11 research outputs found

    Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders

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    The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins, and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Utilizing exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with YnMyr chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), with ages ranging from 1 to 50 years old, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%), and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%), and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%), and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain and small inferior cerebellar vermis (38% each), as well as hypertrophy of the clava (24%) were common neuroimaging findings. acbd6-deficient zebrafish and Xenopus models effectively recapitulated many clinical phenotypes reported in patients including movement disorders, progressive neuromotor impairment, seizures, microcephaly, craniofacial dysmorphism, and midbrain defects accompanied by developmental delay with increased mortality over time. Unlike ACBD5, ACBD6 did not show a peroxisomal localisation and ACBD6-deficiency was not associated with altered peroxisomal parameters in patient fibroblasts. Significant differences in YnMyr-labelling were observed for 68 co- and 18 post-translationally N-myristoylated proteins in patient-derived fibroblasts. N-Myristoylation was similarly affected in acbd6-deficient zebrafish and Xenopus tropicalis models, including Fus, Marcks, and Chchd-related proteins implicated in neurological diseases. The present study provides evidence that bi-allelic pathogenic variants in ACBD6 lead to a distinct neurodevelopmental syndrome accompanied by complex and progressive cognitive and movement disorders

    The Infantile spasm, clinical manifestation of a rare brain tumor: a case report and review in literature

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    Desmoplastic infantile ganglioglioma (DIG) has a favorable prognosis; and is classified as a benign infantile brain tumor; it is more common in children under 2 years of age. In this report, we introduce one 5.5 months-old infant who was referred with infantile spasm and was diagnosed with a brain tumor. EEG showed modified hypsarrhythmia. The patient underwent ACTH treatment and was asked for a brain MRI. MRI of the patient’s brain showed large heterogeneous masses in the right hemisphere with shifting to other side. The patient underwent surgery. The extra-axial mass was completely resected, and the diagnosis of DIG grade I confirmed with the pathology. At present, the patient is only on phenobarbital, and the seizures do not recur, and the general condition is good; also, the growth of the patient’s head and development is normal for age. We found 13 reported cases during the search, of which 9 were boys and 4 were girls. The mean age of tumor diagnosis from the onset of symptoms was between 2 weeks to two months. Of 13 patients, in 8 patients, the origin of the mass was the right hemisphere. The most common tumors observed were glioma (4 patients), Hamartoma hypothalamus (3 patients). Except for three patients who died, the remaining patients found complete recovery with complete control of seizures after the mass's surgical resection

    Participation of Electric Vehicles in a Delay-Dependent Stability Analysis of LFC Considering Demand Response Control

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    Today, time-varying delays may result from a communication network’s engagement in frequency control services. These delays have an impact on the effectiveness of the load frequency control (LFC) system, which can occasionally lead to power system instability. The electric vehicle (EV) can be used as a beneficial source for the LFC system with the development of demand-side response due to its vehicle-to-grid capacity. Although demand response control has certain advantages for the power system, communication networks used in LFC systems result in time delays that reduce the stability of the LFC schemes. A stability study of an LFC system, comprising an EV aggregator with two additive time-varying delays, is demonstrated in this work. An enhanced Lyapunov–Krasovskii functional (LKF), which incorporates time-varying delays using the linear matrix inequality approach, is used to perform a delay-dependent stability analysis of the LFC to determine the stability zone and criterion. In conclusion, the efficiency of the proposed stability criterion is validated by making use of the thorough simulation findings

    A new sensor based on glassy carbon electrode modified with nanocomposite for simultaneous determination of acetaminophen, ascorbic acid and uric acid

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    A chemically-modified electrode has been constructed based on a single walled carbon nanotube/chitosan/room temperature ionic liquid nanocomposite modified glassy carbon electrode (SWCNTs–CHIT–RTIL/GCE). It was demonstrated that this sensor could be used for simultaneous determination of acetaminophen (ACT), uric acid (URI) and ascorbic acid (ASC). The measurements were carried out by application of differential pulse voltammetry (DPV), cyclic voltammetry (CV) and chronoamperometry (CA) methods. Electrochemical studies suggested that the RTIL and SWCNTs provided a synergistic augmentation that can increase current responses by improvement of electron transfers of these compounds on the electrode surface. The presence of the CHIT in the modified electrode can enhance the repeatability of the sensor by its antifouling effect. The modified electrode showed electrochemical responses with high sensitivity for ACT, URI and ASC determination, which makes it a suitable sensor for simultaneous sub-ÎŒmol L−1 detection of ACT, URI and ASC in aqueous solutions. The analytical performance of this sensor has been evaluated for detection of ACT, URI and ASC in human serum and urine with satisfactory results

    The The Effect of Melatonin on Sleep Disorders in Children with Cerebral Palsy A Randomized Clinical Trial: Melatonin usage on sleep disorders in cerebral palsy

