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• This is the first study of quality of life (QOL) in CDKL5 Deficiency Disorder. • A novel validated QOL scale was administered to families in the International CDKL5 Disorder Database. • Quality of life was adversely impacted by the severity of the functional impairment. • Individuals using only one anti-epileptic medication had better quality of life. CDKL5 Deficiency Disorder (CDD) is a rare genetic disorder caused by a mutation in the cyclin-dependent kinase-like 5 (CDKL5) gene. It is now considered to be a developmental and epileptic encephalopathy because of the early onset of seizures in association with severe global delay. Other features include cortical visual impairment, sleep and gastro-intestinal problems. Progress in clinical understanding, especially regarding the spectrum of functional ability, seizure patterns, and other comorbidities was initially slow but accelerated in 2012 with the establishment of the International CDKL5 Database (ICDD). Our aim was to use this data source to investigate quality of life (QOL) and associated factors in this disorder. A follow-up questionnaire was administered in 2018 to parents of children registered with the ICDD who had a pathogenic CDKL5 variant. QOL was assessed using QI Disability, an instrument, specifically developed to measure total and specific domains of QOL (physical health, positive emotions, negative emotions, social interaction, leisure and the outdoors (leisure) and independence) in children with intellectual disability. Associations with functional abilities, physical health, mental health and family factors were investigated, initially using univariate analyses followed by multivariate analyses for each of these groups with a final composite model which included the important variables identified from previous models. Questionnaires were returned by 129/160 families with a child aged >3 years. Functional impairment, including lack of ability to sit, use hands and communicate had the greatest adverse impact on QOL. There were also some relationships with major genotype groupings. Individuals using three or more anti-epileptic medications had poorer QOL than those on one or no medication, particularly in the physical health domain. There was also variation by geographical region with those living in North America typically having the best QOL and those living in middle or lower income countries poorer QOL. Although lower functional abilities were associated with poorer quality of life further research is needed to understand how environmental supports might mitigate this deficit. Comprehensive care and support for both the child and family have important roles to play in helping families to thrive despite the severity of CDD. [ABSTRACT FROM AUTHOR]

Different strategies have been studied to allow a better characterization of the safety profile of orphan drugs soon after their approval. At the end of the development phases only few data are available because of the small number of subjects exposed to an orphan medicine for the treatment of rare or ultra-rare conditions. As a consequence, the evaluation of the safety profile is limited at the time of the first approval. In the post-marketing period, all available sources should be combined for a better understanding of the safety of orphan drugs. These sources, include outputs from large databases such as the European Medicines Agency's EudraVigilance database. Analyses of data from this source are required to be performed by marketing authorization holders (MAHs) as part of their signal management activities. In 2018, the Pharmacovigilance Risk Assessment Committee (PRAC) assessed 114 confirmed signals, 79% of which included data from EudraVigilance. MAHs have access to statistical calculations for drug-event combinations (DECs) from EudraVigilance, provided in the form of measures of disproportionality of ratios of the observed proportion of spontaneous cases for a DEC in relation to the proportion of cases that would be expected if no association existed between the drug and the event. However, such statistical summaries for orphan drugs could be misleading because of the very limited safety data available for orphan drugs (under-reporting together with low numbers of exposed patients). In addition, the applied statistical methodology in most instances is constrained by different confounding factors such as indications of specific medicines and the wide spectrum of medical conditions/diseases of patients from whom reporting of disproportionality ratios are derived (i.e. proportions of DECs for orphan drugs (ODECs) from a small patient population suffering the rare disease and the proportion of DECs in the rest of the population represented in the whole database who have been treated with other medicines for a wide range of indications, and prescribed to treat completely different medical conditions). As expected, these statistical calculations produced not only signals of disproportionate reporting (SDRs) that are false positives, but also not sensitive enough to detect certain SDRs, thus resulting in false negatives. In the context of rare/ultra-rare life-threatening diseases where new molecules have been made available on the market on the basis of their proven efficacy, but with only limited safety data at the time of approval, false negatives could be a special concern since unlikely converted in positives or becoming positives with notable delay. Subgroup analyses (using a limited dataset comprising ADRs within specific individual case safety reports (ICSRs), sorted by indication/disease relevant to the drug of interest could, at least in part, possibly reduce some of the weaknesses resulting from the abovementioned confounding factors. On the other hand it could also cause the loss of some identification of SDRs that would be captured if no database restrictions had been undertaken. Therefore, data subgroup analysis should not be selected as a preferred approach to quantitative signal detection for orphan drugs but rather evaluated as complementary possibly to confirm negatives or to further characterize detected SDRs. Some examples of false negatives originating from quantitative signal detection in EudraVigilance applied to orphan drugs are discussed in this article., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2019.)

The assessment of the safety of medicines for rare diseases during the development phase is often limited by the few data available from small numbers of patients. This also applies to a lesser extent during the postmarketing phase of the lifecycle of a medicine. By using all available sources of data for rare diseases drugs, and by carefully assessing these data, the most informed safety profile can be obtained. This should also allow a clear view of data that are not available at any given time point and facilitates planning of strategies to obtain data through appropriate postmarketing risk management. Although it is not always easy, there are possibilities to increase the speed by which data in the postmarketing period can be generated by better use of data from ongoing formal clinical trials, by early planning of drug or disease registries and leveraging the power of both disease patient support groups, which are often well established, and networks to facilitate international research, specifically in rare diseases. The future may offer approaches using personal medical monitoring data tools and 'big data' to further facilitate the availability of information and to determine the effectiveness and safety profiles of drugs used for rare diseases and thus allow the benefit/risk of these drugs to be optimized. These issues will be discussed here., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

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.

Thrombotic microangiopathy (TMA) is characterized by the presence of microangiopathic hemolytic anemia and thrombocytopenia along with organ dysfunction, and pathologically, by the presence of microthrombi in multiple microvascular beds. Delays in diagnosis and initiation of therapy are common due to the low incidence, variable presentation, and poor awareness of these diseases, underscoring the need for interdisciplinary approaches to clinical care for TMA. We describe a new approach to improve clinical management via a TMA team that originally stemmed from an Affinity Research Collaborative team focused on thrombosis and hemostasis. The TMA team consists of clinical faculty from different disciplines who together are charged with the responsibility to quickly analyze clinical presentations, guide laboratory testing, and streamline prompt institution of treatment. The TMA team also includes faculty members from a broad range of disciplines collaborating to elucidate the pathogenesis of TMA. To this end, a clinical database and biorepository have been constructed. TMA leaders educate front-line providers from other departments through presentations in various forums across multiple specialties. Facilitated by an Affinity Research Collaborative mechanism, we describe an interdisciplinary team dedicated to improving both clinical care and translational research in TMA., (Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

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.

Purpose: The purpose of this project was to gather parents' expertise to inform an educational leaflet for parents to share with professionals caring for children with 22q11.2 deletion syndrome (22q11.2 DS)., Design and Methods: A mixed-method design was adopted. Data were collected by one focus group interview (n = 8) and questionnaires with 92 other parents of children with 22q11.2 DS., Results: Quantitative and qualitative responses informed the development of an information leaflet., Practice Implications: Parents are well positioned to assist in development of information leaflets that can minimize "repeated storytelling" during professional encounters., (© 2014, Wiley Periodicals, Inc.)