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Mutations in Adenosine deaminase acting on RNA 1 (ADAR1) gene encoding RNA editing enzyme ADAR1 results in the neuroinflammatory leukodystrophy Aicardi Goutières Syndrome (AGS). AGS is an early onset leukoencephalopathy with an exacerbated interferon response leading to neurological regression with intellectual disability, spasticity, and motor deficits. We have generated three induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells (PBMCs) of individuals with ADAR1 G1007R mutation. The generated iPSCs were investigated to confirm a normal karyotype, pluripotency, and trilineage differentiation potential. The reprogrammed iPSCs will allow us to model AGS, dissect the cellular mechanisms and testing different treatment targets., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Adeline Vanderver reports financial support was provided by Commonwealth Universal Research Enhancement (C.U.R.E.), U01 (NS106845) and R21 Grant. Adeline Vanderver Eli Lilly, Boehringer Ingelhiem, Gilead, Biogen, Illumina, Takeda, Orchard, Passage Bio, Homology, Myrtelle, Synaptixbio, Sanofi, Sana, Affinia related to work in the leukodystrophies., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: To evaluate the concordance of conventional autopsy (CA) and postmortem magnetic resonance (MR) after termination of pregnancy (TOP) in fetuses with prenatally detected central nervous system (CNS) anomalies. Second, to determine the most informative postmortem investigation in parental counseling., Methods: All TOPs between 2006 and 2016 with prenatally detected CNS involvement and having a postmortem MR and CA as postmortem examinations were retrospectively analyzed and concordance levels were established., Results: Of 764 TOPs, 255 cases had a CNS anomaly detected prenatally (33.4%). Fetal genetic anomalies ( n  = 40) and cases without both postmortem MR and CA were excluded, leaving 68 cases for analysis.Disagreement between postmortem MR and CA was observed in 22 cases (32.4%). In eight cases (11.8%), more information was obtained by CA compared with MR. However, only two cases with major additional findings were found when compared with prenatal diagnosis. In 14 cases (20.6%), MR was superior to CA either because of additional cerebral anomalies undetected by CA ( n  = 5) and/or because of severe autolysis hindering pathology of the CNS ( n  = 9)., Conclusions: Our data point out that an adequate postmortem evaluation, valuable in parental counseling, can be provided by a postmortem MR in 97% of the cases.Key PointsAn adequate postmortem evaluation, valuable in parental counseling, can be provided by a postmortem (PM) magnetic resonance (MR) in the majority of cases.PM MR is an excellent postmortem imaging tool for the brain.In cases with brain autolysis, PM MR is often the only informative PM investigation tool.PM MR is an essential adjunct to CA in the PM evaluation of pregnancies terminated for a central nervous system (CNS) anomaly.

Background Mounting evidence suggests that perivascular spaces (PVSs) visible at MRI reflect the function of the glymphatic system. Understanding PVS burden in neonates may guide research on early glymphatic-related pathologic abnormalities. Purpose To perform a visual and volumetric evaluation of PVSs that are visible at MRI in neonates and to evaluate potential associations with maturation, sex, and preterm birth. Materials and Methods In this retrospective study, T2-weighted brain MRI scans in neonates from the Developing Human Connectome Project were used for visual grading (grades 0-4) of PVSs in the basal ganglia (BG) and white matter (WM) and for volumetric analysis of BG PVSs. The BG PVS fraction was obtained by dividing the BG PVS volume by the deep gray matter volume. The association between postmenstrual age at MRI and BG PVS burden was evaluated using linear regression. PVS burden was compared according to sex and preterm birth using the Mann-Whitney test. Results A total of 244 neonates were evaluated (median gestational age at birth, 39 weeks; IQR, 6 weeks; 145 male neonates; 59%), including 88 preterm neonates (median gestational age at birth, 33 weeks; IQR, 6 weeks; 53 male neonates; 60%) and 156 term neonates (median gestational age at birth, 40 weeks; IQR, 2 weeks; 92 male neonates; 59%). For BG PVSs, all neonates showed either grade 0 (90 of 244; 37%) or grade 1 (154 of 244; 63%), and for WM PVSs, most neonates showed grade 0 (227 of 244; 93%). The BG PVS fraction demonstrated a negative relationship with postmenstrual age at MRI ( r = -0.008; P < .001). No evidence of differences was found between the sexes for BG PVS volume ( P = .07) or BG PVS fraction ( P = .28). The BG PVS volume was smaller in preterm neonates than in term neonates (median, 45.3 mm 3 [IQR, 15.2 mm 3 ] vs 49.9 mm 3 [IQR, 21.3 mm 3 ], respectively; P = .04). Conclusion The fraction of perivascular spaces (PVSs) in the basal ganglia (BG) was lower with higher postmenstrual age at MRI. Preterm birth affected the volume of PVSs in the BG, but sex did not. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Huisman in this issue.

Lyme disease is the most common vector-borne infectious disease in the United States. Post-treatment Lyme disease (PTLD) is a condition affecting 10-20% of patients in which symptoms persist despite antibiotic treatment. Cognitive complaints are common among those with PTLD, suggesting that brain changes are associated with the course of the illness. However, there has been a paucity of evidence to explain the cognitive difficulties expressed by patients with PTLD. This study administered a working memory task to a carefully screened group of 12 patients with well-characterized PTLD and 18 healthy controls while undergoing functional MRI (fMRI). A subset of 12 controls and all 12 PTLD participants also received diffusion tensor imaging (DTI) to measure white matter integrity. Clinical variables were also assessed and correlated with these multimodal MRI findings. On the working memory task, the patients with PTLD responded more slowly, but no less accurately, than did controls. FMRI activations were observed in expected regions by the controls, and to a lesser extent, by the PTLD participants. The PTLD group also hypoactivated several regions relevant to the task. Conversely, novel regions were activated by the PTLD group that were not observed in controls, suggesting a compensatory mechanism. Notably, three activations were located in white matter of the frontal lobe. DTI measures applied to these three regions of interest revealed that higher axial diffusivity correlated with fewer cognitive and neurological symptoms. Whole-brain DTI analyses revealed several frontal lobe regions in which higher axial diffusivity in the patients with PTLD correlated with longer duration of illness. Together, these results show that the brain is altered by PTLD, involving changes to white matter within the frontal lobe. Higher axial diffusivity may reflect white matter repair and healing over time, rather than pathology, and cognition appears to be dynamically affected throughout this repair process., Competing Interests: The authors have declared that no competing interests exist.

