Severe Behavioral Abnormalities Research Articles

N-acetyl cysteine (NAC) administration induces behavioral abnormalities in mice experiencing proteotoxic cardiac disease

Background: The co-occurrence of cardiac and neurological complications is becoming increasingly common among individuals diagnosed with either of these disorders. Hypothesis: We tested the hypothesis that elevating glutathione (GSH) levels through N-acetyl cysteine (NAC), a precursor for GSH synthesis, leads to behavioral abnormalities in a mouse model with proteotoxic heart disease. Approach: We used a transgenic mouse model expressing a cardiac-specific human mutant R120G-αB-crystallin (hR120GCryAB-TG), which develops progressive heart failure due to proteotoxicity. Our investigation aimed to understand the effects of NAC on brain redox and behavior in this model. Results: Administering NAC for a period of 12 weeks, we observed an increase in glutathione levels and its redox state (GSH/GSSG) in both heart (1.0 vs. 3.0 Fold in NTG vs. TG; p>0.001) and brain (1.0 vs. 4.0 Fold in NTG vs. TG; p>0.01) tissues. Interestingly, this increase was associated with exacerbated cardiac dysfunction and abnormal behavior. The administration of NAC worsened both structural and functional defects in the hearts of the transgenic (TG) mice, indicating that enhancing antioxidant defense mechanisms could trigger proteotoxic insults through reductive stress (RS). Additionally, the brain of TG mice exhibited enhanced reductive capacity (p>0.01), accompanied by significant alterations in the levels of Tau and α-Synuclein proteins, when compared to non-transgenic (NTG) mice. While NTG mice, with or without NAC treatment, displayed normal behavior, TG mice treated with NAC developed severe behavioral abnormalities, including cognitive impairment (p>0.01). Conclusions: These findings suggest that increased GSH levels (i.e. RS) in progressive heart failure could cause behavioral issues. Thus, further research into the underlying redox mechanisms in other organs, including the brain, is necessary to better understand the use of antioxidant supplements for heart failure treatment. This study will aid in developing personalized therapeutic strategies. National Institute of Health - NHLBI R01 (R01-2RHL118067; Namakkal-Soorappan) American Heart Assocaition (20POST35200085; Sunny). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Implications of organophosphate pesticides on brain cells and their contribution towardprogression of Alzheimer's disease.

The most widespread neurodegenerative disorder, Alzheimer's disease (AD) is marked by severe behavioral abnormalities, cognitive and functional impairments. It is inextricably linked with the deposition of amyloid β (Aβ) plaques and tau protein in the brain. Loss of white matter, neurons, synapses, and reactive microgliosis are also frequently observed in patients of AD. Although the causative mechanisms behind the neuropathological alterations in AD are not fully understood, they are likely influenced by hereditary and environmental factors. The etiology and pathogenesis of AD are significantly influenced by the cells of the central nervous system, namely, glial cells and neurons, which are directly engaged in the transmission of electrical signals and the processing of information. Emerging evidence suggests that exposure to organophosphate pesticides (OPPs) can trigger inflammatory responses in glial cells, leading to various cascades of events that contribute to neuroinflammation, neuronal damage, and ultimately, AD pathogenesis. Furthermore, there are striking similarities between the biomarkers associated with AD and OPPs, including neuroinflammation, oxidative stress, dysregulation of microRNA, and accumulation of toxic protein aggregates, such as amyloid β. These shared markers suggest a potential mechanistic link between OPP exposure and AD pathology. In this review, we attempt to address the role of OPPs on altered cell physiology of the brain cells leading to neuroinflammation, mitochondrial dysfunction, and oxidative stress linked with AD pathogenesis.

Multiple Early Life Stressors as Risk Factors for Neurodevelopmental Abnormalities in the F1 Wistar Rats.

