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Objective: This scoping review aims to comprehend the nature and the extent of the available evidence regarding tools to assess patients with Fabry Disease (FD). Introduction: Due to its heterogeneous presentation and rare frequency in the population, FD is significantly misdiagnosed. In this context, understanding the current knowledge of tools to assess FD patients is crucial to ensure appropriate screening, early diagnosis, accurate classification, and timely treatment. A preliminary search of PubMed and the Cochrane Database of Systematic Reviews was conducted, and no published or underway systematic reviews or scoping reviews on our research question were identified. Inclusion criteria: We will include human-based research articles based on qualitative or quantitative methods, published in peer-reviewed journals that examine any assessment tool for FD, particularly, those that contribute to the diagnosis, screening, classification, stratification, and evaluation. Only articles with full text available, published between 2017 and 2022, and written in English and Spanish will be included. Methods: Search will be developed by a librarian and conducted on the following databases: Cochrane Database of Systematic Reviews, Epistemonikos, Biblioteca Virtual en Salud, Otseeker, PEDro, Pubmed, IngentaConnect, Directory of Open Access Journals, SpringerLink, Wiley, SAGE, and Scielo. Selection of studies will be independently conducted by calibrated reviewers through the title, abstract, and full-text screening, followed by data charting and drafting of tables, figures, and diagrams.

Objective: To understand the extent and type of evidence regarding existing assessment tools to screen, diagnose, stratify, and evaluate patients with Bardet Biedl Syndrome (BBS) around the world. Introduction: As a rare disease, diagnosing BBS often comes associated with several difficulties, including under-diagnosis and incorrect management due to lack of access to information about the disease. Despite the complexity of BBS, only a few articles expose clear assessment and guidance for this disease. Inclusion criteria: We will include human-based research articles based on qualitative or quantitative methods, published in peer-reviewed journals that examine any assessment tool for screening, diagnostic, evaluation, and stratification purposes in BBS. Only articles with full text available will be included. All patients from included studies need to have a confirmed genetic diagnosis AND/OR fulfill the required clinical criteria. We will include articles published between 2017 and 2022, written in English and Spanish due to authors’ proficiency skills. Methods: Search will be conducted on Cochrane Database of Systematic Reviews, Epistemonikos, Biblioteca Virtual en Salud, Otseeker, PEDro, Pubmed, IngentaConnect, Directory of Open Access Journals, SpringerLink, Wiley, SAGE, and Scielo. Selection of studies will be independently done by calibrated reviewers through title, abstract, and full-text screening, followed by data charting and drafting of tables, figures, and diagrams.

BACKGROUND: People with rare disorders face significant global health inequalities; the challenge is how to raise awareness and develop a nucleus of experts in a country who are then able to provide guidance to others in that country. The International Prader-Willi Syndrome Organisation (IPWSO) established Project ECHO® with the aim of facilitating the sharing of knowledge and the building of international partnerships to reduce global health inequalities for a particular rare genetically-determined neurodevelopmental disorder, Prader-Willi Syndrome (PWS). Four different ECHO programmes were established for the following groups: (a) Individuals (usually parents) who had taken on a leadership role in their country; (b) health professionals interested in PWS; (c) professional care providers supporting children and adults with PWS; and (d) a Latin American ECHO in Spanish. The programme started in 2020 and an evaluation was undertaken after one year to determine: the extent to which IPWSO had been able to recruit and retain individuals globally; the nature and extent of any benefits gained from the sessions; and examples of how individual involvement in the programme had led to local benefits. The methods included analysing routinely kept process indicators and survey data from the attendees of one component of the programme (the Leadership ECHO), together with a qualitative analysis of survey data and recorded interviews of attendees from countries of differing socio-economic status. RESULTS: We describe the IPWSO ECHO programme and report on the outcomes from the evaluation of one aspect of the programme, the Leadership ECHO. Attendance of the Leadership ECHO sessions was satisfactory, with a mean of 24.7 participants, with participants attending a mean of 5.67 sessions, i.e., 30% of sessions. There was also good global reach, with individuals attending from 34 countries, although there were notable geographic regions with very limited representation. Feedback and interviews demonstrated the positive impact of the programme with some early evidence of positive developments at national level. CONCLUSIONS: Families and professionals from countries with a range of expertise and services offered to people with PWS remained engaged throughout the ECHO programme, established networks of support and fostered the development of good practice.

