Strategies to improve retention in randomised trials

Acknowledgements We thank Jayne Tierney, Sally Stenning, Seeromanie Harding, Sarah Meredith, and Irwin Nazareth for their contributions to earlier versions of this review. We also thank all authors of included published studies who provided additional or unreported data and Principal investigators for data on studies in progress or completed and unpublished. This update was funded by a National Institute for Health Research (NIHR) Incentive Award Scheme 2019 Reference 130660. The Health Services Research Unit, University of Aberdeen receives core funding from the Chief Scientist Office of the Scottish Government Health Directorates. The views expressed in this review are those of the authors and do not necessarily reflect those of the NIHR, the Department of Health and Social Care or these other funders. Sources of support Internal sources: No sources of support supplied External sources: National Institue for Health Research Incentive Award, UK; This update was funded by a National Institue for Health Research Incentive Award [NIHR IA 130660].Peer reviewedPublisher PD

De novo mutations in GRIN1 cause extensive bilateral polymicrogyria

Polymicrogyria is a malformation of cortical development. The aetiology of polymicrogyria remains poorly understood. Using whole-exome sequencing we found de novo heterozygous missense GRIN1 mutations in 2 of 57 parent-offspring trios with polymicrogyria. We found nine further de novo missense GRIN1 mutations in additional cortical malformation patients. Shared features in the patients were extensive bilateral polymicrogyria associated with severe developmental delay, postnatal microcephaly, cortical visual impairment and intractable epilepsy. GRIN1 encodes GluN1, the essential subunit of the N-methyl-d-aspartate receptor. The polymicrogyria-associated GRIN1 mutations tended to cluster in the S2 region (part of the ligand-binding domain of GluN1) or the adjacent M3 helix. These regions are rarely mutated in the normal population or in GRIN1 patients without polymicrogyria. Using two-electrode and whole-cell voltage-clamp analysis, we showed that the polymicrogyria-associated GRIN1 mutations significantly alter the in vitro activity of the receptor. Three of the mutations increased agonist potency while one reduced proton inhibition of the receptor. These results are striking because previous GRIN1 mutations have generally caused loss of function, and because N-methyl-d-aspartate receptor agonists have been used for many years to generate animal models of polymicrogyria. Overall, our results expand the phenotypic spectrum associated with GRIN1 mutations and highlight the important role of N-methyl-d-aspartate receptor signalling in the pathogenesis of polymicrogyria

Craniodigital syndromes and chromosome 7p

Craniosynostosis or premature closure of the cranial sutures is a common abnormality occuring in about 1 m 2000 children. There is evidence of Mendelian inheritance in some 20% of cases. A number of autosomal dominant craniosynostosis syndromes exist in which craniosynostosis occurs in association with various limb anomalies. Although relatively rare, this group of monogenic craniodigital syndromes provides a way of mapping, by molecular genetic methods, genes important in craniofacial and limb development. The aims of the present work were to determine the chromosomal location of the mutations responsible for some of the human craniodigital syndromes. Chromosome 7 was chosen as a suitable starting point as premature sutural fusion is a relatively uncommon finding in patients with chromosome anomalies but has been reported in at least 10 patients with a variety of structural alterations of 7p. Craniosynostosis appears to be consistently associated with deletion of one of two specific and separate regions, either deletion of part of band 7p21/proximal 7p22 or deletion of 7p13-p14. Many of the patients with deletions of the more proximal region 7p13-7p14 have features of the Greig cephalopolysyndactyly syndrome (GCPS), whereas those with more distal deletions have features reminiscent of the non-Apert acrocephalosyndactylies. The karyotypic findings in these cases suggest that two or more genes responsible for craniosynostosis and limb anomalies may be situated on chromosome 7p. The localisation, identification and characterisation of one or more of the genes responsible for such autosomal dominant craniodigital syndromes will help lead to determination of the genetic elements involved in the complex process of normal craniofacial and limb formation and the consequences of mutation in these developmental genes. The results of clinical and molecular genetic studies undertaken to investigate the possible localisation of GCPS and the non-Apert acrocephalosyndactyly syndromes to chromosome 7p are reported. It is demonstrated that GCPS maps to 7p13 whilst the gene responsible for Saethre-Chotzen syndrome is localised to 7p21-22. Evidence to show that GCPS and the acrocallosal syndrome are not allelic disorders is also provided. The outcome of a clinical study of the non-Apert acrocephalosyndactylies is presented in detail. This helps to define the degree of variability within and between families and the question of genetic heterogeneity in this group of conditions is addressed

Neuropathy in a human without the PMP22 gene.

BACKGROUND Haploinsufficiency of PMP22 causes hereditary neuropathy with liability to pressure palsies. However, the biological functions of the PMP22 protein in humans have largely been unexplored owing to the absence of patients with PMP22-null mutations. OBJECTIVE To investigate the function of PMP22 in the peripheral nervous system by studying a boy without the PMP22 gene and mice without the Pmp22 gene. DESIGN The clinical and pathological features of a patient with a PMP22 homozygous deletion are compared with those of Pmp22-null mice. SETTING Clinical evaluation was performed at tertiary hospitals in the United Kingdom. Molecular diagnosis was performed at the West Midlands Regional Genetics Laboratory. Immunohistochemistry and electron microscopy analyses were conducted at Wayne State University, Detroit, Michigan. Analysis of the Pmp22 +/- and null mice was performed at Vanderbilt University, Nashville, Tennessee. PARTICIPANT A 7-year-old boy without the PMP22 gene. RESULTS Motor and sensory deficits in the proband were nonlength-dependent. Weakness was found in cranial muscles but not in the limbs. Large fiber sensory modalities were profoundly abnormal, which started prior to the maturation of myelin. This is in line with the temporal pattern of PMP22 expression predominantly in cranial motor neurons and dorsal root ganglia during embryonic development, becoming undetectable in adulthood. Moreover, there were conspicuous maturation defects of myelinating Schwann cells; these defects were more significant in motor nerve fibers than in sensory nerve fibers. CONCLUSIONS Taken together, the data suggest that PMP22 is important for the normal function of neurons that express PMP22 during early development, such as cranial motor neurons and spinal sensory neurons. Moreover, PMP22 deficiency differentially affects myelination between motor and sensory nerves, which may have contributed to the unique clinical phenotype in the patient with an absence of PMP22