Clinical genetics
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Array comparative genomic hybridization (array CGH) is now widely adopted as a first-tier clinical diagnostic test in individuals with unexplained developmental delay/intellectual disability (DD/ID) and congenital anomalies. Our study aimed at enlarging the phenotypic spectrum associated with clinically relevant copy number variants (CNVs) as well as delineating clinical criteria, which may help separating patients with pathogenic CNVs from those without pathogenic CNVs. We performed a retrospective review of clinical and array CGH data of 342 children with unexplained DD/ID. ⋯ Array CGH detected pathogenic CNVs in 13.2% of the patients. Congenital anomalies, especially heart defects, as well as primary microcephaly, short stature and failure to thrive were clearly more frequent in children with pathogenic CNVs compared with children with normal array CGH results. Thus, we assume that in patients with unexplained DD/ID, array CGH will more probably detect a significant CNV if any of these features is part of the patient's phenotype.
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There are now several strong opioids available to choose from for the relief of moderate to severe pain. On a population level, there is no difference in terms of analgesic efficacy or adverse reactions between these drugs; however, on an individual level there is marked variation in response to a given opioid. ⋯ If personalized prescribing could be achieved this would have a major impact at an individual level to facilitate safe, effective and rapid symptom control. This review presents some of the recent positive advances in opioid pharmacogenetic studies, focusing on associations between candidate genes and the three main elements of opioid response: analgesic, upper gastrointestinal and central adverse reactions.
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Small fiber neuropathy (SFN) is a disorder typically dominated by neuropathic pain and autonomic dysfunction, in which the thinly myelinated Aδ-fibers and unmyelinated C-fibers are selectively injured. The diagnosis SFN is based on a reduced intraepidermal nerve fiber density and/or abnormal thermal thresholds in quantitative sensory testing. The etiologies of SFN are diverse, although no apparent cause is frequently seen. ⋯ Functional testing showed that these variants altered fast inactivation, slow inactivation or resurgent current and rendered dorsal root ganglion neurons hyperexcitable. In this review, we discuss the role of Na(V)1.7 in pain and highlight the molecular genetics and pathophysiology of SCN9A-gene variants in SFN. With increasing knowledge regarding the underlying pathophysiology in SFN, the development of specific treatment in these patients seems a logical target for future studies.
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Pain severity ratings and the analgesic dosing requirements of patients with apparently similar pain conditions may differ considerably between individuals. Contributing factors include those of genetic and environmental origin with epigenetic mechanisms that enable dynamic gene-environment interaction, more recently implicated in pain modulation. Insight into genetic factors underpinning inter-patient variability in pain sensitivity has come from rodent heritability studies as well as familial aggregation and twin studies in humans. ⋯ A large number of genetic association studies conducted in patients with a variety of clinical pain types or in humans exposed to experimentally induced pain stimuli in the laboratory setting, have examined the impact of single-nucleotide polymorphisms in various target genes on pain sensitivity and/or analgesic dosing requirements. However, the findings of such studies have generally failed to replicate or have been only partially replicated by independent investigators. Deficiencies in study conduct including use of small sample size, inappropriate statistical methods and inadequate attention to the possibility that between-study differences in environmental factors may alter pain phenotypes through epigenetic mechanisms, have been identified as being significant.