Cumulative exposure to multiple early life stressors is expected to affect behavioral development, causing increased susceptibility to neuropsychiatric disorders. The present study was designed to mimic such conditions in a rat model to study behavioral impairments during adolescence and adulthood. Female Wistar rats (n = 32; 140-150 gm) were switched to a low protein (LP; 8% protein) or control (20% protein) diet 15 days prior to conception, and then the diet regime was maintained throughout the experimental period. Pups born to control and LP dams were intraperitoneally injected with deltamethrin (DLT-pyrethroid insecticide; 0.7 mg/kg body weight; PND 1 to 7), lipopolysaccharide (LPS-bacterial endotoxin; 0.3 mg/kg body weight; PND 3 and 5), or DLT+LPS, on designated days forming eight experimental groups (Control, LP, Control+LPS, LP+LPS, Control+DLT, LP+DLT, Control+DLT+LPS and LP+DLT+LPS). Neurobehavioral assessments were performed in F1 rats (1, 3, 6 months) by open field, elevated plus maze, light and dark box, and rotarod tests. LP rats were found to be highly susceptible to either singular or cumulative exposure as compared to their age-matched control counterparts, showing significantly severe behavioral abnormalities, such as hyperactivity, attention deficits and low anxiety, the hallmark symptoms of neuropsychiatric disorders like schizophrenia and ADHD, suggesting thereby that early life multi-hit exposure may predispose individuals to developmental disorders.

MYT1L variant inherited by a mosaic father in a case of severe developmental and epileptic encephalopathy.

The MYT1L gene plays a critical role in brain development, promoting the differentiation and proliferation of cells, important for the formation of brain connections. MYT1L is also involved in regulating the development of the hypothalamus, which is a crucial actor in weight regulation. Genetic variants in the MYT1L are associated with a range of developmental disorders, including intellectual disability, autism spectrum disorder, facial dysmorphisms, and epilepsy. The specific role of MYT1L in epilepsy remains elusive and no patients with developmental and epileptic encephalopathy (DEE) have been described so far. In this study, we report a patient with DEE presenting with severe refractory epilepsy, obesity and behavioral abnormalities. Exome sequencing led to the identification of the heterozygous variant NM_001303052.2: c.1717G>A, p.(Gly573Arg) (chr2-1910340-C-T; GRCh38.p14) in the MYT1L gene. This variant was found to be inherited by the father, who was a mosaic and did not suffer from any neuropsychiatric disorders. Our observations expand the molecular and phenotype spectrum of MYT1L related disorders, suggesting that affected individuals may present with severe epileptic phenotype leading to neurocognitive deterioration. Furthermore, we show that mosaic parents may not display the disease phenotype, with relevant implications for genetic counseling.

Genotype–phenotype correlation in contactin-associated protein-like 2 (CNTNAP-2) developmental disorder

Contactin-associated protein-like 2 (CNTNAP2) gene encodes for CASPR2, a presynaptic type 1 transmembrane protein, involved in cell–cell adhesion and synaptic interactions. Biallelic CNTNAP2 loss has been associated with “Pitt-Hopkins-like syndrome-1” (MIM#610042), while the pathogenic role of heterozygous variants remains controversial. We report 22 novel patients harboring mono- (n = 2) and bi-allelic (n = 20) CNTNAP2 variants and carried out a literature review to characterize the genotype–phenotype correlation. Patients (M:F 14:8) were aged between 3 and 19 years and affected by global developmental delay (GDD) (n = 21), moderate to profound intellectual disability (n = 17) and epilepsy (n = 21). Seizures mainly started in the first two years of life (median 22.5 months). Antiseizure medications were successful in controlling the seizures in about two-thirds of the patients. Autism spectrum disorder (ASD) and/or other neuropsychiatric comorbidities were present in nine patients (40.9%). Nonspecific midline brain anomalies were noted in most patients while focal signal abnormalities in the temporal lobes were noted in three subjects. Genotype–phenotype correlation was performed by also including 50 previously published patients (15 mono- and 35 bi-allelic variants). Overall, GDD (p < 0.0001), epilepsy (p < 0.0001), hyporeflexia (p = 0.012), ASD (p = 0.009), language impairment (p = 0.020) and severe cognitive impairment (p = 0.031) were significantly associated with the presence of biallelic versus monoallelic variants. We have defined the main features associated with biallelic CNTNAP2 variants, as severe cognitive impairment, epilepsy and behavioral abnormalities. We propose CASPR2-deficiency neurodevelopmental disorder as an exclusively recessive disease while the contribution of heterozygous variants is less likely to follow an autosomal dominant inheritance pattern.