BACKGROUND: People with rare disorders face significant global health inequalities; the challenge is how to raise awareness and develop a nucleus of experts in a country who are then able to provide guidance to others in that country. The International Prader-Willi Syndrome Organisation (IPWSO) established Project ECHO® with the aim of facilitating the sharing of knowledge and the building of international partnerships to reduce global health inequalities for a particular rare genetically-determined neurodevelopmental disorder, Prader-Willi Syndrome (PWS). Four different ECHO programmes were established for the following groups: (a) Individuals (usually parents) who had taken on a leadership role in their country; (b) health professionals interested in PWS; (c) professional care providers supporting children and adults with PWS; and (d) a Latin American ECHO in Spanish. The programme started in 2020 and an evaluation was undertaken after one year to determine: the extent to which IPWSO had been able to recruit and retain individuals globally; the nature and extent of any benefits gained from the sessions; and examples of how individual involvement in the programme had led to local benefits. The methods included analysing routinely kept process indicators and survey data from the attendees of one component of the programme (the Leadership ECHO), together with a qualitative analysis of survey data and recorded interviews of attendees from countries of differing socio-economic status. RESULTS: We describe the IPWSO ECHO programme and report on the outcomes from the evaluation of one aspect of the programme, the Leadership ECHO. Attendance of the Leadership ECHO sessions was satisfactory, with a mean of 24.7 participants, with participants attending a mean of 5.67 sessions, i.e., 30% of sessions. There was also good global reach, with individuals attending from 34 countries, although there were notable geographic regions with very limited representation. Feedback and interviews demonstrated the positive impact of the programme with some early evidence of positive developments at national level. CONCLUSIONS: Families and professionals from countries with a range of expertise and services offered to people with PWS remained engaged throughout the ECHO programme, established networks of support and fostered the development of good practice.

Background Experienced fatigue is an under-recognized and under-researched feature in persons with many different rare diseases. A better overview of the characteristics of existing research on experienced fatigue in children and adults with rare diseases is needed. The purpose of this review was to map and describe characteristics of existing research on experienced fatigue in a selection of rare diseases in rare developmental defects or anomalies during embryogenesis and rare genetic diseases. Furthermore, to identify research gaps and point to research agendas. Methods We applied a scoping review methodology, and performed a systematic search in March 2020 in bibliographic databases. References were sorted and evaluated for inclusion using EndNote and Rayyan. Data were extracted on the main research questions concerning characteristics of research on experienced fatigue (definition and focus on fatigue, study populations, research questions investigated and methods used). Results This review included 215 articles on ten different rare developmental defects/anomalies during embryogenesis and 35 rare genetic diseases. Of the 215 articles, 82 had investigation of experienced fatigue as primary aim or outcome. Included were 9 secondary research articles (reviews) and 206 primary research articles. A minority of articles included children. There were large differences in the number of studies in different diseases. Only 29 of 215 articles gave a description of how they defined the concept of experienced fatigue. The most common research-question reported on was prevalence and/ -or associations to fatigue. The least common was diagnostics (development or validation of fatigue assessment methods for a specific patient group). A large variety of methods were used to investigate experienced fatigue, impeding comparisons both within and across diagnoses. Conclusion This scoping review on the characteristics of fatigue research in rare diseases found a large variety of research on experienced fatigue. However, the minority of studies had investigation of experienced fatigue as a primary aim. There was large variation in how experienced fatigue was defined and also in how it was measured, both within and across diagnoses. More research on experienced fatigue is needed, both in children and adults with rare diseases. This review offers a basis for further research.

