The RD-Connect Genome-Phenome Analysis Platform: Accelerating diagnosis, research, and gene discovery for rare diseases.

Rare disease patients are more likely to receive a rapid molecular diagnosis nowadays thanks to the wide adoption of next-generation sequencing. However, many cases remain undiagnosed even after exome or genome analysis, because the methods used missed the molecular cause in a known gene, or a novel causative gene could not be identified and/or confirmed. To address these challenges, the RD-Connect Genome-Phenome Analysis Platform (GPAP) facilitates the collation, discovery, sharing, and analysis of standardized genome-phenome data within a collaborative environment. Authorized clinicians and researchers submit pseudonymised phenotypic profiles encoded using the Human Phenotype Ontology, and raw genomic data which is processed through a standardized pipeline. After an optional embargo period, the data are shared with other platform users, with the objective that similar cases in the system and queries from peers may help diagnose the case. Additionally, the platform enables bidirectional discovery of similar cases in other databases from the Matchmaker Exchange network. To facilitate genome-phenome analysis and interpretation by clinical researchers, the RD-Connect GPAP provides a powerful user-friendly interface and leverages tens of information sources. As a result, the resource has already helped diagnose hundreds of rare disease patients and discover new disease causing genes.

The impact of toxic oil syndrome on physical and psychological health status using the HAQ and the PHQ-9 questionnaires.

BACKGROUND: Toxic oil syndrome (TOS) is a multisystemic disease due to a massive intoxication. To evaluate physical and mental health of TOS patients, we used the Health Assessment Questionnaire (HAQ) and the Patient Health Questionnaire-9 (PHQ-9). Additionally, we correlated both questionnaires with the results of the Short Form-36v2 (SF-36v2) Health Survey obtained in the same patients' sample. METHODS: 895 TOS patients who participated in the prior SF-36v2 study were invited to participate. We described patients' demographic and clinical characteristics, HAQ and PHQ-9 results. HAQ and PHQ-9 scores were correlated to the standardised SF-36v2 results obtained in our previous study. RESULTS: In total, 828 (92.5%) TOS annual follow-up and HAQ and 810 (90.5%) PHQ-9 valid questionnaires were analysed. Participants' average age was 65.4 (Standard Deviation (SD): 13.4), 521 (62.9%) were women, 725 (87.6%) reported having at least other chronic disease and 789 (95.3%) an additional TOS-related health problem. Average scores were 0.91 (SD: 0.83) for HAQ, 35.8 (SD: 10.1) for PCS and 37.8 (SD: 11.6) for MCS. Overall, 467 (57.7%) participants had moderate/severe depression (PHQ-9 ≥ 10), but only 229 (49.6%) of them reported having a depression diagnosis. Correlation between questionnaires was very strong for HAQ and physical function SF-36v2 dimension and moderate/fair for the rest of combinations. CONCLUSIONS: TOS cohort presented low/very low health status measured with SF-36v2, moderate difficulties in performing daily activities according to HAQ, and a high prevalence of major depression measured with PHQ-9. High proportion of undiagnosed depression was detected, proving PHQ-9 useful in terms of detecting and promoting depression diagnosis in the cohort.

The ASDEU autism prevalence study in northern Spain.

The prevalence of autism spectrum disorders (ASD) was studied in children in the County of Gipuzkoa (Basque Country, Spain) as part of the European Union's Autism Spectrum Disorder in Europe project (ASDEU- https://asdeu.eu ). To identify cases in a total community sample of 7- to 9-year-old pupils (N = 14,734), a multistage approach was adopted: in the first stage, a teacher nomination (TN) form was completed by school teachers; and in the second stage, all families with a child nominated by their teachers were invited to complete the Social Communication Questionnaire (SCQ). A total of 108 (59%) schools participated fully, yielding a final sample of 9177 of 14.734 (61.9%) pupils. A total of 212 (2.3%) children were nominated via the TN form, and of these, 105 (49.5%) returned the completed SCQ. Twenty-five (23.8%) cases with SCQ scores ≥ 15 were invited to undergo a free clinical assessment, and 10 (40%) new cases of ASD were identified. The prevalence estimate included the 55 cases already being supported by the Gipuzkoa's only ASD association, the Gipuzkoa Autism Society (Asociación Guipuzcoana de Autismo/GAUTENA)), as well as the 10 new subjects identified by the ASDEU field diagnostic process. A sensitivity analysis was performed to estimate new potential ASD cases among the non-participant schools, leading to a final figure of 87 cases of ASD in this age-bracket at the date of the study. This global probabilistic estimate, including non-participating schools, would thus provide a population prevalence of 0.59% (95% CI 0.48-0.73), a result lower than those reported by some other studies. Attrition rates in cross-sectional studies are challenging and support the need for developing longitudinal ASD incidence surveillance study areas (ASD observatories).

