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1.
Annu Int Conf IEEE Eng Med Biol Soc ; 2021: 194-197, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34891270

RESUMEN

Studies on intracranial electroencephalography (icEEG) recordings of patients with drug resistant epilepsy (DRE) show that epilepsy biomarkers propagate in time across brain areas. Here, we propose a novel method that estimates critical features of these propagations for different epilepsy biomarkers (spikes, ripples, and fast ripples), and assess their common onset as a reliable biomarker of the epileptogenic zone (EZ). For each biomarker, an automatic algorithm ranked the icEEG electrodes according to their timing occurrence in propagations and finally dichotomized them as onset or spread. We validated our algorithm on icEEG recordings of 8 children with DRE having a good surgical outcome (Engel score = 1). We estimated the overlap of the onset, spread, and entire zone of propagation with the resection (RZ) and the seizure onset zone (SOZ). Spike and ripple propagations were seen in all patients, whereas fast ripple propagations were seen in 6 patients. Spike, ripple, and fast ripple propagations had a mean duration of 28.3 ± 24.3 ms, 38.7 ± 37 ms, and 25 ± 14 ms respectively. Onset electrodes predicted the RZ and SOZ with higher specificity compared to the entire zone for all three biomarkers (p<0.05). Overlap of spike and ripple onsets presented a higher specificity than each separate biomarker onset: for the SOZ, the onsets overlap was more specific (97.89 ± 2.36) than the ripple onset (p=0.031); for the RZ, the onsets overlap was more specific (98.48 ± 1.5) than the spike onset (p=0.016). Yet, the entire zone for spike and ripple propagations predicted the RZ with higher sensitivity compared to each biomarker's onset (or spread) (p<0.05). We present, for the first time, preliminary evidence from icEEG data that fast ripples propagate in time across large areas of the brain. The onsets overlap of spike and ripple propagations constitutes an extremely specific (but not sensitive) biomarker of the EZ, compared to areas of spread (and entire areas) in propagation.

2.
Annu Int Conf IEEE Eng Med Biol Soc ; 2021: 382-385, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34891314

RESUMEN

There is growing evidence that seizures are accompanied by multi-system changes, not only in the brain but also in organs and systems under its control. Non-EEG measurements from these systems could be leveraged to improve seizure prediction, which is difficult but critical to the success of next-generation epilepsy therapies. Clinical electrophysiology studies during presurgical patient evaluations routinely collect continuous EEG but also ECG data that span multiple days. Prior work has reported electrocardiographic changes but has primarily focused on ventricular activity and brief peri-ictal intervals. Using novel data-driven classification and separation of the ECG high-dimensional signal space, this study investigated seizure-related changes in both ventricular and atrial activity. Measures of complexity as well as heart rate and R-R interval length were analyzed over time in continuous ECGs from 22 pediatric patients with pharmacoresistant seizures and no diagnosed cardiovascular anomalies. Fifteen patients (>68%) had significant changes in atrial or ventricular activity (or both) in intervals containing seizures. Thus, for a substantial number of patients, cardiac markers may be specifically modulated by seizures and could be leveraged to improve and personalize seizure prediction.