A case-control study of aggressiveness in adolescents with schizophrenia family history

IntroductionViolence is a common behavioral and health concern among adolescents, aged 12 to 18 years old. In fact, aggressiveness may result in severe outcome in a critical age characterised by biological, psychological, and social changes. Schizophrenia is a severe and chronic condition, with elevated level of aggressiveness. Since unaffected biological relatives of schizophrenia patients share similar though less severe neurocognitive and behavioral abnormalities seen in their affected relatives, they are at increased risk of violence mainly during adolescence. However, studies including adolescents with schizophrenia first degree history are scarce.ObjectivesThe aim of this survey was to evaluate the aggressiveness among unaffected adolescents with fist degree family history of schizophrenia and in a control group of adolescents with no family psychiatric history.MethodsIn this purpose wo conducted a case-control cross sectional study in Razi hospital during three months: from July to September 2022. Unaffected adolescents aged 12 to 18 whom first-degree relatives were diagnosed with schizophrenia according to DSM-5 criteria were included. Adolescents with psychiatric conditions or medical affections associated with psychiatric presentation were not included. Control group was selected amongst the population. Sociodemographic data were collected on a preestablished questionnaire and the following scales were used: The Life History of Aggression LHA, an 11 items self-reported tool, in the Arabic version, The Aggression Questionnaire AQ which is a 29 items self-reported scale in Arabic version. Written informed consent was obtained from the legal tutor of each adolescent.ResultsResults of this survey are ongoing.ConclusionsResults of this survey are ongoing.Disclosure of InterestNone Declared

Aggressiveness and emotion dysregulation among adolescents first degree relatives of schizophrenia patients

IntroductionSchizophrenia is a severe debilitating condition, with elevated level of aggressiveness reaching 33% in a large sample of patients. Unaffected biological relatives of schizophrenia patients share similar though less severe neurocognitive and behavioral abnormalities seen in their affected relatives. Recent findings demonstrates that first degree relatives of schizophrenia patients are at increased risk of violence and aggressive behavior, especially during adolescence, with poor outcome. Besides, adolescents aged from 12 to 18 years old, may experience aversive and overwhelming emotions difficult to regulate due to immaturity of neuronal networks. There are evidence of an association of emotion dysregulation and violent conduct among youth. However, to our knowledge, studies among first degree relatives of psychotic patients were not performed.ObjectivesThe aim of this study was to evaluate the aggressiveness and emotion dysregulation among unaffected adolescents with fist degree family history of schizophrenia and to investigate the association linking these two entities.MethodsIn this purpose wo conducted a cross sectional descriptive study in Razi hospital during three months: from July to September 2022. Unaffected adolescents aged 12 to 18 whom first-degree relatives were diagnosed with schizophrenia according to DSM-5 criteria were included. Adolescents with psychiatric conditions or medical affections associated with psychiatric presentation were not included. Sociodemographic data were collected on a preestablished questionnaire and the following scales were used: The Life History of Aggression LHA, an 11 items self-reported tool, in the Arabic version, The Aggression Questionnaire AQ which is a 29 items self-reported scale in Arabic version and the The Emotion Regulation Questionnaire (ERQ), a 10 items self-reported measure rated on a likert scale, in the validated Arabic version. Written informed consent was obtained from the legal tutor of each adolescent.ResultsResults of this survey are ongoing.ConclusionsResults of this survey are ongoing.Disclosure of InterestNone Declared

Proteomic alterations in the cerebellum and hippocampus in an Alzheimer’s disease mouse model: Alleviating effect of palmatine

Alzheimer’s disease (AD) is one of the most prevalent diseases that lead to memory deficiencies, severe behavioral abnormalities, and ultimately death. The need for more appropriate treatment of AD continues, and remains a sought-after goal. Previous studies showed palmatine (PAL), an isoquinoline alkaloid, might have the potential for combating AD because of its in vitro and in vivo activities. In this study, we aimed to assess PAL’s therapeutic potential and gain insights into the working mechanism on protein level in the AD mouse model brain, for the first time. To this end, PAL was administered to 12-month-old 5xFAD mice at two doses after its successful isolation from the Siberian barberry shrub. PAL (10 mg/kg) showed statistically significant improvement in the memory and learning phase on the Morris water maze test. The PAL’s ability to pass through the blood-brain barrier was verified via Multiple Reaction Monitoring (MRM). Label-free proteomics analysis revealed PAL administration led to changes most prominently in the cerebellum, followed by the hippocampus, but none in the cortex. Most of the differentially expressed proteins in PAL compared to the 5xFAD control group (ALZ) were the opposite of those in ALZ in comparison to healthy Alzheimer’s littermates (ALM) group. HS105, HS12A, and RL12 were detected as hub proteins in the cerebellum. Collectively, here we present PAL as a potential therapeutic candidate owing to its alleviating effect in 5xFAD mice on not only cognitive impairment but also proteomes in the cerebellum and hippocampus.