Background and Purpose: Parry-Romberg syndrome is a rare disorder characterized by progressive hemifacial atrophy. Concomitant brain abnormalities have been reported, frequently resulting in epilepsy, but the frequency and spectrum of brain involvement are not well-established. This study aimed to characterize brain abnormalities in Parry-Romberg syndrome and their association with epilepsy., Materials and Methods: This is a single-center, retrospective review of patients with a clinical diagnosis of Parry-Romberg syndrome and brain MR imaging. The degree of unilateral hemispheric atrophy, white matter disease, microhemorrhage, and leptomeningeal enhancement was graded as none, mild, moderate, or severe. Other abnormalities were qualitatively reported. Findings were considered potentially Parry-Romberg syndrome-related when occurring asymmetrically on the side affected by Parry-Romberg syndrome., Results: Of 80 patients, 48 (60%) had brain abnormalities identified on MR imaging, with 26 (32%) having abnormalities localized to the side of the hemifacial atrophy. Sixteen (20%) had epilepsy. MR imaging brain abnormalities were more common in the epilepsy group (100% versus 48%, P < .001) and were more frequently present ipsilateral to the hemifacial atrophy in patients with epilepsy (81% versus 20%, P < .001). Asymmetric white matter disease was the predominant finding in patients with (88%) and without (23%) epilepsy. White matter disease and hemispheric atrophy had a higher frequency and severity in patients with epilepsy ( P < .001). Microhemorrhage was also more frequent in the epilepsy group ( P = .015)., Conclusions: Ipsilateral MR imaging brain abnormalities are common in patients with Parry-Romberg syndrome, with a higher frequency and greater severity in those with epilepsy. The most common findings in both groups are white matter disease and hemispheric atrophy, both presenting with greater severity in patients with epilepsy., (© 2022 by American Journal of Neuroradiology.)

Innate DNA sensors detect foreign and endogenous DNA to induce responses to infection and cellular stress or damage. Inappropriate activation by self-DNA triggers severe autoinflammatory conditions, including Aicardi-Goutières syndrome (AGS) that can be caused by defects of the cytosolic DNase 3'repair exonuclease 1 (TREX1). TREX1 loss-of-function alleles are also associated with systemic lupus erythematosus (SLE). Chronic activation of innate antiviral immunity in TREX1-deficient cells depends on the DNA sensor cGAS, implying that accumulating TREX1 DNA substrates cause the inflammatory pathology. Retrotransposon-derived cDNAs were shown to activate cGAS in TREX1-deficient neuronal cells. We addressed other endogenous sources of cGAS ligands in cells lacking TREX1. We find that induced loss of TREX1 in primary cells induces a rapid IFN response that requires ongoing proliferation. The inflammatory phenotype of Trex1 -/- mice was partially rescued by additional knock out of exonuclease 1, a multifunctional enzyme providing 5' flap endonuclease activity for Okazaki fragment processing and postreplicative ribonucleotide excision repair. Our data imply genome replication as a source of DNA waste with pathogenic potential that is efficiently degraded by TREX1., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schubert, Schumann, Daum, Flade, Ge, Hagedorn, Edelmann, Müller, Schmitz, Kuut, Hornung, Behrendt and Roers.)

Primary microcephaly and megalencephaly are severe brain malformations defined by reduced and increased brain size, respectively. Whether these two pathologies arise from related alterations at the molecular level is unclear. Microcephaly has been largely associated with centrosomal defects, leading to cell death. Here, we investigate the consequences of WDR81 loss of function, which causes severe microcephaly in patients. We show that WDR81 regulates endosomal trafficking of EGFR and that loss of function leads to reduced MAP kinase pathway activation. Mouse radial glial progenitor cells knocked-out for WDR81 exhibit reduced proliferation rate, subsequently leading to reduced brain size. These proliferation defects are rescued in vivo by expressing a megalencephaly-causing mutant form of Cyclin D2. Our results identify the endosomal machinery as an important regulator of proliferation rates and brain growth, demonstrating that microcephaly and megalencephaly can be caused by opposite effects on the proliferation rate of radial glial progenitors., (© 2022. The Author(s).)

Corpus callosum anomalies (CCA) is a common congenital brain anomaly with various etiologies. Although one of the most important etiologies is genetic factors, the genetic background of CCA is heterogenous and diverse types of variants are likely to be causative. In this study, we analyzed 16 Japanese patients with corpus callosum anomalies to delineate clinical features and the genetic background of CCAs. We observed the common phenotypes accompanied by CCAs: intellectual disability (100%), motor developmental delay (93.8%), seizures (60%), and facial dysmorphisms (50%). Brain magnetic resonance imaging showed colpocephaly (enlarged posterior horn of the lateral ventricles, 84.6%) and enlarged supracerebellar cistern (41.7%). Whole exome sequencing revealed genetic alterations in 9 of the 16 patients (56.3%), including 8 de novo alterations (2 copy number variants and variants in ARID1B, CDK8, HIVEP2, and TCF4) and a recessive variant of TBCK. De novo ARID1B variants were identified in three unrelated individuals, suggesting that ARID1B variants are major genetic causes of CCAs. A de novo TCF4 variant and somatic mosaic deletion at 18q21.31-qter encompassing TCF4 suggest an association of TCF4 abnormalities with CCAs. This study, which analyzes CCA patients usung whole exome sequencing, demonstrates that comprehensive genetic analysis would be useful for investigating various causal variants of CCAs., (© 2021. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Background: Minocycline (MIN) is a tetracycline with antioxidant, anti-inflammatory, and neuroprotective properties. Given the likely involvement of inflammation and oxidative stress (IOS) in schizophrenia, MIN has been proposed as a potential adjuvant treatment in this pathology. We tested an early therapeutic window, during adolescence, as prevention of the schizophrenia-related deficits in the maternal immune stimulation (MIS) animal model., Methods: On gestational day 15, Poly I:C or vehicle was injected in pregnant Wistar rats. A total 93 male offspring received MIN (30 mg/kg) or saline from postnatal day (PND) 35-49. At PND70, rats were submitted to the prepulse inhibition test. FDG-PET and T2-weighted MRI brain studies were performed at adulthood. IOS markers were evaluated in frozen brain tissue., Results: MIN treatment did not prevent prepulse inhibition test behavioral deficits in MIS offspring. However, MIN prevented morphometric abnormalities in the third ventricle but not in the hippocampus. Additionally, MIN reduced brain metabolism in cerebellum and increased it in nucleus accumbens. Finally, MIN reduced the expression of iNOS (prefrontal cortex, caudate-putamen) and increased the levels of KEAP1 (prefrontal cortex), HO1 and NQO1 (amygdala, hippocampus), and HO1 (caudate-putamen)., Conclusions: MIN treatment during adolescence partially counteracts volumetric abnormalities and IOS deficits in the MIS model, likely via iNOS and Nrf2-ARE pathways, also increasing the expression of cytoprotective enzymes. However, MIN treatment during this peripubertal stage does not prevent sensorimotor gating deficits. Therefore, even though it does not prevent all the MIS-derived abnormalities evaluated, our results suggest the potential utility of early treatment with MIN in other schizophrenia domains., (© The Author(s) 2021. Published by Oxford University Press on behalf of CINP.)

The RNA deaminase ADAR1 is an essential negative regulator of the RNA sensor MDA5, and loss of ADAR1 function triggers inappropriate activation of MDA5 by self-RNAs. Mutations in ADAR, the gene that encodes ADAR1, cause human immune diseases, including Aicardi-Goutières syndrome (AGS). However, the mechanisms of MDA5-dependent disease pathogenesis in vivo remain unknown. Here we generated mice with a single amino acid change in ADAR1 that models the most common human ADAR AGS mutation. These Adar mutant mice developed lethal disease that required MDA5, the RIG-I-like receptor LGP2, type I interferons, and the eIF2α kinase PKR. A small-molecule inhibitor of the integrated stress response (ISR) that acts downstream of eIF2α phosphorylation prevented immunopathology and rescued the mice from mortality. These findings place PKR and the ISR as central components of immunopathology in vivo and identify therapeutic targets for treatment of human diseases associated with the ADAR1-MDA5 axis., Competing Interests: Declaration of interests C.S. is an employee of Calico Life Sciences and is listed as an inventor on a patent application WO2017193063 describing 2BAct. D.B.S. is a co-founder and shareholder of Danger Bio, LLC, and a scientific advisor for Related Sciences, LLC., (Copyright © 2021 Elsevier Inc. All rights reserved.)

