SGCA, SGCB, SGCG, and SGCD, respectively. SGPs are relatively rare in Japan. This study aims to profile the genetic variants that cause SGPs in Japanese patients.

Methods: Clinical course and pathological findings were retrospectively reviewed in Japanese patients with SGP. Genetic analyses were performed using a combination of targeted resequencing with a hereditary muscle disease panel, whole genome sequencing, multiplex ligation-dependent probe amplification, and long-read sequencing. The structures of transcripts with aberrant splicing were also determined by RT-PCR, RNA-seq, and in silico prediction.

Results: We identified biallelic variants in SGC genes in 53 families, including three families with LGMDR6, which had not been identified in Japan so far. SGCA was the most common causative gene, accounting for 56% of cases, followed by SGCG, SGCB, and SGCD, at 17%, 21%, and 6%, respectively. Missense variants in SGCA were very frequent at 78.3%, while they were relatively rare in SGCB, SGCG, and SGCD at 11.1%, 18.2%, and 16.6%, respectively. We also analyzed the haplotypes of alleles carrying three variants found in multiple cases: c.229C > T in SGCA, c.325C > T in SGCB, and exon 6 deletion in SGCG; two distinct haplotypes were found for c.229C > T in SGCA, while each of the latter two variants was on single haplotypes.

Conclusions: We present genetic profiles of Japanese patients with SGPs. Haplotype analysis indicated common ancestors of frequent variants. Our findings will support genetic diagnosis and gene therapy.

Background: Spinal muscular atrophy (SMA) is a genetic neuromuscular disease associated with progressive loss of motor function. Risdiplam, a daily oral therapy, was approved in the United States for the treatment of SMA. Risdiplam's effectiveness depends on patient adherence to the treatment regimen. This retrospective claims database analysis assessed real-world treatment adherence and persistence, and all-cause health care costs by adherence status, for patients with SMA receiving risdiplam. Outcomes were summarized by SMA types (1-4) and age groups (0-2, 3-5, 6-17, and ≥ 18 years).

Results: 86 patients with ≥ 1 SMA diagnosis, risdiplam treatment, and ≥ 6 months of continuous enrollment after the index date (SMA diagnosis) were identified in the IQVIA PharMetrics^® Plus database (01/01/2020-06/30/2022). One patient had SMA type 1 (a 1-year-old boy), 18 had type 2 (mean ± SD age: 7.9 ± 5.7 years; 61% female), 47 had type 3 (17.3 ± 10.2 years; 55% female), and 20 had type 4 (38.2 ± 11.6 years; 55% female). The mean proportion of days covered (PDC) with risdiplam was 0.89 overall, ranging from 0.88 for SMA type 4 to 0.97 for type 1. The majority (83.7%) of patients were adherent to risdiplam (PDC ≥0.80), ranging from 75.0% for type 4 to 100% for type 1. Adherence ranged from 76.5% among 6-12-year-olds to 100% among 0-2-year-olds. Compared with adherent patients, nonadherent patients had higher median total health care costs by $335,049 for type 2, $41,204 for type 3, and $12,223 for type 4. Among adherent patients, patients with PDC between 0.90 and 1.00 had lower costs compared with patients with PDC between 0.80 and 0.90.

Conclusions: Nonadherence to risdiplam was observed in the first year of treatment, especially for patients with SMA type 4 and patients aged 6-12 years. Nonadherence was associated with higher all-cause health care costs, with the most pronounced cost difference for SMA type 2. For adherent patients, those who were highly adherent incurred lower health care costs. These findings underscore the importance of treatment adherence and persistence for patients with SMA receiving risdiplam, particularly for younger children and those with greater disease severity.

Introduction: After diagnosis of Ehlers Danlos Syndrome (EDS), it is unclear what information patients and parents need and understand about EDS. The objective of this study is to characterize patient and parent knowledge and concerns about EDS after a diagnosis of EDS is made to determine patient and parent concerns and identify barriers that cause discomfort with the diagnosis.6 METHODS: A convenience sample of patient and parent dyads were recruited after new diagnosis of EDS. Patients and parents completed questionnaires that assessed knowledge, comfort, and barriers of EDS before and after diagnosis, EDS education materials accessed, and additional clinical needs and concerns.

Results: Seventy-two dyads completed the survey.

Conclusion: Many respondents actively seek information on the diagnosis and management of EDS. Parents and patients look for information about EDS differently. Parents have more concerns after diagnosis and both want well-constructed, empirically supported educational materials delivered via multiple modalities, which makes clinical guidelines more essential.

Background: Friedreich's ataxia (FA) is a rare genetic disorder caused by silencing of the frataxin gene (FXN), which leads to multiorgan damage. Nrf2 is a regulator of FXN, which is a modulator of oxidative stress in animals and humans. Omaveloxolone (Omav) is an Nrf2 activator and has been reported to have antioxidative potential in various disease conditions. The present review was conducted to determine the use of Omav, the only FDA-approved treatment for FA.

Methods: Three electronic databases, Cochrane, PubMed and Google Scholar, were searched with terms such as 'Omaveloxolone', 'Friedreich ataxia', 'genetic diseases', 'autosomal recessive', and 'rare disorders' using various advanced search filters. Articles were screened, extracted, and assessed for quality, and a qualitative synthesis of the data was performed. The study protocol was registered in PROSPERO (CRD42024531449).

Results: A total of 201 records were found, with very few published research articles on the topic. Only two randomized clinical trials published in a series of three research articles were included in the current systematic review. Peak load exercise and modified Friedreich's Ataxia Rating Scale (mFARS) values were considered the major outcome measures for determining the efficacy of 150 mg Omav capsules/day in FA. Exploratory outcome measures, such as low-contrast letter visual acuity test, exercise test, T25-FW, 9-HPT, health-related quality of life, and biochemical tests, were also assessed along with adverse events in all the studies.

Conclusion: Although, the quality of the articles demonstrated low bias. However, the short duration, small sample size, and missing data, including the values of different measures of mFARS scores in patients, limit the generalizability of the results. Further studies with longer durations and in severe patients with foot deformities are needed to clearly define the efficacy of Omav in FA and to determine the optimal drug for FA patients in India.