Orphanet Journal of Rare Diseases最新文献

Background: Osteogenesis imperfecta (OI) is a connective tissue disorder in which the Type 1 collagen is defective. The eye is a structure rich in collagen Type 1 and is heavily impacted by the disease. Many vision-threatening eye diseases have been associated with OI. The onset of these diseases also tend to occur at an earlier age in individuals with OI. Despite the research on these risks, appropriate ophthalmological screening or care guidelines for individuals with OI remain unknown. As such, the purpose of this scoping review was to explore and describe existing ophthalmological screening and care guidelines to orient OI patient care.

Main body: A scoping review based on the Joanna Briggs Institute (JBI) methodology was conducted. A search of databases (PubMed and Medline) was completed in consultation with a research librarian. A total of 256 studies were imported for screening. Primary sources matching the inclusion and exclusion criteria were screened, extracted, and analyzed using Covidence.

Conclusion: A total of 12 primary articles met inclusion and exclusion criteria, containing case reports, case series and cohort studies. Despite the risk of blindness associated with the consequences of OI on the eye, the primary literature fails to provide detailed screening and care guidelines aimed at identifying disease early. We provide general recommendations based on the review findings to guide the ophthalmological care of patients with OI and call upon the experts to convene globally to create screening guidelines. Further investigations of ophthalmological screening are warranted to limit these vision-threatening risks with early detection and treatment. Standardized ophthalmological screening guidelines for OI remain an area for research.

Background: Fatty acid oxidation defects are rare autosomal recessive disorders with variable clinical manifestations and outcome. Early detection by systematic neonatal screening may improve their prognosis. Long-term outcome studies of these disorders in the Middle East and North Africa region are limited. The purpose of this study is to report the diagnostic challenges and outcome of fatty acid oxidation defects in a major tertiary care center in Lebanon, a resource-constrained country in the Middle East.

Methods: A retrospective review of charts of all fatty acid oxidation defects sequential patients diagnosed and followed at our center was conducted. Collected data included: parental consanguinity, age at diagnosis, clinical presentation, biochemical profile, confirmatory diagnosis, treatment and outcome. A genotype-phenotype correlation was also performed, when available.

Results: Seven types of fatty acid oxidation defects were identified in a total of 34 patients from 21 families. Most families (79%) were consanguineous (first-degree cousins). The majority were diagnosed when clinically symptomatic (78%), at various ages between 10 days and 19 years (average: 2 years). Follow-up duration spanned between 2 months and 15 years (average: 5 years). The remainder of the patients were detected while still asymptomatic by systematic neonatal screening (9%) or due to positive family history (9%). The most common defect was carnitine transporter deficiency (50%) with an exclusive cardiac presentation related to a founder variant c.981C > T, (p.Arg254*) in the SLC22A5 gene. Medium chain acyl-CoA dehydrogenase deficiency was found in 13% only, which could be explained by the absence of systematic neonatal screening. Rare gene variants were detected in very long chain and multiple acyl-CoA dehydrogenase deficiency. The worse prognosis was observed in very long chain acyl-CoA dehydrogenase deficiency. The overall survival at last follow-up reached 75% with a complete reversal of symptoms with treatment in most patients (63%), despite their late diagnosis.

Conclusions: Our experience highlights the diagnostic challenges and outcome of fatty acid oxidation defects in a resource-constrained country with high consanguinity rates. Physicians' awareness and systematic neonatal screening are key for diagnosis. Larger genotype-phenotype studies are still needed to understand the natural history of these rare diseases and possibly improve their outcome.

Turner syndrome (TS) results from the loss of one X chromosome in phenotypic females, leading to a range of complications such as short stature, cardiovascular issues, autoimmune disorders, metabolic imbalances, osteoporosis, neurocognitive deficits, hearing loss, abnormalities in endocrine functions, infertility, disruptions in bone metabolism, and neurocognitive deficits. These diverse clinical manifestations necessitate a comprehensive and multidisciplinary approach to diagnosis and management. Growth hormone therapy stands out as a fundamental treatment for addressing the challenges associated with TS. Ongoing clinical and genomic advancements contribute to an evolving understanding of TS, shedding light on its complexities and potential therapeutic interventions. Despite progress, further research is crucial to identify candidate pathways and critical biomarkers that can alleviate the syndrome's burden. By uncovering these insights, we aim to empower individuals with TS, enhancing their overall functioning and quality of life. In this review, we have explored the prevalent co-morbidities associated with TS, drawing insights from the current literature.

Background: To investigate the impact of children's inborn error of metabolism (IEMs) on the children's and their parents' lives from the parents' perspective. We focused on disease-related restrictions in various issues of daily life, experienced discrimination, parental family planning, and management of metabolic emergencies.

Methods: We conducted a questionnaire-based survey with 108 parents of 119 children with IEM who attended a metabolic outpatient clinic. The children were categorized into 4 cohorts, based on increasing disease severity (cohort 1: IEMs with lowest severity, cohort 4: IEMs with highest severity), and compared by using Tobit regressions.

