Attentional bias towards and away from fearful faces is modulated by developmental amygdala damage

The amygdala is believed to play a major role in orienting attention towards threat-related stimuli. However, behavioral studies on amygdala-damaged patients have given inconsistent results-variously reporting decreased, persisted, and increased attention towards threat. Here we aimed to characterize the impact of developmental amygdala damage on emotion perception and the nature and time-course of spatial attentional bias towards fearful faces. We investigated SF, a 14-year-old with selective bilateral amygdala damage due to Urbach-Wiethe disease (UWD), and ten healthy controls. Participants completed a fear sensitivity questionnaire, facial expression classification task, and dot-probe task with fearful or neutral faces for spatial cueing. Three cue durations were used to assess the time-course of attentional bias. SF expressed significantly lower fear sensitivity, and showed a selective impairment in classifying fearful facial expressions. Despite this impairment in fear recognition, very brief (100 msec) fearful cues could orient SF's spatial attention. In healthy controls, the attentional bias emerged later and persisted longer. SF's attentional bias was due solely to facilitated engagement to fear, while controls showed the typical phenomenon of difficulty in disengaging from fear. Our study is the first to demonstrate the separable effects of amygdala damage on engagement and disengagement of spatial attention. The findings indicate that multiple mechanisms contribute in biasing attention towards fear, which vary in their timing and dependence on amygdala integrity. It seems that the amygdala is not essential for rapid attention to emotion, but probably has a role in assessment of biological relevance

Biallelic truncation variants in ATP9A are associated with a novel autosomal recessive neurodevelopmental disorder.

Intellectual disability (ID) is a highly heterogeneous disorder with hundreds of associated genes. Despite progress in the identification of the genetic causes of ID following the introduction of high-throughput sequencing, about half of affected individuals still remain without a molecular diagnosis. Consanguineous families with affected individuals provide a unique opportunity to identify novel recessive causative genes. In this report, we describe a novel autosomal recessive neurodevelopmental disorder. We identified two consanguineous families with homozygous variants predicted to alter the splicing of ATP9A which encodes a transmembrane lipid flippase of the class II P4-ATPases. The three individuals homozygous for these putatively truncating variants presented with severe ID, motor and speech impairment, and behavioral anomalies. Consistent with a causative role of ATP9A in these patients, a previously described Atp9a-/- mouse model showed behavioral changes

Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia.

Alterations of Ca2+ homeostasis have been implicated in a wide range of neurodegenerative diseases. Ca2+ efflux from the endoplasmic reticulum into the cytoplasm is controlled by binding of inositol 1,4,5-trisphosphate to its receptor. Activated inositol 1,4,5-trisphosphate receptors are then rapidly degraded by the endoplasmic reticulum-associated degradation pathway. Mutations in genes encoding the neuronal isoform of the inositol 1,4,5-trisphosphate receptor (ITPR1) and genes involved in inositol 1,4,5-trisphosphate receptor degradation (ERLIN1, ERLIN2) are known to cause hereditary spastic paraplegia (HSP) and cerebellar ataxia. We provide evidence that mutations in the ubiquitin E3 ligase gene RNF170, which targets inositol 1,4,5-trisphosphate receptors for degradation, are the likely cause of autosomal recessive HSP in four unrelated families and functionally evaluate the consequences of mutations in patient fibroblasts, mutant SH-SY5Y cells and by gene knockdown in zebrafish. Our findings highlight inositol 1,4,5-trisphosphate signaling as a candidate key pathway for hereditary spastic paraplegias and cerebellar ataxias and thus prioritize this pathway for therapeutic interventions

Clinical and molecular spectrum of P/Q type calcium channel Cav2.1 in epileptic patients