Fabry Nephropathy: An Evidence-Based Narrative Review.

Fabry disease (FD) is a rare, X-linked disorder caused by mutations in the GLA gene encoding the enzyme α-galactosidase A. Complete or partial deficiency in this enzyme leads to intracellular accumulation of globotriaosylceramide (Gb3) and other glycosphingolipids in many cell types throughout the body, including the kidney. Progressive accumulation of Gb3 in podocytes, endothelial cells, epithelial cells, and tubular cells contribute to the renal symptoms of FD, which manifest as proteinuria and reduced glomerular filtration rate leading to renal insufficiency. A correct diagnosis of FD, although challenging, has considerable implications regarding treatment, management, and counseling. The diagnosis may be confirmed by demonstrating the enzyme deficiency in males and by identifying the specific GLA gene mutation in male and female patients. Treatment with enzyme replacement therapy, as part of the therapeutic strategy to prevent complications of the disease, may be beneficial in stabilizing renal function or slowing its decline, particularly in the early stages of the disease. Emergent treatments for FD include the recently approved chaperone molecule migalastat for patients with amenable mutations. The objective of this report is to provide an updated overview on Fabry nephropathy, with a focus on the most relevant aspects of its epidemiology, diagnosis, pathophysiology, and treatment options.

Building a theoretical framework for autism spectrum disorders screening instruments in Europe.

BACKGROUND: This study addresses the need for a theoretical base to develop more effective early autism spectrum disorders (ASD) detection tools. The structure that underlies early ASD detection is explored by evaluating the opinions of experts on ASD screening tools currently used in Europe. METHOD: A process of face and content validity was performed. First, the best constructs were selected from the relevant tests: Checklist for Early Signs of Developmental Disorders (CESDD), Checklist for Autism in Toddlers (CHAT), Early Screening of Autistic Traits Questionnaire (ESAT), Modified Checklist for Autism in Toddlers (M-CHAT), Social Communication Questionnaire (SCQ) and Communication and Symbolic Behaviour Scales Developmental Profile (CSBS-DP). The diagnostic content validity model by Fehring (1986, 1994) was adapted to make the selection. Afterwards, the items, taken from these tests, were selected to fit into each construct, using the same methodology. RESULTS: Twelve of the 18 constructs were selected by the experts and 11 items were chosen from a total of 130, reduced to eight after eliminating tautologies. CONCLUSIONS: Mapping these constructs and items on to the DSM-5 diagnostic criteria for ASD indicated good face and content validity. Results of this research will contribute to efforts to improve early ASD screening instruments and identify the key behaviours that experts in ASD see as the most relevant for early detection.

Rare Diseases: Joining Mainstream Research and Treatment Based on Reliable Epidemiological Data.

