Common data elements for clinical research in mitochondrial disease: a National Institute for Neurological Disorders and Stroke project

Objectives The common data elements (CDE) project was developed by the National Institute of Neurological Disorders and Stroke (NINDS) to provide clinical researchers with tools to improve data quality and allow for harmonization of data collected in different research studies. CDEs have been created for several neurological diseases; the aim of this project was to develop CDEs specifically curated for mitochondrial disease (Mito) to enhance clinical research. Methods Nine working groups (WGs), composed of international mitochondrial disease experts, provided recommendations for Mito clinical research. They initially reviewed existing NINDS CDEs and instruments, and developed new data elements or instruments when needed. Recommendations were organized, internally reviewed by the Mito WGs, and posted online for external public comment for a period of eight weeks. The final version was again reviewed by all WGs and the NINDS CDE team prior to posting for public use

Position Statement:Emerging genetic therapies for rare disorders

Emerging genetic therapies for rare disorders at high cost, cannot realistically address the global burden of disease. Stakeholders must develop new pathways to ensure safe, fair and sustainable provision of such therapies

Cultivation technology influences the occurrence of potato early blight (Alternaria solani) in an organic farming system

Abstract Nowadays, organically produced products have become more popular than ever and interest in them is still growing fast. The early blight causal pathogen Alternaria solani has not been considered a great threat to potato in northern climate conditions in the past and has not been routinely sprayed against. During our study early blight was evaluated in 2010 and 2011 on the plants of a potato cultivar 'Reet' in an organic farming experiment. In our study, both growing seasons were very favourable for early blight development. Significant differences between the two cultivation technologies were found (F 1,12 = 4.84, p = 0.048). In 2010, the area under disease progress curve (AUDPC) value was 303 on cover crop (CC) plots and 990 on CC + M (manure) plots that is three times higher, whereas in 2011, the AUDPC value was 967 on CC plots and 1195 on CC + M plots. Our results confirm that potato early blight has become a serious problem in North-East European organic potato fields and thus susceptible potato cultivars cannot be recommended for growing in an organic farming system. However, it is possible to influence the development severity of early blight by selecting the proper growing technology. Since, in the changing climate conditions and in susceptible cultivars, early blight is a potato disease that can cause early defoliation of plants and crop death, there is a need for resistant potato cultivars

Bi-allelic loss-of-function CACNA1B mutations in progressive epilepsy-dyskinesia

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment

Prevalence and architecture of de novo mutations in developmental disorders

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

Expected future developments in child neurology

We stand on the shoulders of giants on the threshold of many new exciting developments in the field of child neurology due to innovations in clinical approach, diagnostic technologies and treatment strategies. There are many exciting new technologies, but we must never forget the power of clinical medicine which allows us to interpret and use these tools with precision and with clinical wisdom. Strong collaborations continue to be needed: between clinicians for the meticulous clinical phenotyping, expansion of the range of phenotypic expression, and the entry of patients into international RCTs (randomised controlled trials); between the biochemists for the biochemical phenotyping and understanding of the basic pathophysiology of the underlying dysregulations and disease mechanisms arising from the protein dysfunctions and the development of robust biomarkers, to evaluate disease severity and response to therapies; and between the geneticists for the understanding of the impact of the exonic or intronic mutations, roles of other regulatory genes on the affected pathway, and epigenetic factors. These collaborations in the aggregate will lead the field forward in terms of increased insight into disease pathophysiology for the development of targeted precision medicine treatment strategies and effective preventative measures. This review is meant to highlight certain selected areas of future development and is not meant to be a comprehensive survey beyond the scope of this review. The subspecialty areas which will be highlighted will include intellectual disability, epilepsy, neuroprotection, neonatal and fetal neurology, CNS infections, headache, autoimmune/inflammatory disorders, demyelinating disorders, stroke, movement disorders, neurotransmitter defects, neuromuscular diseases, neurometabolic disorders, neurogenetic diseases, neuropsychiatry/autism, and neurooncology. In each subspecialty area, I will endeavor to identify emerging diseases, new specific diagnostic technologies and novel therapeutic approaches, but will need to be selective. This review is the culmination of a literature survey for current developments, discussions with leaders in each of the subspecialty fields, who I will acknowledge at the end, and certain personal projections.</jats:p