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Academic literature on the topic 'Developmental Delay Encephalopathy Functional Spectroscopy'
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Journal articles on the topic "Developmental Delay Encephalopathy Functional Spectroscopy"
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Kr. Roy, Deep, Darpana Kalita, Rupak Bhuyan, Aniruddha Basu, and Suresh Killing. "MRI EVALUATION OF BRAIN IN CHILDREN WITH DEVELOPMENTAL DELAY: AN EXPERIENCE OF TWELVE CASES IN A TERTIARY CARE CENTRE OF RURAL INDIA." International Journal of Advanced Research 11, no. 05 (2023): 156–61. http://dx.doi.org/10.21474/ijar01/16863.
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Background: The term developmental delay denotes a significant delay in one or more developmental domains in humans. The importance of evaluation of a child with developmental delay lies in early diagnosis and treatment and also parental counseling regarding the outcome of their child and to identify any possible risk of recurrence in the siblings. This study is done to evaluate Magnetic Resonance Imaging (MRI) as an investigative modality for evaluation and to correlate the spectrum of findings in such patients with developmental delay. Methods: This is a prospective observational study done at the Department of Radiodiagnosis, Jorhat Medical College and Hospital from January 2022 to December 2022 with a sample size of 12 cases. All patients were evaluated clinically and underwent an MRI of the brain performed using a 1.5 Tesla MRI scanner. MRI scan was done and findings are recorded. Results: Among the cases, 3 have white matter disorders, 3 cases have Hypoxic Ischemic Encephalopathy (HIE), 2 cases have Cerebral atrophy with encephalomalacic changes, 1 case showing sub-ependymal heterotopia and 3 cases have normal findings. Conclusions: The spectrum of developmental delay is wide and MRI brain helps in proper diagnosis. This leads to appropriate treatment and parent counselling. Further, advanced imaging modalities like Functional MRI, MR Spectroscopy, Diffusion Tensor Imaging etc. helps in further evaluation of developmental delay.
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Rumping, Lynne, Federico Tessadori, Petra J. W. Pouwels, et al. "GLS hyperactivity causes glutamate excess, infantile cataract and profound developmental delay." Human Molecular Genetics 28, no. 1 (2018): 96–104. http://dx.doi.org/10.1093/hmg/ddy330.
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Abstract Loss-of-function mutations in glutaminase (GLS), the enzyme converting glutamine into glutamate, and the counteracting enzyme glutamine synthetase (GS) cause disturbed glutamate homeostasis and severe neonatal encephalopathy. We report a de novo Ser482Cys gain-of-function variant in GLS encoding GLS associated with profound developmental delay and infantile cataract. Functional analysis demonstrated that this variant causes hyperactivity and compensatory downregulation of GLS expression combined with upregulation of the counteracting enzyme GS, supporting pathogenicity. Ser482Cys-GLS likely improves the electrostatic environment of the GLS catalytic site, thereby intrinsically inducing hyperactivity. Alignment of +/−12.000 GLS protein sequences from >1000 genera revealed extreme conservation of Ser482 to the same degree as catalytic residues. Together with the hyperactivity, this indicates that Ser482 is evolutionarily preserved to achieve optimal—but submaximal—GLS activity. In line with GLS hyperactivity, increased glutamate and decreased glutamine concentrations were measured in urine and fibroblasts. In the brain (both grey and white matter), glutamate was also extremely high and glutamine was almost undetectable, demonstrated with magnetic resonance spectroscopic imaging at clinical field strength and subsequently supported at ultra-high field strength. Considering the neurotoxicity of glutamate when present in excess, the strikingly high glutamate concentrations measured in the brain provide an explanation for the developmental delay. Cataract, a known consequence of oxidative stress, was evoked in zebrafish expressing the hypermorphic Ser482Cys-GLS and could be alleviated by inhibition of GLS. The capacity to detoxify reactive oxygen species was reduced upon Ser482Cys-GLS expression, providing an explanation for cataract formation. In conclusion, we describe an inborn error of glutamate metabolism caused by a GLS hyperactivity variant, illustrating the importance of balanced GLS activity.