Despite growing acceptance of patient registries and natural history studies to provide useful information, the rare disease community suffers from the absence of reliable epidemiological data on the prevalence and incidence of most rare diseases in national and global populations. Likewise, the patients and health care providers lack adequate information on the pathophysiology of rare diseases and expected outcomes of these disorders. The rare diseases community includes all of the stakeholders involved in the research and development and dissemination of products and information for the diagnosis, prevention or treatment of rare diseases or conditions. To replace many of the perceptions with realities, several global efforts have been implemented to sustain and increase the reported progress with the thousands of rare diseases. The first efforts is to develop a global research infrastructure of qualified investigators to stimulate and coordinate research efforts by seeking ways to provide access to clinical trials at multi-national research sites with common protocols and multi-disciplinary research teams. Next, is the continued identification and expansion of worldwide partnerships and collaborations of Patient Advocacy Groups (PAGs), research investigators, the biopharmaceutical and medical devices industries, and the government research and regulatory agencies for a specific rare disease or group of related diseases. Gaining access to information about rare diseases, patient advocacy groups, ongoing and planned research studies and products in research protocols continue to improve the lives of patients and their families. Many basic, clinical and translational research investigators, public and private sector funding organizations, patient advocacy groups, foundations, and the pharmaceutical, biotechnology, and medical devices industries are committed to translating research discoveries that will be useful in the treatment and care of patients with rare diseases over their lifespan. Evidence from well-constructed epidemiological studies will provide the evidence that point to the value of additional clinical studies to increase the understanding of rare diseases.

Rare Disease Biospecimens and Patient Registries: Interoperability for Research Promotion, a European Example: EuroBioBank and SpainRDR-BioNER.

Well-annotated and properly preserved specimens are crucial both for diagnostic purposes and for use in basic and pre-clinical research, and are especially important for rare disease (RD) studies. Several consortia have been established in the recent years in order to facilitate research and to maximise access to rare biological samples and data stored in rare disease biobanks and registries, among them the EuroBioBank network and the Spain National Rare Disease Registry (RDR) and Biobank (BioNER).EuroBioBank, established in 2001, was the first network of RD biobanks to operate in Europe as a service distributing human DNA, cells, and tissue to the scientific community conducting research on rare diseases.The Spanish RDR and BioNER were created for facilitating rare disease research and health-related matters. The coordination of these two bodies represents an example of great scientific value as biological samples donated by patients at BioNER are linked to clinical information collected in the RDR.Rare disease biobanks and registries will need for the future to increase their effort to improve interconnection so to enable investigators to better locate samples and associated data, while protecting security of the data and privacy of the participants and adhering to international ethical and legal requirements.

Congenital Anomalies: Cluster Detection and Investigation.

This work summarizes the main aspects to be considered around birth defects (or congenital anomalies) clusters. Most birth defects (BD), considered individually, fall into the definition of rare diseases (RD), according to their low frequency. Likewise, many RD are congenital, because their manifestations are present at birth or can be even evident before the delivery. It has been estimated that overall 7.9 million children are born each year with serious BD of genetic or partially genetic origin, and additional hundreds of thousands more are born with serious BD of post-conception origin.A "birth defect cluster" can be defined as an unusual aggregation of cases (grouped in place and time) that is suspected to be greater than expected, even though the expected number may not be known. These clusters are incidents or occurrences that let us turn the challenge of identifying the causal agent(s) involved in the origin of such clusters, into an opportunity to exert primary prevention, and thus achieve the ultimate goal of enabling infants being born healthy. Therefore, any program or system involved in BD surveillance and research should devote part of its activities to detect and investigate clusters, to ensure that such opportunity for primary prevention will be conveniently leveraged. Regardless the type of cluster, there are several phases that must be undertaken sequentially for proper control and the maximum benefit for the population: cluster detection, evaluation and investigation, management, adoption of preventive measures, and communication of the results to the public or target population.

Preparing for the Future of Rare Diseases.

