Neuronal intranuclear inclusion disease is genetically heterogeneous

Neuronal intranuclear inclusion disease (NIID) is a clinically heterogeneous neurodegenerative condition characterized by pathological intranuclear eosinophilic inclusions. A CGG repeat expansion in NOTCH2NLC was recently identified to be associated with NIID in patients of Japanese descent. We screened pathologically confirmed European NIID, cases of neurodegenerative disease with intranuclear inclusions and applied in silico-based screening using whole-genome sequencing data from 20 536 participants in the 100 000 Genomes Project. We identified a single European case harbouring the pathogenic repeat expansion with a distinct haplotype structure. Thus, we propose new diagnostic criteria as European NIID represents a distinct disease entity from East Asian cases

A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease

Purpose: The mediator (MED) multisubunit-complex modulates the activity of the transcriptional machinery, and genetic defects in different MED subunits (17, 20, 27) have been implicated in neurologic diseases. In this study, we identified a recurrent homozygous variant in MED11 (c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families. Methods: To investigate the genetic cause of the disease, exome or genome sequencing were performed in 5 unrelated families identified via different research networks and Matchmaker Exchange. Deep clinical and brain imaging evaluations were performed by clinical pediatric neurologists and neuroradiologists. The functional effect of the candidate variant on both MED11 RNA and protein was assessed using reverse transcriptase polymerase chain reaction and western blotting using fibroblast cell lines derived from 1 affected individual and controls and through computational approaches. Knockouts in zebrafish were generated using clustered regularly interspaced short palindromic repeats/Cas9. Results: The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death. Functional studies on patient-derived fibroblasts did not show a loss of protein function but rather disruption of the C-terminal of MED11, likely impairing binding to other MED subunits. A zebrafish knockout model recapitulates key clinical phenotypes. Conclusion: Loss of the C-terminal of MED subunit 11 may affect its binding efficiency to other MED subunits, thus implicating the MED-complex stability in brain development and neurodegeneration

De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects

Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function

De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects.

Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function

Altered Disrupted-in-Schizophrenia-1 function affects the development of cortical parvalbumin interneurons by an indirect mechanism.

<div><p><i>Disrupted-in-Schizophrenia-1 (DISC1)</i> gene has been linked to schizophrenia and related major mental illness. Mouse Disc1 has been implicated in brain development, mainly in the proliferation, differentiation, lamination, neurite outgrowth and synapse formation and maintenance of cortical excitatory neurons. Here, the effects of two loss-of-function point mutations in the mouse <i>Disc1</i> sequence (Q31L and L100P) on cortical inhibitory interneurons were investigated. None of the mutations affected the overall number of interneurons. However, the 100P, but not the 31L, mutation resulted in a significant decrease in the numbers of interneurons expressing parvalbumin mRNA and protein across the sensory cortex. To investigate role of Disc1 in regulation of parvalbumin expression, mouse wild-type Disc-1 or the 100P mutant form were electroporated <i>in utero</i> into cortical excitatory neurons. Overexpression of wild-type Disc1 in these cells caused increased densities of parvalbumin-expressing interneurons in the electroporated area and in areas connected with it, whereas expression of Disc1-100P did not. We conclude that the 100P mutation prevents expression of parvalbumin by a normally sized cohort of interneurons and that altering Disc1 function in cortical excitatory neurons indirectly affects parvalbumin expression by cortical interneurons, perhaps as a result of altered functional input from the excitatory neurons.</p></div

Scavenger receptor class B type i (SR-BI) regulates perivascular macrophages and modifies amyloid pathology in an Alzheimer mouse model

Scavenger receptor class B type I (SR-BI) is a high-density lipoprotein receptor that regulates cholesterol efflux fromthe peripheral tissues to the liver. SR-BI has been identified on astrocytes and vascular smooth muscle cells in Alzheimer&apos;s disease brain and has been shown to mediate adhesion of microglia to fibrillar amyloid-β (Aβ). Here we report that SR-BI mediates perivascular macrophage response and regulates Aβ-related pathology and cerebral amyloid angiopathy in an Alzheimer&apos;s mouse model. Reduction or deletion of SR-BI gene in heterozygous or homozygous deficient mice (SR-BI +/-, -/-) resulted in a significant increase in perivascularmacrophages in the brain. SR-BI deletion had no effect on apolipoprotein E or apolipoproteinAI levels in themouse brain.Our analysis revealed increased levels of SR-BI expression in the brains of human amyloid precursor protein (Swedish, Indiana) transgenic mice (J20 line). To evaluate the role of SR-BI in Alzheimer&apos;s disease pathogenesis, we inactivated one SR-BI allele in J20 transgenic mice. SR-BI reduction in J20/SR-BI+/- mice enhanced fibrillar amyloid deposition and cerebral amyloid angiopathy and also exacerbated learning andmemory deficits compared with J20 littermates. Immunohistochemical analysis revealed localization of SR-BI on perivascular macrophages in tight association with Aβ deposits. Our data suggest that SR-BI reduction impairs the response of perivascularmacrophages to Aβ and enhances theAβ-relatedphenotype andcerebralamyloidangiopathy in J20 mice. These results reveal that SR-BI, a scavenger receptor primarily involved in high-density lipoprotein cholesterol transport, plays an essential role in Alzheimer&apos;s disease and cerebral amyloid angiopathy

What Makes the Difference? Community Mental Health Providers’ and Users’ Perceptions on Dealing with the Crisis in Greece

A crisis is associated with instability, but also with the potential for change. The prolonged socioeconomic crisis in Greece has raised such challenges in the mental health system. This paper presents a case study using a mixed-method design to collect data from 170 professionals and 120 users in a community mental health agency nationwide regarding (a) the effects of the crisis, (b) the protective factors, and (c) the possibilities for integration of adverse experiences into the therapeutic milieu. Data were collected in the initial phase of the crisis (2009) and 7 years later (2016). Results showed significant differences among providers and users in dealing with the threats from the crisis over the years. The role of the relationship (e.g. therapists-users, group-level, agency level) emerged as a common protective factor. The results provide clues on the personal and organizational variables that promote empowerment in the community mental health care system. © 2018, Springer (India) Private Ltd., part of Springer Nature

Giant Metastatic Liver Tumor of Unknown Primary Origin: Thoracic Autopsy Solves the Mystery

A 59-year-old male patient was hospitalized in the Internal Medicine Department for investigation of hepatic metastases from an unknown primary neoplasm. During the hospitalization the patient died from acute myocardial infarction. The autopsy revealed a 8.2 kilograms (kg) liver that was diffusely infiltrated by whitish metastatic masses. No other tumor was detected, apart from a 2.5 centimeters (cm) pulmonary nodule next to the right intermediate bronchus that was histologically compatible with small cell lung cancer (SCLC). Despite the fact that hepatic metastases from SCLCs are common, diffuse metastatic hepatomegaly from a malignant pulmonary nodule are rarely seen. Given that the most common cause of malignancy-related death is lung cancer, early diagnosis and appropriate management of pulmonary nodules is of paramount importance