Rare Disease Patients Research Articles

Enfermedad de Wilson en España: validación de fuentes utilizadas por los Registros de Enfermedades Raras

ObjectiveTo evaluate the sources of information used by the Regional Population-based Registries of Rare Diseases (RRD) for Wilson's Disease identification in Spain; to calculate its prevalence and mortality; and to describe the sociodemographic characteristics of those affected. MethodCross-sectional epidemiological study, period 2010-2015. Possible cases were identified by codes 275.1 (ICD-9-CM), E83.0 (ICD-10) and 905 (ORPHAcode) in: 15 participating RRD and the Rare Disease Patients Registry of the Carlos III Health Institute. The diagnoses were confirmed through a clinical documentation review. The positive predictive value (PPV) of the sources of information used by RRD and their combinations were obtained. The prevalence, mortality and the distribution of sociodemographic characteristics were calculated. ResultsThe Hospital Discharge Database (HDD) was the most used source by the RRD (PPV=39.4%), followed by the Orphan Drugs Registry (ODR) (PPV=81.9%). The Clinical History of Primary Care (PC) obtains PPV=55.9%. The combinations with highest PPV were the ODR with HDD (PPV=95.8%) and the ODR with PC (PPV=92.9%). 514 cases were confirmed, 57.2% men, with a median age of diagnosis of 21.3 years. The prevalence was 1.64/100,000 inhabitants in 2015 and mortality rate was 3.0%, being both higher in men. ConclusionsIncorporation of ODR and PC into the RRD is recommended, as its combination and ODR with HDD could be used as an automatic validation criterion for Wilson's disease. The prevalence obtained was similar to that of countries close to Spain.

Genetic testing offer for inherited neuromuscular diseases within the EURO-NMD reference network: A European survey study.

The genetic diagnostics of inherited neuromuscular diseases (NMDs) is challenging due to their clinical and genetic heterogeneity. We launched an online survey within the EURO-NMD European Reference Network (ERN) to collect information about the availability/distribution of genetic testing across 61 ERN health care providers (HCPs). A 17 items questionnaire was designed to address methods used, the number of genetic tests available, the clinical pathway to access genetic testing, the use of next-generation sequencing (NGS) and participation to quality assessment schemes (QAs). A remarkable number of HCPs (49%) offers ≥ 500 genetic tests per year, 43,6% offers 100-500 genetic tests per year, and 7,2% ≤ 100 per year. NGS is used by 94% of centres, Sanger sequencing by 84%, MLPA by 66% and Southern blotting by 36%. The majority of centres (60%) offer NGS for all patients that fulfil criteria for NMD of genetic origin. Pipelines for NGS vary amongst centres, even within the same national system. Referral of patients to genetic laboratories by specialists was frequently reported (58%), and 65% of centres participates in genetic testing QAs. We specifically evaluated how many centres cover SMA, DMD, Pompe, LGMDs, and TTR genes/diseases genetic diagnosis, since these rare diseases benefit from personalised therapies. We used the Orphanet EUGT numbers, provided by 82% of HCPs. SMA, DMD, LGMD, TTR and GAA genes are covered by EUGTs although with different numbers and modalities. The number of genetic tests for NMDs offered across HCPs National Health systems is quite high, including routine techniques and NGS. The number and type of tests offered and the clinical practices differ among centres. We provided evidence that survey tools might be useful to learn about the state-of-the-art of ERN health-related activities and to foster harmonisation and standardisation of the complex care for the rare disease patients in the EU.

A crucial role for Jagunal homolog 1 in humoral immunity and antibody glycosylation in mice and humans.