3.
Annu Int Conf IEEE Eng Med Biol Soc ; 2021: 408-411, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34891320

RESUMEN

Children with medically refractory epilepsy (MRE) require resective neurosurgery to achieve seizure freedom, whose success depends on accurate delineation of the epileptogenic zone (EZ). Functional connectivity (FC) can assess the extent of epileptic brain networks since intracranial EEG (icEEG) studies have shown its link to the EZ and predictive value for surgical outcome in these patients. Here, we propose a new noninvasive method based on magnetoencephalography (MEG) and high-density (HD-EEG) data that estimates FC metrics at the source level through an "implantation" of virtual sensors (VSs). We analyzed MEG, HD-EEG, and icEEG data from eight children with MRE who underwent surgery having good outcome and performed source localization (beamformer) on noninvasive data to build VSs at the icEEG electrode locations. We analyzed data with and without Interictal Epileptiform Discharges (IEDs) in different frequency bands, and computed the following FC matrices: Amplitude Envelope Correlation (AEC), Correlation (CORR), and Phase Locking Value (PLV). Each matrix was used to generate a graph using Minimum Spanning Tree (MST), and for each node (i.e., each sensor) we computed four centrality measures: betweenness, closeness, degree, and eigenvector. We tested the reliability of VSs measures with respect to icEEG (regarded as benchmark) via linear correlation, and compared FC values inside vs. outside resection. We observed higher FC inside than outside resection (p<0.05) for AEC [alpha (8-12 Hz), beta (12-30 Hz), and broadband (1-50 Hz)] on data with IEDs and AEC theta (4-8 Hz) on data without IEDs for icEEG, AEC broadband (1-50 Hz) on data without IEDs for MEG-VSs, as well as for all centrality measures of icEEG and MEG/HD-EEG-VSs. Additionally, icEEG and VSs metrics presented high correlation (0.6-0.9, p<0.05). Our data support the notion that the proposed method can potentially replicate the icEEG ability to map the epileptogenic network in children with MRE.Clinical Relevance - The estimation of FC with noninvasive techniques, such as MEG and HD-EEG, via VSs is a promising tool that would help the presurgical evaluation by delineating the EZ without waiting for a seizure to occur, and potentially improve the surgical outcome of patients with MRE undergoing surgery.

4.
Annu Int Conf IEEE Eng Med Biol Soc ; 2021: 2668-2671, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34891801

RESUMEN

Interictal epileptiform discharges (IEDs) serve as sensitive but not specific biomarkers of epilepsy that can delineate the epileptogenic zone (EZ) in patients with drug resistant epilepsy (DRE) undergoing surgery. Intracranial EEG (icEEG) studies have shown that IEDs propagate in time across large areas of the brain. The onset of this propagation is regarded as a more specific biomarker of epilepsy than areas of spread. Yet, the limited spatial resolution of icEEG does not allow to identify the onset of this activity with high precision. Here, we propose a new method of mapping the spatiotemporal propagation of IEDs (and identify its onset) by using Electrical Source Imaging (ESI) on icEEG bypassing the spatial limitations of icEEG. We validated our method on icEEG recordings from 8 children with DRE who underwent surgery with good outcome (Engel score =1). On each icEEG channel, we detected IEDs and identified the propagation onset using an automated algorithm. We localized the propagation of IEDs with dynamic Statistical Parametric Mapping (dSPM) using a time-sliding window approach. We defined two brain regions: the ESI-onset and ESI-spread zone. We estimated the overlap of these regions with resection volume (in percentage), which served as the gold-standard of the EZ. We also estimated the mean distance of these regions from resection and clinically defined seizure onset zone (SOZ). We observed spatio-temporal propagation of IEDs in all patients across several channels (98 [85-102]) with a mean duration of 155 ms [96-186 ms]. A higher overlap with resection was seen for the ESI-onset zone compared to spread (73.3 % [ 47.4-100 %], 36.5 % [20.3-59.9 %], p = 0.008). The distance of the ESI-onset from resection was shorter compared to the ESI-spread zone (4.3 mm [3.4-5.5 mm], 7.4 mm [6.0-20.6 mm], p = 0.008) and the same trend was observed for the distance from the SOZ (11.9 mm [7.2-15.1 mm], 20.6 mm [15.4-27.2 mm], p = 0.02). These findings show that our method can map the spatiotemporal propagation of IEDs and de-lineate its onset, which is a reliable and focal biomarker of the EZ in children with DRE.Clinical Relevance - ESI on icEEG recordings of children with DRE can localize the spikes propagation phenomenon and help in the delineation of the EZ.