Members of the rare disease community have devoted significant financial and personnel resources to address the numerous issues surrounding rare diseases. The past has been devoted to developing an emphasis on rare diseases including an emphasis on research studies or locating information on rare diseases and the requirements and limitations of conducting clinical trials with small patient populations. The expanded role of patient advocacy organizations and patient engagement in all aspects of clinical research continues to gain acceptance within the research community. The future will require a greater understanding and interpretation of available information from multiple sources including electronic health records and big data sources. The pipeline of potential orphan products continues to grow significantly and holds great promise for novel interventions due to advances in clinical trial design and data analyses. Expanding diagnostic procedures with improved sequencing methods will speed up the diagnosis or rare diseases. Accepting agreed upon nomenclature and codification of rare diseases will assist in differentiating diseases and identifying selected sub-populations of rare diseases. Improvements in patient recruitment and increased flexibility in the product review and approval procedures by regulatory agencies will facilitate product approvals. Children particularly will need help and assistance dealing with feelings of isolation from their peers due to their rare disease. During the transition from childhood to adolescence to adult, difficulties of fitting in with peers and not wanting to be different are a major concern. In response to increasing costs of treatments, Value-Based Care is gaining greater acceptance by the reimbursement and the payer community as a basis for payment for interventions. Mobile Health (M-health) Technologies have the potential to revolutionize how clinical research is conducted in the future. Wearable devices, remote sensors, and the development of mobile device applications (apps) will all assist in constant monitoring of patients for safety and efficacy of approved and investigational compounds. Tele Health and Tele Medicine may provide the necessary access to expert clinicians with a better understanding of individual rare diseases. The future promises great advances and even greater personalized treatments with the introduction of novel treatments and approaches to care.

Mortality Statistics and their Contribution to Improving the Knowledge of Rare Diseases Epidemiology: The Example of Hereditary Ataxia in Europe.

Official mortality statistics provide population-based data and serve to improve epidemiological knowledge of rare diseases (RDs), by helping with the description of the natural history of the disease. They are an important complement of registries and estimates of disease burden and costs. At the same time, they heighten both the visibility of these diseases and the interest in their study and the search for treatments that may increase survival. This chapter contains a European analysis of hereditary ataxia mortality, which considers the time trend in different countries and the geographical variability in risk of death. Despite the limitations of applying this data source to RDs, mortality statistics share criteria which facilitate international comparisons and are of great utility for obtaining sufficiently uniform and robust time series for analysis of low-prevalence diseases.

Data Quality in Rare Diseases Registries.

In the field of rare diseases, registries are considered power tool to develop clinical research, to facilitate the planning of appropriate clinical trials, to improve patient care and healthcare planning. Therefore high quality data of rare diseases registries is considered to be one of the most important element in the establishment and maintenance of a registry. Data quality can be defined as the totality of features and characteristics of data set that bear on its ability to satisfy the needs that result from the intended use of the data. In the context of registries, the 'product' is data, and quality refers to data quality, meaning that the data coming into the registry have been validated, and ready for use for analysis and research. Determining the quality of data is possible through data assessment against a number of dimensions: completeness, validity; coherence and comparability; accessibility; usefulness; timeliness; prevention of duplicate records. Many others factors may influence the quality of a registry: development of standardized Case Report Form and security/safety controls of informatics infrastructure. With the growing number of rare diseases registries being established, there is a need to develop a quality validation process to evaluate the quality of each registry. A clear description of the registry is the first step when assessing data quality or the registry evaluation system. Here we report a template as a guide for helping registry owners to describe their registry.

Improved Diagnosis and Care for Rare Diseases through Implementation of Precision Public Health Framework.

Public health relies on technologies to produce and analyse data, as well as effectively develop and implement policies and practices. An example is the public health practice of epidemiology, which relies on computational technology to monitor the health status of populations, identify disadvantaged or at risk population groups and thereby inform health policy and priority setting. Critical to achieving health improvements for the underserved population of people living with rare diseases is early diagnosis and best care. In the rare diseases field, the vast majority of diseases are caused by destructive but previously difficult to identify protein-coding gene mutations. The reduction in cost of genetic testing and advances in the clinical use of genome sequencing, data science and imaging are converging to provide more precise understandings of the 'person-time-place' triad. That is: who is affected (people); when the disease is occurring (time); and where the disease is occurring (place). Consequently we are witnessing a paradigm shift in public health policy and practice towards 'precision public health'.Patient and stakeholder engagement has informed the need for a national public health policy framework for rare diseases. The engagement approach in different countries has produced highly comparable outcomes and objectives. Knowledge and experience sharing across the international rare diseases networks and partnerships has informed the development of the Western Australian Rare Diseases Strategic Framework 2015-2018 (RD Framework) and Australian government health briefings on the need for a National plan.The RD Framework is guiding the translation of genomic and other technologies into the Western Australian health system, leading to greater precision in diagnostic pathways and care, and is an example of how a precision public health framework can improve health outcomes for the rare diseases population.Five vignettes are used to illustrate how policy decisions provide the scaffolding for translation of new genomics knowledge, and catalyze transformative change in delivery of clinical services. The vignettes presented here are from an Australian perspective and are not intended to be comprehensive, but rather to provide insights into how a new and emerging 'precision public health' paradigm can improve the experiences of patients living with rare diseases, their caregivers and families.The conclusion is that genomic public health is informed by the individual and family needs, and the population health imperatives of an early and accurate diagnosis; which is the portal to best practice care. Knowledge sharing is critical for public health policy development and improving the lives of people living with rare diseases.