Background Acroscyphodysplasia has been described as a phenotypic variant of acrodysostosis type 2 and pseudohypoparathyroidism. In acrodysostosis, skeletal features can include brachydactyly, facial hypoplasia, cone-shaped epiphyses, short stature, and advanced bone age. To date, reports on this disorder have focused on phenotypic findings, endocrine changes, and genetic variation. We present a 14-year overview of a patient, from birth to skeletal maturity, with acroscyphodysplasia, noting the significant orthopaedic challenges and the need for a multidisciplinary team, including specialists in genetics, orthopaedics, endocrinology, and otolaryngology, to optimize long-term outcomes. Case presentation The patient presented as a newborn with dysmorphic facial features, including severe midface hypoplasia, malar flattening, nasal stenosis, and feeding difficulties. Radiologic findings were initially subtle, and a skeletal survey performed at age 7 months was initially considered normal. Genetic evaluation revealed a variant in PDE4D and subsequent pseudohypoparathyroidism. The patient presented to the department of orthopaedics, at age 2 years 9 months with a leg length discrepancy, right knee contracture, and severely crouched gait. Radiographs demonstrated cone-shaped epiphyses of the right distal femur and proximal tibia, but no evidence of growth plate changes in the left leg. The child developed early posterior epiphyseal arrest on the right side and required multiple surgical interventions to achieve neutral extension. Her left distal femur developed late posterior physeal arrest and secondary contracture without evidence of schypho deformity, which improved with anterior screw epiphysiodesis. The child required numerous orthopaedic surgical interventions to achieve full knee extension bilaterally. At age 13 years 11 months, she was an independent ambulator with erect posture. The child underwent numerous otolaryngology procedures and will require significant ongoing care. She has moderate intellectual disability. Discussion and conclusions Key challenges in the management of this case included the subtle changes on initial skeletal survey and the marked asymmetry of her deformity. While cone-shaped epiphyses are a hallmark of acrodysostosis, posterior tethering/growth arrest of the posterior distal femur has not been previously reported. Correction of the secondary knee contracture was essential to improve ambulation. Children with acroscyphodysplasia require a multidisciplinary approach, including radiology, genetics, orthopaedics, otolaryngology, and endocrinology specialties.

Moyamoya disease is a rare, chronic, idiopathic progressive disease characterized by irreversible vascular occlusion of the vessels of the Circle of Willis. The disease was initially considered to be limited to the East Asian population, but now the disease is being reported all over the globe in people of multiple ethnicities. It is crucial that clinicians are aware of the disease and its presentation to prevent under-recognition of the condition. We describe the case of a 44-year-old Caucasian female with a history of hypertension, depression, gastroesophageal reflux disease (GERD), and morbid obesity diagnosed with Moyamoya disease after she presented to the emergency department with recurrent stroke-like symptoms.

The Budd–Chiari syndrome (BCS) is a rare disorder due to chronic liver disease (CLD), which is caused by the obstruction of hepatic venous outflow that can be located at any place from the small hepatic venules up to the entrance of the inferior vena cava (IVC) into the right atrium. Among the causes of BCS, the rarer one is coagulation factor deficiencies. Here, we report a case of BCS associated with deficiency of protein C resulting in thrombus in IVC. The patient was a 50-year-old male, who had been suffering from recurrent abdominal and leg swelling for a long period of 7 years. He was evaluated thoroughly, and other causes of liver cirrhosis were excluded. How to cite this article Begum R, Al Mahtab M, Al Mamun A, Moben AL, Hossain SMS, Das DC, Malakar D, Rashid HO, Roy PP, Rahman S. Budd–Chiari Syndrome Due to Protein C Deficiency: A Rare Disorder to cause Chronic Liver Disease. Euroasian J Hepato-Gastroenterol 2016;6(2):194-197.