Background: Epilepsy is a neurological disorder characterized by the potential to induce seizure and accompanied by cognitive, psychological, and social consequences. CACNA1A gene is a voltage-gated P/Q-type Cav2.1 channel that is broadly expressed in the central nervous system, and the pathogenic variants within this gene may be associated with the epileptic phenotype. In the present study, we collected clinical and molecular data related to epileptic patients with CACNA1A pathogenic variants and investigated possible meaningful relationship between age at onset, neurodevelopmental disorders, type of seizures, brain imaging abnormalities, genotype, and protein domains. Results: In our retrospective literature studies, from among 890 articles reviewed, a total of 90 individuals were related to epilepsy phenotype. Our findings showed that about 90 percent of patients have shown the first symptoms in childhood and teenage years and different types of neurodevelopmental disorders, such as intellectual disability, developmental arrest, and behavioral disorders, have been common findings for these patients. Further, a wide range of abnormalities have been observed in their brain imaging, and generalized seizures have been the most type of seizures in these patients. However, our data showed no specific genotype�phenotype correlation in epileptic patients with CACNA1A pathogenic alterations. Conclusions: Our study focused on epileptic phenotype in patients with CACNA1A pathogenic variants and showed a wide range of clinical and molecular heterogeneity with no specific genotype�phenotype correlation. It seems that incomplete penetrance, de-novo variants, and modifier genes are obstacles in predicting the clinical outcome. © 2021, The Author(s)

Quantitative evaluation of BAFF, HMGB1, TLR 4 and TLR 7 expression in patients with relapsing remitting multiple sclerosis

Multiple sclerosis is a chronic inflammatory disease of the central nervous system characterized by a complex immune response. Because of the complex nature of MS pathogenesis, a panel of biomarkers derived from different platforms will be required to reflect disease-related alterations. Monitoring and evaluation of molecules associated with the pathogenesis of the disease would provide useful information on disease progression and therapeutic assessment. In view of this, we evaluated the mRNA expression levels of B-cell activating factor (BAFF), high mobility group box 1 (HMGB-1), Toll like receptor (TLR) 4 and TLR7 in MS. These molecules are implicated in the pathogenesis of MS; however, they have received little attention. PBMCs were isolated from whole blood of 84 relapsing remitting multiple sclerosis patients and 70 healthy controls. Relative quantitative RT-PCR was applied to quantify the transcriptional levels of the immune markers. The mRNA expression levels of TLR7 were significantly elevated in RRMS patients than healthy controls. TLR4 expression was found to be significantly lower in the patients than control group. We found no difference analyzing the mRNA levels of BAFF and HMGB1. Our data highlights the immune marker correlates in RRMS patients. However, further in-depth studies are warranted to check the role and the relevance of these immune markers in autoimmune diseases such as MS. © Copyright Winter 2016, Iran J Allergy Asthma Immunol. All rights reserved

Tongue Protrusion Dystonia in Pantothenate Kinase-Associated Neurodegeneration

Background: Tongue protrusion dystonia is an uncommon focal dystonia involving the lingual muscles. Causes of tongue protrusion dystonia include tardive dystonia, posthypoxic dystonia, neuroacanthocytosis, pantothenate kinase-associated neurodegeneration, and Lesch-Nyhan syndrome. Method: We summarize three children with pantothenate kinase-associated neurodegeneration and tongue protrusion dystonia. All three patients underwent careful neurological examination, brain magnetic resonance imaging, and genetic testing. Results: Tongue protrusion dystonia was a prominent and disabling symptom in all three patients. Brain magnetic resonance imaging revealed a typical eye of the tiger sign in all patients. Two patients had the same genetic mutation (c.1168 A>T mutation, p.I390F). Conclusions: Tongue protrusion dystonia may be a clue to the underlying etiology of dystonia, including hereditary forms of dystonia. Among them, pantothenate kinase-associated neurodegeneration is an important cause, especially in children. © 2019 Elsevier Inc

A systematic review of resting-state and task-based fmri in juvenile myoclonic epilepsy