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Dinoi, Giorgia, Michael Morin, Elena Conte, et al. "Clinical and Functional Study of a De Novo Variant in the PVP Motif of Kv1.1 Channel Associated with Epilepsy, Developmental Delay and Ataxia." International Journal of Molecular Sciences 23, no. 15 (2022): 8079. http://dx.doi.org/10.3390/ijms23158079.
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Mutations in the KCNA1 gene, encoding the voltage-gated potassium channel Kv1.1, have been associated with a spectrum of neurological phenotypes, including episodic ataxia type 1 and developmental and epileptic encephalopathy. We have recently identified a de novo variant in KCNA1 in the highly conserved Pro-Val-Pro motif within the pore of the Kv1.1 channel in a girl affected by early onset epilepsy, ataxia and developmental delay. Other mutations causing severe epilepsy are located in Kv1.1 pore domain. The patient was initially treated with a combination of antiepileptic drugs with limited benefit. Finally, seizures and ataxia control were achieved with lacosamide and acetazolamide. The aim of this study was to functionally characterize Kv1.1 mutant channel to provide a genotype–phenotype correlation and discuss therapeutic options for KCNA1-related epilepsy. To this aim, we transfected HEK 293 cells with Kv1.1 or P403A cDNAs and recorded potassium currents through whole-cell patch-clamp. P403A channels showed smaller potassium currents, voltage-dependent activation shifted by +30 mV towards positive potentials and slower kinetics of activation compared with Kv1.1 wild-type. Heteromeric Kv1.1+P403A channels, resembling the condition of the heterozygous patient, confirmed a loss-of-function biophysical phenotype. Overall, the functional characterization of P403A channels correlates with the clinical symptoms of the patient and supports the observation that mutations associated with severe epileptic phenotype cluster in a highly conserved stretch of residues in Kv1.1 pore domain. This study also strengthens the beneficial effect of acetazolamide and sodium channel blockers in KCNA1 channelopathies.
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Boemer, François, Claire Josse, Géraldine Luis, et al. "Novel Loss of Function Variant in BCKDK Causes a Treatable Developmental and Epileptic Encephalopathy." International Journal of Molecular Sciences 23, no. 4 (2022): 2253. http://dx.doi.org/10.3390/ijms23042253.
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Branched-chain amino acids (BCAA) are essential amino acids playing crucial roles in protein synthesis and brain neurotransmission. Branched-chain ketoacid dehydrogenase (BCKDH), the flux-generating step of BCAA catabolism, is tightly regulated by reversible phosphorylation of its E1α-subunit. BCKDK is the kinase responsible for the phosphorylation-mediated inactivation of BCKDH. In three siblings with severe developmental delays, microcephaly, autism spectrum disorder and epileptic encephalopathy, we identified a new homozygous in-frame deletion (c.999_1001delCAC; p.Thr334del) of BCKDK. Plasma and cerebrospinal fluid concentrations of BCAA were markedly reduced. Hyperactivity of BCKDH and over-consumption of BCAA were demonstrated by functional tests in cells transfected with the mutant BCKDK. Treatment with pharmacological doses of BCAA allowed the restoring of BCAA concentrations and greatly improved seizure control. Behavioral and developmental skills of the patients improved to a lesser extent. Importantly, a retrospective review of the newborn screening results allowed the identification of a strong decrease in BCAA concentrations on dried blood spots, suggesting that BCKDK is a new treatable metabolic disorder probably amenable to newborn screening programs.
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Chen, Wenlin, Yang Ge, Jie Lu, et al. "Distinct Functional Alterations and Therapeutic Options of Two Pathological De Novo Variants of the T292 Residue of GABRA1 Identified in Children with Epileptic Encephalopathy and Neurodevelopmental Disorders." International Journal of Molecular Sciences 23, no. 5 (2022): 2723. http://dx.doi.org/10.3390/ijms23052723.