Background: Pathological mutations in cyclin-dependent kinase-like 5 cause CDKL5 deficiency disorder (CDD), a genetic syndrome associated with severe epilepsy, cognitive, motor, visual and autonomic disturbances. CDD is a relatively common genetic cause of early-life epilepsy. A specific severity assessment is lacking, required to monitor clinical course, define the natural history and for clinical trial readiness.Methods: A severity assessment was developed based on clinical and research experience from the International Foundation for CDKL5 Research Centers of Excellence consortium and the NIH Rett and Rett-related disorders Natural History Study consortium. An initial draft severity assessment was presented and reviewed at the annual CDKL5 Forum meeting (Boston, 2017). Subsequently it was iterated through four cycles of a modified Delphi process by a group of clinicians, researchers, industry, patient advisory groups and parents familiar with this disorder until consensus was achieved. The revised version of the severity assessment was presented for review, comment and piloting to families at the International Foundation for CDKL5 Research sponsored family meeting (Colorado, 2018). Final revisions were based on this additional input.Results: The final severity assessment comprised 51 items that comprehensively describe domains of epilepsy, motor, cognition, behavior, vision, speech and autonomic function. Parental ratings of therapy effectiveness, child and family functioning are also included.Conclusions: A severity assessment was rapidly developed with input from multiple stake-holders. Refinement through ongoing validation is required for future clinical trials. The consensus methods employed for the development of the severity assessment may be applicable to similar rare disorders.Key words: CDKL5; rare disorder; severity assessment; epilepsy; cortical visual impairment; intellectual disability.

Background There is relatively little literature on the oral health experiences of individuals with Rett syndrome. This study described the incidence of dental extractions and restorations in a population-based cohort, according to a range of demographic and clinical factors. The association between bruxism and age was also investigated. Methods Existing questionnaire data in the population-based Australian Rett Syndrome Database for the years 2004, 2006, 2009 or 2011 on genetically confirmed female cases (n = 242) were analysed. Results The incidence rate of restorations and extractions were 6.8 per 100 person years (py) and 9.3 per 100 py respectively. The incidence of extractions decreased with increasing levels of income. Compared to those with a C-terminal mutation, the incidence rate of extraction was higher for those with large deletions (Incidence Rate Ratio (IRR) 4.93; 95% CI 1.46–16.7, p = 0.01). There was a 5% decrease in the risk of frequent bruxism for every one-year increase in age (Risk Ratio 0.95; 95% CI 0.94–0.97). Conclusions Social advantage may provide some protection for dental health in individuals with Rett syndrome. Those with more severe genotypes seemed to have poorer oral health outcomes.

Background Stiff person syndrome (SPS) is a progressive neurological disorder characterized by axial muscle rigidity and involuntary spasms. Autoimmune and neoplastic diseases are associated with SPS. Our study objectives were to describe inpatient care for SPS in the United States and characterize 30-day readmissions. Methods We queried the 2014 Nationwide Readmission Database for hospitalizations where a diagnosis of SPS was recorded. For readmission analyses, we excluded encounters with missing length of stay, hospitalization deaths, and out-of-state and December discharges. National estimates of index hospitalizations and 30-day readmissions were computed using survey weighting methods. Unconditional logistic regression was used to examine associations between demographic, clinical, and hospital characteristics and readmission. Results There were 836 patients with a recorded diagnosis of SPS during a 2014 hospitalization. After exclusions, 703 patients remained, 9.4% of which were readmitted within 30 days. Frequent reasons for index hospitalization were SPS (27.8%) and diabetes with complications (5.1%). Similarly, readmissions were predominantly for diabetes complications (24.2%) and SPS. Most readmissions attributed to diabetes complications (87.5%) were to different hospitals. Female sex (OR, 3.29; CI: 1.22–8.87) and routine discharge (OR, 0.26; CI: 0.10–0.64) were associated with readmission, while routine discharge (OR, 0.18; CI: 0.04–0.89) and care at for-profit hospitals (OR, 10.87; CI: 2.03–58.25) were associated with readmission to a different hospital. Conclusions Readmissions in SPS may result from disease complications or comorbid conditions. Readmissions to different hospitals may reflect specialty care, gaps in discharge planning, or medical emergencies. Studies are required to determine if readmissions in SPS are preventable.