Jagunal homolog 1 (JAGN1) has been identified as a critical regulator of neutrophil biology in mutant mice and rare-disease patients carrying JAGN1 mutations. Here, we report that Jagn1 deficiency results in alterations in the endoplasmic reticulum (ER) of antibody-producing cells as well as decreased antibody production and secretion. Consequently, mice lacking Jagn1 in B cells exhibit reduced serum immunoglobulin (Ig) levels at steady state and fail to mount an efficient humoral immune response upon immunization with specific antigens or when challenged with viral infections. We also demonstrate that Jagn1 deficiency in B cells results in aberrant IgG N-glycosylation leading to enhanced Fc receptor binding. Jagn1 deficiency in particular affects fucosylation of IgG subtypes in mice as well as rare-disease patients with loss-of-function mutations in JAGN1. Moreover, we show that ER stress affects antibody glycosylation. Our data uncover a novel and key role for JAGN1 and ER stress in antibody glycosylation and humoral immunity in mice and humans.

The influence of social determinants of health on the genetic diagnostic odyssey: who remains undiagnosed, why, and to what effect?

Although Mendelian genetic disorders are individually rare, they are collectively more common and contribute disproportionately to pediatric morbidity and mortality. Remarkable advances in the last decade have led to identification of the precise genetic variants responsible for many of these conditions. Confirming the molecular diagnosis through genetic testing allows for individualized treatment plans in addition to ending the diagnostic odyssey, which not only halts further unnecessary testing but also may result in immense psychological benefit, leading to improved quality of life. However, ensuring equitable application of these advances in genomic technology has been challenging. Though prior studies have revealed disparities in testing for genetic predisposition to cancer in adults, little is known about the prevalence and nature of disparities in diagnostic testing in the pediatric rare disease population. While it seems logical those with impaired access to healthcare would be less likely to receive the genetic testing needed to end their odyssey, few studies have addressed this question directly and the potential impact on health outcomes. This review synthesizes the available evidence regarding disparities in pediatric genetic diagnosis, defining the need for further, prospective studies with the ultimate goal of delivering precision medicine to all who stand to benefit.

Improving diagnosis for rare diseases: the experience of the Italian undiagnosed Rare diseases network

BackgroundFor a number of persons with rare diseases (RDs) a definite diagnosis remains undiscovered with relevant physical, psychological and social consequences. Undiagnosed RDs (URDs) require other than specialised clinical centres, outstanding molecular investigations, common protocols and dedicated actions at national and international levels; thus, many “Undiagnosed RDs programs” have been gradually developed on the grounds of a well-structured multidisciplinary approach.MethodsThe Italian Undiagnosed Rare Diseases Network (IURDN) was established in 2016 to improve the level of diagnosis of persons with URD living in Italy. Six Italian Centres of Expertise represented the network. The National Centre for Rare Diseases at the Istituto Superiore di Sanità coordinates the whole project. The software PhenoTips was used to collect the information of the clinical cases.ResultsOne hundred and ten cases were analysed between March 2016 and June 2019. The age of onset of the diseases ranged from prenatal age to 51 years. Conditions were predominantly sporadic; almost all patients had multiple organs involvements. A total of 13/71 family cases were characterized by WES; in some families more than one individual was affected, so leading to 20/71 individuals investigated. Disease causing variants were identified in two cases and were associated to previously undescribed phenotypes. In 5 cases, new candidate genes were identified, although confirmatory tests are pending. In three families, investigations were not completed due to the scarce compliance of members and molecular investigations were temporary suspended. Finally, three cases (one familial) remain still unsolved. Twelve undiagnosed clinical cases were then selected to be shared at International level through PhenomeCentral in accordance to the UDNI statement.ConclusionsOur results showed a molecular diagnostic yield of 53,8%; this value is comparable to the diagnostic rates reported in other international studies. Cases collected were also pooled with those collected by UDNI International Network. This represents a unique example of global initiative aimed at sharing and validating knowledge and experience in this field. IURDN is a multidisciplinary and useful initiative linking National and International efforts aimed at making timely and appropriate diagnoses in RD patients who still do not have a confirmed diagnosis even after a long time.

