当前期刊: Orphanet Journal of Rare Diseases Go to current issue    加入关注   
显示样式:        排序: 导出
我的关注
我的收藏
您暂时未登录!
登录
  • Etiologic spectrum of interstitial lung diseases in Chinese children older than 2 years of age
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2020-01-22
    Xiaolei Tang; Huimin Li; Hui Liu; Hui Xu; Haiming Yang; Jinrong Liu; Shunying Zhao

    Childhood interstitial lung diseases (ILD) (chILD) refer to a rare heterogeneous group of disorders. Global collaborations have been working on the etiologies and classification scheme of chILD. With the development of medical technologies, some new diseases were identified to be associated with chILD and its etiologic spectrum is expanding. The aim of this study is to describe the etiologic spectrum of chILD in children older than 2 years of age and summarize the approaches to diagnosis of chILD. We made a retrospective analysis of children older than 2 years of age with chILD who referred to Beijing Children’s Hospital from 21 provinces all over China from 2013 to 2018. After excluding pulmonary infection, congenital heart disease, bronchopulmonary dysplasia, bronchiolitis obliterans and bronchiectasis, 133 patients were included and categorized by etiology. Clinical manifestations, high-resolution computed tomography, laboratory data, genetic data and pathologic findings were all collected and reviewed. Systemic disease associated ILD were the most common causes, accounting for 49.6% of the patients, followed by alveolar structure disorder-associated ILD (27%), exposure related ILD (13.5%), and disorders masquerading as ILD (3.8%). In systemic disease associated ILD, in addition to common etiologies such as vasculitis (10.5%) and connective tissue diseases (9.0%), primary immunodeficiency diseases (PID) associated ILD (9.8%), interstitial pneumonia with autoimmune features (6.8%), and metabolic diseases (6.8%) were not rarely found. Some newly reported etiologies such as STING–associated vasculopathy with onset in infancy, COPA syndrome and STAT3 mutation were included in PID associated ILD. Genetic tests contributed to 15% of the diagnoses which mainly distributed in PID associated ILD, metabolic diseases and surfactant dysfunction disorders, and contributed to the final diagnoses more than lung biopsies (13.5%) and biopsies of rashes or other tissues (12%). This study first demonstrated an etiologic spectrum of chILD in Chinese children older than 2 years of age and summarized the approaches to diagnosis. The etiologic spectrum of chILD is expanding with more genetic etiologies being recognized.

    更新日期:2020-01-23
  • Comparison of liver MRI R2(FerriScan®) VS liver MRI T2* as a measure of body iron load in a cohort of beta thalassaemia major patients
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2020-01-22
    Padmapani Padeniya; Shirom Siriwardana; Dileepa Ediriweera; Nayana Samarasinghe; Sasanka Silva; Ishari Silva; Nizri Ahamed; Madunil Niriella; Anuja Premawardhena

    To compare the similarity of the non-patented T2* and the high cost patented R2 (Ferriscan®) MRI techniques in the measurement of liver iron concentration (LIC) in heavily transfused patients with thalassaemia major in a real- life Sri Lankan hospital setup. We compared LIC measured by MRI, obtained 2 weeks apart, using both T2* and R2 techniques in 15 patients with beta thalassaemia major. They all had a history of > 100 units of blood transfusions life long and also a history of sub optimal chelation. MRI R2 and MRI T2* scan values showed a negative correlation (co-rrelation coefficient = − 0.63, p = 0.01) This correlation was strong in lower LICs and progressively decreased with upper LIC values. Thus a significant discrepancy was observed between median values of two MRI technologies (p = 0.0005) with T2* tending to underestimate iron overload especially in those with very high LIC identified by R2. The lack of concordance of T2* and R2 especially in those with very high reading on R2 suggest the potential errors in interpretations that can occur in “non-expert centres”; which are likely to lead to errors in clinical judgement on the intensity of chelation therapy needed.

    更新日期:2020-01-23
  • Brain metabolism and neurological symptoms in combined malonic and methylmalonic aciduria
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2020-01-22
    Sara Tucci

    Combined malonic and methylmalonic aciduria (CMAMMA) is an inborn error of metabolism which has been proposed being a benign condition. However, older patients may present with neurological manifestations such as seizures, memory problems, psychiatric problems and/ or cognitive decline. In fibroblasts from CMAMMA patients we have recently demonstrated a dysregulation of energy metabolism with increased dependency on β-oxidation for energy production. Because of the inability of the brain to rely efficiently on this pathway to retrieve the required energy to a great extent, we hypothesize an alternative disease-causing mechanism that does not only include the accumulation of the metabolites malonic and methylmalonic acids. Here, we suggest a novel hypothesis on the possible pathophysiological mechanism responsible for the development of neurological symptoms in the long-run.

    更新日期:2020-01-23
  • A systematic review on the burden of illness in individuals with tuberous sclerosis complex (TSC)
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2020-01-21
    Johann Philipp Zöllner; David Neal Franz; Christoph Hertzberg; Rima Nabbout; Felix Rosenow; Matthias Sauter; Susanne Schubert-Bast; Adelheid Wiemer-Kruel; Adam Strzelczyk

    This review will summarize current knowledge on the burden of illness (BOI) in tuberous sclerosis complex (TSC), a multisystem genetic disorder manifesting with hamartomas throughout the body, including mainly the kidneys, brain, skin, eyes, heart, and lungs. We performed a systematic analysis of the available literature on BOI in TSC according to the PRISMA guidelines. All studies irrespective of participant age that reported on individual and societal measures of disease burden (e.g. health care resource use, costs, quality of life) were included. We identified 33 studies reporting BOI in TSC patients. Most studies (21) reported health care resource use, while 14 studies reported quality of life and 10 studies mentioned costs associated with TSC. Only eight research papers reported caregiver BOI. Substantial BOI occurs from most manifestations of the disorder, particularly from pharmacoresistant epilepsy, neuropsychiatric, renal and skin manifestations. While less frequent, pulmonary complications also lead to a high individual BOI. The range for the mean annual direct costs varied widely between 424 and 98,008 International Dollar purchasing power parities (PPP-$). Brain surgery, end-stage renal disease with dialysis, and pulmonary complications all incur particularly high costs. There is a dearth of information regarding indirect costs in TSC. Mortality overall is increased compared to general population; and most TSC related deaths occur as a result of complications from seizures as well as renal complications. Long term studies report mortality between 4.8 and 8.3% for a follow-up of 8 to 17.4 years. TSC patients and their caregivers have a high burden of illness, and TSC patients incur high costs in health care systems. At the same time, the provision of inadequate treatment that does not adhere to published guidelines is common and centralized TSC care is received by no more than half of individuals who need it, especially adults. Further studies focusing on the cost effectiveness and BOI outcomes of coordinated TSC care as well as of new treatment options such as mTOR inhibitors are necessary.

    更新日期:2020-01-22
  • Perinatal features of Prader-Willi syndrome: a Chinese cohort of 134 patients
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2020-01-21
    Lili Yang; Qiong Zhou; Bo Ma; Shujiong Mao; Yanli Dai; Mingqiang Zhu; Chaochun Zou

    Prader-Willi syndrome (PWS) is a rare and complex genetic disorder caused by lacking expression of imprinted genes on the paternally derived chromosome 15q11-q13 region. This study aimed to characterize the perinatal features of 134 Chinese individuals with PWS. This study included the patients of a PWS registry in China. Anonymous data of 134 patients were abstracted. Perinatal and neonatal presentations were analyzed, and compared between the two PWS genetic subtypes. We also compared the perinatal features of PWS patients with the general population and other previous reported large cohorts from France, UK and USA. This study included 134 patients with PWS (115 patients with 15q11-q13 deletion and 19 with maternal uniparental disomy). Higher mean maternal age was found in this cohort (30.5 vs. 26.7), particularly in the maternal uniparental disomy (UPD) group (36.0 vs. 26.7) comparing with the general population. 88.6% of mothers reported a decrease of fetal movements. 42.5 and 18.7% of mothers had polyhydramnios and oligohydramnios during pregnancy, respectively. 82.8% of the patients were born by caesarean section. 32.1% of neonates had birth asphyxia, 98.5% had hypotonia and 97.8% had weak cry or even no cry at neonatal period. Feeding difficulty existed in 99.3% of the infants, 94.8% of whom had failure to thrive. 69.4% of the infants ever used feeding tube during hospitalization, however, 97.8% of them discontinued tube feeding after discharge. Maternal age and pre-pregnancy weight were significantly higher in the UPD group (both P < 0.05). Differential diagnosis of PWS should be highlighted if infants having following perinatal factors including polyhydramnios, decreased intrauterine fetal movements, caesarean section, low birth weight, feeding difficulty, hypotonia and failure to thrive. Higher maternal age may be a risk factor of PWS, especially for UPD. Further studies are needed for elucidating the mechanism of PWS.

    更新日期:2020-01-22
  • Asymptomatic intracranial aneurysms in beta-thalassemia: a three-year follow-up report
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2020-01-20
    Renzo Manara; Martina Caiazza; Rosanna Di Concilio; Angela Ciancio; Elisa De Michele; Caterina Maietta; Daniela Capalbo; Camilla Russo; Domenico Roberti; Maddalena Casale; Andrea Elefante; Fabrizio Esposito; Sara Ponticorvo; Andrea Gerardo Russo; Antonietta Canna; Mario Cirillo; Silverio Perrotta; Immacolata Tartaglione

    No information is currently available regarding the natural history of asymptomatic intracranial aneurysms in beta-thalassemia, raising several concerns about their proper management. We performed a prospective longitudinal three-year-long MR-angiography study on nine beta-thalassemia patients (mean-age 40.3 ± 7.5, six females, 8 transfusion dependent) harboring ten asymptomatic intracranial aneurysms. In addition, we analyzed the clinical files of all adult beta-thalassemia patients (160 patients including those followed with MR-angiography, 121 transfusion dependent) referring to our Centers between 2014 and 2019 searching for history of subarachnoid hemorrhage or history of symptomatic intracranial aneurysms. At the end of the three-year-long follow-up, no patient showed any change in the size and shape of the aneurysms, none presented new intracranial aneurysms or artery stenoses, none showed new brain vascular-like parenchymal lesions or enlargement of the preexisting ones. Besides, in our database of all adult beta-thalassemia patients, no one had history of subarachnoid hemorrhage or history of symptomatic intracranial aneurysms. Incidental asymptomatic intracranial aneurysms do not seem to be associated, in beta-thalassemia, with an increased risk of complications (enlargement or rupture) at least in the short term period, helping to optimize human and economic resources and patient compliance during their complex long-lasting management.

    更新日期:2020-01-21
  • A study of voice and non-voice processing in Prader-Willi syndrome
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2020-01-20
    Kuzma Strenilkov; Jimmy Debladis; Juliette Salles; Marion Valette; Carine Mantoulan; Denise Thuilleaux; Virginie Laurier; Catherine Molinas; Pascal Barone; Maïthé Tauber

    Prader-Willi syndrome (PWS) is a rare and complex neurodevelopmental disorder of genetic origin. It manifests itself in endocrine and cognitive problems, including highly pronounced hyperphagia and severe obesity. In many cases, impaired acquisition of social and communication skills leads to autism spectrum features, and individuals with this syndrome are occasionally diagnosed with autism spectrum disorder (ASD) using specific scales. Given that communicational skills are largely based on vocal communication, it is important to study human voice processing in PWS. We were able to examine a large number of participants with PWS (N = 61) recruited from France’s national reference center for PWS and other hospitals. We tested their voice and nonvoice recognition abilities, as well as their ability to distinguish between voices and nonvoices in a free choice task. We applied the hierarchical drift diffusion model (HDDM) with Bayesian estimation to compare decision-making in participants with PWS and controls. We found that PWS participants were impaired on both voice and nonvoice processing, but displayed a compensatory ability to perceive voices. Participants with uniparental disomy had poorer voice and nonvoice perception than participants with a deletion on chromosome 15. The HDDM allowed us to demonstrate that participants with PWS need to accumulate more information in order to make a decision, are slower at decision-making, and are predisposed to voice perception, albeit to a lesser extent than controls. The categorization of voices and nonvoices is generally preserved in participants with PWS, though this may not be the case for the lowest IQ.

    更新日期:2020-01-21
  • Education and information needs for physicians about rare diseases in Spain
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2020-01-17
    Enrique Ramalle-Gómara; Elena Domínguez-Garrido; María Gómez-Eguílaz; María Eugenia Marzo-Sola; José Luis Ramón-Trapero; Josefa Gil-de-Gómez

    Rare diseases are a priority objective for public health systems. Given its complexity, late and misdiagnoses occur very often which causes mental and physical burden for patients and family. This would be caused, in part, for unprepared clinicians in this field. The aim of this study was to report the training needs and the perceived shortcomings of Spanish physicians of the public health system in the diagnosis, treatment and monitoring of patients with rare diseases. We used a descriptive cross-sectional study through an “ad hoc” survey of 26 questions was completed by 132 primary care physicians and 37 specialists during April and May 2018. Less than a third of the physicians had received training in rare disease during their undergraduate or postgraduate years, and for hospital professionals, they received more training in the postgraduate period. Primary care physicians and specialists showed low training level in rare diseases. An academical and continuous program on rare disease, as well as, multidisciplinary units and high quality practice guidelines are necessary to help to prevention and support clinical decisions and improve quality of care of patients and families.

    更新日期:2020-01-17
  • Finnish gelsolin amyloidosis causes significant disease burden but does not affect survival: FIN-GAR phase II study
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2020-01-17
    Eeva-Kaisa Schmidt; Tuuli Mustonen; Sari Kiuru-Enari; Tero T. Kivelä; Sari Atula

    Hereditary gelsolin (AGel) amyloidosis is an autosomal dominantly inherited systemic amyloidosis that manifests with the characteristic triad of progressive ophthalmological, neurological and dermatological signs and symptoms. The National Finnish Gelsolin Amyloidosis Registry (FIN-GAR) was founded in 2013 to collect clinical data on patients with AGel amyloidosis, including altogether approximately one third of the Finnish patients. We aim to deepen knowledge on the disease burden and life span of the patients using data from the updated FIN-GAR registry. We sent an updated questionnaire concerning the symptoms and signs, symptomatic treatments and subjective perception on disease progression to 240 members of the Finnish Amyloidosis Association (SAMY). We analyzed the lifespan of 478 patients using the relative survival (RS) framework. The updated FIN-GAR registry includes 261 patients. Symptoms and signs corresponding to the classical triad of ophthalmological (dry eyes in 93%; corneal lattice amyloidosis in 89%), neurological (numbness, tingling and other paresthesias in 75%; facial paresis in 67%), and dermatological (drooping eyelids in 86%; cutis laxa in 84%) manifestations were highly prevalent. Cardiac arrhythmias were reported by 15% of the patients and 5% had a cardiac pacemaker installed. Proteinuria was reported by 13% and renal failure by 5% of the patients. A total of 65% of the patients had undergone a skin or soft tissue surgery, 26% carpal tunnel surgery and 24% at least unilateral cataract surgery. As regards life span, relative survival estimates exceeded 1 for males and females until the age group of 70–74 years, for which it was 0.96. AGel amyloidosis causes a wide variety of ophthalmological, neurological, cutaneous, and oral symptoms that together with repeated surgeries cause a clinically significant disease burden. Severe renal and cardiac manifestations are rare as compared to other systemic amyloidoses, explaining in part the finding that AGel amyloidosis does not shorten the life span of the patients at least for the first 75 years.