Primary hyperoxalurias (PHs) are rare inherited disorders of liver glyoxylate metabolism, characterized by the abnormal production of endogenous oxalate, a metabolic end-product that is eliminated by urine. The main symptoms are related to the precipitation of calcium oxalate crystals in the urinary tract with progressive renal damage and, in the most severe form named Primary Hyperoxaluria Type I (PH1), to systemic oxalosis. The therapies currently available for PH are either poorly effective, because they address the symptoms and not the causes of the disease, or highly invasive. In the last years, advances in our understanding of the molecular bases of PH have paved the way for the development of new therapeutic strategies. They include (i) substrate-reduction therapies based on small-molecule inhibitors or the RNA interference technology, (ii) gene therapy, (iii) enzyme administration approaches, (iv) colonization with oxalate-degrading intestinal microorganisms, and, in PH1, (v) design of pharmacological chaperones. This paper reviews the basic principles of these new therapeutic strategies and what is currently known about their application to PH.

Background Pathologic mutations in SYNGAP1 cause a genetically defined form of intellectual disability (ID) with comorbid epilepsy and autistic features. While only recently discovered, pathogenicity of this gene is a relatively frequent genetic cause of classically undefined developmental delay that progresses to ID with commonly occurring comorbidities. Main body A meeting of 150 people was held that included affected individuals and their caregivers, clinicians that treat this and related brain disorders, neuroscientists that study SYNGAP1 biology or the function of related genes, and representatives from government agencies that fund science and approve new medical treatments. The meeting focused on developing a consensus among all stakeholders as to how best to achieve a more fundamental and profound understanding of SYNGAP1 biology and its role in human disease. Short conclusion From all of these proceedings, several areas of consensus emerged. The clinicians and geneticists agreed that the prevalence of epilepsy and sensory processing impairments in SYNGAP1-related brain disorders approached 100%. The neurobiologists agreed that more basic research is needed to better understand the molecular and cellular functions of the Syngap1 gene, which will lead to targets for therapeutic intervention. Finally, everyone agreed that there is a pressing need to form a robust patient registry as an initial step toward a prospective natural history study of patients with pathogenic SYNGAP1 variants.

Background Twenty-five to 30 million Americans live with a rare disease (RD) and share challenges unique to RD. The majority of research on RDs has focused on etiology, treatment and care, while the limited health-related quality of life (HRQL) research has been restricted to single RDs, small samples, or non-validated measures. This study reports HRQL among adults with diverse RDs, and compares their scores to those of the U.S. population and people with common chronic health conditions. Methods We conducted a cross-sectional survey of adults living in the U.S. diagnosed with any RD. Participants were recruited through RD organizations and completed the online survey between December 2016 and May 2017 (n = 1218). HRQL was assessed using the standardized Patient-Reported Outcomes Measurement Information System (PROMIS). RDs were classified into categories defined by Orphanet. Means and 95% confidence intervals were calculated for the main sample and for RD categories and were compared to published U.S. population norms and common chronic disease norms. Intercorrelations were conducted between HRQL, demographics, and RD experiences. Results When compared to the norms for the U.S. population and for those with common chronic diseases, mean HRQL scores were significantly poorer across all six PROMIS domains for the main sample, and were usually poorer when analyzed by sub-sets of specific RD classifications. People with rare systemic and rheumatologic, neurological, and immune diseases had the poorest HRQL. Participants had poorer HRQL if they had multiple RDs, lower income, were female, or older. Having symptoms longer was associated with worse HRQL, however, having a formal diagnosis longer was associated with better HRQL. Conclusions This study is the first to examine HRQL in a large, heterogeneous sample of RDs using validated measures. There is a significant disparity in HRQL among people with RD compared to the general population and people with common chronic diseases. Poor HRQL could be attributed to challenges accessing diagnoses, medical information, treatment, psychosocial support, and coping with stigma and uncertainty. As most individuals with RDs will not be cured in their lifetimes, identifying ways to improve HRQL is crucial to patient-centered care and should be a funding priority.