TRIP4 is one of the subunits of the transcriptional coregulator ASC-1, a ribonucleoprotein complex that participates in transcriptional coactivation and RNA processing events. Recessive variants in the TRIP4 gene have been associated with spinal muscular atrophy with bone fractures as well as a severe form of congenital muscular dystrophy. Here we present the diagnostic journey of a patient with cerebellar hypoplasia and spinal muscular atrophy (PCH1) and congenital bone fractures. Initial exome sequencing analysis revealed no candidate variants. Reanalysis of the exome data by inclusion in the Solve-RD project resulted in the identification of a homozygous stop-gain variant in the TRIP4 gene, previously reported as disease-causing. This highlights the importance of analysis reiteration and improved and updated bioinformatic pipelines. Proteomic profile of the patient's fibroblasts showed altered RNA-processing and impaired exosome activity supporting the pathogenicity of the detected variant. In addition, we identified a novel genetic form of PCH1, further strengthening the link of this characteristic phenotype with altered RNA metabolism., (© 2021. The Author(s).)

Aicardi-Goutieres Syndrome (AGS) is a heterogeneous genetic syndrome, manifesting early as encephalopathy and is associated with abnormal neurologic findings, hepatosplenomegaly, elevated liver enzymes, thrombocytopenia and intracranial calcification. The most severe neonatal type, AGS1, is caused by biallelic disease-causing variants in TREX1. In this study, we describe four patients with TREX1-related AGS1 whose phenotype overlaps with intra-uterine infections and neonatal lupus. Exome sequencing identified a previously reported TREX1 variant, c.223dup (NM&#95;016381.5; p. Glu75GlyfsTer82) in all the four patients belonging to the Indian subcontinent. The functional consequence of the disease-causing variant was predicted by using a new combination of bioinformatics softwares. The recurrence of this pathogenic variant indicates a possible founder effect in TREX1 for AGS1 in this population. The phenotypic variability in those with this founder mutation can mimic intrauterine infections and neonatal lupus, thereby leading to misdiagnosis warranting a targeted genetic testing approach to be a part of the diagnostic workup to obtain a definite, early and cost-effective diagnosis in patients from Indian subcontinent with early onset encephalopathy., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Background: Dysfunction in non-motile cilia is associated with a broad spectrum of developmental disorders characterised by clinical heterogeneity. While over 100 genes have been associated with primary ciliopathies, with wide phenotypic overlap, some patients still lack a molecular diagnosis., Objective: To investigate and functionally characterise the molecular cause of a malformation disorder observed in two sibling fetuses characterised by microphthalmia, cleft lip and palate, and brain anomalies., Methods: A trio-based whole exome sequencing (WES) strategy was used to identify candidate variants in the TOGARAM1 gene. In silico, in vitro and in vivo ( Caenorhabditis elegans ) studies were carried out to explore the impact of mutations on protein structure and function, and relevant biological processes., Results: TOGARAM1 encodes a member of the Crescerin1 family of proteins regulating microtubule dynamics. Its orthologue in C. elegans , che-12 , is expressed in a subset of sensory neurons and localises in the dendritic cilium where it is required for chemosensation. Nematode lines harbouring the corresponding missense variant in TOGARAM1 were generated by CRISPR/Cas9 technology. Although chemotaxis ability on a NaCl gradient was not affected, che-12 point mutants displayed impaired lipophilic dye uptake, with shorter and altered cilia in sensory neurons. Finally, in vitro analysis of microtubule polymerisation in the presence of wild-type or mutant TOG2 domain revealed a faster polymerisation associated with the mutant protein, suggesting aberrant tubulin binding., Conclusions: Our data are in favour of a causative role of TOGARAM1 variants in the pathogenesis of this novel disorder, connecting this gene with primary ciliopathy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

The blood-brain barrier is a dynamic endothelial cell barrier in the brain microvasculature that separates the blood from the brain parenchyma. Specialized brain endothelial cells, astrocytes, neurons, microglia and pericytes together compose the neurovascular unit and interact to maintain blood-brain barrier function. A disturbed brain barrier function is reported in most common neurological disorders and may play a role in disease pathogenesis. However, a comprehensive overview of how the neurovascular unit is affected in a wide range of rare disorders is lacking. Our aim was to provide further insights into the neuropathology of the neurovascular unit in leukodystrophies to unravel its potential pathogenic role in these diseases. Leukodystrophies are monogenic disorders of the white matter due to defects in any of its structural components. Single leukodystrophies are exceedingly rare, and availability of human tissue is unique. Expression of selective neurovascular unit markers such as claudin-5, zona occludens 1, laminin, PDGFRβ, aquaporin-4 and α-dystroglycan was investigated in eight different leukodystrophies using immunohistochemistry. We observed tight junction rearrangements, indicative of endothelial dysfunction, in five out of eight assessed leukodystrophies of different origin and an altered aquaporin-4 distribution in all. Aquaporin-4 redistribution indicates a general astrocytic dysfunction in leukodystrophies, even in those not directly related to astrocytic pathology or without prominent reactive astrogliosis. These findings provide further evidence for dysfunction in the orchestration of the neurovascular unit in leukodystrophies and contribute to a better understanding of the underlying disease mechanism.

The comorbid association of autoimmune diseases with cancers has been a major obstacle to successful anti-cancer treatment. Cancer survival rate decreases significantly in patients with preexisting autoimmunity. However, to date, the molecular and cellular profiles of such comorbidities are poorly understood. We used Aicardi-Goutières syndrome (AGS) as a model autoimmune disease and explored the underlying mechanisms of genome instability in AGS-associated-gene-deficient patient cells. We found that R-loops are highly enriched at transcription-replication conflict regions of the genome in fibroblast of patients bearing SAMHD1 mutation, which is the AGS-associated-gene mutation most frequently reported with tumor and malignancies. In SAMHD1-depleted cells, R-loops accumulated with the concomitant activation of DNA damage responses. Removal of R-loops in SAMHD1 deficiency reduced cellular responses to genome instability. Furthermore, downregulation of SAMHD1 expression is associated with various types of cancer and poor survival rate. Our findings suggest that SAMHD1 functions as a tumor suppressor by resolving R-loops, and thus, SAMHD1 and R-loop may be novel diagnostic markers and targets for patient stratification in anti-cancer therapy., Competing Interests: The authors have declared that no competing interests exist.