    更新日期:2020-01-17
  • Evaluation of retinal microvascular perfusion in hereditary angioedema: a case-control study
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2020-01-17
    Paola Triggianese; Massimo Cesareo; Maria Domenica Guarino; Paola Conigliaro; Maria Sole Chimenti; Francesca Cedola; Caterina Mazzeo; Carlo Nucci; Roberto Perricone

    Evidence supports that hereditary angioedema (HAE) may be considered as a paroxysmal permeability disorder with defective but self-limiting endothelial barrier dysfunction. A potential subclinical abnormal vascular permeability at retinal capillaries could induce damage resulting in retinopathy. We aimed at exploring for the first time the presence of microangiopathy at retinal level from a highly selective cohort of patients with HAE due to C1 esterase inhibitor protein (C1INH) deficiency (type I). We conducted a pilot, prospective, case-control study including 20 type I HAE patients and 20 age−/sex-matched healthy controls (HC). All participants underwent standard ophthalmological examination including visual fields. Superficial and deep capillary plexi in the retina were analyzed by using new optical coherence tomography angiography (OCT-A). A total of 40 eyes from 20 HAE patients and 20 eyes from HC were evaluated. Perimetric indices of visual field were slightly worse in HAE than in controls. OCT-angiograms documented in HAE patients a lower retinal capillary density in both superficial and deep scans and a higher retinal thickness compared to healthy eyes. Our findings firstly documented subclinical abnormalities in retinal microvascular network in type I HAE patients that might be associated with early subtle functional changes. This preliminary evidence supports the hypothesis of a recurrent endothelial barrier failure at retinal level in HAE patients potentially resulting in chronic damage.

    更新日期:2020-01-17
  • Nationwide carrier detection and molecular characterization of β-thalassemia and hemoglobin E variants in Bangladeshi population
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2020-01-15
    Farjana Akther Noor; Nusrat Sultana; Golam Sarower Bhuyan; Md Tarikul Islam; Mohabbat Hossain; Suprovath Kumar Sarker; Khaleda Islam; Waqar Ahmed Khan; Mujahida Rahman; Syeda Kashfi Qadri; Hossain Uddin Shekhar; Firdausi Qadri; Syed Saleheen Qadri; Kaiissar Mannoor

    ß-thalassemia is one of the most common inherited blood disorders in the world and a major deterrent to the public health of Bangladesh. The management of thalassemia patients requires lifelong frequent blood transfusion and the available treatment options are unsatisfactory. A national policy on thalassemia prevention is mandatory in Bangladesh. However, precise and up-to-date information on the frequency of ß-thalassemia carriers are missing due to lack of accurate diagnostic approaches, limited access to information and absence of national screening program. This study aims to determine the nationwide carrier frequency of hemoglobin E (HbE) and β- thalassemia and mutation spectrum among the carriers using molecular, hematological and biochemical methods. The study enrolled a total of 1877 individuals (60.1% male and 39.9% female) aged between 18 and 35 years. Total sample size and its division-wise breakdown were calculated in proportion to national and division-wise population. Venous blood was collected and subjected to CBC analysis and Hb-electrophoresis for each participant. Serum ferritin was measured to detect coexistence of iron deficiency anemia with thalassemia carrier. DNA-based High Resolution Melting (HRM) curve analysis was performed for confirmation of carrier status by mutation detection. Of 11.89% (95% CI, 10.43–13.35) carriers of β-globin gene mutations, 8.68% (95% CI, 7.41–9.95) had HbE trait (ETT) and 2.24% (95% CI, 1.57–2.91) had beta-thalassemia trait (BTT). Among eight divisions, Rangpur had the highest carrier frequency of 27.1% (ETT-25%, BTT-2.1%), whereas Khulna had the lowest frequency of 4.2% (ETT-4.2% only). Moreover, α- thalassemia, HbD trait, HbE disease, hereditary persistence of HbF were detected in 0.11, 0.16, 0.43 and 0.16% participants, respectively. HRM could identify two individuals with reported pathogenic mutations in both alleles who were erroneously interpreted as carriers by hematological indices. Finally, a total of nine different mutations including a novel mutation (c.151A > G) were detected in the β-globin gene. Since carrier frequency for both HbE and β-thalassemia is alarmingly high in Bangladesh, a nationwide awareness and prevention program should be made mandatory to halt the current deteriorating situations. Mutation-based confirmation is highly recommended for the inconclusive cases with conventional carrier screening methods to avoid any faulty detection of thalassemia carriers.

    更新日期:2020-01-15
  • Cross-cutting view of current challenges in paediatric solid organ and haematopoietic stem cell transplantation in Europe: the European Reference Network TransplantChild
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2020-01-15
    P. Jara; A. Baker; U. Baumann; A. M. Borobia; S. Branchereu; M. Candusso; A. J. Carcas; C. Chardot; J. Cobas; L. D’Antiga; C. Ferreras; E. Fitzpatrick; E. Frauca; F. Hernández-Oliveros; P. Kaliciński; C. Lindemans; M. F. Lopes; E. López-Granados; C. de Magnée; C. Mota; J. M. Muñoz; J. J. Ojeda; A. Pérez-Martínez; G. Perilongo; J. Rascon; M. Sciveres; R. Stone; V. Tarutis; J. Toporski; J. M. Torres; L. Wennberg

    The low prevalence of European paediatric transplanted patients and scarcity of resources and expertise led to the need for a multidisciplinary network able to improve the quality of life of paediatric patients and families requiring a solid organ or haematopoietic stem cell transplantation. The European Reference Network (ERN) TransplantChild is one of the 24 ERNs established in a European legal framework to improve the care of patients with rare diseases. ERN TransplantChild is the only ERN focused on both solid organ and haematopoietic stem cell paediatric transplantation, based on the understanding of paediatric transplantation as a complex and highly specialised process where specific complications appear regardless the organ involved, thus linking the skills and knowledge of different organ disciplines. Gathering European centres of expertise in paediatric transplantation will give access to a correct and timely diagnosis, share expertise and knowledge and collect a critical mass of patients and data that increases the speed and value of clinical research outcomes. Therefore, the ERN TransplantChild aims for a paediatric Pan-European, Pan-transplant approach.

    更新日期:2020-01-15
  • European lipodystrophy registry: background and structure
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2020-01-15
    Julia von Schnurbein; Claire Adams; Baris Akinci; Giovanni Ceccarini; Maria Rosaria D’Apice; Alessandra Gambineri; Raoul C. M. Hennekam; Isabelle Jeru; Giovanna Lattanzi; Konstanze Miehle; Gabriele Nagel; Giuseppe Novelli; Ferruccio Santini; Ermelinda Santos Silva; David B. Savage; Paolo Sbraccia; Jannik Schaaf; Ekaterina Sorkina; George Tanteles; Marie-Christine Vantyghem; Camille Vatier; Corinne Vigouroux; Elena Vorona; David Araújo-Vilar; Martin Wabitsch

    Lipodystrophy syndromes comprise a group of extremely rare and heterogeneous diseases characterized by a selective loss of adipose tissue in the absence of nutritional deprivation or catabolic state. Because of the rarity of each lipodystrophy subform, research in this area is difficult and international co-operation mandatory. Therefore, in 2016, the European Consortium of Lipodystrophies (ECLip) decided to create a registry for patients with lipodystrophy. The registry was build using the information technology Open Source Registry System for Rare Diseases in the EU (OSSE), an open-source software and toolbox. Lipodystrophy specific data forms were developed based on current knowledge of typical signs and symptoms of lipodystrophy. The platform complies with the new General Data Protection Regulation (EU) 2016/679 by ensuring patient pseudonymization, informational separation of powers, secure data storage and security of communication, user authentication, person specific access to data, and recording of access granted to any data. Inclusion criteria are all patients with any form of lipodystrophy (with the exception of HIV-associated lipodystrophy). So far 246 patients from nine centres (Amsterdam, Bologna, Izmir, Leipzig, Münster, Moscow, Pisa, Santiago de Compostela, Ulm) have been recruited. With the help from the six centres on the brink of recruitment (Cambridge, Lille, Nicosia, Paris, Porto, Rome) this number is expected to double within the next one or 2 years. A European registry for all patients with lipodystrophy will provide a platform for improved research in the area of lipodystrophy. All physicians from Europe and neighbouring countries caring for patients with lipodystrophy are invited to participate in the ECLip Registry. ClinicalTrials.gov (NCT03553420). Registered 14 March 2018, retrospectively registered.

    更新日期:2020-01-15
  • Outcomes in pediatric studies of medium-chain acyl-coA dehydrogenase (MCAD) deficiency and phenylketonuria (PKU): a review
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2020-01-14
    Michael Pugliese; Kylie Tingley; Andrea Chow; Nicole Pallone; Maureen Smith; Alvi Rahman; Pranesh Chakraborty; Michael T. Geraghty; Julie Irwin; Laure Tessier; Stuart G. Nicholls; Martin Offringa; Nancy J. Butcher; Ryan Iverson; Tammy J. Clifford; Sylvia Stockler; Brian Hutton; Karen Paik; Jessica Tao; Becky Skidmore; Doug Coyle; Kathleen Duddy; Sarah Dyack; Cheryl R. Greenberg; Shailly Jain Ghai; Natalya Karp; Lawrence Korngut; Jonathan Kronick; Alex MacKenzie; Jennifer MacKenzie; Bruno Maranda; John J. Mitchell; Murray Potter; Chitra Prasad; Andreas Schulze; Rebecca Sparkes; Monica Taljaard; Yannis Trakadis; Jagdeep Walia; Beth K. Potter

    Inherited metabolic diseases (IMDs) are a group of individually rare single-gene diseases. For many IMDs, there is a paucity of high-quality evidence that evaluates the effectiveness of clinical interventions. Clinical effectiveness trials of IMD interventions could be supported through the development of core outcome sets (COSs), a recommended minimum set of standardized, high-quality outcomes and associated outcome measurement instruments to be incorporated by all trials in an area of study. We began the process of establishing pediatric COSs for two IMDs, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency and phenylketonuria (PKU), by reviewing published literature to describe outcomes reported by authors, identify heterogeneity in outcomes across studies, and assemble a candidate list of outcomes. We used a comprehensive search strategy to identify primary studies and guidelines relevant to children with MCAD deficiency and PKU, extracting study characteristics and outcome information from eligible studies including outcome measurement instruments for select outcomes. Informed by an established framework and a previously published pediatric COS, outcomes were grouped into five, mutually-exclusive, a priori core areas: growth and development, life impact, pathophysiological manifestations, resource use, and death. For MCAD deficiency, we identified 83 outcomes from 52 articles. The most frequently represented core area was pathophysiological manifestations, with 33 outcomes reported in 29/52 articles (56%). Death was the most frequently reported outcome. One-third of outcomes were reported by a single study. The most diversely measured outcome was cognition and intelligence/IQ for which eight unique measurement instruments were reported among 14 articles. For PKU, we identified 97 outcomes from 343 articles. The most frequently represented core area was pathophysiological manifestations with 31 outcomes reported in 281/343 articles (82%). Phenylalanine concentration was the most frequently reported outcome. Sixteen percent of outcomes were reported by a single study. Similar to MCAD deficiency, the most diversely measured PKU outcome was cognition and intelligence/IQ with 39 different instruments reported among 82 articles. Heterogeneity of reported outcomes and outcome measurement instruments across published studies for both MCAD deficiency and PKU highlights the need for COSs for these diseases, to promote the use of meaningful outcomes and facilitate comparisons across studies.

    更新日期:2020-01-15
  • Out-of-pocket expenses for myasthenia gravis patients in China: a study on patients insured by basic medical insurance in China, 2013–2015
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2020-01-14
    Tao-yu Lin; Xiao-yan Zhang; Peng-qian Fang; Rui Min

    Myasthenia gravis is a rare autoimmune neuromuscular disorder. The disorder requires long-term use of expensive medication to control clinical symptoms. This study analyzed the change in trends of total medical expenses and out-of-pocket expenses for patients with myasthenia gravis and explored the factors influencing them. In this retrospective study, data were derived from a survey of medical service utilization for patients insured by the Urban Basic Medical Insurance in China from 2013 to 2015. The cost data of 3347 patients with myasthenia gravis were included in this study. The baseline characteristics and medical expenses for patients with myasthenia gravis were analyzed using a descriptive method. The difference and influencing factors of the out-of-pocket ratio were analyzed from both outpatient and inpatient expenses by using the quantile regression method. The total expenses reimbursed by the Urban Basic Medicine Insurance for all patients with myasthenia gravis fell progressively from 73.1 to 58.7% during the study period. Patients’ out-of-pocket expenses increased gradually, of which expenses within the scope of Basic Medicine Insurance increased from 14.7 to 22.6% and expenses outside of the Basic Medicine Insurance scope increased from 12.6 to 18.7%. Moreover, the panel quantile results showed a positive correlation between the year of receiving treatment and the out-of-pocket ratio. In addition to the 25th quantile of the out-of-pocket ratio among outpatients with myasthenia gravis, there were significant differences in medical insurance and medical institution among all the other quantiles. Significant regional differences were found in all quantiles of the out-of-pocket ratio, except for the 75th quantile among inpatients. Lastly, age had a negative effect on inpatients with myasthenia gravis across all quantiles, but not on outpatients. From 2013 to 2015, patients with myasthenia gravis’s out-of-pocket expenses increased progressively. Moreover, the individual out-of-pocket ratio was affected by the year, medical insurance, medical institution, region, and age. The current medical insurance policy for the general public has a low ability to cater for patients with myasthenia gravis.

