Evolution of Brain Glucose Metabolic Abnormalities in Children With Epilepsy and <i>SCN1A</i> Gene Variants

Kumar, Ananyaa; Juhász, Csaba; Luat, Aimee F.; Govil-Dalela, Tuhina; Behen, Michael E.; Hicks, Melissa A.; Chugani, Harry T.

doi:10.1177/0883073818796373

Cited by 10 publications

(5 citation statements)

References 25 publications

(29 reference statements)

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“…Finally, we report for the first time an FDG-PET study in a DS murine model, which could be an indirect, but clinically relevant marker for brain function in this disease. In contrast with the pioneering reports in DS patients 28,29 , we found an increase in glucose uptake in different brain structures. This is not surprising, taking into account the unbalanced excitatory activity resulting from the insufficient Scn1a function.…”

Section: Discussioncontrasting

confidence: 99%

“…It has been recently described that DS patients develop abnormal brain glucose uptake starting at 6 years of age 28,29 . In particular, reduced glucose uptake was reported in the fronto-temporo-parietal cortices.…”

Section: Resultsmentioning

confidence: 99%

“…took cerebellum as a reference 28 , whereas Kumar et al . used basal ganglia 29 . Our data indicate that both brain regions have elevated uptake positron emission, which complicates the interpretation of results.…”

Section: Discussionmentioning

confidence: 99%

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Epilepsy and neuropsychiatric comorbidities in mice carrying a recurrent Dravet syndrome SCN1A missense mutation

Ricobaraza

Mora-Jimenez

Puerta

et al. 2019

Sci Rep

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Dravet Syndrome (DS) is an encephalopathy with epilepsy associated with multiple neuropsychiatric comorbidities. In up to 90% of cases, it is caused by functional happloinsufficiency of the SCN1A gene, which encodes the alpha subunit of a voltage-dependent sodium channel (Nav1.1). Preclinical development of new targeted therapies requires accessible animal models which recapitulate the disease at the genetic and clinical levels. Here we describe that a C57BL/6 J knock-in mouse strain carrying a heterozygous, clinically relevant SCN1A mutation (A1783V) presents a full spectrum of DS manifestations. This includes 70% mortality rate during the first 8 weeks of age, reduced threshold for heat-induced seizures (4.7 °C lower compared with control littermates), cognitive impairment, motor disturbances, anxiety, hyperactive behavior and defects in the interaction with the environment. In contrast, sociability was relatively preserved. Electrophysiological studies showed spontaneous interictal epileptiform discharges, which increased in a temperature-dependent manner. Seizures were multifocal, with different origins within and across individuals. They showed intra/inter-hemispheric propagation and often resulted in generalized tonic-clonic seizures. 18F-labelled flourodeoxyglucose positron emission tomography (FDG-PET) revealed a global increase in glucose uptake in the brain of Scn1aWT/A1783V mice. We conclude that the Scn1aWT/A1783V model is a robust research platform for the evaluation of new therapies against DS.

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Section: Discussioncontrasting

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Epilepsy and neuropsychiatric comorbidities in mice carrying a recurrent Dravet syndrome SCN1A missense mutation

Ricobaraza

Mora-Jimenez

Puerta

et al. 2019

Sci Rep

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“…Therapeutic success of the KD provides indirect evidence that the metabolic and bioenergetics state might be altered in patients with Dravet syndrome, rendering it a valuable target for therapeutic intervention. Further evidence for changes in brain bioenergetics came from a limited number of 18 F‐labeled fluorodeoxyglucose positron emission tomography (FDG‐PET) studies reporting alterations in glucose uptake in a Dravet mouse model and in patients with Dravet syndrome 15‐17 …”