Monitoring Huntington's Disease Mortality across a 30-Year Period: Geographic and Temporal Patterns.

BACKGROUND: Huntington's disease (HD) is a progressive neurodegenerative condition characterized by chorea, dystonia, behavioral disturbances and cognitive decline. The aim of this study is to assess temporal and spatial changes on mortality attributable to HD over 30 years in Spain. METHODS: HD data were extracted from the nationwide mortality registry for the period 1984-2013. Annual and 5-year gender- and age-specific rates adjusted for the standard European population were calculated. Geographic analysis was performed by districts from 1999 through 2013, and then estimated standardized mortality ratios (SMRs) and smoothed SMRs. RESULTS: There were 1,556 HD-related deaths across the study period. An increasing trend in age-adjusted HD mortality was in evidence, specifically from 1994 through 1998. On a year-by-year basis, age-adjusted mortality rates increased from 0.076 per 100,000 population in 1984 to 0.157 in 2013. Geographical differences among districts were evident in specific areas and in the southwest of Spain with a significantly higher HD mortality risk. CONCLUSION: HD mortality rising trends in Spain might be attributable to improvements in diagnosis leading to a rise in prevalence. Geographical variability in HD mortality could be related to regional differences in disease prevalence, health-care disparities, or other factors which call for in-depth assessment in future studies.

Clinical and genetic characterization of patients with eye diseases included in the Spanish Rare Diseases Patient Registry.

BACKGROUND: The low prevalence of rare diseases poses a significant challenge in advancing their understanding. This study aims to delineate the clinical and genetic characteristics of patients with rare eye diseases (RED) enrolled in the Spanish Rare Diseases Patient Registry. METHODS: A total of 864 patients from the registry database were included. Diseases were categorized into inherited retinal dystrophies (n=688); anterior segment diseases (n=48); congenital malformations (n=27); and syndromic diseases with ocular involvement including muscular (n=46), neurological (n=34), or metabolic (n=13); inflammatory diseases (n=4); and tumors (n=4). Data on visual acuity (VA) and/or visual field (VF), symptoms and signs, concurrent diseases in syndromic cases, age of onset and at diagnosis, affected genes, disability rating, inability to work and dependency grade recognition were collected. RESULTS: A mean diagnostic delay of 7 years from symptom onset was observed. Commonly reported symptoms included photophobia, night blindness, and progressive vision loss (≥57% of patients). Cataract was the most prevalent secondary disease (46%), with pseudophakia being the most common ocular surgery (26%). Hearing loss and cardiovascular diseases were the most prevalent concurrent systemic diseases (≥13%). Certificates of disability, incapacity for work, and dependency were held by 87%, 42%, and 19% of patients, respectively. Among the 719 patients with available VA data, 193 (27%) were blind, and 188 (26%) had moderate to severe visual impairment. Over half of the patients (54%) exhibited VF defects, and 216 (25%) had concentric contraction ≤5° or abolished VF. Most had genetic diseases with autosomal recessive (55%), autosomal dominant (30%), X-linked (9%), and mitochondrial (6%) patterns. One patient had mutations in both recessive USH2A and dominant RHO genes simultaneously. Of the 656 patients (75.7%) who underwent genetic testing, only 461 (70.3%) received a positive result (pathogenic or likely pathogenic mutations explaining the phenotype). We found 62 new gene variants related to RED not previously reported in databases of genetic variants related to specific phenotypes. CONCLUSIONS: This study delineates the clinical and genotypic profiles of RED in Spain. Genetic diseases, particularly retinal disorders, predominate, but a significant proportion of affected patients remain genetically undiagnosed, hindering potential gene therapy endeavors. Despite notable improvements in reducing diagnosis delays, it is still remarkable. RED frequently lead to disability and blindness among young populations.