    更新日期:2020-01-15
  • Mutational spectrum of autosomal recessive limb-girdle muscular dystrophies in a cohort of 112 Iranian patients and reporting of a possible founder effect
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2020-01-14
    Marzieh Mojbafan; Reza Bahmani; Samira Dabbagh Bagheri; Zohreh Sharifi; Sirous Zeinali

    Limb-girdle muscular dystrophies are a group of genetically heterogeneous diseases that are inherited in both autosomal dominant (LGMDD) and autosomal recessive forms (LGMDR), the latter is more common especially in populations with high consanguineous marriages like Iran. In the present study, we aimed to investigate the genetic basis of patients who are suspicious of being affected by LGMDR. DNA samples of 60 families suspected of LGMD were extracted from their whole blood. Four short tandem repeat (STR) markers for each candidate genes related to LGMD R1 (calpain3 related)- R6 (δ-sarcoglycan-related) were selected, and all these 24 STRs were applied in two sets of multiplex PCR. After autozygosity mapping, Sanger sequencing and variant analysis were done. Predicting identified variants’ effect was performed using in-silico tools, and they were interpreted according to the American College of Medical Genomics and Genetics (ACMG) guideline. MLPA was used for those patients who had large deletions. Fresh muscle specimens were taken from subjects and were evaluated using the conventional panel of histochemical stains. forty out of sixty families showed homozygote haplotypes in CAPN3, DYSF, SGCA, and SGCB genes. The exons and intron-exon boundaries of the relevant genes were sequenced and totally 38 mutations including CAPN3 (n = 15), DYSF (n = 9), SGCB (n = 11), and SGCA (n = 3) were identified. Five out of them were novel. The most prevalent form of LGMDs in our study was calpainopathy followed by sarcoglycanopathy in which beta-sarcoglycanopathy was the most common form amongst them. Exon 2 deletion in the SGCB gene was the most frequent mutation in this study. We also reported evidence of a possible founder effect in families with mutations in DYSF and SGCB genes. We also detected a large consanguineous family suffered from calpainopathy who showed allelic heterogeneity. This study can expand our knowledge about the genetic spectrum of LGMD in Iran, and also suggest the probable founder effects in some Iranian subpopulations which confirming it with more sample size can facilitate our genetic diagnosis and genetic counseling.

    更新日期:2020-01-15
  • Rare diseases in Chile: challenges and recommendations in universal health coverage context
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-12-11
    Gonzalo Encina; Carla Castillo-Laborde; Juan A. Lecaros; Karen Dubois-Camacho; Juan F. Calderón; Ximena Aguilera; Andrés D. Klein; Gabriela M. Repetto

    Rare diseases (RDs) are a large number of diverse conditions with low individual prevalence, but collectively may affect up to 3.5–5.9% of the population. They have psychosocial and economic impact on patients and societies, and are a significant problem for healthcare systems, especially for countries with limited resources. In Chile, financial protection exists for 20 known RDs through different programs that cover diagnosis and treatments. Although beneficial for a number of conditions, most RD patients are left without a proper legal structure that guarantees a financial coverage, and in a vulnerable situation. In this review, we present and analyze the main challenges of the Chilean healthcare system and legislation on RDs, and other ambits of the RD ecosystem, including patient advocacy groups and research. Finally, we propose a set of policy recommendations that includes creating a patient registry, eliciting social preferences on health and financial coverage, improving access to clinical genetic services and therapies, promoting research on RDs and establishing a Latin-American cooperation network, all aimed at promoting equitable quality healthcare access for people living with RDs.

    更新日期:2020-01-14
  • The Latin American experience with a next generation sequencing genetic panel for recessive limb-girdle muscular weakness and Pompe disease
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2020-01-13
    Jorge A. Bevilacqua; Maria del Rosario Guecaimburu Ehuletche; Abayuba Perna; Alberto Dubrovsky; Marcondes C. Franca; Steven Vargas; Madhuri Hegde; Kristl G. Claeys; Volker Straub; Nadia Daba; Roberta Faria; Magali Periquet; Susan Sparks; Nathan Thibault; Roberto Araujo

    Limb-girdle muscular dystrophy (LGMD) is a group of neuromuscular disorders of heterogeneous genetic etiology with more than 30 directly related genes. LGMD is characterized by progressive muscle weakness involving the shoulder and pelvic girdles. An important differential diagnosis among patients presenting with proximal muscle weakness (PMW) is late-onset Pompe disease (LOPD), a rare neuromuscular glycogen storage disorder, which often presents with early respiratory insufficiency in addition to PMW. Patients with PMW, with or without respiratory symptoms, were included in this study of Latin American patients to evaluate the profile of variants for the included genes related to LGMD recessive (R) and LOPD and the frequency of variants in each gene among this patient population. Over 20 institutions across Latin America (Brazil, Argentina, Peru, Ecuador, Mexico, and Chile) enrolled 2103 individuals during 2016 and 2017. Nine autosomal recessive LGMDs and Pompe disease were investigated in a 10-gene panel (ANO5, CAPN3, DYSF, FKRP, GAA, SGCA, SGCB, SGCD, SGCG, TCAP) based on reported disease frequency in Latin America. Sequencing was performed with Illumina’s NextSeq500 and variants were classified according to ACMG guidelines; pathogenic and likely pathogenic were treated as one category (P) and variants of unknown significance (VUS) are described. Genetic variants were identified in 55.8% of patients, with 16% receiving a definitive molecular diagnosis; 39.8% had VUS. Nine patients were identified with Pompe disease. The results demonstrate the effectiveness of this targeted genetic panel and the importance of including Pompe disease in the differential diagnosis for patients presenting with PMW.

    更新日期:2020-01-14
  • Prevalence of Fabry disease in dialysis patients: Western Australia Fabry disease screening study - the FoRWARD study
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2020-01-13
    Sadia Jahan; Subashini Sarathchandran; Shamina Akhter; Jack Goldblatt; Samantha Stark; Douglas Crawford; Andrew Mallett; Mark Thomas

    To determine the prevalence of undiagnosed Fabry Disease (FD) in Western Australian (WA) patients undergoing dialysis. FD is a multisystem X-linked lysosomal storage disease caused by deficient activity of alpha-galactosidase-A (α-GAL-A). Affected individuals are at risk of developing small-fibre neuropathy, rash, progressive kidney disease, hypertrophic cardiomyopathy and ischaemic stroke. Diagnosis is often delayed by years or even decades. Screening high risk population such as dialysis patients may identify patients with undiagnosed Fabry disease. A cross-sectional study was undertaken of all adult patients receiving dialysis in WA, without previously known FD. After informed consent they were screened for α-GAL-A activity by dried blood spot samples. Low or inconclusive activity were repeated via Centogene in Rostock, Germany with GLA genetic analysis. Ethics approval was granted by Royal Perth Hospital Human Research Ethic Committee REG 14–136; site-specific approval was granted from appropriate authorities; ANZ Clinical Trials Registry U1111–1163-7629. Between February 2015 & September 2017, α-GAL-A activity was performed on 526 patients at 16 dialysis sites. Twenty-nine patients had initial low α-GAL-A; repeat testing & GLA genotyping showed no confirmed FD cases. The causes of false positive rates were thought to be secondary to impaired protein synthesis due to patient malnutrition and chronic inflammation, which is common among dialysis patients, in addition to poor sampling handling. Analysis of this dialysis population has shown a prevalence of 0% undiagnosed FD. False positives results may occur through impaired protein synthesis and sample handling.

    更新日期:2020-01-13
  • Natural history of X-linked hypohidrotic ectodermal dysplasia: a 5-year follow-up study
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2020-01-10
    Sigrun Wohlfart; Ralph Meiller; Johanna Hammersen; Jung Park; Johannes Menzel-Severing; Volker O. Melichar; Kenneth Huttner; Ramsey Johnson; Florence Porte; Holm Schneider

    X-linked hypohidrotic ectodermal dysplasia (XLHED) is caused by pathogenic variants of the gene EDA disrupting the prenatal development of ectodermal derivatives. Cardinal symptoms are hypotrichosis, lack of teeth, and hypo- or anhidrosis, but the disease may also evoke other clinical problems. This study aimed at investigating the clinical course of XLHED in early childhood as the basis for an evaluation of the efficacy of potential treatments. 25 children (19 boys and 6 girls between 11 and 35 months of age) with genetically confirmed XLHED were enrolled in a long-term natural history study. Clinical data were collected both retrospectively using parent questionnaires and medical records (pregnancy, birth, infancy) and prospectively until the age of 60 months. General development, dentition, sweating ability, ocular, respiratory, and skin involvement were assessed by standardized clinical examination and yearly quantitative surveys. All male subjects suffered from persistent anhidrosis and heat intolerance, although a few sweat ducts were detected in some patients. Sweating ability of girls with XLHED ranged from strongly reduced to almost normal. In the male subjects, 1–12 deciduous teeth erupted and 0–8 tooth germs of the permanent dentition became detectable. Tooth numbers were higher but variable in the female group. Most affected boys had no more than three if any Meibomian glands per eyelid, most girls had fewer than 10. Many male subjects developed additional, sometimes severe health issues, such as obstructive airway conditions, chronic eczema, or dry eye disease. Adverse events included various XLHED-related infections, unexplained fever, allergic reactions, and retardation of psychomotor development. This first comprehensive study of the course of XLHED confirmed the early involvement of multiple organs, pointing to the need of early therapeutic intervention.

    更新日期:2020-01-11
  • Management and current status of spinal muscular atrophy: a retrospective multicentre claims database analysis
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2020-01-10
    Josep Darbà

    The interest in patient demographics and disease management has increased in the past years due to their utility in developing measures that allow healthcare providers to reflect disease complexity. To revise the current status of spinal muscular atrophy in the region of Catalonia, and to validate the utility of the database for this aim. Five hundred twenty-four patients diagnosed with a spinal muscular atrophy were identified in the region of Catalonia via the novel program of data analysis for research and innovation in health (PADRIS). Patient records included in the analysis corresponded to primary care, hospital, emergency room, extended care and mental health admissions between 2007 and 2017. 58.02% of patients with a SMA diagnosis were males while 40.84% were females. Average age of diagnosis was 38.31 ± 24.49 years ±SD. Significantly lower was the age of diagnosis of spinal muscular atrophy type I, 1.81 ± 3.01 years. An average of 22 patients died per year during the study period, with a mean decease age of 62.96 ± 25.41 years. Patients were generally attended in hospitals, and the use of healthcare resources was focused on resolving respiratory issues and scoliosis. The highest ratio of admissions per patient was registered in those aged 0 to 4 years. Patients presented a higher risk than the general population and a higher frequency of multimorbidites. Patients exhibited similar characteristics to prior European studies. Multiple admissions in younger patients, mostly due to respiratory issues, have a central role in increasing medical costs of SMA. Equally, the higher risk of patients and increased number of multimorbidity groups translate in an elevated number of admissions in health centres and ER, deriving in higher expenses.

    更新日期:2020-01-11
  • Immunological features of patients affected by Barraquer-Simons syndrome
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2020-01-10
    Fernando Corvillo; Giovanni Ceccarini; Pilar Nozal; Silvia Magno; Caterina Pelosini; Sofía Garrido; Alberto López-Lera; Manuela Moraru; Carlos Vilches; Silvia Fornaciari; Sabrina Gabbriellini; Ferruccio Santini; David Araújo-Vilar; Margarita López-Trascasa

    C3 hypocomplementemia and the presence of C3 nephritic factor (C3NeF), an autoantibody causing complement system over-activation, are common features among most patients affected by Barraquer-Simons syndrome (BSS), an acquired form of partial lipodystrophy. Moreover, BSS is frequently associated with autoimmune diseases. However, the relationship between complement system dysregulation and BSS remains to be fully elucidated. The aim of this study was to provide a comprehensive immunological analysis of the complement system status, autoantibody signatures and HLA profile in BSS. Thirteen subjects with BSS were recruited for the study. The circulating levels of complement components, C3, C4, Factor B (FB) and Properdin (P), as well as an extended autoantibody profile including autoantibodies targeting complement components and regulators were assessed in serum. Additionally, HLA genotyping was carried out using DNA extracted from peripheral blood mononuclear cells. C3, C4 and FB levels were significantly reduced in patients with BSS as compared with healthy subjects. C3NeF was the most frequently found autoantibody (69.2% of cases), followed by anti-C3 (38.5%), and anti-P and anti-FB (30.8% each). Clinical data showed high prevalence of autoimmune diseases (38.5%), the majority of patients (61.5%) being positive for at least one of the autoantibodies tested. The HLA allele DRB1*11 was present in 54% of BSS patients, and the majority of them (31%) were positive for *11:03 (vs 1.3% in the general population). Our results confirmed the association between BSS, autoimmunity and C3 hypocomplementemia. Moreover, the finding of autoantibodies targeting complement system proteins points to complement dysregulation as a central pathological event in the development of BSS.

    更新日期:2020-01-11
  • Genetic profiling and cardiovascular phenotypic spectrum in a Chinese cohort of Loeys-Dietz syndrome patients
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2020-01-08
    Hang Yang; Yanyun Ma; Mingyao Luo; Guoyan Zhu; Yinhui Zhang; Binbin Li; Chang Shu; Zhou Zhou

    Loeys-Dietz syndrome (LDS) is a rare connective tissue disorder for which 6 genes in the TGF-β pathway have been identified as causative. With the widespread use of genetic testing, the range of known clinical and genetic profiles has broadened, but these features have not been fully elucidated thus far. Using gene panel sequencing or whole exome sequencing, we identified 54 unique rare variants in LDS genes in 57 patients with thoracic aneurysms/dissections, including 27 pathogenic mutations (P + LP) and 27 variants of unknown significance (VUSLP + VUS). Genotype-phenotype correlation analysis revealed that carriers with P/LP/ VUSLP variants in TGFBR1/TGFBR2/SMAD3 genes had significantly more severe cardiovascular features (cardiovascular death/dissection) than carriers with VUSs in these 3 genes at an early age and had less favorable event-free survival. Additionally, carriers with VUS in combination with other risk factors, such as hypertension, might be prone to developing an aortic dissection, as indicated by the fact that 5/8 (62.5%) patients with VUSs in our cohort developed aortic dissections in the presence of hypertension, compared with 25.0% (3/12) in the absence of hypertension (p = 0.047). To date, this was the largest cohort of LDS patients ever reported in China, and the present study expanded the known mutation and phenotypic spectra of LDS, which might help refine our knowledge of LDS.