Section: Introductionmentioning

confidence: 99%

Metabolomic signature of the Dravet syndrome: A genetic mouse model study

et al. 2021

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Objective Alterations in metabolic homeostasis can contribute to neuronal hyperexcitability and seizure susceptibility. Although the pivotal role of impaired bioenergetics is obvious in metabolic epilepsies, there is a gap of knowledge regarding secondary changes in metabolite patterns as a result of genetic Scn1a deficiency and ketogenic diet in the Dravet syndrome. Methods A comprehensive untargeted metabolomics analysis, along with assessment of epileptiform activity and behavioral tests, was completed in a Dravet mouse model. Data sets were compared between animals on a control and a ketogenic diet, and metabolic alterations associated with Dravet mice phenotype and ketogenic diet were identified. Results Hippocampal metabolomic data revealed complex alterations in energy metabolism with an effect of the genotype on concentrations of glucose and several glycolysis and tricarboxylic acid (TCA) cycle intermediates. Although low glucose, lactate, malate, and citrate concentrations became evident, the increase of several intermediates suggested a genotype‐associated activation of catabolic processes with enhanced glycogenolysis and glycolysis. Moreover, we observed an impact on the glutamate/γ‐aminobutyric acid (GABA)‐glutamine cycle with reduced levels of all components along with a shift toward an increased GABA‐to‐glutamate ratio. Further alterations comprised a reduction in hippocampal levels of noradrenaline, corticosterone, and of two bile acids. Significance Considering that energy depletion can predominantly compromise the function of GABAergic interneurons, the changes in energy metabolism may contribute to seizure susceptibility and ictogenesis. They may also explain the therapeutic potential of the ketogenic diet, which aims to shift energy metabolism toward a more fat‐based energy supply. Conversely, the increased GABA‐to‐glutamate ratio might serve as an endogenous compensatory mechanism, which can be further supported by GABAergic drugs, representing the mainstay of therapeutic management of Dravet syndrome. In view of a possible neuroprotective function of bile acids, it might be of interest to explore a possible therapeutic potential of bile acid–mediated therapies, already in discussion for neurodegenerative disorders.

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“…The observed metabolic abnormalities may be characteristic of the SCN1A variant itself and may serve as a useful imaging biomarker to monitor disease progression and evaluate response to treatments being developed for SCN1A gene variants in the future. 32 Specifically, the option of palliative surgery including vagus nerve stimulation (VNS) treatment has been explored. Response to these treatment modalities has been mixed, but a recent meta-analysis of 13 case studies published in the literature reported that 53% of 68 patients with DS experienced at least 50% seizure reduction.…”

Section: Clinical Presentationmentioning

confidence: 99%

SCN1A and Its Related Epileptic Phenotypes

Sullo

Pasquetti

Patanè

et al. 2021

Journal of Pediatric Neurology

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Epilepsy is one of the most common neurological disorders, with a lifetime incidence of 1 in 26. Approximately two-thirds of epilepsy has a substantial genetic component in its etiology. As a result, simultaneous screening for mutations in multiple genes and performing whole exome sequencing (WES) are becoming very frequent in the clinical evaluation of children with epilepsy. In this setting, mutations in voltage-gated sodium channel (SCN) α-subunit genes are the most commonly identified cause of epilepsy, with sodium channel genes (i.e., SCN1A, SCN2A, SCN8A) being the most frequently identified causative genes. SCN1A mutations result in a wide spectrum of epilepsy phenotypes ranging from simple febrile seizures to Dravet syndrome, a severe epileptic encephalopathy. In case of mutation of SCN1A, it is also possible to observe behavioral alterations, such as impulsivity, inattentiveness, and distractibility, which can be framed in an attention deficit hyperactivity disorder (ADHD) like phenotype. Despite more than 1,200 SCN1A mutations being reported, it is not possible to assess a clear phenotype–genotype correlations. Treatment remains a challenge and seizure control is often partial and transitory.

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Evolution of Brain Glucose Metabolic Abnormalities in Children With Epilepsy and SCN1A Gene Variants

Cited by 10 publications

References 25 publications

Epilepsy and neuropsychiatric comorbidities in mice carrying a recurrent Dravet syndrome SCN1A missense mutation

Epilepsy and neuropsychiatric comorbidities in mice carrying a recurrent Dravet syndrome SCN1A missense mutation

Metabolomic signature of the Dravet syndrome: A genetic mouse model study

SCN1A and Its Related Epileptic Phenotypes

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