Glycaemic Imbalances in Seizures and Epilepsy of Paediatric Age: A Literature Review

Bartolini, Emanuele; Ferrari, Anna Rita; Fiori, Simona; Vecchia, Stefania Della

doi:10.3390/jcm12072580

Cited by 10 publications

(5 citation statements)

References 160 publications

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“…It is also important to consider the impact that all these metabolic disturbances might have on the behavioural phenotypes and the occurrence of seizures found in Fus Δ14/Δ14 mice (both sexes). Seizures are observed in over 200 different metabolic diseases ( Rahman et al, 2013 ; Almannai et al, 2021 ), by multiple mechanisms, including neurotransmission alterations and energy deficiency and hypoglycaemia ( Bartolini et al, 2023 ). Cognition and behavioural alterations are also known to be greatly influenced by metabolic alterations ( Tanaka et al, 2020 ; Morys et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Mutation in the FUS nuclear localisation signal domain causes neurodevelopmental and systemic metabolic alterations

Ali,

Godoy-Corchuelo,

Martins-Bach

et al. 2023

Disease Models &Amp; Mechanisms

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Mutations in the ubiquitously expressed DNA/RNA binding protein FUS cause aggressive juvenile forms of amyotrophic lateral sclerosis (ALS). While most FUS mutation studies have focused on motor neuron degeneration, little is known about wider systemic or developmental effects. We studied pleiotropic phenotypes in a physiological knock-in mouse model carrying the pathogenic FUSDelta14 mutation in homozygosity. RNA sequencing of multiple organs aimed to identify pathways altered by the mutant protein in the systemic transcriptome, including metabolic tissues given the link between ALS-FTD and altered metabolism. Few genes were commonly altered across all tissues, and most genes and pathways affected were generally tissue-specific. Phenotypic assessment of mice revealed systemic metabolic alterations related to the pathway changes identified. MRI brain scans and histological characterisation revealed that homozygous FUSDelta14 brains were smaller and displayed significant morphological alterations including a thinner cortex, reduced neuronal number and increased gliosis, which correlated with early cognitive impairment and fatal seizures. We show that the disease aetiology of FUS mutations can include both neurodevelopmental and systemic alterations.

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Section: Discussionmentioning

confidence: 99%

Mutation in the FUS nuclear localisation signal domain causes neurodevelopmental and systemic metabolic alterations

Ali,

Godoy-Corchuelo,

Martins-Bach

et al. 2023

Disease Models &Amp; Mechanisms

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“…Since recent studies have shown significant differences in the abundance of amino acids in different anatomical regions of the brain [36], we anticipate that transient fluctuations in specific amino acids may sensitize people with GATOR1 mutations to seizures at the variable foci associated with GATOR1-dependent familial focal epilepsies (FFEVFs) [1,34]. Neurologically, these deficiencies may occur at discrete times when nutrients are limited, which may provide a rationale for the association of GATOR1 with nocturnal seizures [34,37,38], similar to seizures caused by poor glycemic control in diabetes [39]. Other processes downstream of mTORC1 signaling could further exacerbate cellular defects, at least in part due to a deficiency in TFEB-dependent gene expression and lysosomal function [25,40].…”

Section: Discussionmentioning

confidence: 99%

GATOR1 Mutations Impair PI3 Kinase-Dependent Growth Factor Signaling Regulation of mTORC1

Muller,

Bélanger,

Hadj-Aissa

et al. 2024

IJMS

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GATOR1 (GAP Activity TOward Rag 1) is an evolutionarily conserved GTPase-activating protein complex that controls the activity of mTORC1 (mammalian Target Of Rapamycin Complex 1) in response to amino acid availability in cells. Genetic mutations in the GATOR1 subunits, NPRL2 (nitrogen permease regulator-like 2), NPRL3 (nitrogen permease regulator-like 3), and DEPDC5 (DEP domain containing 5), have been associated with epilepsy in humans; however, the specific effects of these mutations on GATOR1 function and mTORC1 regulation are not well understood. Herein, we report that epilepsy-linked mutations in the NPRL2 subunit of GATOR1, NPRL2-L105P, -T110S, and -D214H, increase basal mTORC1 signal transduction in cells. Notably, we show that NPRL2-L105P is a loss-of-function mutation that disrupts protein interactions with NPRL3 and DEPDC5, impairing GATOR1 complex assembly and resulting in high mTORC1 activity even under conditions of amino acid deprivation. Furthermore, our studies reveal that the GATOR1 complex is necessary for the rapid and robust inhibition of mTORC1 in response to growth factor withdrawal or pharmacological inhibition of phosphatidylinositol-3 kinase (PI3K). In the absence of the GATOR1 complex, cells are refractory to PI3K-dependent inhibition of mTORC1, permitting sustained translation and restricting the nuclear localization of TFEB, a transcription factor regulated by mTORC1. Collectively, our results show that epilepsy-linked mutations in NPRL2 can block GATOR1 complex assembly and restrict the appropriate regulation of mTORC1 by canonical PI3K-dependent growth factor signaling in the presence or absence of amino acids.

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“… 15 One of the hypotheses in humans is that acute hypoglycemia affects high metabolic‐demand brain sites, such as the mesial temporal lobe and the peri‐rolandic cortex, and it triggers motor presentations of seizures. 16 Although the appearance of hypoglycemic symptoms also depends on the glucose concentration, the threshold for glucose levels associated with seizures is unclear. 15 Our current study showed no difference in the initial glucose levels between patients with and without seizures.…”

Section: Discussionmentioning

confidence: 99%

Seizure occurrences among hypoglycemic patients in the emergency department

Urushidani,

Tanabe,

Baek

et al. 2024

Acute Medicine & Surgery

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AimSymptomatic hypoglycemia is a common problem in the emergency department (ED). However, without appropriate recognition and management, hypoglycemia remains a potentially fatal condition. The cause of sudden death associated with hypoglycemia might be attributed to cardiac arrhythmias and hypoxia with seizures. Despite advances in diabetes mellitus management and social background, the frequency and characteristics of patients with hypoglycemia‐related seizures have remained unknown. Hence, our study aimed to investigate the frequency and characteristics of patients with hypoglycemia presenting with seizures in the ED.MethodsThis retrospective observational study was conducted in a single tertiary care center. Patient information was retrieved from the final diagnostic records in the ED. We reviewed all medical records and included patients with symptomatic hypoglycemia aged 16 years or older. The primary outcome was the frequency of seizures in patients with hypoglycemia. We also compared the initial blood sugar levels of the patients with and without seizures.ResultsWe included a total of 380 patients (median age, 72 years, IQR 64–80 years; median initial blood sugar, 34 mg/dL, IQR 24–46; 62.9% male). Nineteen of 380 patients (5.0%) had seizures. Although 16 of the 19 patients had diabetes mellitus, none of the 19 patients had a history of epilepsy. The initial blood sugar levels of the patients with and without seizures were not significantly different (p = 0.97).ConclusionApproximately 5% of the patients with hypoglycemia presented with seizures. Blood glucose levels of hypoglycemic patients with and without seizures did not differ.

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Glycaemic Imbalances in Seizures and Epilepsy of Paediatric Age: A Literature Review

Cited by 10 publications

References 160 publications

Mutation in the FUS nuclear localisation signal domain causes neurodevelopmental and systemic metabolic alterations

Mutation in the FUS nuclear localisation signal domain causes neurodevelopmental and systemic metabolic alterations

GATOR1 Mutations Impair PI3 Kinase-Dependent Growth Factor Signaling Regulation of mTORC1

Seizure occurrences among hypoglycemic patients in the emergency department

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