    更新日期:2020-01-08
  • Future treatments for hereditary hemorrhagic telangiectasia
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2020-01-07
    Florian Robert; Agnès Desroches-Castan; Sabine Bailly; Sophie Dupuis-Girod; Jean-Jacques Feige

    Hereditary Hemorrhagic Telangiectasia (HHT), also known as Rendu-Osler syndrome, is a genetic vascular disorder affecting 1 in 5000–8000 individuals worldwide. This rare disease is characterized by various vascular defects including epistaxis, blood vessel dilations (telangiectasia) and arteriovenous malformations (AVM) in several organs. About 90% of the cases are associated with heterozygous mutations of ACVRL1 or ENG genes, that respectively encode a bone morphogenetic protein receptor (activin receptor-like kinase 1, ALK1) and a co-receptor named endoglin. Less frequent mutations found in the remaining 10% of patients also affect the gene SMAD4 which is part of the transcriptional complex directly activated by this pathway. Presently, the therapeutic treatments for HHT are intended to reduce the symptoms of the disease. However, recent progress has been made using drugs that target VEGF (vascular endothelial growth factor) and the angiogenic pathway with the use of bevacizumab (anti-VEGF antibody). Furthermore, several exciting high-throughput screenings and preclinical studies have identified new molecular targets directly related to the signaling pathways affected in the disease. These include FKBP12, PI3-kinase and angiopoietin-2. This review aims at reporting these recent developments that should soon allow a better care of HHT patients.

    更新日期:2020-01-07
  • Hereditary haemorrhagic telangiectasia and pregnancy: a review of the literature
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2020-01-07
    Olivier Dupuis; Laura Delagrange; Sophie Dupuis-Girod

    Hereditary haemorrhagic telangiectasia (HHT) is a dominantly inherited genetic vascular disorder that has prevalence of 1:5000 to 1:8000, and which is characterised by recurrent epistaxis, cutaneous telangiectasia, and arteriovenous malformations (AVMs) that affect many organs including the lungs, gastrointestinal tract, liver, and central nervous system. The aim here was to carry out a review of the literature on HHT complications during pregnancy in order to guide management decisions. A literature review was carried out to analyse all publications on complications that occurred during pregnancy in women with HHT. The PubMed/Medline and Scopus databases were searched. The complications observed in HHT women during pregnancy were then described. The authors identified 5 case series and 31 case reports that describe the evolution of 1577 pregnancies in 630 women with HHT. The overall maternal death rate described in the case series was estimated at 1.0% of pregnancies in the case series and 2 maternal deaths occurred in 31 pregnancy case reports. Severe maternal complications occurred in 2.7 to 6.8% of pregnancies in the case series. Severe complications occurred mostly in the second and third trimester in non-diagnosed and non-screened HHT patients. Severe complications were related to visceral involvement. The most frequent complications were related to pulmonary arteriovenous malformations (PAVMs) (haemothorax (n = 10), haemoptysis (n = 4), and severe hypoxaemia (n = 3)). Neurological complications were related to PAVMs in one case (right to left shunt) and to cerebral arteriovenous malformations (CAVM) and intracranial haemorrhage in 2 cases. Complications were related to hepatic arteriovenous malformations (HAVMs) in 8 cases (acutely decompensated heart failure due to hepatic involvement (n = 1), dyspnoea related to heart failure (n = 5), and hepatobiliary necrosis (n = 2)). Based on the literature review, most pregnancies in HHT women occur normally. However, these pregnancies should be considered high-risk, given the potential life-threatening events related to AVM rupture. Furthermore, there is currently no international consensus regarding the medical follow-up of pregnancy in women with HHT and the aim here was to carry out a review of the literature in order to guide screening and management decisions for this rare disease.

    更新日期:2020-01-07
  • Availability, accessibility and delivery to patients of the 28 orphan medicines approved by the European Medicine Agency for hereditary metabolic diseases in the MetabERN network
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2020-01-06
    Jean-Michel Heard; Charlotte Vrinten; Michael Schlander; Cinzia Maria Bellettato; Corine van Lingen; Maurizio Scarpa

    The European Medicine Agency granted marketing approval to 164 orphan medicinal products for rare diseases, among which 28 products intended for the treatment of hereditary metabolic diseases. Taking advantage of its privileged connection with 69 healthcare centres of excellence in this field, MetabERN, the European Reference Network for hereditary metabolic diseases, performed a survey asking health care providers from 18 European countries whether these products are available on the market, reimbursed and therefore accessible for prescription, and actually delivered in their centre. Responses received from 52 centres (75%) concerned the design of treatment plans, the access to marketed products, and the barriers to delivery. Treatment options are always discussed with patients, who are often involved in their treatment plan. Most products (26/28) are available in most countries (15/18). Among the 15 broadly accessible products (88.5% of the centres), 9 are delivered to most patients (mean 70.1%), and the others to only few (16.5%). Among the 10 less accessible products (40.2% of the centres), 6 are delivered to many patients (66.7%), and 4 are rarely used (6.3%). Information was missing for 3 products. Delay between prescription and delivery is on average one month. Beside the lack of availability or accessibility, the most frequent reasons for not prescribing a treatment are patients’ clinical status, characteristic, and personal choice. Data collected from health care providers in the MetabERN network indicate that two-third of the orphan medicines approved by EMA for the treatment of hereditary metabolic diseases are accessible to treating patients, although often less than one-half of the patients with the relevant conditions actually received the approved product to treat their disease. Thus, in spite of the remarkable achievement of many products, patients concerned by EMA-approved orphan medicinal products have persistent unmet needs, which deserve consideration. The enormous investments made by the companies to develop products, and the high financial burden for the Member States to purchase these products emphasize the importance of a scrupulous appreciation of treatment value involving all stakeholders at early stage of development, before marketing authorization, and during follow up.

    更新日期:2020-01-06
  • The challenges of living with and managing epidermolysis bullosa: insights from patients and caregivers
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2020-01-03
    Anna L. Bruckner; Michael Losow; Jayson Wisk; Nita Patel; Allen Reha; Hjalmar Lagast; Jamie Gault; Jayne Gershkowitz; Brett Kopelan; Michael Hund; Dedee F. Murrell

    Little information is available regarding the burden of living with and managing epidermolysis bullosa, including the distinct challenges faced by patients with different disease types/subtypes. A 90-question/item survey was developed to collect demographics, diagnostic data, management practices, and burden of illness information for patients with epidermolysis bullosa living in the United States. Recruitment was conducted via email and social media in partnership with epidermolysis bullosa patient advocacy organizations in the United States, and the survey was conducted via telephone interview by a third-party health research firm. Respondents aged ≥ 18 years with a confirmed diagnosis of epidermolysis bullosa or caring for a patient with a confirmed diagnosis of epidermolysis bullosa were eligible to participate in the survey. In total, 156 responses were received from patients (n = 63) and caregivers (n = 93) representing the epidermolysis bullosa types of simplex, junctional, and dystrophic (subtypes: dominant and recessive). A large proportion of patients (21%) and caregivers (32%) reported that the condition was severe or very severe, and 19% of patients and 26% of caregivers reported a visit to an emergency department in the 12 months prior to the survey. Among the types/subtypes represented, recessive dystrophic epidermolysis bullosa results in the greatest wound burden, with approximately 60% of patients and caregivers reporting wounds covering > 30% of total body area. Wound care is time consuming and commonly requires significant caregiver assistance. Therapeutic options are urgently needed and reducing the number and severity of wounds was generally ranked as the most important treatment factor. Survey responses demonstrate that epidermolysis bullosa places a considerable burden on patients, their caregivers, and their families. The limitations caused by epidermolysis bullosa mean that both patients and caregivers must make difficult choices and compromises regarding education, career, and home life. Finally, survey results indicate that epidermolysis bullosa negatively impacts quality of life and causes financial burden to patients and their families.

    更新日期:2020-01-04
  • Healthcare trajectory of children with rare bone disease attending pediatric emergency departments
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2020-01-03
    David Dawei Yang; Geneviève Baujat; Antoine Neuraz; Nicolas Garcelon; Claude Messiaen; Arnaud Sandrin; Gérard Cheron; Anita Burgun; Zagorka Pejin; Valérie Cormier-Daire; François Angoulvant

    Children with rare bone diseases (RBDs), whether medically complex or not, raise multiple issues in emergency situations. The healthcare burden of children with RBD in emergency structures remains unknown. The objective of this study was to describe the place of the pediatric emergency department (PED) in the healthcare of children with RBD. We performed a retrospective single-center cohort study at a French university hospital. We included all children under the age of 18 years with RBD who visited the PED in 2017. By cross-checking data from the hospital clinical data warehouse, we were able to trace the healthcare trajectories of the patients. The main outcome of interest was the incidence (IR) of a second healthcare visit (HCV) within 30 days of the index visit to the PED. The secondary outcomes were the IR of planned and unplanned second HCVs and the proportion of patients classified as having chronic medically complex (CMC) disease at the PED visit. The 141 visits to the PED were followed by 84 s HCVs, giving an IR of 0.60 [95% CI: 0.48–0.74]. These second HCVs were planned in 60 cases (IR = 0.43 [95% CI: 0.33–0.55]) and unplanned in 24 (IR = 0.17 [95% CI: 0.11–0.25]). Patients with CMC diseases accounted for 59 index visits (42%) and 43 s HCVs (51%). Multivariate analysis including CMC status as an independent variable, with adjustment for age, yielded an incidence rate ratio (IRR) of second HCVs of 1.51 [95% CI: 0.98–2.32]. The IRR of planned second HCVs was 1.20 [95% CI: 0.76–1.90] and that of unplanned second HCVs was 2.81 [95% CI: 1.20–6.58]. An index PED visit is often associated with further HCVs in patients with RBD. The IRR of unplanned second HCVs was high, highlighting the major burden of HCVs for patients with chronic and severe disease.

    更新日期:2020-01-04
  • Novel phenotypes and genotypes in Antley-Bixler syndrome caused by cytochrome P450 oxidoreductase deficiency: based on the first cohort of Chinese children
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-12-30
    Lijun Fan; Xiaoya Ren; Yanning Song; Chang Su; Junfen Fu; Chunxiu Gong

    Antley-Bixler syndrome (ABS) caused by P450 oxidoreductase deficiency (PORD) is a congenital adrenal hyperplasia with skeletal malformations and disordered sex development in both sexes. There have been no reports of ABS caused by PORD in Chinese children. We described the clinical and genetic characteristics of eight Chinese children with ABS caused by PORD and compared them with those of subjects in previous studies. Eight patients, aged 6 months–17.8 years, showed strikingly similar craniofacial malformations. We first described four unreported features: lower eyelid fat pads (4/8), prominent lower eyelid-zygoma transverse line (4/8), underdeveloped or absent antihelix (5/8) and single earlobe crease (5/8). Five 46, XY patients presented various degrees of undervirilization, while three 46, XX cases showed masculinization. Basal endocrine measurements revealed the following consistent results: normal cortisol; elevated adrenocorticotropic hormone, progesterone, pregnenolone, 17-hydroxypropgesterone, and corticosterone; and decreased or normal testosterone/oestradiol. We identified three previously reported variants and four novel variants (c.51719_51710delGGCCCCTGTGinsC, p.D210G, p.Y248X and p.R554X) of POR. The most prevalent variant was p.R457H (8/16). The hydrocortisone dosages of patients differed because of variable degrees of adrenal insufficiency. We described novel phenotypes and genotypes of ABS caused by PORD. The variant p.R457H was the most prevalent in this cohort. All subjects had combined characteristics of 17-hydroxylase and 21-hydroxylase deficiency. Steroid replacement therapy for patients with PORD requires individually tailored dosing.

    更新日期:2019-12-31
  • The evolving therapeutic landscape of genetic skeletal disorders
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-12-30
    Ataf Hussain Sabir; Trevor Cole

    Rare bone diseases account for 5% of all birth defects yet very few have personalised treatments. Developments in genetic diagnosis, molecular techniques and treatment technologies however, are leading to unparalleled therapeutic advance. This review explores the evolving therapeutic landscape of genetic skeletal disorders (GSDs); the key conditions and there key differentials. A retrospective literature based review was conducted in December 2018 using a systematic search strategy for relevant articles and trials in Pubmed and clinicaltrials.gov respectively. Over 140 articles and 80 trials were generated for review. Over 20 personalised therapies are discussed in addition to several novel disease modifying treatments in over 25 GSDs. Treatments discussed are at different stages from preclinical studies to clinical trials and approved drugs, including; Burosumab for X-linked hypophosphatemia, Palovarotene for Hereditary Multiple Exostoses, Carbamazepine for Metaphyseal Chondrodysplasia (Schmid type), Lithium carbonate and anti-sclerostin therapy for Osteoporosis Pseudoglioma syndrome and novel therapies for Osteopetrosis. We also discuss therapeutic advances in Achondroplasia, Osteogenesis Imperfecta (OI), Hypophosphotasia (HPP), Fibrodysplasia Ossificans Progressiva, and RNA silencing therapies in preclinical studies for OI and HPP. It is an exciting time for GSD therapies despite the challenges of drug development in rare diseases. In discussing emerging therapies, we explore novel approaches to drug development from drug repurposing to in-utero stem cell transplants. We highlight the improved understanding of bone pathophysiology, genetic pathways and challenges of developing gene therapies for GSDs.

    更新日期:2019-12-31
  • Retinal hyperreflective foci in Fabry disease
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-12-26
    Yevgeniya Atiskova; Rahman Rassuli; Anja Friederike Koehn; Amir Golsari; Lars Wagenfeld; Marcel du Moulin; Nicole Muschol; Simon Dulz

    Fabry disease (FD) is an X-linked inherited storage disorder caused by deficiency of lysosomal alpha-Galactosidase A. Here we describe new retinal findings in patients with FD assessed by Spectral domain optical coherence tomography (SD-OCT) and their possible clinical relevance. 54 eyes of 27 FD patients and 54 eyes of 27 control subjects were included. The ophthalmic examination included visual acuity testing, tonometry, slit lamp and fundus examination. SD-OCT imaging of the macula was performed in all subjects. Central retinal thickness and retinal nerve fiber layer analysis were quantified. Vessel tortuosity was obtained by a subjective scoring and mathematically calculated. Inner retinal hyperreflective foci (HRF) were quantified, clinically graded and correlated with a biomarker of Fabry disease (lyso-Gb3). In comparison to an age-matched control group, a significant amount of HRF was identified in macular SD-OCT images in FD patients. These HRF were localized within the inner retinal layers. Furthermore, lyso-Gb3 levels correlated significantly with the quantitative evaluation of HRF (p < 0,001). In addition, the vessel tortuosity was remarkably increased in FD patients compared to control persons and correlated significantly with lyso-G3 levels (p = 0.005). A further subanalysis revealed significantly higher HRF and vessel tortuosity scores in male patients with the classic FD phenotype. The observational, cross sectional, comparative study describes novel intraretinal findings in patients with FD. We were able to identify suspicious HRF within the inner retinal layers. These findings were not accompanied by functional limitations, as visual acuity remained unchanged. However, HRF correlated well with lyso-Gb3, a degradation product of the accumulating protein Gb3 and might potentially indicate Gb3 accumulation within the highly metabolic and densely vascularized macula.