Impact of COVID-19 pandemic on patients with rare disease in Hong Kong

The COVID-19 pandemic has had significant health, social, and economic consequences internationally. While the pandemic has direct implications on infected patients and families, there is a need to examine the pandemic's effect on patients with non-COVID-19-related diseases. This study examines the impact of the COVID-19 pandemic on 272 rare disease patients with 89 distinct rare diseases in Hong Kong using a cross-sectional online survey between April 10 and April 29, 2020 from the patient and caregiver perspective. The pandemic has impacted patient's health status in 46%, service use patterns in 71%, mental health in 79%, daily living in 82%, social life in 92%, and financial status in 81% of patients. Patient's health status, medical and rehabilitation, and mental health were more impacted by the COVID-19 pandemic in the group of patients with any level of dependency according to the Barthel Index for Activities of Daily Living compared with that in the group of patients who are fully independent (p < 0.0001; p < 0.0001; p = 0.0420). This study is the first study to examine the impact of COVID-19 pandemic on the rare disease population in Hong Kong, and demonstrates the pandemic's effect on service and resource utilization, and patient's physical and mental well-being.

The case for open science: rare diseases.

The premise of Open Science is that research and medical management will progress faster if data and knowledge are openly shared. The value of Open Science is nowhere more important and appreciated than in the rare disease (RD) community. Research into RDs has been limited by insufficient patient data and resources, a paucity of trained disease experts, and lack of therapeutics, leading to long delays in diagnosis and treatment. These issues can be ameliorated by following the principles and practices of sharing that are intrinsic to Open Science. Here, we describe how the RD community has adopted the core pillars of Open Science, adding new initiatives to promote care and research for RD patients and, ultimately, for all of medicine. We also present recommendations that can advance Open Science more globally.

Expanded access: opening doors to personalized medicine for rare disease patients and patients with neurodegenerative diseases.

In neurodegenerative diseases, a select set of neuron population displays early vulnerability and undergoes progressive degeneration. The heterogeneity of the cerebral cortex and the heterogeneity of patient populations diagnosed with the same disease offer many challenges for developing effective and long-term treatment options. Currently, patients who are considered to have a 'rare' disease are left with no hopes for cure, and many of the neurodegenerative diseases progress fast without any effective solutions. However, as our understanding of disease mechanisms evolve, we begin to realize that the boundaries between diseases are not as sharp as once believed. There are many patients who develop disease due to common underlying causes and mechanisms. As we move forward with drug discovery effort, it becomes obvious that we will have to shift our focus from finding a cure for a disease, to finding solutions to the disease-causing cellular mechanisms so that patients can be treated by mechanism-based strategies. This paradigm shift will lay the foundation for personalized medicine approaches for neurodegenerative disease patients and patients diagnosed with a rare disease.

FDA orphan products clinical trial grants: assessment of outcomes and impact on rare disease product development

BackgroundThe Office of Orphan Products Development (OOPD) of the United States (U.S.) Food and Drug Administration (FDA) has awarded over 700 grants to conduct clinical trials of medicals products for rare diseases since 1983, leading to over 70 marketing approvals. However, despite recent progress in rare disease product development, thousands of rare diseases still have no approved treatments. An assessment of this clinical trial grants program was undertaken to provide an in-depth analysis of the characteristics and outcomes of the program. Results of this analysis will be used to inform future goals of the program, as well as internal data collection to continue to maximize the program’s impact in supporting rare disease product development.ResultsBetween fiscal years 2007—2011, OOPD funded 85 clinical trial grants. These grants spanned 18 therapeutic areas, included all pre-approval phases (Phases 1–3), and approximately 75% of the grants studied small molecule drugs. Nine (11%) product approvals, of seven drugs and two devices, were at least partially supported by grants funded within this 5-year timeframe. Four of the seven drugs approved were new molecular entities (NMEs). The average time from funding to approval was seven years. We also found a suggested association between collaboration with multiple types of stakeholders and the success of grants, where we defined success as either positive or negative study findings or a future marketing approval.ConclusionsThe clinical trials funded by OOPD provided valuable information for future product development, and there were a notable number of approvals that occurred using the support of the grants program. There was a suggested association between collaboration and successful outcomes. Efficient and innovative trial designs and collaboration among stakeholders appear vital to continue to effectively bring products to rare disease patients. Ongoing program assessments will ensure that the funding continues to be used to optimally meet the treatment needs of the rare disease community.