MDA5 is a cytoplasmic sensor of viral RNA, triggering type I interferon (IFN-I) production. Constitutively active MDA5 has been linked to autoimmune diseases such as systemic lupus erythematosus, Singleton-Merten syndrome (SMS) and Aicardi-Goutières syndrome (AGS), a genetically determined inflammatory encephalopathy. However, AGS research is challenging due to the lack of animal models. We previously reported lupus-like nephritis and SMS-like bone abnormalities in adult mice with constitutively active MDA5 (Ifih1G821S/+), and herein demonstrate that these mice also exhibit high lethality and spontaneous encephalitis with high IFN-I production during the early postnatal period. Increases in the number of microglia were observed in MDA5/MAVS signaling- and IFN-I-dependent manners. Furthermore, microglia showed an activated state with an increased phagocytic capability and reduced expression of neurotrophic factors. Although multiple auto-antibodies including lupus-related ones were detected in the sera of the mice as well as AGS patients, Ifih1G821S/+Rag2-/- mice also exhibited up-regulation of IFN-I, astrogliosis and microgliosis, indicating that auto-antibodies or lymphocytes are not required for the development of the encephalitis. The IFN-I signature without lymphocytic infiltration observed in Ifih1G821S/+ mice is a typical feature of AGS. Collectively, our results suggest that the Ifih1G821S/+ mice are a model recapitulating AGS and that microglia are a potential target for AGS therapy., (© The Japanese Society for Immunology. 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Congenital hydrocephalus is a potentially devastating, highly heterogeneous condition whose genetic subset remains incompletely known. We here report a consanguineous family where three fetuses presented with brain ventriculomegaly and limb contractures and shared a very rare homozygous variant of KIDINS220, consisting of an in-frame deletion of three amino acids adjacent to the fourth transmembrane domain. Fetal brain imaging and autopsy showed major ventriculomegaly, reduced brain mass, and with no histomorphologic abnormalities. We demonstrate that the binding of KIDINS220 to TrkA is diminished by the deletion mutation. This family is the second that associates a KIDINS220 genetic variant with human ventriculomegaly and limb contractures, validating causality of the gene and indicating TrkA as a likely mediator of the phenotype., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Autoimmune and autoinflammatory diseases are rare but often devastating disorders, underpinned by abnormal immune function. While some autoimmune disorders are thought to be triggered by a burden of infection throughout life, others are thought to be genetic in origin. Among these heritable disorders are the type I interferonopathies, including the rare Mendelian childhood-onset encephalitis Aicardi-Goutières syndrome. Patients with Aicardi Goutières syndrome are born with defects in enzymes responsible for nucleic acid metabolism and develop devastating white matter abnormalities resembling congenital cytomegalovirus brain infection. In some cases, common infections preceded the onset of the disease, suggesting immune stimulation as a potential trigger. Thus, the antiviral immune response has been actively studied in an attempt to provide clues on the pathological mechanisms and inform on the development of therapies. Animal models have been fundamental in deciphering biological mechanisms in human health and disease. Multiple rodent and zebrafish models are available to study type I interferonopathies, which have advanced our understanding of the human disease by identifying key pathological pathways and cellular drivers. However, striking differences in phenotype have also emerged between these vertebrate models, with zebrafish models recapitulating key features of the human neuropathology often lacking in rodents. In this review, we compare rodent and zebrafish models, and summarize how they have advanced our understanding of the pathological mechanisms in Aicardi Goutières syndrome and similar disorders. We highlight recent discoveries on the impact of laboratory environments on immune stimulation and how this may inform the differences in pathological severity between mouse and zebrafish models of type I interferonopathies. Understanding how these differences arise will inform the improvement of animal disease modeling to accelerate progress in the development of therapies for these devastating childhood disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rutherford, Kasher and Hamilton.)

The c-RET proto-oncogene encodes a receptor-tyrosine kinase. Loss-of-function mutations of RET have been shown to be associated with Hirschsprung disease and Down's syndrome (HSCR-DS) in humans. DS is known to involve cerebellar hypoplasia, which is characterized by reduced cerebellar size. Despite the fact that c-Ret has been shown to be associated with HSCR-DS in humans and to be expressed in Purkinje cells (PCs) in experimental animals, there is limited information about the role of activity of c-Ret/c-RET kinase in cerebellar hypoplasia. We found that a loss-of-function mutation of c-Ret Y1062 in PCs causes cerebellar hypoplasia in c-Ret mutant mice. Wild-type mice had increased phosphorylation of c-Ret in PCs during postnatal development, while c-Ret mutant mice had postnatal hypoplasia of the cerebellum with immature neurite outgrowth in PCs and granule cells (GCs). c-Ret mutant mice also showed decreased numbers of glial fibers and mitogenic sonic hedgehog (Shh)-positive vesicles in the external germinal layer of PCs. c-Ret-mediated cerebellar hypoplasia was rescued by subcutaneous injection of a smoothened agonist (SAG) as well as by reduced expression of Patched1, a negative regulator for Shh. Our results suggest that the loss-of-function mutation of c-Ret Y1062 results in the development of cerebellar hypoplasia via impairment of the Shh-mediated development of GCs and glial fibers in mice with HSCR-DS., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Variants in genes belonging to the tubulin superfamily account for a heterogeneous spectrum of brain malformations referred to as tubulinopathies. Variants in TUBB2A have been reported in 10 patients with a broad spectrum of brain imaging features, ranging from a normal cortex to polymicrogyria, while one patient has been reported with progressive atrophy of the cerebellar vermis., Methods: In order to further refine the phenotypical spectrum associated with TUBB2A , clinical and imaging features of 12 patients with pathogenic TUBB2A variants, recruited via the international network of the authors, were reviewed., Results: We report 12 patients with eight novel and one recurrent variants spread throughout the TUBB2A gene but encoding for amino acids clustering at the protein surface. Eleven patients (91.7%) developed seizures in early life. All patients suffered from intellectual disability, and 11 patients had severe motor developmental delay, with 4 patients (36.4 %) being non-ambulatory. The cerebral cortex was normal in five individuals and showed dysgyria of variable severity in seven patients. Associated brain malformations were less frequent in TUBB2A patients compared with other tubulinopathies. None of the patients had progressive cerebellar atrophy., Conclusion: The imaging phenotype associated with pathogenic variants in TUBB2A is highly variable, ranging from a normal cortex to extensive dysgyria with associated brain malformations. For recurrent variants, no clear genotype-phenotype correlations could be established, suggesting the role of additional modifiers., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: UBA5 is the activating enzyme of UFM1 in the ufmylation post-translational modification system. Different neurological phenotypes have been associated with UBA5 pathogenic variants including epilepsy, intellectual disability, movement disorders and ataxia., Methods and Results: We describe a large multigenerational consanguineous family presenting with a severe congenital neuropathy causing early death in infancy. Whole exome sequencing and linkage analysis identified a novel homozygous UBA5 NM&#95;024818.3 c.31C>T (p.Arg11Trp) mutation. Protein expression assays in mouse tissue showed similar levels of UBA5 in peripheral nerves to the central nervous system. CRISPR-Cas9 edited HEK (human embrionic kidney) cells homozygous for the UBA5 p.Arg11Trp mutation showed reduced levels of UBA5 protein compared with the wild-type. The mutant p.Arg11Trp UBA5 protein shows reduced ability to activate UFM1., Conclusion: This report expands the phenotypical spectrum of UBA5 mutations to include fatal peripheral neuropathy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder caused by the loss of function of a set of imprinted genes on chromosome 15q11-15q13. One of these genes, NDN, encodes necdin, a protein that is important for neuronal differentiation and survival. Loss of Ndn in mice causes defects in the formation and function of the nervous system. Necdin is a member of the melanoma-associated antigen gene (MAGE) protein family. The functions of MAGE proteins depend highly on their interactions with other proteins, and in particular MAGE proteins interact with E3 ubiquitin ligases and deubiquitinases to form MAGE-RING E3 ligase-deubiquitinase complexes. Here, we used proximity-dependent biotin identification (BioID) and mass spectrometry (MS) to determine the network of protein-protein interactions (interactome) of the necdin protein. This process yielded novel as well as known necdin-proximate proteins that cluster into a protein network. Next, we used BioID-MS to define the interactomes of necdin proteins carrying coding variants. Variant necdin proteins had interactomes that were distinct from wildtype necdin. BioID-MS is not only a useful tool to identify protein-protein interactions, but also to analyze the effects of variants of unknown significance on the interactomes of proteins involved in genetic disease.