    更新日期:2019-12-27
  • Primary hypertrophic osteoarthropathy related gastrointestinal complication has distinctive clinical and pathological characteristics: two cases report and review of the literature
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-12-26
    Qiang Wang; Ying-he Li; Guo-le Lin; Yue Li; Wei-xun Zhou; Jia-ming Qian; Wei-bo Xia; Dong Wu

    Primary hypertrophic osteoarthropathy (PHO) is a rare disease related to HPGD and SLCO2A1 gene mutation. Gastrointestinal involvement of PHO is even rarer with unknown pathogenesis. Clinical features of GI complication in PHO mimics other auto-immune based bowel entities, such as inflammatory bowel diseases and cryptogenic multifocal ulcerous stenosing enteritis (CMUSE). We aimed to analyze the clinical, genetic, radiological and pathological features of Chinese patients with PHO and determine the difference between PHO patients presenting with and without GI involvement. We reported two PHO cases with gastrointestinal involvement and reviewed all the studies of PHO in Chinese population published from January 1, 2000, to April 30, 2018. Clinical and genetic presentations of PHO in Chinese patients were analyzed. We compared the characteristics of those patients with gastrointestinal involvement against those without. The two patients were both males with complete-form PHO for more than 10 years. GI related symptoms included diarrhea, chronic gastrointestinal hemorrhage, incomplete intestinal obstruction, anemia, and edema, which were unresponsive to etoricoxib treatment. Radiological examinations revealed segmental intestinal stenosis and thickened intestinal wall. Endoscopic findings included multiple ulcers and mucosal inflammation. Both patients had mutations of SLCO2A1 according to sequence analysis. The surgical pathology revealed chronic inflammation involving the intestinal mucosa and submucosa, similar to histological changes in CMUSE. According to the systemic review of 158 Chinese patients with PHO, 17.2% had gastrointestinal involvement, including peptic ulcer, gastric polyps, hypertrophic gastritis, and segmental intestinal stenosis. Patients with gastrointestinal involvement were more likely to have anemia (40.0% vs. 4.5%, P < 0.001), hypoalbuminemia (16.7% vs. 0.9%, P = 0.003), and myelofibrosis (19.0% vs. 0.9%, P = 0.002) than those without. Most patients with gastrointestinal complication had SLCO2A1 mutation (86.7%, 13 /15). Digestive tract involvement is uncommon in patients with PHO and often presents with anemia, and hypoalbuminemia resulted from intestinal inflammation. The intestinal pathologic characteristics are distinct from Crohn’s disease but similar to CMUSE. Mutations in SLCO2A1 might be the pathogenic cause of GI involvement of PHO. NSAIDs may not be effective for PHO patients with gastrointestinal complications.

    更新日期:2019-12-27
  • Safety of antithrombotic therapy in subjects with hereditary hemorrhagic telangiectasia: prospective data from a multidisciplinary working group
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-12-26
    Eleonora Gaetani; Fabiana Agostini; Angelo Porfidia; Igor Giarretta; Daniela Feliciani; Luigi Di Martino; Annalisa Tortora; Antonio Gasbarrini; Roberto Pola

    Subjects with the rare autosomal dominant disease Hereditary Hemorrhagic Telangiectasia (HHT) may develop medical conditions that require antithrombotic therapy (AT). However, safety of AT is uncertain in these patients and the only data currently available derive from retrospective analyses of registries and/or databases. At the HHT Centre of the ‘Fondazione Policlinico Universitario A. Gemelli IRCCS’ (Rome, Italy), a prospective study is currently ongoing to evaluate the safety of AT in subjects affected by HHT. The study is enrolling subjects with a definite diagnosis of HHT who receive an AT prescription by one of the physicians of the HHT Centre. The primary outcome is the number of hemorrhagic events, distinguished in major, clinically relevant non-major (CRNM), and minor bleedings, according to the criteria of the International Society on Thrombosis and Hemostasis (ISTH). Another primary outcome is worsening of epistaxis upon initiation of AT, assessed using the internationally accepted Epistaxis Severity Score (ESS). Additional outcomes are changes in hemoglobin levels and changes in the need of blood transfusion after initiation of AT. Here, we present the results of an interim analysis, conducted on the 12 HHT subjects that have been enrolled so far. After a mean follow-up of 6.5 ± 0.8 months, no major bleedings, no CRNM bleedings, and no minor bleedings different from epistaxis were recorded. Worsening of epistaxis upon initiation of AT was documented only in one patient, but did not require discontinuation of AT. There were no significant changes in the mean ESS measured before and after initiation of AT. There were no significant changes in hemoglobin levels and need for blood transfusion after initiation of AT. Although preliminary, these are the first prospective data on the safety of AT in HHT patients. Our interim analysis suggests that, when prescribed by experienced physicians in a multidisciplinary setting, AT is well tolerated by HHT patients. More patients and a longer follow-up are needed to confirm these findings.

    更新日期:2019-12-27
  • Novel mutations in the 3-box motif of the BACK domain of KLHL7 associated with nonsyndromic autosomal dominant retinitis pigmentosa
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-12-19
    Jin Kyun Oh; Jose Ronaldo Lima de Carvalho; Young Joo Sun; Sara Ragi; Jing Yang; Sarah R. Levi; Joseph Ryu; Alexander G. Bassuk; Vinit B. Mahajan; Stephen H. Tsang

    Mutations in the Kelch-like protein 7 (KLHL7) represent a recently described and, to date, poorly characterized etiology of inherited retinal dystrophy. Dominant mutations in KLHL7 are a cause of isolated, non-syndromic retinitis pigmentosa (RP). In contrast, recessive loss-of-function mutations are known to cause Crisponi or Bohring-Opitz like cold induced sweating syndrome-3 (BOS-3). In this study, the phenotype and progression of five unrelated patients with KLHL7 mediated autosomal dominant RP (adRP) are characterized. Clinical evaluation of these patients involved a complete ophthalmic exam, full-field electroretinography (ffERG), and imaging, including fundus photography, spectral domain optical coherence tomography (SD-OCT), short wavelength fundus autofluorescence (SW-AF), and near-infrared fundus autofluorescence (NIR-AF). Molecular diagnoses were performed using whole-exome sequencing or gene panel testing. Disease progression was monitored in three patients with available data for a mean follow up time of 4.5 ± 2.9 years. Protein modeling was performed for all variants found in this study in addition to those documented in the literature for recessive loss-of-function alleles causing Crisponi or Bohring-Opitz like cold-induced sweating syndrome. Genetic testing in three patients identified two novel variants within the 3-box motif of the BACK domain: c.472 T > C:p.(Cys158Arg) and c.433A > T:p.(Asn145Tyr). Clinical imaging demonstrated hyperautofluorescent ring formation on both SW-AF and NIR-AF in three patients, with diffuse peripheral and peripapillary atrophy seen in all but one case. SD-OCT demonstrated a phenotypic spectrum, from parafoveal atrophy of the outer retina with foveal sparing to widespread retinal thinning and loss of photoreceptors. Incidence of cystoid macular edema was high with four of five patients affected. Protein modeling of dominant alleles versus recessive loss-of-function alleles showed dominant alleles localized to the BTB and BACK domains while recessive alleles were found in the Kelch domain. We report the phenotype in five patients with KLHL7 mediated adRP, two novel coding variants, and imaging biomarkers using SW-AF and NIR-AF. These findings may influence future gene-based therapies for adRP and pave the way for mechanistic studies that elucidate the pathogenesis of KLHL7-mediated RP.

    更新日期:2019-12-20
  • Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-12-19
    M. M. Hitzert; S. N. van der Crabben; G. Baldewsingh; H. K. Ploos van Amstel; A. van den Wijngaard; C. M. A. van Ravenswaaij-Arts; C. W. R. Zijlmans

    Mandibuloacral Dysplasia with type B lipodystrophy (MADB) is a rare premature aging disorder with an autosomal recessive inheritance pattern. MADB is characterized by brittle hair, mottled, atrophic skin, generalized lipodystrophy, insulin resistance, metabolic complications and skeletal features like stunted growth, mandibular and clavicular hypoplasia and acro-osteolysis of the distal phalanges. MADB is caused by reduced activity of the enzyme zinc metalloprotease ZMPSTE24 resulting from compound heterozygous or homozygous mutations in ZMPSTE24. In 2012, and again in 2018, eight related patients from the remote tropical rainforest of inland Suriname were analysed for dysmorphic features. DNA analysis was performed and clinical features were documented. We also analysed all previously reported genetically confirmed MADB patients from literature (n = 12) for their clinical features. Based on the features of all cases (n = 20) we defined major criteria as those present in 85–100% of all MADB patients and minor criteria as those present in 70–84% of patients. All the Surinamese patients are of African descent and share the same homozygous c.1196A > G, p.(Tyr399Cys) missense variant in the ZMPSTE24 gene, confirming MADB. Major criteria were found to be: short stature, clavicular hypoplasia, delayed closure of cranial sutures, high palate, mandibular hypoplasia, dental crowding, acro-osteolysis of the distal phalanges, hypoplastic nails, brittle and/or sparse hair, mottled pigmentation, atrophic and sclerodermic skin, and calcified skin nodules. Minor criteria were (generalized or partial) lipoatrophy of the extremities, joint contractures and shortened phalanges. Based on our detailed clinical observations, and a review of previously described cases, we propose that the clinical diagnosis of MADB is highly likely if a patient exhibits ≥4 major clinical criteria OR ≥ 3 major clinical criteria and ≥ 2 minor clinical criteria. We report on eight related Surinamese patients with MADB due to a homozygous founder mutation in ZMPSTE24. In low-income countries laboratory facilities for molecular genetic testing are scarce or lacking. However, because diagnosing MADB is essential for guiding clinical management and for family counselling, we defined clinical diagnostic criteria and suggest management guidelines.

    更新日期:2019-12-19
  • Oral health-related quality of life in Loeys-Dietz syndrome, a rare connective tissue disorder: an observational cohort study
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-12-16
    Quynh C. Nguyen; Olivier Duverger; Rashmi Mishra; Gabriela Lopez Mitnik; Priyam Jani; Pamela A. Frischmeyer-Guerrerio; Janice S. Lee

    Loeys-Dietz syndrome (LDS) is a rare connective tissue disorder whose oral manifestations and dental phenotypes have not been well-characterized. The aim of this study was to explore the influence of oral manifestations on oral health-related quality of life (OHRQoL) in LDS patients. LDS subjects were assessed by the craniofacial team at the National Institutes of Health Clinical Center Dental Clinic between June 2015 and January 2018. Oral Health Impact Profile (OHIP-14) questionnaire, oral health self-care behavior questionnaire and a comprehensive dental examination were completed for each subject. OHRQoL was assessed using the OHIP-14 questionnaire with higher scores corresponding to worse OHRQoL. Regression models were used to determine the relationship between each oral manifestation and the OHIP-14 scores using a level of significance of p ≤ 0.05. A total of 33 LDS subjects (51.5% female) aged 3–57 years (19.6 ± 15.1 years) were included in the study. The OHIP-14 scores (n = 33) were significantly higher in LDS subjects (6.30 [SD 6.37]) when compared to unaffected family member subjects (1.50 [SD 2.28], p < 0.01), and higher than the previously reported scores of the general U.S. population (2.81 [SD 0.12]). Regarding oral health self-care behavior (n = 32), the majority of LDS subjects reported receiving regular dental care (81%) and maintaining good-to-excellent daily oral hygiene (75%). Using a crude regression model, worse OHRQoL was found to be associated with dental hypersensitivity (β = 5.24; p < 0.05), temporomandibular joints (TMJ) abnormalities (β = 5.92; p < 0.01), self-reported poor-to-fair oral health status (β = 6.77; p < 0.01), and cumulation of four or more oral manifestations (β = 7.23; p < 0.001). Finally, using a parsimonious model, self-reported poor-to-fair oral health status (β = 5.87; p < 0.01) and TMJ abnormalities (β = 4.95; p < 0.01) remained significant. The dental hypersensitivity, TMJ abnormalities, self-reported poor-to-fair oral health status and cumulation of four-or-more oral manifestations had significant influence on worse OHRQoL. Specific dental treatment guidelines are necessary to ensure optimal quality of life in patients diagnosed with LDS.

    更新日期:2019-12-17
  • Methylmalonic and propionic acidemia among hospitalized pediatric patients: a nationwide report
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-12-16
    Yi-Zhou Jiang; Yu Shi; Ying Shi; Lan-Xia Gan; Yuan-Yuan Kong; Zhi-Jun Zhu; Hai-Bo Wang; Li-Ying Sun

    Methylmalonic acidemia (MMA) and propionic acidemia (PA) are two kinds of diseases caused by inborn errors of metabolism. So far, the epidemiological data on them are limited in China. The aim of our study is to investigate the proportion and characteristics of hospitalized pediatric patients with MMA and PA in China. The data in this study were obtained from the Hospital Quality Monitoring System, a national inpatient database in China, with information on the patients hospitalized during the period from 2013 to 2017. We identified the data related to the patients who were under 18 years old and were diagnosed with MMA/PA, and extracted the information on demographic characteristics, hospital location, total cost and other related clinical presentations from the data. Among all hospitalized pediatric patients with liver diseases, there were increasing trends in the proportion of individuals diagnosed with MMA or PA during the period from 2013 (0.76% for MMA; 0.13% for PA) to 2017 (1.61% for MMA; 0.32% for PA). For both MMA and PA, children under 2-year-old accounted for the highest proportion. The median of total cost per hospitalization was relatively high (RMB 7388.53 for MMA; RMB 4999.66 for PA). Moreover, most patients hospitalized in tertiary class A hospitals (MMA: 80.96%, PA: 76.21%); and a majority of pediatric patients admitted in the hospitals in Shanghai and Beijing are from outside districts. Manifestations of nervous system-related symptoms, and metabolic acidosis or anemia in laboratory findings were more common during hospitalization. The study is the first nationwide one in providing epidemiological and clinical information on hospitalized pediatric patients with MMA/PA. An increasing hospitalization with various presentations and a heavy financial burden were observed. In addition, geographically, the medical resources in China have been unevenly distributed.