Participation in patient support forums may put rare disease patient data at risk of re-identification

BackgroundRare disease patients often struggle to find both medical advice and emotional support for their diagnosis. Consequently, many rare disease patient support forums have appeared on hospital webpages, social media sites, and on rare disease foundation sites. However, we argue that engagement in these groups may pose a healthcare data privacy threat to many participants, since it makes a series of patient indirect identifiers ‘readily available’ in combination with rare disease conditions. This information produces a risk of re-identification because it may allow a motivated attacker to use the unique combination of a patient’s identifiers and disease condition to re-identify them in anonymized data.ResultsTo assess this risk of re-identification, patient direct and indirect identifiers were mined from patient support forums for 80 patients across eight rare diseases. This data mining consisted of scanning patient testimonials, social media sites, and public records for the collection of identifiers linked to a rare disease patient. The number of people in the United States that may share each patient’s combination of marital status, 3-digit ZIP code, age, and sex, as well as their rare disease condition, was then estimated, as such information is commonly found in health records which have undergone de-identification by HIPAA’s ‘Safe Harbor.’ The study showed that by these estimations, nearly 75% of patients could be at high risk for re-identification in healthcare datasets in which they appear, due to their unique combination of identifiers.ConclusionsThe results of this study show that these rare disease patients, due to their choice to provide support for their community, are putting all their healthcare data at risk of re-identification. This paper demonstrates how simple adjustments to participation guidelines in such support forums, in combination with improved privacy measures at the organizational level, could mitigate this risk of re-identification. Additionally, this paper suggests the potential for future investigation into consideration of certain ‘risky’ International Classification of Diseases (ICD) codes as quasi-identifiers in de-identified datasets to further protect patients’ privacy, while maintaining the utility of such rare disease support groups.

Providing high-quality care remotely to patients with rare bone diseases during COVID-19 pandemic

During the COVID-19 outbreak, the European Reference Network on Rare Bone Diseases (ERN BOND) coordination team and Italian rare bone diseases healthcare professionals created the “COVID-19 Helpline for Rare Bone Diseases” in an attempt to provide high-quality information and expertise on rare bone diseases remotely to patients and healthcare professionals. The present position statement describes the key characteristics of the Helpline initiative, along with the main aspects and topics that recurrently emerged as central for rare bone diseases patients and professionals. The main topics highlighted are general recommendations, pulmonary complications, drug treatment, trauma, pregnancy, children and elderly people, and patient associations role. The successful experience of the “COVID-19 Helpline for Rare Bone Diseases” launched in Italy could serve as a primer of gold-standard remote care for rare bone diseases for the other European countries and globally. Furthermore, similar COVID-19 helplines could be considered and applied for other rare diseases in order to implement remote patients’ care.

Making a big impact with small datasets using machine-learning approaches.

Making a big impact with small datasets using machine-learning approaches.

Disease-associated and patient-specific immune cell signatures in juvenile-onset systemic lupus erythematosus: patient stratification using a machine-learning approach.