6.
J Child Neurol ; : 8830738211015012, 2021 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-34809499

RESUMEN

OBJECTIVE: To describe quantitative EEG (electroencephalography) suppression ratio in children with increased intracranial pressure comparing acute suppression ratio changes to imaging and/or examination findings. METHODS: We retrospectively reviewed the suppression ratio from patients with neuroimaging and /or examination findings of increased intracranial pressure while on continuous EEG. The time of the first change in the suppression ratio was compared to the time of the first image and/or examination change confirming increased intracranial pressure. RESULTS: Thirteen patients with a median age of 3.1 years(interquartile range 1.8-6.3) had a rise in the suppression ratio with median time from identification to acute neuroimaging or examination of increased intracranial pressure of 3.12 hours (interquartile range 2.2-33.5) after the first increase in the suppression ratio. CONCLUSIONS: Acute suppression ratio increase is seen prior to imaging and/or examination findings of increased intracranial pressure. With further study, the suppression ratio can be targeted with intracranial pressure-lowering agents to prevent morbidity and mortality associated with increased intracranial pressure.

7.
Diagnostics (Basel) ; 11(7)2021 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-34359317

RESUMEN

About 30% of children with drug-resistant epilepsy (DRE) continue to have seizures after epilepsy surgery. Since epilepsy is increasingly conceptualized as a network disorder, understanding how brain regions interact may be critical for planning re-operation in these patients. We aimed to estimate functional brain connectivity using scalp EEG and its evolution over time in patients who had repeated surgery (RS-group, n = 9) and patients who had one successful surgery (seizure-free, SF-group, n = 12). We analyzed EEGs without epileptiform activity at varying time points (before and after each surgery). We estimated functional connectivity between cortical regions and their relative centrality within the network. We compared the pre- and post-surgical centrality of all the non-resected (untouched) regions (far or adjacent to resection) for each group (using the Wilcoxon signed rank test). In alpha, theta, and beta frequency bands, the post-surgical centrality of the untouched cortical regions increased in the SF group (p < 0.001) whereas they decreased (p < 0.05) or did not change (p > 0.05) in the RS group after failed surgeries; when re-operation was successful, the post-surgical centrality of far regions increased (p < 0.05). Our data suggest that removal of the epileptogenic focus in children with DRE leads to a gain in the network centrality of the untouched areas. In contrast, unaltered or decreased connectivity is seen when seizures persist after surgery.

8.
EMBO Mol Med ; 13(9): e14712, 2021 09 07.
Artículo en Inglés | MEDLINE | ID: mdl-34423905

RESUMEN

This commentary provides an overview of the putamen as an established target site for gene therapy in treating aromatic l-amino acid decarboxylase (AADC) deficiency and Parkinson's disease, two debilitating neurological disorders that involve motor dysfunction caused by dopamine deficiencies. The neuroanatomy and the function of the putamen in motor control provide good rationales for targeting this brain structure. Additionally, the efficacy and safety of intraputaminal gene therapy demonstrate that restoration of dopamine synthesis in the putamen by using low doses of adeno-associated viral vector serotype 2 to deliver the hAADC gene is well tolerated. This restoration leads to sustained improvements in motor and nonmotor symptoms of AADC deficiency and improved uptake and conversion of exogenous l-DOPA into dopamine in Parkinson's patients.


Asunto(s)
Carboxiliasas , Enfermedad de Parkinson , Descarboxilasas de Aminoácido-L-Aromático/genética , Descarboxilasas de Aminoácido-L-Aromático/metabolismo , Terapia Genética , Humanos , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/terapia , Putamen/metabolismo
9.
J Child Neurol ; 36(13-14): 1223-1230, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34463169

RESUMEN

Succinic semialdehyde dehydrogenase deficiency (SSADHD), a rare disorder of GABA metabolism, presents with significant neurodevelopmental morbidity. Although there is a growing interest in the concept of quality of life through patient reports as a meaningful outcome in rare disease clinical trials, little is known about the overall impact of SSADHD from the patient/family perspective. The purpose of this study was to determine issues related to quality of life and patient/family experience through a focus group discussion with family caregivers of patients with SSADHD. The discussion included the input of 5 family caregivers, and highlighted concerns related to physical function, cognitive and intellectual function, psychological and behavioral function, social function, and family impact. These themes represent appropriate starting points in the development of a quality-of-life survey that may serve as a meaningful clinical tool in future studies of SSADHD.