    更新日期:2019-12-17
  • Histopathological features of condylar hyperplasia and condylar Osteochondroma: a comparison study
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-12-16
    Jingshuang Yu; Tong Yang; Jiewen Dai; Xudong Wang

    Both mandibular condylar hyperplasia and condylar osteochondroma can lead to maxillofacial skeletal asymmetry and malocclusion, although they exhibit different biological behavior. This study attempted to compare the histological features of mandibular condylar hyperplasia and condylar osteochondroma using hematoxylin-and-eosin (H&E) staining, and immunohistochemistry staining of PCNA and EXT1 with quantitative analysis method. The H&E staining showed that condylar hyperplasia and condylar osteochondroma could be divided into four histological types and exhibited features of different endochondral ossification stages. There was evidence of a thicker cartilage cap in condylar osteochondroma as compared condylar hyperplasia (P = 0.018). The percentage of bone formation in condylar osteochondroma was larger than was found in condylar hyperplasia (P = 0.04). Immunohistochemical staining showed that PCNA was mainly located in the undifferentiated mesenchymal layer and the hypertrophic cartilage layer, and there were more PCNA positive cells in the condylar osteochondroma (P = 0.007). EXT1 was mainly expressed in the cartilage layer, and there was also a higher positive rate of EXT1 in condylar osteochondroma (P = 0.0366). The thicker cartilage cap, higher bone formation rate and higher PCNA positive rate indicated a higher rate of proliferative activity in condylar osteochondroma. The more significant positive rate of EXT1 in condylar osteochondroma implied differential biological characteristic as compared to condylar hyperplasia. These features might be useful in histopathologically distinguishing condylar hyperplasia and osteochondroma.

    更新日期:2019-12-17
  • Expanding the clinical and genetic spectrum of Heimler syndrome
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-12-12
    Feng-Juan Gao; Fang-Yuan Hu; Ping Xu; Yu-He Qi; Jian-Kang Li; Yong-Jin Zhang; Fang Chen; Qing Chang; Fang Song; Si-Mai Shen; Ge-Zhi Xu; Ji-Hong Wu

    Heimler syndrome (HS) is a rare hereditary systemic disorder, partial clinically overlapping with Usher syndrome. So far, our knowledge of HS is very limited, many cases are misdiagnosed or may not even be diagnosed at all. This study aimed to analyze the clinical and genetic characteristics of HS, and to evaluate potential phenotype–genotype correlations. Two HS cases caused by PEX1 mutations were identified, and a novel likely pathogenic mutation, PEX1 c.895_896insTATA, was found. The main ophthalmic finding of the two patients was consistent with retinitis pigmentosa accompanied by cystoid macular edema, but short axial length and hyperopia were also observed as two previously unreported ocular phenotypes. Analysis of the literature showed that of the 29 HS patients previously reported, 12 had PEX6 mutations, 10 had PEX1 mutations, two had PEX26 mutations, and the remaining patients were not genetically tested. Three novel genotype–phenotype correlations were revealed from analysis of these patients. First, most genotypes of every HS patient include at least one missense variant; second, at least one mutation in PEX1 or PEX6 gene affects the AAA-ATPase region in every HS patient with retinal dystrophy, suggesting AAA-ATPase region is a hypermutable region in patients with a retinal dystrophy; third, there are no significant differences between PEX1-, PEX6-, and PEX26-associated phenotypes. Next-generation sequencing is important for the diagnosis of HS. This study expands the clinical and genetic spectrum of HS, and provides additional insights into genotype–phenotype correlations, which is vital for accurate clinical practice, genetic counseling, and pathogenesis studies.

    更新日期:2019-12-13
  • An analysis of orphan medicine expenditure in Europe: is it sustainable?
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-12-11
    Jorge Mestre-Ferrandiz; Christina Palaska; Tom Kelly; Adam Hutchings; Adam Parnaby

    Orphan medicinal product (OMP) prices are considered by some to be a challenge to the sustainability of healthcare expenditure. These concerns are compounded by the increasing number of OMPs receiving marketing authorisation (MA) annually. The aim of this study was to explore the sustainability of OMP expenditure within the context of total European pharmaceutical expenditure. Using historical IQVIA data, an analysis was conducted on total pharmaceutical and OMP expenditure in eight countries (using values / volumes) in the branded, non-branded and overall pharmaceutical market. Country level and aggregated data was considered for EU5 countries, Austria, Belgium and Ireland. Three key analyses were conducted: Across countries, OMP share of total pharmaceutical expenditure has increased each year since 2000, rising to 7.2% of total pharmaceutical expenditure in 2017. OMP expenditure has increased at a CAGR of 16% since 2010. The number of OMPs receiving MA each year showed a CAGR of 11% since 2001, four percentage points greater than the CAGR for all medicines receiving MA over the same period. OMP share of total pharmaceutical expenditure is higher than forecasted in 2011 due to slower than expected growth in the non-OMP market. OMP growth has been offset by reduced expenditure in the general market and increased use of generics and biosimilars. Relative spending on OMPs has increased over the last 20 years, but this has been largely compensated for within the current allocation of total pharmaceutical spending by flat expenditure for non-OMPs and increased volumes of (lower-priced) generics/biosimilars, reflecting a shift towards expenditure in higher cost, lower volume patient populations and a shift in drug development towards more specialised targeting of diseases.

    更新日期:2019-12-11
  • Outcomes of 4 years of molecular genetic diagnosis on a panel of genes involved in premature aging syndromes, including laminopathies and related disorders
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-12-11
    Maude Grelet; Véronique Blanck; Sabine Sigaudy; Nicole Philip; Fabienne Giuliano; Khaoula Khachnaoui; Godelieve Morel; Sarah Grotto; Julia Sophie; Céline Poirsier; James Lespinasse; Laurent Alric; Patrick Calvas; Gihane Chalhoub; Valérie Layet; Arnaud Molin; Cindy Colson; Luisa Marsili; Patrick Edery; Nicolas Lévy; Annachiara De Sandre-Giovannoli

    Segmental progeroid syndromes are a heterogeneous group of rare and often severe genetic disorders that have been studied since the twentieth century. These progeroid syndromes are defined as segmental because only some of the features observed during natural aging are accelerated. Since 2015, the Molecular Genetics Laboratory in Marseille La Timone Hospital proposes molecular diagnosis of premature aging syndromes including laminopathies and related disorders upon NGS sequencing of a panel of 82 genes involved in these syndromes. We analyzed the results obtained in 4 years on 66 patients issued from France and abroad. Globally, pathogenic or likely pathogenic variants (ACMG class 5 or 4) were identified in about 1/4 of the cases; among these, 9 pathogenic variants were novel. On the other hand, the diagnostic yield of our panel was over 60% when the patients were addressed upon a nosologically specific clinical suspicion, excepted for connective tissue disorders, for which clinical diagnosis may be more challenging. Prenatal testing was proposed to 3 families. We additionally detected 16 variants of uncertain significance and reclassified 3 of them as benign upon segregation analysis in first degree relatives. High throughput sequencing using the Laminopathies/ Premature Aging disorders panel allowed molecular diagnosis of rare disorders associated with premature aging features and genetic counseling for families, representing an interesting first-level analysis before whole genome sequencing may be proposed, as a future second step, by the National high throughput sequencing platforms (“Medicine France Genomics 2025” Plan), in families without molecular diagnosis.

    更新日期:2019-12-11
  • Cutis marmorata telangiectatica congenita: a literature review
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-12-04
    Teresa Nu Phuong Trinh Bui; Ayse Corap; Anette Bygum

    Cutis marmorata telangiectatica congenita (CMTC) is a rare capillary malformation characterised by persistent reticulated marbled erythema. It tends to be associated with cutaneous atrophy, ulcerations and body asymmetry. CMTC is usually reported to be a benign condition; however, associated anomalies are not rare. Here, we have compiled information on published CMTC patients with the aim to evaluate the proposed diagnostic criteria by Kienast et al. and address the clinical manifestations, associated anomalies, differential diagnoses, management and prognosis. Our review is based on a search of the PubMed database which retrieved studies between 1922 and April 2019. The search yielded 148 original articles with a total of 485 patients. Of the identified patients, 24.5% had generalised CMTC, 66.8% had localised and 8.7% had a non-specified distribution of CMTC. Associated anomalies were observed in 42.5% of patients, predominantly body asymmetry and neurological defects like seizure and developmental delay. Fewer patients (10.1%) had ophthalmological defects, usually glaucoma. The major criterium “absence of venectasia” was not met in 20.4% of patients. We suggest that children with CMTC should be referred to an ophthalmologist for regular follow-up, and children with CMTC affecting the legs should be monitored for leg length discrepancy throughout the growth period. Furthermore, we suggest reconsideration of the major criterium “absence of venectasia” from the proposed diagnostic criteria, and instead include body asymmetry.

    更新日期:2019-12-05
  • Treatment needs and expectations for Fabry disease in France: development of a new Patient Needs Questionnaire
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-12-04
    Esther Noël; Bertrand Dussol; Didier Lacombe; Najya Bedreddine; Alain Fouilhoux; Pierre Ronco; Delphine Genevaz; Soumeya Bekri; Albert Hagège; Frédérique Dupuis-Siméon; Valérie Derrien Ansquer; Dominique P. Germain; Olivier Lidove

    Fabry disease (FD) is a rare, X-linked, inherited lysosomal disease caused by absent or reduced α-galactosidase A activity. Due to the heterogeneity of disease presentation and progression, generic patient-reported outcome (PRO) tools do not provide accurate insight into patients’ daily lives and impact of disease specific treatments. Also, the French National Health Authority, (HAS) actively encourages a patient-centric approach to improve the quality of care throughout the patient journey. In response to this initiative, we aimed to develop and validate a specific, self-reported, Patient Needs Questionnaire for people living with Fabry disease to appraise patient needs and expectations towards their treatment (PNQ Fabry). This endeavour was led with the help of French patient associations (APMF & VML) and dedicated expert centres. PNQ Fabry was developed according to the FDA/EMA methodologies and best practices for the development of PRO tools in rare diseases. Our approach comprised of three steps, as follows: concept elicitation and item generation, item reduction, and final validation of the questionnaire through a two-stage survey. Intrinsic and extrinsic reliability was established, using a validated benchmark questionnaire. With the invaluable help of patient associations, we recruited a satisfactory population in this rare disease setting, to ensure robust participation to validate our PNQ (final number of questionnaires: 76). At the end of the process, a 26-item patient-reported questionnaire was obtained with excellent psychometric properties, exhibiting very satisfactory measurement outcomes for reliability and validity. The results of this initiative demonstrate that the PNQ Fabry is accurate, suitable and tailored to FD patients, as it addresses themes identified during patient interviews, that were further validated through statistical analyses of quantitative surveys. An ongoing phase IV study is using this tool. We believe the PNQ Fabry will be a reliable and insightful tool in clinical practice, to improve patient management in FD.

    更新日期:2019-12-05
  • Emotional and behavioral problems, quality of life and metabolic control in NTBC-treated Tyrosinemia type 1 patients
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-12-04
    Kimber van Vliet; Willem G. van Ginkel; Rianne Jahja; Anne Daly; Anita MacDonald; Corinne De Laet; Roshni Vara; Yusof Rahman; David Cassiman; Francois Eyskens; Corrie Timmer; Nicky Mumford; Jörgen Bierau; Peter M. van Hasselt; Paul Gissen; Philippe J. Goyens; Patrick J. McKiernan; Gisela Wilcox; Andrew A. M. Morris; Elisabeth A. Jameson; Stephan C. J. Huijbregts; Francjan J. van Spronsen

    Treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) and dietary phenylalanine and tyrosine restriction improves physical health and life expectancy in Tyrosinemia type 1 (TT1). However, neurocognitive outcome is suboptimal. This study aimed to investigate behavior problems and health-related quality of life (HR-QoL) in NTBC-dietary-treated TT1 and to relate this to phenylalanine and tyrosine concentrations. Thirty-one TT1 patients (19 males; mean age 13.9 ± 5.3 years) were included in this study. Emotional and behavioral problems, as measured by the Achenbach System of Empirically Based Assessment, were present in almost all domains. Attention and thought problems were particularly evident. HR-QoL was assessed by the TNO AZL Children’s and Adults QoL questionnaires. Poorer HR-QoL as compared to reference populations was observed for the domains: independent daily functioning, cognitive functioning and school performance, social contacts, motor functioning, and vitality. Both internalizing and externalizing behavior problems were associated with low phenylalanine (and associated lower tyrosine) concentrations during the first year of life. In contrast, high tyrosine (and associated higher phenylalanine) concentrations during life and specifically the last year before testing were associated with more internalizing behavior and/or HR-QoL problems. TT1 patients showed several behavior problems and a lower HR-QoL. Associations with metabolic control differed for different age periods. This suggests the need for continuous fine-tuning and monitoring of dietary treatment to keep phenylalanine and tyrosine concentrations within target ranges in NTBC-treated TT1 patients.