Functional neuroimaging modalities have enhanced our understanding of juvenile myoclonic epilepsy (JME) underlying neural mechanisms. Due to its non-invasive, sensitive and analytical nature, functional magnetic resonance imaging (fMRI) provides valuable insights into relevant functional brain networks and their segregation and integration properties. We systematically reviewed the contribution of resting-state and task-based fMRI to the current understanding of the pathophysiology and the patterns of seizure propagation in JME Altogether, despite some discrepancies, functional findings suggest that corticothalamo-striato-cerebellar network along with default-mode network and salience network are the most affected networks in patients with JME. However, further studies are required to investigate the association between JME’s main deficiencies, e.g., motor and cognitive deficiencies and fMRI findings. Moreover, simultaneous electroencephalography-fMRI (EEG-fMRI) studies indicate that alterations of these networks play a role in seizure modulation but fall short of identifying a causal relationship between altered functional properties and seizure propagation. This review highlights the complex pathophysiology of JME, which necessitates the design of more personalized diagnostic and therapeutic strategies in this group

Quantitative evaluation of BAFF, HMGB1, TLR 4 and TLR 7 expression in patients with relapsing remitting multiple sclerosis

Multiple sclerosis is a chronic inflammatory disease of the central nervous system characterized by a complex immune response. Because of the complex nature of MS pathogenesis, a panel of biomarkers derived from different platforms will be required to reflect disease-related alterations. Monitoring and evaluation of molecules associated with the pathogenesis of the disease would provide useful information on disease progression and therapeutic assessment. In view of this, we evaluated the mRNA expression levels of B-cell activating factor (BAFF), high mobility group box 1 (HMGB-1), Toll like receptor (TLR) 4 and TLR7 in MS. These molecules are implicated in the pathogenesis of MS; however, they have received little attention. PBMCs were isolated from whole blood of 84 relapsing remitting multiple sclerosis patients and 70 healthy controls. Relative quantitative RT-PCR was applied to quantify the transcriptional levels of the immune markers. The mRNA expression levels of TLR7 were significantly elevated in RRMS patients than healthy controls. TLR4 expression was found to be significantly lower in the patients than control group. We found no difference analyzing the mRNA levels of BAFF and HMGB1. Our data highlights the immune marker correlates in RRMS patients. However, further in-depth studies are warranted to check the role and the relevance of these immune markers in autoimmune diseases such as MS. © Copyright Winter 2016, Iran J Allergy Asthma Immunol. All rights reserved

Leu226Trp CACNA1A variant associated with juvenile myoclonic epilepsy with and without intellectual disability

Objective: Epilepsy is a disease of Central Nervous System (CNS) characterized by abnormal brain activity and recurrent seizures and is considered a clinically and genetically heterogeneous disease. Here, we investigated pathogenic genetic alteration and described the clinical characteristics of three Iranian family members affected by Idiopathic Generalized Epilepsy (IGE) with and without intellectual disability. Methods: A non-consanguineous Iranian family with juvenile myoclonic epilepsy was enrolled in the study. The comprehensive neurological evaluation included motor and sensory skills, vision, hearing, speech, coordination, and mood. Whole-exome Sequencing (WES) was performed on the proband to detect probable pathogenic variant, and after the filtering process, probable variants were evaluated with familial segregation analysis using Sanger sequencing. Results: Using WES, we identified a heterozygous missense substitution (NM023035.3:c.T677G:p.Leu226Trp) in CACNA1A gene in the studied family with juvenile myoclonic epilepsy with and without intellectual disability and psychiatric phenotype. Considering the patients� clinical synopsis, familial segregation analysis, and literature review, we postulated this variant to be causative of the disease. Indeed, the resulting missense mutation of Leu226Trp affects a highly conserved residue supporting our hypothesis that this mutation is potentially pathogenic. Conclusion: To the best of our knowledge, this is the first report of juvenile myoclonic epilepsy related to CACNA1A gene. Our results provide evidence for expanding the clinical and molecular findings related to the CACNA1A gene. © 2022 Elsevier B.V