Results: The severity of the child's IEM was associated with an increase in the intensity of perceived restrictions from the parents' perspective for themselves and their children in all aspects of life: in general, in contact with friends, in the pursuit of hobbies, in childcare/school/occupation, and due to emotional stress. The highest intensity of restrictions in all cohorts was found for the parents themselves in contact with friends (compared to cohort 1: cohort 2: c. 3.556, p = 0.002; cohort 3: c. 4.159, p = 0.003; cohort 4: c. 7.224, p < 0.001). Parents of 8% of children reported that their children were discriminated against because of IEM, with the highest proportion of affected children (43%) in cohort 4. Parental family planning decisions were influenced in 34% of parents, with fear of recurrence being a predominant aspect. Of the parents of children diagnosed with IEMs associated with metabolic emergencies, 68% stated that they felt well or very well prepared for the occurrence of a metabolic emergency, and 100% of parents were able to name the necessary action steps from memory. Nevertheless, 58% stated that they experienced an occurring emergency as rather or very stressful.

Conclusions: From the parents' perspective, the intensity of restrictions increased with the severity of the child's IEM. The study shows the high impact of IEM on parents of children with IEM and the daily challenges they face. These findings emphasize the importance of comprehensive support for parents of children with IEM.

Introduction: We present a systematic review of phenotypes of McLeod syndrome (MLS) and a case of a 73-year-old female carrier of the genetic alteration leading to MLS with the typical progressive supranuclear palsy (PSP) phenotype.

Methods: To facilitate clinical reasoning and enable targeted diagnosis, we conducted a systematic review of the papers describing symptomatic cases of confirmed McLeod syndrome. This review follows the PRISMA 2020 statement: an updated guideline for reporting systematic reviews (Page et al in Syst Rev 10(1):89, 2021).

Results: The average onset of MLS was at 40.2 years of age with chorea (46%), seizures and psychiatric changes (each 13%). Very common are weakened Kell antigen (100%), changes in muscle biopsy (100%), genetic alterations in XK (100%), elevated creatine kinase (97%), acanthocytes (96%), MRI changes (95%), chorea (84%) and hyporeflexia (82%).

Conclusion: This review of 65 males and 11 females gives a concise overview of clinical phenotypes in MLS, reinforcing our view that this female patient had PSP independent of MLS carrier status. This report highlights the pitfalls of anchoring in medical decision-making, particularly the possible diagnostic bias of a known genetic carrier status of a very rare disease.

Background: An increasing number of clinical trials for new therapeutic strategies are underway or being considered for dystrophinopathy. Having detailed data on the natural progression of this condition is crucial for assessing the effectiveness of new drugs. However, there's a lack of data regarding the long-term data on the natural course and how it's managed in China. In this study, we offer a comprehensive overview of clinical and molecular findings, as well as treatment outcomes in the Chinese population.

Methods: Institutional data on all patients with dystrophinopathy from August 2011 to August 2021 were retrospectively reviewed. The data included geographic distribution, age at diagnosis, molecular findings, and treatment options, such as corticosteroids, cardiac interventions, and clinical outcomes.

Results: In total, 2097 patients with dystrophinopathy, including 1703 cases of Duchenne muscular dystrophy (DMD), 311 cases of Becker muscular dystrophy (BMD), 46 cases of intermediate muscular dystrophy (IMD), and 37 cases categorized as "pending" (individuals with an undetermined phenotype), were registered in the Children's Hospital of Fudan University database for dystrophinopathy from August 2011 to August 2021. The spectrum of identified variants included exonic deletions (66.6%), exonic duplications (10.7%), nonsense variants (10.3%), splice-site variants (4.5%), small deletions (3.5%), small insertions/duplications (1.8%), and missense variants (0.9%). Four deep intronic variants and two inversion variants were identified. Regarding treatment, glucocorticoids were administered to 54.4% of DMD patients and 39.1% of IMD patients. The median age at loss of ambulation was 2.5 years later in DMD patients who received glucocorticoid treatment. Overall, one cardiac medicine at least was prescribed to 7.4% of DMD patients, 8.3% of IMD patients, and 2.6% of BMD patients. Additionally, ventilator support was required by four DMD patients. Eligibility for exon skipping therapy was found in 55.3% of DMD patients, with 12.9%, 10%, and 9.6% of these patients being eligible for skipping exons 51, 53, and 45, respectively.

Conclusions: This is one of the largest studies to have evaluated the natural history of dystrophinopathy in China, which is particularly conducive to the recruitment of eligible patients for clinical trials and the provision of real-world data to support drug development.

Background: Previous observational studies have highlighted potential relationships between the telomerase reverse transcriptase (TERT) gene, short leukocyte telomere length (LTL), and cerebrovascular disease. However, it remains to be established as to whether TERT gene variants are associated with an elevated risk of cerebral small vessel disease (CSVD), and whether there is a causal relationship between LTL and CSVD.