Microphthalmia, coloboma and cataract are part of a spectrum of developmental eye disorders in humans affecting ~12 per 100 000 live births. Currently, variants in over 100 genes are known to underlie these conditions. However, at least 40% of affected individuals remain without a clinical genetic diagnosis, suggesting variants in additional genes may be responsible. Calpain 15 (CAPN15) is an intracellular cysteine protease belonging to the non-classical small optic lobe (SOL) family of calpains, an important class of developmental proteins, as yet uncharacterized in vertebrates. We identified five individuals with microphthalmia and/or coloboma from four independent families carrying homozygous or compound heterozygous predicted damaging variants in CAPN15. Several individuals had additional phenotypes including growth deficits, developmental delay and hearing loss. We generated Capn15 knockout mice that exhibited similar severe developmental eye defects, including anophthalmia, microphthalmia and cataract, and diminished growth. We demonstrate widespread Capn15 expression throughout the brain and central nervous system, strongest during early development, and decreasing postnatally. Together, these findings demonstrate a critical role of CAPN15 in vertebrate developmental eye disorders, and may signify a new developmental pathway., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

PIGT is one of over 29 glycosylphosphatidylinositol biosynthesis defect genes. Mutations cause genetically determined disorders characterized mainly by epilepsy with fever-sensitivity, central hypotonia, psychomotor delay and congenital malformations. The disease is known as multiple congenital anomalies-hypotonia-seizures syndrome 3 (MCAHS3) or glycosylphosphatidylinositol biosynthesis defect-7. Twenty-eight cases have been reported until today. We present seven novel Polish patients, all harboring 1582G>A variant in a homozygous or compound heterozygous state which seems to cause a milder phenotype of the disease., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Congenital Zika virus (ZIKV) exposure results in a spectrum of disease ranging from severe birth defects to delayed onset neurodevelopmental deficits. ZIKV-related neuropathogenesis, predictors of birth defects, and neurodevelopmental deficits are not well defined in people. Here we assess the methodological and statistical feasibility of a congenital ZIKV exposure macaque model for identifying infant neurobehavior and brain abnormalities that may underlie neurodevelopmental deficits. We inoculated five pregnant macaques with ZIKV and mock-inoculated one macaque in the first trimester. Following birth, growth, ocular structure/function, brain structure, hearing, histopathology, and neurobehavior were quantitatively assessed during the first week of life. We identified the typical pregnancy outcomes of congenital ZIKV infection, with fetal demise and placental abnormalities. We estimated sample sizes needed to define differences between groups and demonstrated that future studies quantifying brain region volumes, retinal structure, hearing, and visual pathway function require a sample size of 14 animals per group (14 ZIKV, 14 control) to detect statistically significant differences in at least half of the infant exam parameters. Establishing the parameters for future studies of neurodevelopmental outcomes following congenital ZIKV exposure in macaques is essential for robust and rigorous experimental design., Competing Interests: DHO is a paid consultant for Battelle, devoted to research in the areas of assisting in the design and interpretation of their nonhuman primate ZIKV studies. His relationship does not carry with it any restrictions on publication, and any associated intellectual property will be disclosed and processed according to UW-Madison policy. None of the animals used in this study are involved in any studies with Battelle.

Background: Preterm birth is associated with increased infant mortality. However, it is not clear whether prematurity is associated with mortality after 1 year of age. There is a lack of research on mortality rate and causes of death after infancy in preterm babies in Korea. We aimed to analyze the mortality rates and causes of deaths up to 5 years of age in Korea., Methods: Using the Microdata Integrated Service of Statistics Korea database, this retrospective cohort study screened infants born between 2010 and 2012. After applying the exclusion criteria, 1,422,913 live births were classified into the following groups by gestational age: those born at < 32 weeks' gestation (n = 10,411), those born between 32 and 36 weeks' gestation (n = 75,657), and those born at ≥ 37 weeks' gestation (n = 1,336,845). The association of gestational age with mortality in infancy (< 1 year of age) and childhood (1-5 years of age) was analyzed, with and without covariates. The major causes of death in infancy and childhood were analyzed by gestational age., Results: Overall, 4,930 (0.3%) children died between birth and 5 years of age, with 19.1% of these deaths occurring after infancy. Adjusted hazard ratios (HRs) for infant death were 78.79 (95% confidence interval [CI], 71.33-87.04) and 4.62 (95% CI, 4.07-5.24) for the < 32 and 32-36 weeks groups, respectively, compared to the full-term group; the adjusted HRs for deaths occurring at ages 1-5 years were 9.25 (95% CI, 6.85-12.50) and 2.42 (95% CI, 1.95-3.01), respectively. In infancy, conditions originating in the perinatal period were the most common cause of deaths in the < 32 and 32-36 weeks groups (88.7% and 41.9%, respectively). Contrarily, in the ≥ 37 weeks group, conditions originating in the perinatal period explained 22.7% of infant deaths, with congenital malformations primarily accounting for 29.6% of these deaths. The most common cause of death in children (after infancy) in the < 32 weeks group was perinatal causes (25.0%); in the 32-36 weeks group, congenital malformation and nervous system disease were the common causes (21.7% and 19.1%, respectively). In the ≥ 37 weeks group, injury, poisoning, and other consequences of external causes explained 26.6% of childhood deaths, followed by neoplasms and nervous system disease (15.7% and 14.7%, respectively)., Conclusion: Low gestational age is associated with not only infant mortality but also child mortality. The major causes of death differed by gestational age in infancy and childhood. For the care of preterm infants, especially those born at < 32 weeks' gestation, particular attention and continuous monitoring are needed in consideration of the major causes of deaths until 5 years of age., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2020 The Korean Academy of Medical Sciences.)

Hydrocephalus is a serious condition that impacts patients of all ages. The standards of care are surgical options to divert, or inhibit production of, cerebrospinal fluid; to date, there are no effective pharmaceutical treatments, to our knowledge. The causes vary widely, but one commonality of this condition is aberrations in salt and fluid balance. We have used a genetic model of hydrocephalus to show that ventriculomegaly can be alleviated by inhibition of the transient receptor potential vanilloid 4, a channel that is activated by changes in osmotic balance, temperature, pressure and inflammatory mediators. The TRPV4 antagonists do not appear to have adverse effects on the overall health of the WT or hydrocephalic animals.

