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New insights into Perrault syndrome, a clinically and genetically heterogeneous disorder.Hearing loss and impaired fertility are common human disorders each with multiple genetic causes. Sometimes deafness and impaired fertility, which are the hallmarks of Perrault syndrome, co-occur in a person. Perrault syndrome is inherited as an autosomal recessive disorder characterized by bilateral mild to severe childhood sensorineural hearing loss with variable age of onset in both sexes and ovarian dysfunction in females who have a 46, XX karyotype. Since the initial clinical description of Perrault syndrome 70 years ago, the phenotype of some subjects may additionally involve developmental delay, intellectual deficit and other neurological disabilities, which can vary in severity in part dependent upon the genetic variants and the gene involved. Here, we review the molecular genetics and clinical phenotype of Perrault syndrome and focus on supporting evidence for the eight genes (CLPP, ERAL1, GGPS1, HARS2, HSD17B4, LARS2, RMND1, TWNK) associated with Perrault syndrome. Variants of these eight genes only account for approximately half of the individuals with clinical features of Perrault syndrome where the molecular genetic base remains under investigation. Additional environmental etiologies and novel Perrault disease-associated genes remain to be identified to account for unresolved cases. We also report a new genetic variant of CLPP, computational structural insight about CLPP and single cell RNAseq data for eight reported Perrault syndrome genes suggesting a common cellular pathophysiology for this disorder. Some unanswered questions are raised to kindle future research about Perrault syndrome. [Abstract copyright: © 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.]
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Risk Governance of Emerging Technologies Demonstrated in Terms of its Applicability to Nanomaterials.Nanotechnologies have reached maturity and market penetration that require nano-specific changes in legislation and harmonization among legislation domains, such as the amendments to REACH for nanomaterials (NMs) which came into force in 2020. Thus, an assessment of the components and regulatory boundaries of NMs risk governance is timely, alongside related methods and tools, as part of the global efforts to optimise nanosafety and integrate it into product design processes, via Safe(r)-by-Design (SbD) concepts. This paper provides an overview of the state-of-the-art regarding risk governance of NMs and lays out the theoretical basis for the development and implementation of an effective, trustworthy and transparent risk governance framework for NMs. The proposed framework enables continuous integration of the evolving state of the science, leverages best practice from contiguous disciplines and facilitates responsive re-thinking of nanosafety governance to meet future needs. To achieve and operationalise such framework, a science-based Risk Governance Council (RGC) for NMs is being developed. The framework will provide a toolkit for independent NMs' risk governance and integrates needs and views of stakeholders. An extension of this framework to relevant advanced materials and emerging technologies is also envisaged, in view of future foundations of risk research in Europe and globally. [Abstract copyright: © 2020 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.]
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Mechanisms of Network Changes in Cognitive Impairment in Multiple Sclerosis.Cognitive impairment in multiple sclerosis (MS) is associated with functional connectivity abnormalities. While there have been calls to use functional connectivity measures as biomarkers there remains to be a full understanding of why they are affected in MS. In this cross-sectional study we tested the hypothesis that functional network regions may be susceptible to disease-related 'wear-and-tear' and that this can be observable on co-occuring abnormalities on other MR metrics. We tested whether functional connectivity abnormalities in cognitively impaired MS patients co-occur with either 1) overlapping, 2) local, or 3) distal changes in anatomical connectivity and cerebral blood flow abnormalities. Multimodal 3T MRI and assessment with the Brief Repeatable Battery of Neuropsychological tests was performed in 102 relapsing-remitting MS patients and 27 healthy controls. MS patients were classified as cognitively impaired if they scored ≥1.5 standard deviations below the control mean on ≥2 tests (n=55), or else cognitively preserved (n=47). Functional connectivity was assessed with Independent Component Analysis and dual regression of resting-state fMRI images. Cerebral blood flow maps were estimated and anatomical connectivity was assessed with anatomical connectivity mapping and fractional anisotropy of diffusion-weighted MRI. Changes in cerebral blood flow and anatomical connectivity were assessed within resting state networks that showed functional connectivity abnormalities in cognitively impaired MS patients. Functional connectivity was significantly decreased in the anterior and posterior default mode networks and significantly increased in the right and left frontoparietal networks in cognitively impaired relative to cognitively preserved MS patients (TFCE-corrected at ≤0.05, two-sided). Networks showing functional abnormalities showed altered cerebral blood flow and anatomical connectivity locally and distally but not in overlapping locations. We provide the first evidence that FC abnormalities are accompanied with local cerebral blood flow and structural connectivity abnormalities but also demonstrate that these effects do not occur in exactly the same location. Our findings suggest a possibly shared pathological mechanism for altered functional connectivity in brain networks in MS. [Abstract copyright: Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.]