Methods: Five TERT single nucleotide polymorphisms (SNPs) were analyzed in 307 CSVD patients and 320 healthy controls in whom LTL values were quantified. Allele models and four genetic models were used to explore the relationship between these SNP genotypes and CSVD risk. A Mendelian randomization analysis of CSVD risk was then performed using LTL-related SNPs and the polygenic risk score (PRS) constructed from these SNPs as genetic instrumental variables to predict the causal relationship between LTL and CSVD risk.

Results: Model association analyses identified two SNPs that were significantly associated with CSVD risk. LTL was significantly correlated with age (P < 0.001), and the MR analysis revealed an association between short LTL and an elevated risk of CSVD. PRS-based genetic prediction of short LTLs was also significantly related to an elevated CSVD risk.

Conclusion: Multiple genetic models and MR results indicate that TERT gene SNPs may be related to an elevated risk of CSVD, and that shorter LTL may be causally linked to such CSVD risk.

Background: Primary ciliary dyskinesia (PCD) is a group of rare genetically heterogeneous disorders caused by defective cilia and flagella motility. The clinical phenotype of PCD patients commonly includes chronic oto-sino-pulmonary disease, infertility, and, in about half of cases, laterality defects due to randomization of left-right body asymmetry. To date, pathogenic variants in more than 50 genes responsible for motile cilia structure and assembly have been reported in such patients. While multiple population-specific mutations have been described in PCD cohorts from different countries, the data on genetic spectrum of PCD in Russian population are still extremely limited.

Results: The present study provides a comprehensive clinical and genetic characterization of 21 Russian families with PCD living in various country regions. Anomalies of ciliary beating in patients` respiratory epithelial cells were confirmed by high-speed video microscopy. In the most cases, custom-designed panel sequencing allowed to uncover causative variants in well-known or rarely mentioned PCD-related genes, including DNAH5, DNAH11, CFAP300, LRRC6, ZMYND10, CCDC103, HYDIN, ODAD4, DNAL1, and OFD1. The variations comprised common mutations, as well as novel genetic variants, some of which probably specific for Russian patients. Additional targeted analysis of mRNA transcripts from ciliated cells enabled us to specify functional effects of newly identified genetic variants in DNAH5 (c.2052+3G>T, c.3599-2A>G), HYDIN (c.10949-2A>G, c.1797C>G), and ZMYND10 (c.510+1G>C) on splicing process. In particular, the splice site variant c.2052+3G>T, detected in four unrelated families, resulted in skipping of exon 14 in DNAH5 transcripts and, according to haplotype analysis of affected probands, was proposed as an ancestral founder mutation in Udmurt population.

Conclusions: The reported data provide a vital insight into genetic background of primary ciliary dyskinesia in the Russian population. The findings clearly illustrate the utility of gene panel sequencing coupled with transcriptional analysis in identification and clinical interpretation of novel genetic variants.

Background: The aim of this study was to assess the contribution of the reflective multidisciplinary discussion in determining the value contribution of innovative drugs through the multi-criteria decision analysis (MCDA). This methodology considers all relevant criteria for healthcare decision-making in a global, transparent, and systematic manner and from the perspective of relevant stakeholders. The determination of value contribution of tabelecleucel for the treatment of Epstein-Barr virus-positive post-transplant lymphoproliferative disease (EBV⁺ PTLD) compared to salvage therapy was used as an example.

Results: Tabelecleucel obtained a value contribution score of 0.63 and increased to 0.75 after the reflective discussion. EBV⁺ PTLD was considered a life-threatening disease (5.0 ± 0.0), with a significant unmet need for an approved treatment (5.0 ± 0.0). Tabelecleucel was perceived as bringing improvements in terms of efficacy (4.2 ± 0.8) and safety (3.8 ± 0.8) compared to the salvage therapy. Most experts considered that the high efficacy and safety results could represent an improvement in the quality of life of patients (2.3 ± 1.2) along with savings in medical costs (2.3 ± 2.0) and non-medical costs (2.7 ± 1.6) compared to the salvage therapy. However, others emphasized the need of more evidence to confirm these improvements and savings over time. Tabelecleucel was regarded as potentially modifying the clinical course of the disease (4.3 ± 0.8) and supported by high-quality evidence (3.2 ± 0.4). All contextual criteria were valued highly positively for tabelecleucel. "Safety/Tolerability" and "Other medical costs" were the criteria that experienced the highest change in the re-test conducted after the reflective discussion. The reflective discussion allowed resolving doubts or misinterpretations of the experts, so the re-test obtained more accurate and consistent results of the value contribution of tabelecleucel.

Conclusions: The study shows that the MCDA methodology is a useful tool for decision-making on innovative treatments for the management of rare diseases. It also highlights the importance of reflective multidisciplinary discussion for its ability to resolve doubts or misinterpretations of experts, subsequently allowing to obtain more consistent and reliable results on the value contribution of the drug, being potentially more positive.