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Mutations of GABAAR have reportedly led to epileptic encephalopathy and neurodevelopmental disorders. We have identified a novel de novo T292S missense variant of GABRA1 from a pediatric patient with grievous global developmental delay but without obvious epileptic activity. This mutation coincidentally occurs at the same residue as that of a previously reported GABRA1 variant T292I identified from a pediatric patient with severe epilepsy. The distinct phenotypes of these two patients prompted us to compare the impacts of the two mutants on the receptor function and to search for suitable therapeutics. In this study, we used biochemical techniques and patch-clamp recordings in HEK293 cells overexpressing either wild-type or mutated rat recombinant GABAARs. We found that the α1T292S variant significantly increased GABA-evoked whole-cell currents, shifting the dose–response curve to the left without altering the maximal response. In contrast, the α1T292I variant significantly reduced GABA-evoked currents, shifting the dose–response curve to the right with a severely diminished maximum response. Single-channel recordings further revealed that the α1T292S variant increased, while the α1T292I variant decreased the GABAAR single-channel open time and open probability. Importantly, we found that the T292S mutation-induced increase in GABAAR function could be fully normalized by the negative GABAAR modulator thiocolchicoside, whereas the T292I mutation-induced impairment of GABAAR function was largely rescued with a combination of the GABAAR positive modulators diazepam and verapamil. Our study demonstrated that α1T292 is a critical residue for controlling GABAAR channel gating, and mutations at this residue may produce opposite impacts on the function of the receptors. Thus, the present work highlights the importance of functionally characterizing each individual GABAAR mutation for ensuring precision medicine.
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Sharma, Archana, Kavin Kirit Devani, and Dattatraya Muzumdar. "Anesthetic Management of West Syndrome for Functional Hemispherectomy." Journal of Pediatric Neurosciences 19, no. 3 (2024): 103–6. https://doi.org/10.4103/jpn.jpn_122_23.
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Abstract Infantile Spasms, first described by Dr. William West comprises of most severe, resistant, and disabling epileptic encephalopathy along with developmental delay, leaving the patient crippled. It often has a syndromic association warranting a thorough examination of the patient. Astute anesthetic care and vigilance for such a condition is a must for preventing collateral damage during their surgical management. A 3-year-old male, with developmental delay presents with 6–8 episodes of disabling myoclonic seizures with secondary generalization. The seizures are inadequately controlled despite six anti-epileptic medications in the maximum permissible dose and ACTH requiring surgical intervention. Several neck and peripheral joint contractures, associated cardiac and renal anomalies, multiple anti-epileptic medication-associated complications viz deranged liver functions, thrombocytopenia, drug metabolism, and ACTH-related complications impose a mammoth challenge in their peri-operative anesthesia management. It is meritorious to have a detailed understanding of this rare epileptic encephalopathy and an awareness of the bunch of other affiliated conditions to formulate a detailed peri-operative anesthesia management plan. This prevents any form of collateral peri-operative damage and can lead to better outcomes.
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von Spiczak, Sarah, Katherine L. Helbig, Deepali N. Shinde, et al. "DNM1 encephalopathy." Neurology 89, no. 4 (2017): 385–94. http://dx.doi.org/10.1212/wnl.0000000000004152.
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Objective:To evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling.Methods:We reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function.Results:We identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function.Conclusions:The phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention.
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Sega, Annalisa G., Emily K. Mis, Kristin Lindstrom, et al. "De novo pathogenic variants in neuronal differentiation factor 2 (NEUROD2) cause a form of early infantile epileptic encephalopathy." Journal of Medical Genetics 56, no. 2 (2018): 113–22. http://dx.doi.org/10.1136/jmedgenet-2018-105322.