The RNA exosome is an essential ribonuclease complex required for processing and/or degradation of both coding and non-coding RNAs. We identified five patients with biallelic variants in EXOSC5, which encodes a structural subunit of the RNA exosome. The clinical features of these patients include failure to thrive, short stature, feeding difficulties, developmental delays that affect motor skills, hypotonia and esotropia. Brain MRI revealed cerebellar hypoplasia and ventriculomegaly. While we ascertained five patients, three patients with distinct variants of EXOSC5 were studied in detail. The first patient had a deletion involving exons 5-6 of EXOSC5 and a missense variant, p.Thr114Ile, that were inherited in trans, the second patient was homozygous for p.Leu206His and the third patient had paternal isodisomy for chromosome 19 and was homozygous for p.Met148Thr. The additional two patients ascertained are siblings who had an early frameshift mutation in EXOSC5 and the p.Thr114Ile missense variant that were inherited in trans. We employed three complementary approaches to explore the requirement for EXOSC5 in brain development and assess consequences of pathogenic EXOSC5 variants. Loss of function for exosc5 in zebrafish results in shortened and curved tails/bodies, reduced eye/head size and edema. We modeled pathogenic EXOSC5 variants in both budding yeast and mammalian cells. Some of these variants cause defects in RNA exosome function as well as altered interactions with other RNA exosome subunits. These findings expand the number of genes encoding RNA exosome subunits linked to human disease while also suggesting that disease mechanism varies depending on the specific pathogenic variant., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Our body expresses sensors to detect pathogens through the recognition of expressed molecules, including nucleic acids, lipids, and proteins, while immune tolerance prevents an overreaction with self and the development of autoimmune disease. Adenosine (A)-to-inosine (I) RNA editing, catalyzed by adenosine deaminases acting on RNA (ADARs), is a post-transcriptional modification that can potentially occur at over 100 million sites in the human genome, mainly in Alu repetitive elements that preferentially form a double-stranded RNA (dsRNA) structure. A-to-I conversion within dsRNA, which may induce a structural change, is required to escape from the host immune system, given that endogenous dsRNAs transcribed from Alu repetitive elements are potentially recognized by melanoma differentiation-associated protein 5 (MDA5) as non-self. Of note, loss-of-function mutations in the ADAR1 gene cause Aicardi-Goutières syndrome, a congenital autoimmune disease characterized by encephalopathy and a type I interferon (IFN) signature. However, the loss of ADAR1 in cancer cells with an IFN signature induces lethality via the activation of protein kinase R in addition to MDA5. This makes cells more sensitive to immunotherapy, highlighting the opposing immune status of autoimmune diseases (overreaction) and cancer (tolerance). In this review, we provide an overview of insights into two opposing aspects of RNA editing that functions as a modulator of the immune system in autoimmune diseases and cancer.

Recently, age-related timing dissociation between the superficial and deep venous systems has been observed; this was particularly pronounced in patients with normal pressure hydrocephalus, suggesting a common mechanism of ventriculomegaly. Establishing the relationship between venous drainage and ventricular enlargement would be clinically relevant and could provide insight into the mechanisms underlying brain ageing. To investigate a possible link between venous drainage and ventriculomegaly in both normal ageing and pathological conditions, we compared 225 healthy subjects (137 males and 88 females) and 71 traumatic brain injury patients of varying ages (53 males and 18 females) using MRI-based volumetry and a novel perfusion-timing analysis. Volumetry, focusing on the CSF space, revealed that the sulcal space and ventricular size presented different lifespan profiles with age; the latter presented a quadratic, rather than linear, pattern of increase. The venous timing shift slightly preceded this change, supporting a role for venous drainage in ventriculomegaly. In traumatic brain injury, a small but significant disease effect, similar to idiopathic normal pressure hydrocephalus, was found in venous timing, but it tended to decrease with age at injury, suggesting an overlapping mechanism with normal ageing. Structural bias due to, or a direct causative role of ventriculomegaly was unlikely to play a dominant role, because of the low correlation between venous timing and ventricular size after adjustment for age in both patients and controls. Since post-traumatic hydrocephalus can be asymptomatic and occasionally overlooked, the observation suggested a link between venous drainage and CSF accumulation. Thus, hydrocephalus, involving venous insufficiency, may be a part of normal ageing, can be detected non-invasively, and is potentially treatable. Further investigation into the clinical application of this new marker of venous function is therefore warranted., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Intrauterine infections with the pathogens, including toxoplasmosis, other (syphilis, varicella, mumps, parvovirus, and HIV), rubella, cytomegalovirus, and herpes simplex (TORCH) in susceptible individuals during pregnancy, result in microcephaly, white matter disease, cerebral atrophy, and calcifications in the fetus. Pseudo-TORCH syndrome is an umbrella term, consisting of several syndromes, resultant from different genetic alterations and pathogenetic mechanisms. Band-like calcification with simplified gyration and polymicrogyria (BLC-PMG) is one of these conditions, resultant from biallelic mutations in the OCLN gene, located in the chromosome 5q13.2. OCLN gene encodes occludin, a tight junction protein, which is expressed in the endothelia. The absence of occludin in the developing brain subsequently results in abnormal blood-brain barrier, thus immune-cell mediated tissue damage and cortical malformation. Herein, we present a pediatric patient who had progressive microcephaly, spasticity, multi-drug resistant epilepsy, PMG and intracranial band-type calcifications, accompanied by central diabetes insipidus and renal dysfunction. Whole exome sequencing revealed a homozygote W58Ffs*10 (c.173&#95;194del) frameshift mutation in the OCLN gene. Of 34 BLC-PMG cases with demonstrable OCLN mutations, only three had renal manifestations, which is responsible for the majority of the demises. This is the first case diagnosed as having central diabetes insipidus and responded to desmopressin treatment to the best of our knowledge, however, this clinical improvement could not prevent the patient from renal dysfunction. The patient deceased at four years of age from sepsis, therefore early diagnosis, optimal follow-up for renal involvement and infection prevention measures are necessary for the patients with BLC-PMG., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

A juvenile raccoon ( Procyon lotor ) was submitted dead to the Minnesota Veterinary Diagnostic Laboratory for rabies testing without history. The animal had marked hypoplasia of the cerebellum. Histology demonstrated that most folia lacked granule cells and had randomly misplaced Purkinje cells. Immunohistochemistry revealed the presence of parvoviral antigen in a few neurons and cell processes. PCR targeting feline and canine parvovirus yielded a positive signal. Sequencing analyses from a fragment of the nonstructural protein 1 ( NS1 ) gene and a portion of the viral capsid protein 2 ( VP2 ) gene confirmed the presence of DNA of a recent canine parvovirus variant (CPV-2a-like virus) in the cerebellum. Our study provides evidence that (canine) parvovirus may be associated with cerebellar hypoplasia and dysplasia in raccoons, similar to the disease that occurs naturally and has been reproduced experimentally by feline parvoviral infection of pregnant cats, with subsequent intrauterine or neonatal infections of the offspring.