SummaryBackgroundJuvenile-onset systemic lupus erythematosus (SLE) is a rare autoimmune rheumatic disease characterised by more severe disease manifestations, earlier damage accrual, and higher mortality than in adult-onset SLE. We aimed to use machine-learning approaches to characterise the immune cell profile of patients with juvenile-onset SLE and investigate links with the disease trajectory over time.MethodsThis study included patients who attended the University College London Hospital (London, UK) adolescent rheumatology service, had juvenile-onset SLE according to the 1997 American College of Rheumatology revised classification criteria for lupus or the 2012 Systemic Lupus International Collaborating Clinics criteria, and were diagnosed before 18 years of age. Blood donated by healthy age-matched and sex-matched volunteers who were taking part in educational events in the Centre for Adolescent Rheumatology Versus Arthritis at University College London (London, UK) was used as a control. Immunophenotyping profiles (28 immune cell subsets) of peripheral blood mononuclear cells from patients with juvenile-onset SLE and healthy controls were determined by flow cytometry. We used balanced random forest (BRF) and sparse partial least squares-discriminant analysis (sPLS-DA) to assess classification and parameter selection, and validation was by ten-fold cross-validation. We used logistic regression to test the association between immune phenotypes and k-means clustering to determine patient stratification. Retrospective longitudinal clinical data, including disease activity and medication, were related to the immunological features identified.FindingsBetween Sept 5, 2012, and March 7, 2018, peripheral blood was collected from 67 patients with juvenile-onset SLE and 39 healthy controls. The median age was 19 years (IQR 13–25) for patients with juvenile-onset SLE and 18 years (16–25) for healthy controls. The BRF model discriminated patients with juvenile-onset SLE from healthy controls with 90·9% prediction accuracy. The top-ranked immunological features from the BRF model were confirmed using sPLS-DA and logistic regression, and included total CD4, total CD8, CD8 effector memory, and CD8 naive T cells, Bm1, and unswitched memory B cells, total CD14 monocytes, and invariant natural killer T cells. Using these markers patients were clustered into four distinct groups. Notably, CD8 T-cell subsets were important in driving patient stratification, whereas B-cell markers were similarly expressed across the cohort of patients with juvenile-onset SLE. Patients with juvenile-onset SLE and elevated CD8 effector memory T-cell frequencies had more persistently active disease over time, as assessed by the SLE disease activity index 2000, and this was associated with increased treatment with mycophenolate mofetil and an increased prevalence of lupus nephritis. Finally, network analysis confirmed the strong association between immune phenotype and differential clinical features.InterpretationMachine-learning models can define potential disease-associated and patient-specific immune characteristics in rare disease patient populations. Immunological association studies are warranted to develop data-driven personalised medicine approaches for treatment of patients with juvenile-onset SLE.FundingLupus UK, The Rosetrees Trust, Versus Arthritis, and UK National Institute for Health Research University College London Hospital Biomedical Research Centre.

Rapid whole-exome sequencing facilitates precision medicine in paediatric rare disease patients and reduces healthcare costs

BackgroundRapid whole-exome sequencing (rWES) offers the potential for early diagnosis-predicated precision medicine. Previous evidence focused predominantly on infants from the intensive care unit (ICU). This study sought to examine the diagnostic and clinical utility, and the economic impact on clinical management of rWES in patients beyond infancy and ICU setting. MethodsrWES was performed on a prospective cohort of patients with suspected monogenic disorder referred from territory-wide paediatric ICUs and non-ICUs in Hong Kong urging for rapid genetic diagnosis. All eligible families were invited. We aimed to achieve a rapid turnaround time (TAT) of 14 days. Clinical utility and costs associated with clinical management were assessed in diagnosed cases. Actual quantitative changes in healthcare utilisation were compared with a counterfactual diagnostic trajectory and/or with matched historical control whenever possible. FindingsrWES were offered to 102 families and 32/102 (31%) patients received a molecular diagnosis, with a median TAT of 11 days. Clinical management changed in 28 of 32 diagnosed patients (88%), including but not limited to modifications in treatment, avoidance of surgeries, and informing decisions on redirection of care. Cost analysis was performed in eight patients. rWES was estimated to reduce hospital length of stay by 566 days and decrease healthcare costs by HKD$8,044,250 (GBP£796,460) for these eight patients. The net cost-savings after inclusion of rWES costs were estimated to be HKD$5,325,187 (GBP£527,246). InterpretationThis study replicates the diagnostic capacity and rapid TAT of rWES in predominantly Chinese patients, and demonstrates diagnosis-predicated precision medicine and net healthcare savings. Findings were corroborated by evidence from multinational cohorts, combined as part of a meta-analysis. rWES merits consideration as a first-tier diagnostic tool for patients with urgent needs in the clinical setting. FundingHealth and Medical Research Fund, HKU Seed Fund for Basic Research, The Society for the Relief of Disabled Children, and Edward and Yolanda Wong Fund.