    更新日期:2019-12-05
  • Cutaneous neurofibromas: patients’ medical burden, current management and therapeutic expectations: results from an online European patient community survey
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-12-04
    Marlene Guiraud; Athmane Bouroubi; Roxane Beauchamp; Arnaud Bocquet; Jean-Marc Grégoire; Isabelle Rauly-Lestienne; Ignacio Blanco; Pierre Wolkenstein; Anne-Marie Schmitt

    Neurofibromatosis type 1 is an inherited condition with variable phenotypic expression and a high medical and social burden. The objectives of this patient survey were to better understand the real-world experiences of patients living with cutaneous neurofibromas (cNF), to perceive their satisfaction and feelings about cNF current management (only laser and surgery are currently available), and to highlight their expectations of new therapeutic modalities. One hundred seventy patients from 4 European countries took part in the study, 65% (n = 110) were women and mean age was 39 years old. 96% (n = 164) of respondents have cNF on visible parts of the body and the survey confirmed that total number of cNF and visibility increase with age. Patients reported that cNF mainly impacts everyday mood, general daily life and social life. The visibility of cNF had a higher impact than their number. 92% (n = 156) of patients have a regular and multidisciplinary medical follow-up. The dermatologist is one of the most consulted healthcare professionals. 76% (n = 130) of respondents have treated their cNF: 65% (n = 111) had surgery and 38% (n = 64) had multiple laser sessions. Frequency of operations and regrowth of cNF were the two most unsatisfactory aspects with both treatments for patients. Indeed, after removal, new cNF appear in more than 75% (n = 128) of cases. As a future treatment, patients expected a topical (30%, n = 51) or oral medication (29%, n = 50). Around 2 out of 3 patients would agree to take it at least once a day or more for life but they would like a well-tolerated treatment. According to patients, the most important effectiveness criteria of a new treatment are to block cNF growth and reduce their number. 70% (n = 119) of patients would consider a future treatment moderately effective to very effective if it could clear 30% of cNF. This first cNF European patient community survey confirmed that the visible stigma and unaesthetic aspect of cNF have an important impact on patients’ quality of life. The survey highlighted that patients were not entirely satisfied with the actual surgery and laser treatments and revealed their clear and realistic expectations for future treatment of cNF.

    更新日期:2019-12-05
  • Endocrine and metabolic disorders in patients with Gaucher disease type 1: a review
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-12-02
    Małgorzata Kałużna; Isabella Trzeciak; Katarzyna Ziemnicka; Maciej Machaczka; Marek Ruchała

    Gaucher disease (GD) is one of the most prevalent lysosomal storage diseases and is associated with hormonal and metabolic abnormalities, including nutritional status disorders, hypermetabolic state with high resting energy expenditures, peripheral insulin resistance, hypoadiponectinaemia, leptin and ghrelin impairments, hypolipidaemia, linear growth deceleration and growth hormone deficiency, delayed puberty, hypocalcaemia and vitamin D deficiency. Specific treatments for GD such as enzyme replacement therapy and substrate reduction therapy display significant effects on the metabolic profile of GD patients. Hormonal and metabolic disturbances observed in both adult and paediatric patients with Gaucher disease type 1 (GD1) are discussed in this review. The PubMed database was used to identify articles on endocrine and metabolic disorders in GD1. GD1 appears to facilitate the development of disorders of nutrition, glucose metabolism and vitamin D insufficiency. Metabolic and hormonal diseases may have a significant impact on the course of the underlying disease and patient quality of life. Conditions relating to hormones and metabolism can be wide-ranging in GD1. Obtained findings were intrinsic to GD either as a deleterious process or a compensatory response and some changes detected may represent co-morbidities. Actively seeking and diagnosing endocrine and metabolic disorders are strongly recommended in GD1 patients to optimize healthcare.

    更新日期:2019-12-02
  • Epidemiological study and genetic characterization of inherited muscle diseases in a northern Spanish region
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-12-02
    Inmaculada Pagola-Lorz; Esther Vicente; Berta Ibáñez; Laura Torné; Itsaso Elizalde-Beiras; Virginia Garcia-Solaesa; Fermín García; Josu Delfrade; Ivonne Jericó

    Inherited muscle diseases are a group of rare heterogeneous muscle conditions with great impact on quality of life, for which variable prevalence has previously been reported, probably due to case selection bias. The aim of this study is to estimate the overall and selective prevalence rates of inherited muscle diseases in a northern Spanish region and to describe their demographic and genetic features. Retrospective identification of patients with inherited muscle diseases between 2000 and 2015 from multiple data sources. Demographic and molecular data were registered. On January 1, 2016, the overall prevalence of inherited muscle diseases was 59.00/ 100,000 inhabitants (CI 95%; 53.35–65.26). Prevalence was significantly greater in men (67.33/100,000) in comparison to women (50.80/100,000) (p = 0.006). The highest value was seen in the age range between 45 and 54 (91.32/100,000) years. Myotonic dystrophy type 1 was the most common condition (35.90/100,000), followed by facioscapulohumeral muscular dystrophy (5.15/100,000) and limb-girdle muscular dystrophy type 2A (2.5/100,000). Prevalence of inherited muscle diseases in Navarre is high in comparison with the data reported for other geographical regions. Standard procedures and analyses of multiple data sources are needed for epidemiological studies of this heterogeneous group of diseases.

    更新日期:2019-12-02
  • Schaaf-Yang syndrome shows a Prader-Willi syndrome-like phenotype during infancy
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-12-02
    Yutaka Negishi; Daisuke Ieda; Ikumi Hori; Yasuyuki Nozaki; Takanori Yamagata; Hirofumi Komaki; Jun Tohyama; Keisuke Nagasaki; Hiroko Tada; Shinji Saitoh

    Schaaf-Yang syndrome (SYS) is a newly recognized imprinting related syndrome, which is caused by a truncating variant in maternally imprinted MAGEL2 located in 15q11-q13. Yet, precise pathomechanism remains to be solved. We sequenced MAGEL2 in patients suspected Prader-Willi syndrome (PWS) to delineate clinical presentation of SYS. We examined 105 patients with clinically suspected PWS but without a specific PWS genetic alteration. Sanger sequencing of the entire MAGEL2 gene and methylation-specific restriction enzyme treatment to detect the parent of origin were performed. Clinical presentation was retrospectively assessed in detail. Truncating variants in MAGEL2 were detected in six patients (5.7%), including a pair of siblings. All truncating variants in affected patients were on the paternally derived chromosome, while the healthy father of the affected siblings inherited the variant from his mother. Patients with MAGEL2 variants shared several features with PWS, such as neonatal hypotonia, poor suck, and obesity; however, there were also unique features, including arthrogryposis and a failure to acquire meaningful words. Additionally, an episode of neurological deterioration following febrile illness was confirmed in four of the six patients, which caused severe neurological sequalae. SYS can be present in infants suspected with PWS but some unique features, such as arthrogryposis, can help discriminate between the two syndromes. An episode of neurological deterioration following febrile illness should be recognized as an important complication.

    更新日期:2019-12-02
  • New insights on congenital pulmonary airways malformations revealed by proteomic analyses
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-11-28
    C. Barazzone-Argiroffo; J. Lascano Maillard; I. Vidal; M. L. Bochaton-Piallat; S. Blaskovic; Y. Donati; B. E. Wildhaber; A.-L. Rougemont; C. Delacourt; I. Ruchonnet-Métrailler

    Congenital Pulmonary Airway Malformation (CPAM) has an estimated prevalence between 0.87 and 1.02/10,000 live births and little is know about their pathogenesis. To improve our knowledge on these rare malformations, we analyzed the cellular origin of the two most frequent CPAM, CPAM types 1 and 2, and compared these malformations with adjacent healthy lung and human fetal lungs. We prospectively enrolled 21 infants undergoing surgical resection for CPAM. Human fetal lung samples were collected after termination of pregnancy. Immunohistochemistry and proteomic analysis were performed on laser microdissected samples. CPAM 1 and 2 express mostly bronchial markers, such as cytokeratin 17 (Krt17) or α-smooth muscle actin (ACTA 2). CPAM 1 also expresses alveolar type II epithelial cell markers (SPC). Proteomic analysis on microlaser dissected epithelium confirmed these results and showed distinct protein profiles, CPAM 1 being more heterogeneous and displaying some similarities with fetal bronchi. This study provides new insights in CPAM etiology, showing clear distinction between CPAM types 1 and 2, by immunohistochemistry and proteomics. This suggests that CPAM 1 and CPAM 2 might occur at different stages of lung branching. Finally, the comparison between fetal lung structures and CPAMs shows clearly different protein profiles, thereby arguing against a developmental arrest in a localized part of the lung.

    更新日期:2019-11-29
  • Adult cognitive outcomes in phenylketonuria: explaining causes of variability beyond average Phe levels
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-11-28
    Cristina Romani; Filippo Manti; Francesca Nardecchia; Federica Valentini; Nicoletta Fallarino; Claudia Carducci; Sabrina De Leo; Anita MacDonald; Liana Palermo; Vincenzo Leuzzi

    The objective was to deepen the understanding of the causes of individual variability in phenylketonuria (PKU) by investigating which metabolic variables are most important for predicting cognitive outcomes (Phe average vs Phe variation) and by assessing the risk of cognitive impairment associated with adopting a more relaxed approach to the diet than is currently recommended. We analysed associations between metabolic and cognitive measures in a mixed sample of English and Italian early-treated adults with PKU (N = 56). Metabolic measures were collected through childhood, adolescence and adulthood; cognitive measures were collected in adulthood. Metabolic measures included average Phe levels (average of median values for each year in a given period) and average Phe variations (average yearly standard deviations). Cognition was measured with IQ and a battery of cognitive tasks. Phe variation was as important, if not more important, than Phe average in predicting adult outcomes and contributed independently. Phe variation was particularly detrimental in childhood. Together, childhood Phe variation and adult Phe average predicted around 40% of the variation in cognitive scores. Poor cognitive scores (> 1 SD from controls) occurred almost exclusively in individuals with poor metabolic control and the risk of poor scores was about 30% higher in individuals with Phe values exceeding recommended thresholds. Our results provide support for current European guidelines (average Phe value = < 360 μmol/l in childhood; = < 600 μmo/l from 12 years onwards), but they suggest an additional recommendation to maintain stable levels (possibly Phe SD = < 180 μmol/l throughout life). We investigated the relationship between how well people with phenylketonuria control blood Phe throughout their life and their ability to carry out cognitive tasks in adulthood. We found that avoiding blood Phe peaks was as important if not more important that maintaining average low Phe levels. This was particularly essential in childhood. We also found that blood Phe levels above recommended European guidelines was associated with around 30% increase in the risk of poor cognitive outcomes.

    更新日期:2019-11-29
  • Poor prognostic factors in patients with newly diagnosed intestinal Adamantiades-Behçet’s disease in the Shanghai Adamantiades-Behçet’s disease database: a prospective cohort study
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-11-28
    Liang Zhang; Yun Tian; Jing-Fen Ye; Chen-Hong Lin; Jian-Long Guan

    Adamantiades-Behçet’s Disease (ABD) is an immunological recurrent systemic vasculitis with a chronic course. We investigated the predictors of long-term flare-ups, poor outcomes and event-free survival in Chinese non-surgical patients with intestinal ABD. This was a prospective cohort study of 109 intestinal ABD patients seen in our institution between October 2012 and January 2019 who met the international criteria for ABD and had intestinal ulcers confirmed on colonoscopy. Predictors of relapses and poor outcomes, event-free survival were calculated using logistic regression models and Cox proportional hazard regression models, respectively. Sixty-six intestinal ABD patients (60.55%) had ileocecal ulcers; 19 patients (17.43%) presented with colorectum ulcers; 24 patients (22.02%) showed both ileocecal and colorectum ulcers. 7 patients (6.42%) experienced at least 1 flare-up of intestinal ulcers. 38 patients (34.86%) complained of non-healing intestinal ulcers. In multivariate analysis, location of intestinal ulcers (ileocecal and colorectum) (odd ratio (OR) 7.498 [95% confidence interval [95% CI] 1.844–30.480]), erythrocyte sedimentation rate (ESR) > 24 mm/h (OR 5.966 [95% CI 1.734–20.528]), treatment with infliximab (IFX) (OR 0.130 [95% CI 0.024–0.715]), and poor compliance (OR 11.730 [95% CI 2.341–58.781]) were independently correlated with a poor outcome. After a median follow-up of 28 months, 45 intestinal ABD patients (41.28%) underwent adverse events. Factors independently associated with shorter event-free survival were early onset of ABD (< 7 years) (hazard ratio (HR) 2.431 [95% CI 1.240–4.764]) and poor compliance (HR 3.058 [95% CI 1.612–5.800]). Distribution of intestinal ulcers (ileocecal and colorectum), ESR > 24 mm/h, treatment without IFX, and poor compliance were independent risk factors for poor outcomes in non-surgical intestinal ABD patients.

    更新日期:2019-11-29
  • Ocular manifestations in Gorlin-Goltz syndrome
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-09-18
    Antonietta Moramarco; Ehud Himmelblau; Emanuele Miraglia; Fabiana Mallone; Vincenzo Roberti; Federica Franzone; Chiara Iacovino; Sandra Giustini; Alessandro Lambiase

    Gorlin-Goltz syndrome, also known as nevoid basal cell carcinoma syndrome, is a rare genetic disorder that is transmitted in an autosomal dominant manner with complete penetrance and variable expressivity. It is caused in 85% of the cases with a known etiology by pathogenic variants in the PTCH1 gene, and is characterized by a wide range of developmental abnormalities and a predisposition to multiple neoplasms. The manifestations are multiple and systemic and consist of basal cell carcinomas in various regions, odontogenic keratocistic tumors and skeletal anomalies, to name the most frequent. Despite the scarce medical literature on the topic, ocular involvement in this syndrome is frequent and at the level of various ocular structures. Our study focuses on the visual apparatus and its annexes in subjects with this syndrome, in order to better understand how this syndrome affects the ocular system, and to evaluate with greater accuracy and precision the nature of these manifestations in this group of patients. Our study confirms the presence of the commonly cited ocular findings in the general literature regarding the syndrome [hypertelorism (45.5%), congenital cataract (18%), nystagmus (9%), colobomas (9%)] and highlights strabismus (63% of the patients), epiretinal membranes (36%) and myelinated optic nerve fiber layers (36%) as the most frequent ophthalmological findings in this group of patients. The presence of characteristic and frequent ocular signs in the Gorlin- Goltz syndrome could help with the diagnostic process in subjects suspected of having the syndrome who do not yet have a diagnosis. The ophthalmologist has a role as part of a multidisciplinary team in managing these patients. The ophthalmological follow-up that these patients require, can allow, if necessary, a timely therapy that could improve the visual prognosis of such patients.