A distinct neurodevelopmental phenotype characterised mainly by mild motor and language delay and facial dysmorphism, caused by heterozygous de novo or dominant variants in the TLK2 gene has recently been described. All cases reported carried either truncating variants located throughout the gene, or missense changes principally located at the C-terminal end of the protein mostly resulting in haploinsufficiency of TLK2. Through whole exome sequencing, we identified a homozygous missense variant in TLK2 in a patient showing more severe symptoms than those previously described, including cerebellar vermis hypoplasia and West syndrome. Both parents are heterozygous for the variant and clinically unaffected highlighting that recessive variants in TLK2 can also be disease causing and may act through a different pathomechanism.

We report an inborn error of metabolism caused by TKFC deficiency in two unrelated families. Rapid trio genome sequencing in family 1 and exome sequencing in family 2 excluded known genetic etiologies, and further variant analysis identified rare homozygous variants in TKFC. TKFC encodes a bifunctional enzyme involved in fructose metabolism through its glyceraldehyde kinase activity and in the generation of riboflavin cyclic 4',5'-phosphate (cyclic FMN) through an FMN lyase domain. The TKFC homozygous variants reported here are located within the FMN lyase domain. Functional assays in yeast support the deleterious effect of these variants on protein function. Shared phenotypes between affected individuals with TKFC deficiency include cataracts and developmental delay, associated with cerebellar hypoplasia in one case. Further complications observed in two affected individuals included liver dysfunction and microcytic anemia, while one had fatal cardiomyopathy with lactic acidosis following a febrile illness. We postulate that deficiency of TKFC causes disruption of endogenous fructose metabolism leading to generation of by-products that can cause cataract. In line with this, an affected individual had mildly elevated urinary galactitol, which has been linked to cataract development in the galactosemias. Further, in light of a previously reported role of TKFC in regulating innate antiviral immunity through suppression of MDA5, we speculate that deficiency of TKFC leads to impaired innate immunity in response to viral illness, which may explain the fatal illness observed in the most severely affected individual., (Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Pontocerebellar Hypoplasia type 1 is a rare heterogeneous neurodegenerative disorder with multiple subtypes linked to dysfunction of the exosome complex. Patients with mutations in exosome subunits exhibit a generally lethal phenotype characterized by cerebellar and pontine hypoplasia in association with spinal motor neuropathy and multiple systemic and neurologic features. Recently, two variants in the novel PCH1 associated protein EXOSC9 p.(Leu14Pro) and p.(Arg161*) have been identified in 4 unrelated patients exhibiting a severe phenotype involving cerebellar hypoplasia, axonal motor neuropathy, hypotonia, feeding difficulties, and respiratory insufficiency (PCH1D). We report clinical and molecular characterization of 2 unrelated patients exhibiting a relatively milder phenotype involving hypotonia, brachycephaly, cerebellar atrophy, psychomotor delay, as well as lactic acidosis and aberrant CNS myelination, resulting from the recurring homozygous missense mutation NM&#95;001034194.1: c.41T>C; p.(Leu14Pro) in the EXOSC9 gene. We review the clinical picture of the EXOSC9-related PCH disorder., (Copyright © 2019. Published by Elsevier Masson SAS.)

Aicardi-Goutières syndrome (AGS) is an early-onset monogenic encephalopathy characterized by intracranial calcification, leukodystrophy and cerebrospinal fluid lymphocytosis. To date, seven genes have been related to AGS. Among these, IFIH1 encodes for MDA5, a cytosolic double-stranded RNA receptor, and is responsible for AGS type 7. We generated three isogenic iPSC clones, using a Sendai virus-based vector, starting from fibroblasts of a patient carrying a dominant mutation in IFIH1. All lines were characterized for genomic integrity, genetic uniqueness, pluripotency, and differentiation capability. Our clones might offer a good model to investigate AGS7 pathophysiological mechanism and to discover new biomarkers for this condition treatment., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: To describe a new first-trimester sonographic sign, the 'crash sign', associated with fetal open spina bifida, and to evaluate its clinical usefulness in the first-trimester diagnosis of spina bifida., Methods: This was a retrospective review of patients referred to three fetal medicine centers in the first trimester (11 + 0 to 13 + 6 weeks) with suspected spina bifida. Spina bifida was confirmed by direct visualization of the spinal defect on ultrasound by two experts and, when possible, by fetal postmortem examination. Ultrasound images were reviewed for the presence of the crash sign, which is the posterior displacement of the mesencephalon and deformation against the occipital bone in the axial view. The first-trimester ultrasound images of a mixed group of 10 cases and 40 control fetuses without spina bifida were assessed for the presence of the crash sign by two assessors blinded to the diagnosis., Results: The crash sign was present in 48 out of 53 confirmed cases of spina bifida. Of these, 27 had isolated spina bifida and 21 had an associated anomaly. Of the five cases without the crash sign, one had isolated spina bifida and four had an associated anomaly. The crash sign was not reported in any of the control fetuses., Conclusions: We have described a new first-trimester sonographic marker for the diagnosis of spina bifida. Our results suggest that the crash sign may be a useful tool in the first-trimester detection of spina bifida. Prospective evaluation of the crash sign would be beneficial, ideally in a routine clinical screening ultrasound setting. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.)

Fibroblasts from a patient with Aicardi Goutières Syndrome (AGS) carrying a compound heterozygous mutation in TREX1, were reprogrammed into induced pluripotent stem cells (iPSCs) to establish isogenic clonal stem cell lines: UNIBSi006-A, UNIBSi006-B, and UNIBSi006-C. Cells were transduced using the episomal Sendai viral vectors, containing human OCT4, SOX2, c-MYC and KLF4 transcription factors. The transgene-free iPSC lines showed normal karyotype, expressed pluripotent markers and displayed in vitro differentiation potential toward cells of the three embryonic germ layers., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

We report the generation of three isogenic iPSC clones (UNIBSi007-A, UNIBSi007-B, and UNIBSi007-C) obtained from fibroblasts of a patient with Aicardi Goutières Syndrome (AGS) carrying a homozygous mutation in RNaseH2B. Cells were transduced using a Sendai virus based system, delivering the human OCT4, SOX2, c-MYC and KLF4 transcription factors. The resulting transgene-free iPSC lines retained the disease-causing DNA mutation, showed normal karyotype, expressed pluripotent markers and could differentiate in vitro toward cells of the three embryonic germ layers., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

The leukodystrophies are a family of heritable disorders characterised by white matter degeneration, accompanied by variable clinical symptoms including loss of motor function and cognitive decline. Now thought to include over 50 distinct disorders, there are a vast array of mechanisms underlying the pathology of these monogenic conditions and, accordingly, a range of animal models relating to each disorder. While both murine and zebrafish models continue to aid in the development of potential therapies, many of these models fail to truly recapitulate the human condition - thus leaving substantial weaknesses in our understanding of leukodystrophy pathogenesis. Additionally, the heterogeneity in leukodystrophy presentation - both in patients and in vivo models - often results in a narrow focus on single disorders in isolation across much of the literature. Thus, this review aims to synthesise prominent research regarding the most common leukodystrophies in order to provide an overview of key animal models and their utility in developing novel treatments. We begin by discussing the ongoing revolution across the leukodystrophy field following the rise of next generation sequencing, before focusing more extensively on existing animal models from the mouse and zebrafish fields. Finally, we explore how these preclinical models have shaped the development of therapeutic strategies currently in development. We propose future directions for the field and suggest a more critical view of the dogma which has underpinned leukodystrophy research for decades., (© 2019 Federation of European Biochemical Societies.)