11.
J Child Neurol ; 36(13-14): 1169-1176, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34058900

RESUMEN

BACKGROUND: Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a disorder of GABA degradation with use-dependent downregulation of postsynaptic GABAA/B receptors. We aim to measure the resulting cortical excitation: inhibition ratio using transcranial magnetic stimulation. METHODS: In this single-center observational study, 18 subjects with SSADHD and 8 healthy controls underwent transcranial magnetic stimulation. Resting motor threshold, cortical silent period, and long-interval intracortical inhibition were measured in both groups. Resting motor threshold in focal epilepsy patients from an institutional transcranial magnetic stimulation database were also included. RESULTS: SSADHD subjects had higher resting motor threshold than healthy controls but lower relative to focal epilepsy patients. Resting motor threshold decreased with age in all groups. Cortical silent period was longer in SSADHD subjects than in healthy controls. No difference was detected in long-interval intracortical inhibition between the 2 groups. CONCLUSION: Findings suggest abnormal corticospinal tract physiology in SSADHD, but with preserved developmental trajectory for corticospinal tract maturation. Defining features of these transcranial magnetic stimulation metrics in SSADHD will be better elucidated through this ongoing longitudinal study.

12.
J Clin Neurophysiol ; 2021 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-34144575

RESUMEN

PURPOSE: We evaluated interictal discharges (IEDs) as a biomarker for the time to development of electrographic seizures (ES). METHODS: Prospective observational study of 254 critically ill children who underwent continuous electroencephalography (cEEG) monitoring. We excluded neonates and patients with known epilepsy or the sole cEEG indication to characterize events. Interictal discharges included sporadic epileptiform discharges and periodic and rhythmic patterns. Sporadic epileptiform discharges were categorized as low frequency (rare [<1/hour] and occasional [≥1/hour but <1/minute]) and high frequency (frequent, [≥1/minute] and abundant [≥1/10 seconds]). Time variables included time from cEEG start to first IED and time between first IED and ES. RESULTS: Interictal discharges were present in 33% (83/254) of patients. We identified ES in 20% (50/254), and 86% (43/50) had IEDs. High-frequency sporadic epileptiform discharges (odds ratio [OR], 35; 95% confidence interval [CI], 14.5-88; P < 0.0001) and lateralized periodic discharges (OR, 27; 95% CI, 7.3-100; P < 0.0001) were associated with ES. Mildly abnormal EEG background without IEDs or background asymmetry was associated with the absence of seizures (OR, 0.1; 95% CI, 0.04-0.3; P < 0.0001). Time from cEEG start to first IED was 36 minutes (interquartile range, 3-131 minutes), and time between first IED and ES was 9.6 minutes (interquartile range, 0.6-165 minutes). CONCLUSIONS: Interictal discharges are associated with ES and are identified in the first 3 hours of cEEG. High-frequency sporadic epileptiform discharges and periodic patterns have the highest risk of ES. Our findings define a window of high seizure risk after the identification of IEDs in which to allocate resources to improve seizure identification and subsequent treatment.

14.
Mol Genet Metab ; 2021 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-34183250

RESUMEN

Early-onset forms of hereditary spastic paraplegia and inborn errors of metabolism that present with spastic diplegia are among the most common "mimics" of cerebral palsy. Early detection of these heterogenous genetic disorders can inform genetic counseling, anticipatory guidance, and improve outcomes, particularly where specific treatments exist. The diagnosis relies on clinical pattern recognition, biochemical testing, neuroimaging, and increasingly next-generation sequencing-based molecular testing. In this short review, we summarize the clinical and molecular understanding of: 1) childhood-onset and complex forms of hereditary spastic paraplegia (SPG5, SPG7, SPG11, SPG15, SPG35, SPG47, SPG48, SPG50, SPG51, SPG52) and, 2) the most common inborn errors of metabolism that present with phenotypes that resemble hereditary spastic paraplegia.