Erdheim–Chester disease. Literature review and clinical case

Erdheim–Chester disease (ECD) is a rare and frequently neglected disease, usually with a poor prognosis. The first two cases of ECD were reported by Austrian pathologist: Jakob Erdheim and his apprentice student William Chester in 1930. The etiology and disease incidence are unknown. One of the main components of this disorder is a chronic uncontrollable inflammation. Clinical manifestations of the disease can be very different. ECD affects predominantly adults, usually male population. There is no effective treatment developed yet. In 2016 ECD was classified as histiocytic neoplasm by the World Health Organization and was categorized as “tumors of histiocytes and dendritic cells”. More than half of patients testing positive for the BRAF mutation. There is a Erdheim–Chester Disease Global Alliance (ECDGA), which try to unite and provide with information about diagnostics and treatment of this rare disease both patients and doctors. Today, there are 571 registered patients and only one from Russia. The final diagnosis is made on the basis of histological finding such as infiltration with foamy histiocytes, signs of inflammation and Touton giant cells. Immunohistological analysis is usually CD68 and XIIIa positive. There are radiological finding indicating a possible association with the disease. There is this specific, almost pathognomonic scintigraphic picture of the skeleton, “coated” aorta, “hairy kidney” patterns on computer tomography. We demonstrate a clinical case of a patient with a newly diagnosed ECD with bone and connective tissue involvement, with manifestation of this disease more than 10 years ago. It took four months to make the final diagnosis. There were three biopsies and a wide range of other diagnostic procedures.

Examining Trans-Provincial Diagnosis of Rare Diseases in China: The Importance of Healthcare Resource Distribution and Patient Mobility

(1) Background: Rare disease patients in China usually have to travel a long distance, typically across provinces, for an accurate diagnosis due to the uneven distribution of healthcare resources. This study investigated the impact factors of their trans-provincial diagnosis. (2) Methods: An analysis was made of 1531 cases (1032 adults and 499 children) garnered from the 2018 China Rare Disease Survey, representing a large patient community inflicted with 75 rare diseases from across 31 Chinese provinces. Logistic regression models were used for separate analysis of adult and child patient groups. (3) Results: Nearly half (47.2%) of patients obtained their accurate diagnosis outside their home provinces. The uneven geographical distribution of high-quality healthcare had a significant impact on variation in trans-province diagnosis. Adult patients with lower family income, rural hukou and severer physical disability were disadvantaged in accessing trans-provincial diagnosis. Families with a child patient tended to pour resources into obtaining the trans-provincial diagnosis. The rarity of the disease had only a minimal effect on healthcare utilization across the provinces. (4) Conclusions: In addition to medical care, more attention should be paid to the socioeconomic factors that prevent the timely diagnosis of a rare disease, especially the uneven geographical distribution of high-quality healthcare resources, the financial burden on the family and the differences between adult and child patients.

Fatores de vulnerabilidades em itinerários terapêuticos de doenças raras: uma revisão integrativa

Objetivo: O artigo preocupa-se em ampliar a compreensão sobre conflitos éticos vivenciados por pacientes de doenças raras, identificandoos principais fatores de vulnerabilidades em itinerários terapêuticos de pessoas que vivem nessa condição.Método: Para tanto, realizou-se uma revisão integrativa da literatura desenvolvida nas bases de dados internacionais, publicada entre os anos de 2000 a 2016, compreendendo os idiomas português, inglês e espanhol. Resultados e discussão: Os resultados, a partir da análise qualitativa dos estudos selecionados, possibilitaram identificar os seguintes fatores de vulnerabilidades: falta de informações; despreparo profissional; dificuldade de se chegar a um diagnóstico; longos caminhos percorridos/ diversos serviços de saúde; faltam privacidade e autonomia na participação em pesquisas dedoenças raras; dificuldades de tratamentos e/ ou tratamentos de auto custo; dificuldades financeiras/empobrecimento; falta de organização e estrutura dos serviços de saúde; acolhimento diferenciado seja por discriminação, privações e/ou estigmatização, e sofrimento emocional.Conclusão: Ao discutir essas diferentes dimensões da vulnerabilidade a partir do campo da bioética, o artigo concluí pela necessidade de abordar os itinerários terapêuticos a partir de novas perspectivas interdisciplinares, buscando garantir o respeito ao direito à vida, à saúde e à proteção da dignidade das pessoas que vivem com doenças raras.