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    ObjectivesCerebral palsy (CP) is one of the most common causes of serious physical disability in childhood and is a persistent movement disorder before the age of three. This disorder can negatively affect both the child and their family. In recent years, the use of melatonin as a safe, effective, and cheap drug has been expanding in improving the sleep disorders of these children. Therefore, this study aimed to investigate melatonin’s effect on sleep disorders in children with CP. Materials & MethodsThis double-blind clinical trial was conducted on children aged 2 to 12 years with CP who were referred to the pediatric neurology clinic for sleep problems. The participants were included in the study by convenience sampling. After obtaining informed consent from parents, patients were divided randomly into two intervention (melatonin) and control (placebo) groups. In the intervention group, patients received oral melatonin tablets, and in the control group, patients received a placebo (3 mg oral lactose) 30 minutes before going to sleep.ResultsThe results of this study showed no significant relationship between age and gender with sleep disorders in children with CP (P>0.05). A significant effect of melatonin on sleep disorders was found in children with CP. The greatest effect of melatonin is the time required to start falling asleep. Melatonin was associated with decreased time needed to fall asleep and increased sleep duration. ConclusionThe results of the study demonstrated that sleep disorders are prevalent among children with CP. Therefore, proper and timely treatment of these children is crucial. According to the present study’s findings, melatonin effectively improves the time of falling asleep and these children’s sleep duration

    Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders

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    MED27 is a subunit of the Mediator multiprotein complex, which is involved in transcriptional regulation. Biallelic MED27 variants have recently been suggested to be responsible for an autosomal recessive neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia. We further delineate the clinical phenotype of MED27-related disease by characterizing the clinical and radiological features of 57 affected individuals from 30 unrelated families with biallelic MED27 variants. Utilizing exome sequencing and extensive international genetic data sharing, 39 unpublished affected individuals from 18 independent families with biallelic missense variants in MED27 have been identified (29 females, mean age at last follow-up 17±12.4 years, range 0.1-45). Follow-up and hitherto unreported clinical features were obtained from the published 12 families. Brain MRI scans from 34 cases were reviewed. MED27-related disease manifests as a broad phenotypic continuum ranging from developmental and epileptic-dyskinestic encephalopathy to variable neurodevelopmental disorder with movement abnormalities. It is characterised by mild to profound global developmental delay/intellectual disability (100%), bilateral cataracts (89%), infantile hypotonia (74%), microcephaly (62%), gait ataxia (63%), dystonia (61%), variably combined with epilepsy (50%), limb spasticity (51%), facial dysmorphism (38%), and death before reaching adulthood (16%). Brain MRI revealed cerebellar atrophy (100%), white matter volume loss (76.4%), pontine hypoplasia (47.2%), and basal ganglia atrophy with signal alterations (44.4%). Previously unreported 39 affected individuals had seven homozygous pathogenic missense MED27 variants, five of which were recurrent. An emerging genotype-phenotype correlation was observed. This study provides a comprehensive clinical-radiological description of MED27-related disease, establishes genotype-phenotype and clinical-radiological correlations, and suggests a differential diagnosis with syndromes of cerebello-lental neurodegeneration and other subtypes of “neuro-MEDopathies”

    PIGG variant pathogenicity assessment reveals characteristic features within 19 families.

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    PURPOSE: Phosphatidylinositol Glycan Anchor Biosynthesis, class G (PIGG) is an ethanolamine phosphate transferase catalyzing the modification of glycosylphosphatidylinositol (GPI). GPI serves as an anchor on the cell membrane for surface proteins called GPI-anchored proteins (GPI-APs). Pathogenic variants in genes involved in the biosynthesis of GPI cause inherited GPI deficiency (IGD), which still needs to be further characterized. METHODS: We describe 22 individuals from 19 unrelated families with biallelic variants in PIGG. We analyzed GPI-AP surface levels on granulocytes and fibroblasts for three and two individuals, respectively. We demonstrated enzymatic activity defects for PIGG variants in vitro in a PIGG/PIGO double knockout system. RESULTS: Phenotypic analysis of reported individuals reveals shared PIGG deficiency-associated features. All tested GPI-APs were unchanged on granulocytes whereas CD73 level in fibroblasts was decreased. In addition to classic IGD symptoms such as hypotonia, intellectual disability/developmental delay (ID/DD), and seizures, individuals with PIGG variants of null or severely decreased activity showed cerebellar atrophy, various neurological manifestations, and mitochondrial dysfunction, a feature increasingly recognized in IGDs. Individuals with mildly decreased activity showed autism spectrum disorder. CONCLUSION: This in vitro system is a useful method to validate the pathogenicity of variants in PIGG and to study PIGG physiological functions.RD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted.Accepted version (6 month embargo), submitted versio

    Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders

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