    更新日期:2019-11-28
  • Genotypic characteristics of Chinese patients with BHD syndrome and functional analysis of FLCN variants
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-10-15
    Keqiang Liu; Wenshuai Xu; Xinlun Tian; Meng Xiao; Xinyue Zhao; Qianli Zhang; Tao Qu; Jiaxing Song; Yaping Liu; Kai-Feng Xu; Xue Zhang

    Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominant disease featured by lung cysts, spontaneous pneumothorax, fibrofolliculomas and renal tumors. The causative gene for BHDS is the folliculin (FLCN) gene and more than 200 mutations have been reported in FLCN, mostly truncating mutations. The aim of this study is to better characterize the clinical features and mutation spectrum of Chinese BHDS patients and to systematically evaluate the effects of non-truncating mutations on mRNA splicing pattern. We enrolled 47 patients from 39 unrelated families with symptoms highly suggestive of BHDS after informed consent and detailed clinical data were collected. Exon sequencing followed by multiplex ligation-dependent probe amplification testing were applied for mutation screening. The effects of non-truncating mutations, including 15 missense mutations and 6 in-frame deletions, on mRNA splicing were investigated by minigene assays. A total of 24 FLCN germline variants were found in 39 patients from 31 distinct families. Out of these patients, 100% (36/36) presented with lung cysts and 58.3% (21/36) had experienced spontaneous pneumothorax. Seventeen mutation carriers had skin lesions (47.2%, 17/36) and 9 (30%, 9/30) had kidney lesions including 8 with renal cysts and 1 with renal hamartoma. Among all detected variants 14 (58.3%, 14/24) were novel, including 11 variants classified to be pathogenic and 3 variants of uncertain significance. None of 21 non-truncating mutations changed the mRNA splicing pattern of minigenes. We found different clinical features of Chinese BHDS patients compared with Caucasians, with more lung cysts and pneumothorax but fewer skin lesions and malignant renal cancer. Chinese patients with BHDS also have a different mutation spectrum from other races. Non-truncating mutations in FLCN did not disrupt mRNA splicing pattern, in turn supporting the hypothesis that these mutations impair folliculin function by disrupting the stability of the FLCN gene product.

    更新日期:2019-11-28
  • Update on the management of colchicine resistant Familial Mediterranean Fever (FMF)
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-10-15
    Georges El Hasbani; Ali Jawad; Imad Uthman

    Familial Mediterranean Fever (FMF), an autoinflammatory disease, is characterized by self-limited inflammatory attacks of fever and polyserositis along with high acute phase response. Although colchicine remains the mainstay in treatment, intolerance and resistance in a certain portion of patients have been posing a problem for physicians. Like many autoimmune and autoinflammatory diseases, many colchicine-resistant or intolerant FMF cases have been successfully treated with biologics. In addition, many studies have tested the efficacy of biologics in treating FMF manifestations. Since carriers of FMF show significantly elevated levels of serum TNF alpha, IL-1, and IL-6, FMF patients who failed colchicine were successfully treated with anti IL-1, anti IL-6, or TNF inhibitors drugs. It is best to use colchicine in combination with biologics.

    更新日期:2019-11-28
  • The use or generation of biomedical data and existing medicines to discover and establish new treatments for patients with rare diseases – recommendations of the IRDiRC Data Mining and Repurposing Task Force
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-10-15
    Noel T Southall; Madhusudan Natarajan; Lilian Pek Lian Lau; Anneliene Hechtelt Jonker; Benoît Deprez; Tim Guilliams; Lawrence Hunter; Carin MA Rademaker; Virginie Hivert; Diego Ardigò

    The number of available therapies for rare diseases remains low, as fewer than 6% of rare diseases have an approved treatment option. The International Rare Diseases Research Consortium (IRDiRC) set up the multi-stakeholder Data Mining and Repurposing (DMR) Task Force to examine the potential of applying biomedical data mining strategies to identify new opportunities to use existing pharmaceutical compounds in new ways and to accelerate the pace of drug development for rare disease patients. In reviewing past successes of data mining for drug repurposing, and planning for future biomedical research capacity, the DMR Task Force identified four strategic infrastructure investment areas to focus on in order to accelerate rare disease research productivity and drug development: (1) improving the capture and sharing of self-reported patient data, (2) better integration of existing research data, (3) increasing experimental testing capacity, and (4) sharing of rare disease research and development expertise. Additionally, the DMR Task Force also recommended a number of strategies to increase data mining and repurposing opportunities for rare diseases research as well as the development of individualized and precision medicine strategies.

    更新日期:2019-11-28
  • Cognitive functioning in patients with classical galactosemia: a systematic review
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-10-18
    Merel E. Hermans; Mendy M. Welsink-Karssies; Annet M. Bosch; Kim J. Oostrom; Gert J. Geurtsen

    Patients with the metabolic disorder classical galactosemia suffer from long-term complications despite a galactose-restricted diet, including a below average intelligence level. The aim of the current review was to investigate the incidence and profile of cognitive impairments in patients with classical galactosemia. MEDLINE, EMBASE and PsychINFO were searched up to 23 October 2018 for studies examining information processing speed, attention, memory, language, visuospatial functioning, executive functioning and social cognition in patients with confirmed classical galactosemia utilizing standardized neuropsychological tests. Data synthesis followed a narrative approach, since the planned meta-analysis was not possible due to large variability between the neuropsychological assessments. Eleven studies were included, including case-studies. The quality of most studies was moderate to low. As a group, patients with classical galactosemia exhibit below average to low scores on all cognitive domains. A large proportion of the patients perform on an impaired level on attention, memory and vocabulary. Evidence for impairments in information processing speed, language, visuospatial functioning and aspects of executive functioning was limited due to the small number of studies investigating these cognitive functions. Social cognition was not examined at all. Given the moderate to low quality of the included studies and the limited evidence in many cognitive domains, the incidence of cognitive impairment in patients with classical galactosemia is not yet clear. Both clinicians and researchers encountering patients with classical galactosemia need to be aware of possible cognitive impairments. Future well-designed studies are needed to determine the cognitive profile of classical galactosemia. This can be the basis for the development of intervention strategies.

    更新日期:2019-11-28
  • Real-world clinical course of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in Japan
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-10-21
    Shuntaro Tsutsumi; Tomoo Sato; Naoko Yagishita; Junji Yamauchi; Natsumi Araya; Daisuke Hasegawa; Misako Nagasaka; Ariella L. G. Coler-Reilly; Eisuke Inoue; Ayako Takata; Yoshihisa Yamano

    As human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a rare chronic neurological disease, large scale studies to collect continuous clinical data have been difficult to conduct. Therefore, the incidence of comorbidities and drug utilization data remain unknown. When conducting trials to develop new drugs in rare disease such as HAM/TSP, historical control data obtained from registry studies would be useful, as cohorts in rare disease tend to be small. Long-term follow-up of patients with a chronic disease can also be challenging. In this study, we addressed the following two goals using registry data on patients (n = 486) enrolled in the Japanese HAM/TSP patient registry “HAM-net” from 2012 to 2016: 1) to clarify the epidemiological information of HAM/TSP such as the incidence of comorbidities and drug utilization and 2) to provide the real-world data on changes in lower limb motor dysfunction. In HAM-net-registered patients, common comorbidities were fractures, herpes zoster, and uveitis, with incidences of 55.5, 10.4, and 6.5, respectively, per 1000 person-years. Every year, oral steroid treatment was administered in 48.2–50.7% of the HAM-net-registered patients and interferon-α treatment was used in 2.6–3.5% of patients. The median dose of oral prednisolone was low at 5.0 mg/day. The incidence of fractures and herpes zoster tended to be higher in the steroid-treated group than in the untreated group (fractures: 61.0 vs. 48.3, herpes zoster: 12.7 vs. 8.8, per 1000 person-years). The analysis of chronological change in Osame motor disability score (OMDS) indicated that the mean change in OMDS was + 0.20 [95% confidence intervals (CI): 0.14–0.25] per year in the one-year observation group (n = 346) and + 0.57 (95% CI: 0.42–0.73) over four years in the four-year observation group (n = 148). Significant deterioration of OMDS was noted in all subgroups with varying steroid use status. This study revealed the incidence of comorbidities and drug utilization data in patients with HAM/TSP using registry data. Furthermore, this study provided real-world data on chronological changes in lower limb motor dysfunction in patients with HAM/TSP, indicating the utility of these data as historical controls.

    更新日期:2019-11-28
  • Expanded access with intravenous hydroxypropyl-β-cyclodextrin to treat children and young adults with Niemann-Pick disease type C1: a case report analysis
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-10-21
    Caroline Hastings; Camilo Vieira; Benny Liu; Cyrus Bascon; Claire Gao; Raymond Y. Wang; Alicia Casey; Sharon Hrynkow

    Niemann-Pick Disease Type C (NPC) is an inherited, often fatal neurovisceral lysosomal storage disease characterized by cholesterol accumulation in every cell with few known treatments. Defects in cholesterol transport cause sequestration of unesterified cholesterol within the endolysosomal system. The discovery that systemic administration of hydroxypropyl-beta cyclodextrin (HPβPD) to NPC mice could release trapped cholesterol from lysosomes, normalize cholesterol levels in the liver, and prolong life, led to expanded access use in NPC patients. HPβCD has been administered to NPC patients with approved INDs globally since 2009. Here we present safety, tolerability and efficacy data from 12 patients treated intravenously (IV) for over 7 years with HPβCD in the US and Brazil. Some patients subsequently received intrathecal (IT) treatment with HPβCD following on average 13 months of IV HPβCD. Several patients transitioned to an alternate HPβCD. Moderately affected NPC patients treated with HPβCD showed slowing of disease progression. Severely affected patients demonstrated periods of stability but eventually showed progression of disease. Neurologic and neurocognitive benefits were seen in most patients with IV alone, independent of the addition of IT administration. Physicians and caregivers reported improvements in quality of life for the patients on IV therapy. There were no safety issues, and the drug was well tolerated and easy to administer. These expanded access data support the safety and potential benefit of systemic IV administration of HPβCD and provide a platform for two clinical trials to study the effect of intravenous administration of HPβCD in NPC patients.

    更新日期:2019-11-28
  • Management and outcomes of pneumothorax in adult patients with Langerhans cell Histiocytosis
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-10-21
    Pierre Le Guen; Sylvie Chevret; Emmanuelle Bugnet; Constance de Margerie-Mellon; Gwenaël Lorillon; Agathe Seguin-Givelet; Fanélie Jouenne; Dominique Gossot; Robert Vassallo; Abdellatif Tazi

    Pneumothorax may recur during pulmonary Langerhans cell histiocytosis (PLCH) patients’ follow-up and its management is not standardised. The factors associated with pneumothorax recurrence are unknown. In this retrospective study, PLCH patients who experienced a pneumothorax and were followed for at least 6 months after the first episode were eligible. The objectives were to describe the treatment of the initial episode and pneumothorax recurrences during follow-up. We also searched for factors associated with pneumothorax recurrence and evaluated the effect on lung function outcome. Time to recurrence was estimated by the Kaplan Meier method and the cumulative hazard of recurrence handling all recurrent events was estimated. Univariate Cox models and Andersen-Gill counting process were used for statistical analyses. Fourty-three patients (median age 26.5 years [interquartile range (IQR), 22.9–35.4]; 26 men, 39 current smokers) were included and followed for median time of 49 months. Chest tube drainage was the main management of the initial pneumothorax, which resolved in 70% of cases. Pneumothorax recurred in 23 (53%) patients, and overall 96 pneumothoraces were observed during the study period. In the subgroup of patients who experienced pneumothorax recurrence, the median number of episodes per patient was 3 [IQR, 2–4]. All but one recurrence occurred within 2 years after the first episode. Thoracic surgery neither delayed the time of occurrence of the first ipsilateral recurrence nor reduced the overall number of recurrences during the study period, although the rate of recurrence was lower after thoracotomy than following video-assisted thoracic surgery (p = 0.03). At the time of the first pneumothorax, the presence of air trapping on lung function testing was associated with increased risk of recurrence (hazard ratio = 5.08; 95% confidence interval [1.18, 21.8]; p = 0.03). Pneumothorax recurrence did not predict subsequent lung function decline (p = 0.058). Our results show that pneumothorax recurrences occur during an “active” phase of PLCH. In this observational study, the time of occurrence of the first ipsilateral recurrence and the overall number of pneumothorax recurrences were similar after conservative and thoracic surgical treatments. Further studies are needed to determine the best management to reduce the risk of pneumothorax recurrence in PLCH patients.

    更新日期:2019-11-28
  • Agreement between results of meta-analyses from case reports and clinical studies, regarding efficacy and safety of idursulfase therapy in patients with mucopolysaccharidosis type II (MPS-II). A new tool for evidence-based medicine in rare diseases
    Orphanet J. Rare Dis. (IF 3.687) Pub Date : 2019-10-21
    Miguel Sampayo-Cordero; Bernat Miguel-Huguet; Almudena Pardo-Mateos; Andrea Malfettone; José Pérez-García; Antonio Llombart-Cussac; Javier Cortés; Marc Moltó-Abad; Cecilia Muñoz-Delgado; Marta Pérez-Quintana; Jordi Pérez-López

    A preliminary exploratory study shows solid agreement between the results of case reports and clinical study meta-analyses in mucopolysaccharidosis Type I (MPS-I) adult patients. The aim of the present study is to confirm previous results in another patient population, suffering from mucopolysaccharidosis Type II (MPS-II). A systematic review and meta-analysis of case reports published by April 2018 was conducted for MPS-II patients treated with enzyme replacement therapy (ERT). The study is reported in accordance with PRISMA and MOOSE guidelines (PROSPERO database code CRD42018093408). The assessed population and outcomes were the same as previously analyzed in a meta-analysis of MPS-II clinical studies. The primary endpoint was the percent of clinical cases showing improvement in efficacy outcome, or no harm in safety outcome after ERT initiation. A restrictive procedure to aggregate case reports, by selecting standardized and well-defined outcomes, was proposed. Different sensitivity analyses were able to evaluate the robustness of results. Every outcome classified as “acceptable evidence group” in our case report meta-analysis had been graded as “moderate strength of evidence” in the aforementioned meta-analysis of clinical studies. Sensitivity, specificity, and positive-negative predictive values for results of both meta-analyses reached 100%, and were deemed equivalent. Aggregating case reports quantitatively, rather than analyzing them qualitatively, may improve conclusions in rare diseases and personalized medicine. Additionally, we propose some methods to evaluate publication bias and heterogeneity of the included studies in a meta-analysis of case reports.

    更新日期:2019-11-28
Contents have been reproduced by permission of the publishers.
导出
全部期刊列表>>
2020新春特辑
限时免费阅读临床医学内容
ACS材料视界
科学报告最新纳米科学与技术研究
清华大学化学系段昊泓
自然科研论文编辑服务
加州大学洛杉矶分校
上海纽约大学William Glover
南开大学化学院周其林
课题组网站
X-MOL
北京大学分子工程苏南研究院
华东师范大学分子机器及功能材料
中山大学化学工程与技术学院
试剂库存
天合科研
down
wechat
bug