Expansion of the mutation spectrum and phenotype of USP7-related neurodevelopmental disorder.

Hao-fountain syndrome (HAFOUS) is a neurodevelopmental syndrome characterized by global developmental and severe language delays, behavioral abnormalities (including autism), and mild dysmorphic impairment of intellectual development. It is a dominant genetic disease caused by USP7 gene (*602519) mutations on chromosome 16p13.2. So far, only 15 cases with 14 deleterious variants in the USP7 gene have been reported. This study describes three unrelated patients with USP7 variants. Besides, we identified novel de novo heterozygous USP7 variants using trio-whole exome sequencing and verified by Sanger sequencing. Furthermore, clinical characteristics were evaluated by reviewing the medical records. The three identified variants, i.e., one frameshift variant (c.247_250del, p.Glu83Argfs × 18) and two missense variants (c.992A > G, p.Tyr331Cys; c.835T > G, p.Leu279Val) are unreported. The predominant clinical manifestations of the three patients included: DD/ID; language impairment; abnormal behavior; abnormal brain magnetic resonance (dilation of lateral ventricles, dilation of Virchow-Robin spaces, dilated the third ventricle, abnormal cerebral white matter morphology in bilateral occipital lobes, hypodysplasia of the corpus callosum, arachnoid cyst, delayed myelination, and widened subarachnoid space); some also had facial abnormalities. In summary, DD/ID is the most prevalent clinical phenotype of HAFOUS, although some patients also exhibit language and behavioral abnormalities. For the first time in China, we identified three variants of the USP7 gene using whole-genome sequence data. This work expands the USP7 gene mutation spectrum and provides additional clinical data on the clinical phenotype of HAFOUS.

Phenylalanine hydroxylase mRNA rescues the phenylketonuria phenotype in mice.

Phenylketonuria (PKU) is an inborn error of metabolism caused by a deficiency in functional phenylalanine hydroxylase (PAH), resulting in accumulation of phenylalanine (Phe) in patients’ blood and organs. Affected patients encounter severe developmental delay, neurological deficits, and behavioral abnormalities when not treated. Early diagnosis and treatment are extremely important; newborn screening programs have been implemented in most countries to ensure early identification of patients with PKU. Despite available treatment options, several challenges remain: life-long adherence to a strict diet, approval of some medications for adults only, and lack of response to these therapies in a subpopulation of patients. Therefore, there is an urgent need for treatment alternatives. An mRNA-based approach tested in PKU mice showed a fast reduction in the accumulation of Phe in serum, liver and brain, the most significant organ affected. Repeated injections of LNP-formulated mouse PAH mRNA rescued PKU mice from the disease phenotype for a prolonged period of time. An mRNA-based approach could improve the quality of life tremendously in PKU patients of all ages by replacing standard-of-care treatments.

Structural mechanisms of GABAA receptor autoimmune encephalitis

Autoantibodies targeting neuronal membrane proteins can cause encephalitis, seizures, and severe behavioral abnormalities. While antibodies for several neuronal targets have been identified, structural details on how they regulate function are unknown. Here we determined cryo-electron microscopy structures of antibodies derived from an encephalitis patient bound to the γ-aminobutyric acid type A (GABAA) receptor. These antibodies induced severe encephalitis by directly inhibiting GABAA function, resulting in nervous-system hyperexcitability. The structures reveal mechanisms of GABAA inhibition and pathology. One antibody directly competes with a neurotransmitter and locks the receptor in a resting-like state. The second antibody targets the subunit interface involved in binding benzodiazepines and antagonizes diazepam potentiation. We identify key residues in these antibodies involved in specificity and affinity and confirm structure-based hypotheses for functional effects using electrophysiology. Together these studies define mechanisms of direct functional antagonism of neurotransmission underlying autoimmune encephalitis in a human patient.

Comprehensive analysis of lncRNA‑miRNA‑mRNA regulatory networks for Alzheimer's disease.