Mortality of congenital osteochondrodysplasias: a nationwide registry-based study.

Osteochondrodysplasias are a heterogeneous group of more than 200 entities, characterized by abnormalities of cartilage, bone growth, and skeletal development. The aim of this study was to assess temporal and spatial changes in overall mortality due to these disorders in Spain, using data from a nationwide registry. Annual deaths showing osteochondrodysplasias as the underlying cause of death were selected using the International Classification of Diseases-9th revision (ICD-9) codes for the period 1981 through 1998, and ICD-10 codes for the period 1999 through 2008. Age-adjusted mortality rates were calculated by sex, and geographic analysis was performed by municipality. A total of 679 deaths were recorded (53% men). Age-adjusted mortality rates went from 0.09 (0.06, 0.12) per 100,000 population in 1981 to 0.05 (0.03, 0.08) per 100,000 population in 2008. A changing trend in the age-standardized mortality rate was in evidence, with an annual increase of 2.4% (-0.4, 5.2) from 1981 to 1994, and an annual decrease of -7.3% (-10.9, -3.5) from 1995 onwards. Geographic analysis showed some places situated in the west and south of Spain with greater risk of mortality. There is a need to identify risk factors and to increase overall knowledge about the life expectancy and epidemiology of osteochondrodysplasias.

Epidemiology of hereditary ataxias in Spain: hospital discharge registry and population-based mortality study.

BACKGROUND: Hereditary ataxias (HA) comprise a group of genetically heterogeneous rare diseases. As important public health problems to be monitored, this study analyses the morbimortality of HA in Spain. METHODS: Data were extracted from the national death index (1981-2008), using the International Classification of Diseases (ICD) 9th revision code 334 until 1998, and 10th revision code G11 from 1999 onwards. ICD-9 codes were then selected from the national discharge dataset (1998-2007). Age-adjusted morbidity and mortality rates were obtained by gender and 5-year period. RESULTS: Of the 610 HA deaths from 1981 to 2008, 277 corresponded to Friedreich's ataxia (45.4%) and 333 (54.6%) to other and unspecified ataxias (non-Friedreich group). Both groups showed an increase in mortality trend, which was more pronounced in males from 1985-1989 to 1990-1994. Geographical distribution of mortality revealed higher risk for males, mainly in the north of Spain. A total of 5,341 HA hospitalisations were identified from 1998 to 2007. The average annual age-adjusted hospitalisation rate was 1.19 per 100,000 population, with a rising trend. CONCLUSION: This increase in morbidity and mortality, coupled with the slight interprovincial differences, indicate that more attention should be paid to these rare diseases by public authorities and society alike.

[Is there a place in primary care for rare diseases? The case of fibrodysplasia ossificans progressiva]. / ¿Hay lugar en atención primaria para las enfermedades poco frecuentes? El caso de la fibrodisplasia osificante progresiva.

Fibrodysplasia ossificans progressiva is one of the most devastating constitutional diseases of the bone, and may be a valid example to establish the role of Primary Care in the care of rare diseases. Although rare diseases usually present with marked anomalies, they can mimic signs and symptoms of common disorders, with the risk of going unnoticed. For this reason, all health professionals should proceed with a reasonable suspicion when confronted with a patient with an apparently common disease with atypical symptoms and a non-conventional progress. The care given by the Primary Care team along with other health care services are fundamental in the integrated and individualised follow-up. The quality of care in rare diseases must not be inferior to that provided to the other chronic diseases, since, besides being a requirement of justice and fairness, these patients are, in essence, the "paradigm of chronicity".