15.
Clin Neurophysiol ; 132(7): 1622-1635, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34034087

RESUMEN

OBJECTIVE: To assess whether ictal electric source imaging (ESI) on low-density scalp EEG can approximate the seizure onset zone (SOZ) location and predict surgical outcome in children with refractory epilepsy undergoing surgery. METHODS: We examined 35 children with refractory epilepsy. We dichotomized surgical outcome into seizure- and non-seizure-free. We identified ictal onsets recorded with scalp and intracranial EEG and localized them using equivalent current dipoles and standardized low-resolution magnetic tomography (sLORETA). We estimated the localization accuracy of scalp EEG as distance of scalp dipoles from intracranial dipoles. We also calculated the distances of scalp dipoles from resection, as well as their resection percentage and compared between seizure-free and non-seizure-free patients. We built receiver operating characteristic curves to test whether resection percentage predicted outcome. RESULTS: Resection distance was lower in seizure-free patients for both dipoles (p = 0.006) and sLORETA (p = 0.04). Resection percentage predicted outcome with a sensitivity of 57.1% (95% CI, 34-78.2%), a specificity of 85.7% (95% CI, 57.2-98.2%) and an accuracy of 68.6% (95% CI, 50.7-83.5%) (p = 0.01). CONCLUSION: Ictal ESI performed on low-density scalp EEG can delineate the SOZ and predict outcome. SIGNIFICANCE: Such an application may increase the number of children who are referred for epilepsy surgery and improve their outcome.


Asunto(s)
Electroencefalografía/tendencias , Epilepsia/diagnóstico por imagen , Epilepsia/fisiopatología , Convulsiones/diagnóstico por imagen , Convulsiones/fisiopatología , Adolescente , Niño , Preescolar , Estudios de Cohortes , Epilepsia/cirugía , Femenino , Humanos , Imagen por Resonancia Magnética/tendencias , Masculino , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Convulsiones/cirugía , Tomografía Computarizada de Emisión de Fotón Único/tendencias , Resultado del Tratamiento , Adulto Joven
16.
J Child Neurol ; 36(13-14): 1189-1199, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34015244

RESUMEN

We examined safety, tolerability, and efficacy of SGS-742, a γ-aminobutyric acid B (GABA-B) receptor antagonist, in patients with succinic semialdehyde dehydrogenase deficiency. This was a single-center randomized, double-blind crossover phase II clinical trial of SGS-742 versus placebo in patients with succinic semialdehyde dehydrogenase deficiency. Procedures included transcranial magnetic stimulation and the Adaptive Behavior Assessment Scale. Nineteen subjects were consented and enrolled; the mean age was 14.0 ± 7.5 years and 11 (58%) were female. We did not find a significant effect of SGS-742 on the Adaptive Behavior Assessment Scale score, motor threshold, and paired-pulse stimulation. The difference in recruitment curve slopes between treatment groups was 0.003 (P = .09). There was no significant difference in incidence of adverse effects between drug and placebo arms. SGS-742 failed to produce improved cognition and normalization of cortical excitability as measured by the Adaptive Behavior Assessment Scale and transcranial magnetic stimulation. Our data do not support the current use of SGS-742 in succinic semialdehyde dehydrogenase deficiency.Trial registry number NCT02019667. Phase 2 Clinical Trial of SGS-742 Therapy in Succinic Semialdehyde Dehydrogenase Deficiency. https://clinicaltrials.gov/ct2/show/NCT02019667.