Background Rett syndrome is a severe neurodevelopmental disorder associated with mutations in the MECP2 gene. Irregular breathing patterns and abdominal bloating are prominent but poorly understood features. Our aims were to characterize the abnormal breathing patterns and abdominal bloating, investigate the distribution of these by age and mutation type and examine their impact and management from a caregiver perspective. Methods We invited previously recruited families from the International Rett Syndrome Study to complete a web-based questionnaire concerning their family member with Rett syndrome aged between 2 and 57 years. We used logistic regression to investigate presence, frequency and impact of breath-holding, hyperventilation, or abdominal bloating by age group and mutation type. Age of onset for both breathing abnormalities was investigated using time-to-onset analysis, and the Kaplan–Meier method was used to estimate the failure function for the study sample. Descriptive statistics were used to characterize the management of irregular breathing. Results Questionnaires were returned by 413/482 (85.7%) families. Breath-holding was reported for 68.8%, hyperventilation for 46.4% and abdominal bloating for 42.4%. Hyperventilation was more prevalent and frequent in those younger than 7 years of age and abdominal bloating in those aged over 20 years. Onset of breathing irregularities usually occurred during early childhood. Caregivers perceived that daily life was considerably impacted for almost half (44.1%) of those with abdominal bloating and in just over than a third of those with breath-holding (35.8%) or hyperventilation (35.1%). Although perceived impact was broadly comparable between age and mutation groups for breath-holding, hyperventilation and abdominal bloating, girls and women with a p.Arg294* mutation were considered to be more affected by all three conditions. Only 31 individuals had received medically prescribed treatments including 12 different medications, added oxygen, rebreathing apparatus or non-invasive ventilation. Conclusions Autonomic disturbances are prevalent and burdensome in Rett syndrome. This information may guide the design of inclusion criteria and outcome measures for clinical intervention trials targeting autonomic abnormalities. Further investigation of available treatments is necessary to delineate evidence-based management pathways.

Background Although research in this area remains sparse, raising a child with some genetic disorders has been shown to adversely impact maternal health and family quality of life. The aim of this study was to investigate such impacts in families with a child with the CDKL5 disorder, a newly recognised genetic disorder causing severe neurodevelopmental impairments and refractory epilepsy. Methods Data were sourced from the International CDKL5 Disorder Database to which 192 families with a child with a pathogenic CDKL5 mutation had provided data by January 2016. The Short Form 12 Health Survey Version 2, yielding a Physical Component Summary and a Mental Component Summary score, was used to measure primary caregiver’s wellbeing. The Beach Center Family Quality of Life Scale was used to measure family quality of life. Linear regression analyses were used to investigate relationships between child and family factors and the various subscale scores. Results The median (range) age of the primary caregivers was 37.0 (24.6–63.7) years and of the children was 5.2 (0.2–34.1) years. The mean (SD) physical and mental component scores were 53.7 (8.6) and 41.9 (11.6), respectively. In mothers aged 25–54 years the mean mental but not the physical component score was lower than population norms. After covariate adjustment, caregivers with a tube-fed child had lower mean physical but higher mean mental component scores than those whose child fed orally (coefficient = −4.80 and 6.79; p = 0.009 and 0.012, respectively). Child sleep disturbances and financial hardship were negatively associated with the mental component score. The mean (SD) Beach Center Family Quality of Life score was 4.06 (0.66) and those who had used respite services had lower scores than those who had not across the subscales. Conclusions Emotional wellbeing was considerably impaired in this caregiver population, and was particularly associated with increased severity of child sleep problems and family financial difficulties. Family quality of life was generally rated lowest in those using respite care extensively, suggesting that these families may be more burdened by daily caregiving.

A report on the European Society of Human Genetics conference, held in Paris, France, June 8-11, 2013.