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease, associated with a decreased cognitive function and severe behavioral abnormalities. This study aimed to explore mechanisms of development and progression of AD. Comprehensive analysis of GSE16759 was performed to identify the differentially expressed lncRNAs (DElncRNAs), miRNAs (DEmiRNAs), and mRNAs (DEmRNAs). The differentially expressed RNAs (DERs) were used for the subsequent analysis, including module genes analysis, pathway enrichment analysis, and interaction network analysis. Finally, an AD‑associated network consisting of lncRNA‑miRNA‑mRNA‑pathway was constructed. A total of 431 DEmRNAs, 35 DElncRNAs, and 103 DEmiRNAs between the AD group and the normal control group were identified. DEmRNAs were significantly enriched in 13 pathways, such as focal adhesion, endocytosis, and mTOR signaling pathway. Three modules significantly related to AD were finally screened. The AD‑associated network was constructed, including 2 lncRNAs (A2M‑AS1 and ZNF571‑AS1), 1 miRNA (hsa‑miR‑206), 2 mRNAs (NOTCH3 and JAG1), and 2 pathways (notch signaling pathway and endocrine resistance). A2M‑AS1, ZNF571‑AS1, hsa‑miR‑206, NOTCH3 and JAG1 may be involved in the mechanisms of AD through notch signaling pathway and endocrine resistance.

Clinical Study of 8 Cases of CHD2 Gene Mutation-Related Neurological Diseases and Their Mechanisms.

Background: The chromodomain helicase DNA-binding protein 2 (CHD2) gene, is an ATPase and part of the CHD family of chromatin remodelers. Mutations in the CHD2 gene are inherited in an autosomal-dominant manner and can lead to intellectual disability, epilepsy, and autism. We investigated the clinical characteristics of CHD2-related conditions and their possible pathogenesis. Methods: We collected and analysed the clinical data of patients that were identified as having CHD2 mutations. Genetic testing was performed using targeted sequencing or whole-exome sequencing. We analysed the expression of CHD2 and repressor element 1-silencing transcription factor (REST) in blood samples using quantitative PCR and the conservation of the mutations. The CHD2 mutations we identified were compared with the known mutations reported in the CHD2-related literature. Results: Eight patients with CHD2 gene mutations were analysed. Six mutations were identified; four were unreported previously (c.670C>T; c.4012A>C; c.2416dup; c.1727–1728insAT), and two were known mutations: c.5035C>T (two cases) and c.4173dup (two cases). Among these mutations, seven were de novo mutations, and one could not be determined because the parents refused genetic testing. The clinical manifestations included mild or severe intellectual disability, epilepsy, and behavioural abnormalities. Quantitative PCR showed that the CHD2 gene expression levels among the patients, parents, and the controls were not significantly different. The levels of REST gene expression in the patients were significantly higher than those of the controls; thus, mutation of the CHD2 gene led to an increase in the expression level of the REST gene. The mutations reported were all located in conserved positions in different species. Among the various medications administered for treatment, valproate showed the best results for the treatment of epilepsy caused by CHD2 gene mutation. Conclusion: Mutation in CHD2 did not lead to a significant decrease in its expression level, indicating that the clinical phenotype was unrelated to its expression level, and the mutant protein may retain some function. Most of the mutations relatively stable. In addition, the clinical manifestations from the same mutation in the CHD2 gene were different among the known cases; this may be related to the regulation of REST or other regulatory factors.

Homozygous mutation in MCM7 causes autosomal recessive primary microcephaly and intellectual disability

BackgroundMinichromosomal maintenance (MCM) complex components 2, 4, 5 and 6 have been linked to human disease with phenotypes including microcephaly and intellectual disability. The MCM complex has DNA helicase activity...

Effect of Oral Allylnitrile Administration on Cochlear Functioning in Mice Following Comparison of Different Anesthetics for Hearing Assessment.