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BackgroundEarly infantile epileptic encephalopathies are severe disorders consisting of early-onset refractory seizures accompanied often by significant developmental delay. The increasing availability of next-generation sequencing has facilitated the recognition of single gene mutations as an underlying aetiology of some forms of early infantile epileptic encephalopathies.ObjectivesThis study was designed to identify candidate genes as a potential cause of early infantile epileptic encephalopathy, and then to provide genetic and functional evidence supporting patient variants as causative.MethodsWe used whole exome sequencing to identify candidate genes. To model the disease and assess the functional effects of patient variants on candidate protein function, we used in vivo CRISPR/Cas9-mediated genome editing and protein overexpression in frog tadpoles.ResultsWe identified novel de novo variants in neuronal differentiation factor 2 (NEUROD2) in two unrelated children with early infantile epileptic encephalopathy. Depleting neurod2 with CRISPR/Cas9-mediated genome editing induced spontaneous seizures in tadpoles, mimicking the patients’ condition. Overexpression of wild-type NEUROD2 induced ectopic neurons in tadpoles; however, patient variants were markedly less effective, suggesting that both variants are dysfunctional and likely pathogenic.ConclusionThis study provides clinical and functional support for NEUROD2 variants as a cause of early infantile epileptic encephalopathy, the first evidence of human disease caused by NEUROD2 variants.
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Sun, Jia-Hui, Jiang Chen, Fernando Eduardo Ayala Valenzuela, et al. "X-linked neonatal-onset epileptic encephalopathy associated with a gain-of-function variant p.R660T in GRIA3." PLOS Genetics 17, no. 6 (2021): e1009608. http://dx.doi.org/10.1371/journal.pgen.1009608.
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The X-linked GRIA3 gene encodes the GLUA3 subunit of AMPA-type glutamate receptors. Pathogenic variants in this gene were previously reported in neurodevelopmental diseases, mostly in male patients but rarely in females. Here we report a de novo pathogenic missense variant in GRIA3 (c.1979G>C; p. R660T) identified in a 1-year-old female patient with severe epilepsy and global developmental delay. When exogenously expressed in human embryonic kidney (HEK) cells, GLUA3_R660T showed slower desensitization and deactivation kinetics compared to wildtype (wt) GLUA3 receptors. Substantial non-desensitized currents were observed with the mutant but not for wt GLUA3 with prolonged exposure to glutamate. When co-expressed with GLUA2, the decay kinetics were similarly slowed in GLUA2/A3_R660T with non-desensitized steady state currents. In cultured cerebellar granule neurons, miniature excitatory postsynaptic currents (mEPSCs) were significantly slower in R660T transfected cells than those expressing wt GLUA3. When overexpressed in hippocampal CA1 neurons by in utero electroporation, the evoked EPSCs and mEPSCs were slower in neurons expressing R660T mutant compared to those expressing wt GLUA3. Therefore our study provides functional evidence that a gain of function (GoF) variant in GRIA3 may cause epileptic encephalopathy and global developmental delay in a female subject by enhancing synaptic transmission.
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Silver, Grace, and Saadet Mercimek-Andrews. "Inherited Metabolic Disorders Presenting with Ataxia." International Journal of Molecular Sciences 21, no. 15 (2020): 5519. http://dx.doi.org/10.3390/ijms21155519.
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Ataxia is a common clinical feature in inherited metabolic disorders. There are more than 150 inherited metabolic disorders in patients presenting with ataxia in addition to global developmental delay, encephalopathy episodes, a history of developmental regression, coarse facial features, seizures, and other types of movement disorders. Seizures and a history of developmental regression especially are important clinical denominators to consider an underlying inherited metabolic disorder in a patient with ataxia. Some of the inherited metabolic disorders have disease specific treatments to improve outcomes or prevent early death. Early diagnosis and treatment affect positive neurodevelopmental outcomes, so it is important to think of inherited metabolic disorders in the differential diagnosis of ataxia.