Improved Diagnosis of Rare Disease Patients through Systematic Detection of Runs of Homozygosity

Autozygosity is associated with an increased risk of genetic rare disease, thus being a relevant factor for clinical genetic studies. More than 2400 exome sequencing data sets were analyzed and screened for autozygosity on the basis of detection of >1 Mbp runs of homozygosity (ROHs). A model was built to predict if an individual is likely to be a consanguineous offspring (accuracy, 98%), and probability of consanguinity ranges were established according to the total ROH size. Application of the model resulted in the reclassification of the consanguinity status of 12% of the patients. The analysis of a subset of 79 consanguineous cases with the Rare Disease (RD)–Connect Genome-Phenome Analysis Platform, combining variant filtering and homozygosity mapping, enabled a 50% reduction in the number of candidate variants and the identification of homozygous pathogenic variants in 41 patients, with an overall diagnostic yield of 52%. The newly defined consanguinity ranges provide, for the first time, specific ROH thresholds to estimate inbreeding within a pedigree on disparate exome sequencing data, enabling confirmation or (re)classification of consanguineous status, hence increasing the efficiency of molecular diagnosis and reporting on secondary consanguinity findings, as recommended by American College of Medical Genetics and Genomics guidelines.

The international X-linked hypophosphataemia (XLH) registry (NCT03193476): rationale for and description of an international, observational study

BackgroundX-linked hypophosphataemia (XLH) is a rare, hereditary, progressive and lifelong phosphate wasting disorder characterised by pathological elevations in fibroblast growth factor (FGF) 23 concentration and activity; XLH has an incidence of approximately 1 in 20–25,000 individuals. Excess FGF23 activity leads to increased phosphate excretion in the kidneys – mediated by downregulation of renal tubular phosphate transporters – and reduced phosphate absorption in the intestines – due to impaired vitamin D activation. This results in impaired bone growth and mineralisation, short and disproportionate stature, leg bowing, musculoskeletal pain, spontaneous dental abscesses, rickets, and osteomalacia. The spectrum of manifestations differs between paediatric and adult patients. Those involved in the treatment of this condition face many challenges, including a lack of robust natural history and demographic data. This multicentre, international, rare-disease patient registry (XLH Registry) was established to address the paucity of data in XLH and to help inform future clinical practice.ResultsThe XLH Registry collects standard diagnostic and monitoring practice data, including (where applicable) diagnosis and disease progression history, treatment regimens and family history; the protocol does not mandate any interventions or clinical assessments. The XLH Registry aims to recruit 1200 paediatric and adult patients with XLH over 10 years, and several data analyses and peer-reviewed publications are expected to be generated throughout this period. A post-authorisation safety study for Bburosumab, for which the registry Sponsor is the marketing authorisation holder, will be nested as a sub-study within the XLH Registry via a subsequent protocol amendment.ConclusionThe data collected within this rare-disease patient registry will be utilised to synthesise real-world evidence to inform the management of XLH, to improve the quality of life and standard of care of patients living with this rare debilitating disease.

Charting Early Developmental Trajectory of a Pilot Rare Disease Registry in Slovenia.

Active surveillance of rare diseases enables evidence-informed policymaking, wide-ranging monitoring of rare disease patients, and subsequently assists progressively complex clinical and research needs. This article charts the initial steps for the development of a pilot rare disease registry in Slovenia. The research applies a case study design, while the collection of data was carried out through focus group discussions with 24 eminent experts from the field. The research results reveal the necessity for choosing an adequate development approach and point out that successful development of the national rare disease registry requires well-orchestrated efforts of all stakeholders. This inevitably includes effective preparation and implementation of the national rare disease policy, along with the divergence of clinical, organizational, and technological factors, and their integration with the long-standing public health goals.