Psychosocial impact at the time of a rare disease diagnosis.

Over half of all persons with rare diseases (RDs) in Spain experience diagnostic delay (DD) but little is known about its consequences. This study therefore aimed to analyze the psychological impact of obtaining a diagnosis of an RD, and to ascertain what social determinants are influenced and what the personal consequences are, according to whether or not patients experienced DD. Data were obtained from a purpose-designed form completed by persons registered at the Spanish Rare Diseases Patient Registry. The following were performed: a descriptive analysis; a principal component analysis (PCA); and logistic regressions. Results revealed that while searching for a diagnosis, people who experienced DD were more in need of psychological care than those diagnosed in less than one year (36.2% vs 23.2%; p = 0.002; n = 524). The PCA identified three principal components, i.e., psychological effects, social implications, and functional impact. Reducing DD would improve psychological effects, such as irritability (OR 3.6; 95%CI 1.5-8.5), frustration (OR 3.4; 95%CI 1.7-7.1) and concentration on everyday life (OR 3.3; 95%CI 1.4-7.7). The influence of the social implications and functional repercussions of the disease was greater in persons with DD (scores of 22.4 vs 20 and 10.6 vs 9.4, respectively) in terms of the difficulty in explaining symptoms to close friends and family (3.3 vs 2.9), and loss of independence (3.3 vs 2.9). In conclusion, this is the first study to analyze the psychosocial impact of diagnosis of RDs in Spain and one of few to assess it in the patients themselves, based on data drawn from a purpose-designed form from a national registry open to any RD. People affected by RDs who underwent DD experienced greater psychosocial impact than did those who were diagnosed within the space of one year.

Familial Mediterranean Fever in Spain: Time Trend and Spatial Distribution of the Hospitalizations.

Familial Mediterranean Fever (FMF) is a rare, hereditary, auto-inflammatory disease. The aims of this study were to explore the time trend and geographical distribution of hospitalizations in Spain from 2008 to 2015. We identified hospitalizations of FMF from the Spanish Minimum Basic Data Set at hospital discharge, using ICD-9-CM code 277.31. Age-specific and age-adjusted hospitalization rates were calculated. The time trend and the average percentage change were analyzed using Joinpoint regression. Standardized morbidity ratios were calculated and mapped by province. A total of 960 FMF-related hospitalizations (52% men) were identified across the period 2008-2015, with an increase in hospitalizations of 4.9% per year being detected (p < 0.05). The risk of hospitalization was higher than expected for the national total (SMR > 1) in 13 provinces (5 in the Mediterranean area), and lower (SMR < 1) in 14 provinces (3 in the Mediterranean area). There was an increase in hospitalizations of patients with FMF in Spain throughout the study period, with a risk of hospitalization that was higher, though not exclusively so, in provinces along the Mediterranean coast. These findings contribute to the visibility of FMF and provide useful information for health planning. Further research should take into account new population-based information, in order to continue monitoring this disease.

Predictors of autism spectrum disorder diagnosis in a spanish sample of preterm children with very low birthweight: A cross-sectional study.

Background and Aims: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a higher likelihood of being diagnosed in preterm populations. Likewise, low birthweight has also been connected with an increased likelihood of ASD. The objectives were to study the frequency and define the relationship between ASD, gestational age, birthweight, and growth percentiles for preterm children. Methods: A sample of preterm children with very low birthweight was selected from the Spanish population at 7-10 years old. Families were contacted from the hospital, and they were offered an appointment to conduct a neuropsychological assessment. The children who showed signs of ASD were referred to the diagnostic unit for differential diagnosis. Results: A total of 57 children completed full assessments, with 4 confirmed ASD diagnoses. The estimated prevalence was 7.02%. There were statistically significant weak correlations between ASD and gestational age (τb = -0.23), and birthweight (τb = -0.25), suggesting there is a higher likelihood of developing ASD for those born smaller or earlier in their gestation. Conclusion: These results could improve ASD detection and outcomes for this vulnerable population while also supporting and enhancing previous findings.