Background: Allylnitrile is a compound found in cruciferous vegetables and has the same lethality and toxic effects as the other nitriles. In 2013, a viable allylnitrile ototoxicity mouse model was established. The toxicity of allylnitrile was limited through inhibition of CYP2E1 with trans-1,2-dichloroethylene (TDCE). The allylnitrile intoxication model has been extensively tested in the 129S1 mouse strain for vestibular function, which showed significant HC loss in the vestibular organ accompanied by severe behavioral abnormalities. However, the effect of allylnitrile on auditory function remains to be evaluated. Commonly used anesthetics to conduct hearing measurements are isoflurane and ketamine/xylazine anesthesia but the effect of these anesthetics on hearing assessment is still unknown. In this study we will evaluate the otovestibular effects of oral allylnitrile administration in mice. In addition, we will compare the influence of isoflurane and ketamine/xylazine anesthesia on hearing thresholds.Methods and Materials: Fourteen Coch+/– CBACa mice were randomly allocated into an allylnitrile (n = 8) and a control group (n = 6). Baseline measurements were done with isoflurane and 1 week later under ketamine/xylazine anesthesia. After baseline audiovestibular measurements, mice were co-administered with a single dose of allylnitrile and, to reduce systemic toxicity, three intraperitoneal injections of TDCE were given. Hearing loss was evaluated by recordings of auditory brainstem responses (ABR) and distortion product otoacoustic emissions (DPOAE). Specific behavioral test batteries for vestibular function were used to assess alterations in vestibular function.Results: Hearing thresholds were significantly elevated when using isoflurane anesthesia compared to ketamine/xylazine anesthesia for all frequencies of the ABR and the mid-to-high frequencies in DPOAE. Allylnitrile-treated mice lacked detectable ABR thresholds at each frequency tested, while DPOAE thresholds were significantly elevated in the low-frequency region of the cochlea and completely lacking in the mid-to high frequency region. Vestibular function was not affected by allylnitrile administration.Conclusion: Isoflurane anesthesia has a negative confounding effect on the measurement of hearing thresholds in mice. A single oral dose of allylnitrile induced hearing loss but did not significantly alter vestibular function in mice. This is the first study to show that administration of allylnitrile can cause a complete loss of hearing function in mice.

GABAA receptor β3 subunit mutation D120N causes Lennox-Gastaut syndrome in knock-in mice.

The Lennox–Gastaut syndrome is a devastating early-onset epileptic encephalopathy, associated with severe behavioural abnormalities. Its pathophysiology, however, is largely unknown. A de novo mutation (c.G358A, p.D120N) in the human GABA type-A receptor β3 subunit gene (GABRB3) has been identified in a patient with Lennox–Gastaut syndrome. To determine whether the mutation causes Lennox–Gastaut syndrome in vivo in mice and to elucidate its mechanistic effects, we generated the heterozygous Gabrb3+/D120N knock-in mouse and found that it had frequent spontaneous atypical absence seizures, as well as less frequent tonic, myoclonic, atonic and generalized tonic–clonic seizures. Each of these seizure types had a unique and characteristic ictal EEG. In addition, knock-in mice displayed abnormal behaviours seen in patients with Lennox–Gastaut syndrome including impaired learning and memory, hyperactivity, impaired social interactions and increased anxiety. This Gabrb3 mutation did not alter GABA type-A receptor trafficking or expression in knock-in mice. However, cortical neurons in thalamocortical slices from knock-in mice had reduced miniature inhibitory post-synaptic current amplitude and prolonged spontaneous thalamocortical oscillations. Thus, the Gabrb3+/D120N knock-in mouse recapitulated human Lennox–Gastaut syndrome seizure types and behavioural abnormalities and was caused by impaired inhibitory GABAergic signalling in the thalamocortical loop. In addition, treatment with antiepileptic drugs and cannabinoids ameliorated atypical absence seizures in knock-in mice. This congenic knock-in mouse demonstrates that a single-point mutation in a single gene can cause development of multiple types of seizures and multiple behavioural abnormalities. The knock-in mouse will be useful for further investigation of the mechanisms of Lennox–Gastaut syndrome development and for the development of new antiepileptic drugs and treatments.

Xq22 deletions and correlation with distinct neurological disease traits in females: Further evidence for a contiguous gene syndrome

Xq22 deletions that encompass PLP1 (Xq22-PLP1-DEL) are notable for variable expressivity of neurological disease traits in females ranging from a mild late-onset form of spastic paraplegia type 2 (MIM# 312920), sometimes associated with skewed X-inactivation, to an early-onset neurological disease trait (EONDT) of severe developmental delay, intellectual disability, and behavioral abnormalities. Size and gene content of Xq22-PLP1-DEL vary and were proposed as potential molecular etiologies underlying variable expressivity in carrier females where two smallest regions of overlap (SROs) were suggested to influence disease. We ascertained a cohort of eight unrelated patients harboring Xq22-PLP1-DEL and performed high-density array comparative genomic hybridizationand breakpoint-junction sequencing. Molecular characterization of Xq22-PLP1-DEL from 17 cases (eight herein and nine published) revealed an overrepresentation of breakpoints that reside within repeats (11/17, ~65%) and the clustering of ~47% of proximal breakpoints in a genomic instability hotspot with characteristic non-B DNA density. These findings implicate a potential role for genomic architecture in stimulating the formation of Xq22-PLP1-DEL. The correlation of Xq22-PLP1-DEL gene content with neurological disease trait in female cases enabled refinement of the associated SROs to a single genomic interval containing six genes. Our data support the hypothesis that genes contiguous to PLP1 contribute to EONDT.