Synaptosomal-associated protein 29 ( SNAP29 ) encodes a member of the SNARE family of proteins implicated in numerous intracellular protein trafficking pathways. SNAP29 maps to the 22q11.2 region and is deleted in 90% of patients with 22q11.2 deletion syndrome (22q11.2DS). Moreover, bi-allelic SNAP29 mutations in patients are responsible for CEDNIK (cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma) syndrome. A mouse model that recapitulates abnormalities found in these syndromes is essential for uncovering the cellular basis of these disorders. In this study, we report that mice with a loss of function mutation of Snap29 on a mixed CD1;FvB genetic background recapitulate skin abnormalities associated with CEDNIK, and also phenocopy neurological and ophthalmological abnormalities found in CEDNIK and a subset of 22q11.2DS patients. Our work also reveals an unanticipated requirement for Snap29 in male fertility and supports contribution of hemizygosity for SNAP29 to the phenotypic spectrum of abnormalities found in 22q11.2DS patients., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2019.)

WD40 repeat-containing proteins form a large family of proteins present in all eukaryotes. Here, we identified five pediatric probands with de novo variants in WDR37, which encodes a member of the WD40 repeat protein family. Two probands shared one variant and the others have variants in nearby amino acids outside the WD40 repeats. The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia. The WDR37 protein is highly conserved in vertebrate and invertebrate model organisms and is currently not associated with a human disease. We generated a null allele of the single Drosophila ortholog to gain functional insights and replaced the coding region of the fly gene CG12333/wdr37 with GAL4. These flies are homozygous viable but display severe bang sensitivity, a phenotype associated with seizures in flies. Additionally, the mutant flies fall when climbing the walls of the vials, suggesting a defect in grip strength, and repeat the cycle of climbing and falling. Similar to wall clinging defect, mutant males often lose grip of the female abdomen during copulation. These phenotypes are rescued by using the GAL4 in the CG12333/wdr37 locus to drive the UAS-human reference WDR37 cDNA. The two variants found in three human subjects failed to rescue these phenotypes, suggesting that these alleles severely affect the function of this protein. Taken together, our data suggest that variants in WDR37 underlie a novel syndromic neurological disorder., (Published by Elsevier Inc.)

Herein we present a consanguineous family with three children affected by foveal hypoplasia with infantile nystagmus, following an autosomal recessive mode of inheritance. The patients showed normal electroretinography responses, no signs of albinism, and no anterior segment or brain abnormalities. Upon whole exome sequencing, we identified a homozygous mutation (c.1861C>T;p.Q621*) in the aryl hydrocarbon receptor (AHR) gene that perfectly co-segregated with the disease in the larger family. AHR is a ligand-activated transcription factor that has been intensively studied in xenobiotic-induced toxicity. Further, it has been shown to play a physiological role under normal cellular conditions, such as in immunity, inflammatory response and neurogenesis. Notably, knockout of the Ahr gene in mouse impairs optic nerve myelin sheath formation and results in oculomotor deficits sharing many features with our patients: the eye movement disorder in Ahr-/- mice appears early in development and presents as conjugate horizontal pendular nystagmus. We therefore propose AHR to be a novel disease gene for a new, recessively inherited disorder in humans, characterized by infantile nystagmus and foveal hypoplasia., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Several genes located within the chromosome 8p11.21 region are associated with movement disorders including SLC20A2 and THAP1. SLC20A2 is one of four genes associated with primary familial brain calcification, a syndrome that also includes movement disorders, cognitive decline and psychiatric issues. THAP1 is associated with dystonia type 6, a dominantly inherited dystonia with variable expression. In addition, several reports in the French-Canadian population have described microdeletions within the 8p11.2 region presenting with dystonia-plus syndromes including brain calcifications. This case report describes a 12-year-old boy with brain calcifications and generalised dystonia associated with a deletion in the 8p11.2 region detected via single nucleotide polymorphism microarray. This report emphasises the importance of obtaining a microarray analysis in diagnosing movement disorders and suggests that this copy number variant may be an under-recognised cause of dystonia and brain calcifications., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Breast cancer is the second leading cause of cancer-related deaths in the United States, with the majority of these deaths due to metastatic lesions rather than the primary tumor. Thus, a better understanding of the etiology of metastatic disease is crucial for improving survival. Using a haplotype mapping strategy in mouse and shRNA-mediated gene knockdown, we identified Rnaseh2c, a scaffolding protein of the heterotrimeric RNase H2 endoribonuclease complex, as a novel metastasis susceptibility factor. We found that the role of Rnaseh2c in metastatic disease is independent of RNase H2 enzymatic activity, and immunophenotyping and RNA-sequencing analysis revealed engagement of the T cell-mediated adaptive immune response. Furthermore, the cGAS-Sting pathway was not activated in the metastatic cancer cells used in this study, suggesting that the mechanism of immune response in breast cancer is different from the mechanism proposed for Aicardi-Goutières Syndrome, a rare interferonopathy caused by RNase H2 mutation. These results suggest an important novel, non-enzymatic role for RNASEH2C during breast cancer progression and add Rnaseh2c to a panel of genes we have identified that together could determine patients with high risk for metastasis. These results also highlight a potential new target for combination with immunotherapies and may contribute to a better understanding of the etiology of Aicardi-Goutières Syndrome autoimmunity., Competing Interests: The authors have declared that no competing interests exist.

A hallmark of systemic lupus erythematosus (SLE), and several related autoimmune diseases, is the presence of autoantibodies against nucleic acids and nucleic acid-binding proteins, as well as elevated type I interferons (IFNs), which appear to be instrumental in disease pathogenesis. Here we discuss the sources and proposed mechanisms by which a range of cellular RNA and DNA species can become pathogenic and trigger the nucleic acid sensors that drive type I interferon production. Potentially SLE-promoting DNA may originate from pieces of chromatin, from mitochondria, or from reverse-transcribed cellular RNA, while pathogenic RNA may arise from mis-localized, mis-processed, ancient retroviral, or transposable element-derived transcripts. These nucleic acids may leak out from dying cells to be internalized and reacted to by immune cells or they may be generated and remain to be sensed intracellularly in immune or non-immune cells. The presence of aberrant DNA or RNA is normally counteracted by effective counter-mechanisms, the loss of which result in a serious type I IFN-driven disease called Aicardi-Goutières Syndrome. However, in SLE it remains unclear which mechanisms are most critical in precipitating disease: aberrant RNA or DNA, overly sensitive sensor mechanisms, or faulty counter-acting defenses. We propose that the clinical heterogeneity of SLE may be reflected, in part, by heterogeneity in which pathogenic nucleic acid molecules are present and which sensors and pathways they trigger in individual patients. Elucidation of these events may result in the recognition of distinct "endotypes" of SLE, each with its distinct therapeutic choices.