FAM160B1 deficit associated with microcephaly, severe intellectual disability, ataxia, behavioral abnormalities and speech problems.

Intellectual disability (ID) varies in severity and is often associated with a variety of other clinical features. In consanguineous populations ID is usually inherited in an autosomal recessive fashion. Many genes are known for the condition, but many more are yet to be identified. By linkage analysis and exome sequencing we identified homozygous early truncating variant c.115G > T (p.Glu39*) in FAM160B1 in a 38-year-old woman with severe ID, microcephaly, behavioral abnormalities, speech problems, mild ataxia and mild facial dysmorphism. Recently homozygous missense c.248 T > C (p.Leu83Pro) was reported to underlie the ID syndrome in a 7-year-old boy and his two younger siblings. Some findings for those siblings overlap with those for our patient, but our patient does not have cutis laxa. Our findings confirm FAM160B1, with unknown function, as a syndromic ID gene and indicate that FAM160B1 is not essential for survival but is vital for proper functioning of the nervous system, delineate the FAM160B1-related ID, and describe the disease in a much older age.

Coumarin derivatives as acetyl- and butyrylcholinestrase inhibitors: An in vitro, molecular docking, and molecular dynamics simulations study

Alzheimer's disease is an irreversible and progressive brain disease that can cause problems with memory and thinking skills. It is characterized by loss of cognitive ability and severe behavioral abnormalities, and could lead to death. Cholinesterases (ChEs) play a crucial role in the control of cholinergic transmission, and subsequently, the acetylcholine level in the brain is upgraded by inhibition of ChEs. Coumarins have been shown to display potential cholinesterase inhibitory action, where the aromatic moiety has led to the design of new candidates that could inhibit Aβ aggregation. Accordingly, the present work is an in vitro activity, along with docking and molecular dynamics (MD) simulation studies of synthesized coumarin derivatives, to explore the plausible binding mode of these compounds inside the cholinesterase enzymes. For this purpose, a series of previously prepared N1-(coumarin-7-yl) derivatives were screened in vitro for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities. The assayed compounds exhibited moderate inhibitory activity against AChE, with IC50 values ranging from 42.5 ± 2.68 to 442 ± 3.30 μM. On the other hand, the studied compounds showed remarkable activity against BChE with IC50 values ranging from 2.0 ± 1.4 nM to 442 ± 3.30 μM. In order to better understand the ligand binding site interaction of compounds and the stability of protein-ligand complexes, a molecular docking with molecular dynamics simulation of 5000 ps in an explicit solvent system was carried out for both cholinesterases. We concluded that the tested coumarin derivatives are potential candidates as leads for potent and efficacious ChEs inhibitors.

Liver-specific RORα deletion does not affect the metabolic susceptibility to western style diet feeding

ObjectivesThe nuclear receptor superfamily is a potential target for the development of new treatments for obesity and metabolic diseases. Increasing evidence has pointed towards the retinoic acid-related orphan receptor-alpha (RORα) as an important nuclear receptor involved in several biological processes. RORα full body knockout mice display improved metabolic phenotypes on both chow and high fat (60% fat, 20% carbohydrate) diets, but also have severe behavioral abnormalities. Here we investigated the effect of hepatic RORα by generating mice with liver-specific RORα deletion to elucidate the role of this nuclear receptor on host metabolism. Methods8 week-old mice with liver-specific RORα deletion and littermate controls were fed either chow or western-style diets (40% fat, 40% carbohydrate) for 12 weeks. Metabolic phenotyping was performed at the end of the dietary intervention. ResultsHere, we show that hepatic RORα deletion does not affect the metabolic susceptibility to either chow or western-style diet in terms of glucose metabolism and adiposity. ConclusionsOur data indicate that liver deletion of RORα does not have a pivotal role in the regulation of hepatic glucose and lipid metabolism on chow or western-style diet.