17.
Clin Neurophysiol ; 2021 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-33875376

RESUMEN

OBJECTIVE: To assess the utility of interictal magnetic and electric source imaging (MSI and ESI) using dipole clustering in magnetic resonance imaging (MRI)-negative patients with drug resistant epilepsy (DRE). METHODS: We localized spikes in low-density (LD-EEG) and high-density (HD-EEG) electroencephalography as well as magnetoencephalography (MEG) recordings using dipoles from 11 pediatric patients. We computed each dipole's level of clustering and used it to discriminate between clustered and scattered dipoles. For each dipole, we computed the distance from seizure onset zone (SOZ) and irritative zone (IZ) defined by intracranial EEG. Finally, we assessed whether dipoles proximity to resection was predictive of outcome. RESULTS: LD-EEG had lower clusterness compared to HD-EEG and MEG (p < 0.05). For all modalities, clustered dipoles showed higher proximity to SOZ and IZ than scattered (p < 0.001). Resection percentage was higher in optimal vs. suboptimal outcome patients (p < 0.001); their proximity to resection was correlated to outcome (p < 0.001). No difference in resection percentage was seen for scattered dipoles between groups. CONCLUSION: MSI and ESI dipole clustering helps to localize the SOZ and IZ and facilitate the prognostic assessment of MRI-negative patients with DRE. SIGNIFICANCE: Assessing the MSI and ESI clustering allows recognizing epileptogenic areas whose removal is associated with optimal outcome.

18.
J Child Neurol ; 36(13-14): 1210-1217, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-33757330

RESUMEN

This study reviews the fundamental roles of pre-supplementary motor area (SMA) and SMA-proper responsible for speech-motor functions and auditory perception in succinic semialdehyde dehydrogenase (SSADH) deficiency. We comprehensively searched the databases of PubMed, Google Scholar, and the electronic journals Springer, PreQuest, and Science Direct associated with keywords SSADHD, SMA, auditory perception, speech, and motor with AND operator. Transcranial magnetic stimulation emerged for assessing excitability/inhibitory M1 functions, but its role in pre-SMA and SMA proper dysfunction remains unknown. There was a lack of data on resting-state and task-based functional magnetic resonance imaging (MRI), with a focus on passive and active tasks for both speech and music, in terms of analysis of SMA-related cortex and its connections. Children with SSADH deficiency likely experience a dysfunction in connectivity between SMA portions with cortical and subcortical areas contributing to disabilities in speech-motor functions and auditory perception. Early diagnosis of auditory-motor disabilities in children with SSADH deficiency by neuroimaging techniques invites opportunities for utilizing sensory-motor integration as future interventional strategies.

19.
Ann Neurol ; 89(5): 911-925, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33710676

RESUMEN

OBJECTIVE: Intracranial electroencephalographic (icEEG) studies show that interictal ripples propagate across the brain of children with medically refractory epilepsy (MRE), and the onset of this propagation (ripple onset zone [ROZ]) estimates the epileptogenic zone. It is still unknown whether we can map this propagation noninvasively. The goal of this study is to map ripples (ripple zone [RZ]) and their propagation onset (ROZ) using high-density EEG (HD-EEG) and magnetoencephalography (MEG), and to estimate their prognostic value in pediatric epilepsy surgery. METHODS: We retrospectively analyzed simultaneous HD-EEG and MEG data from 28 children with MRE who underwent icEEG and epilepsy surgery. Using electric and magnetic source imaging, we estimated virtual sensors (VSs) at brain locations that matched the icEEG implantation. We detected ripples on VSs, defined the virtual RZ and virtual ROZ, and estimated their distance from icEEG. We assessed the predictive value of resecting virtual RZ and virtual ROZ for postsurgical outcome. Interictal spike localization on HD-EEG and MEG was also performed and compared with ripples. RESULTS: We mapped ripple propagation in all patients with HD-EEG and in 27 (96%) patients with MEG. The distance from icEEG did not differ between HD-EEG and MEG when mapping the RZ (26-27mm, p = 0.6) or ROZ (22-24mm, p = 0.4). Resecting the virtual ROZ, but not virtual RZ or the sources of spikes, was associated with good outcome for HD-EEG (p = 0.016) and MEG (p = 0.047). INTERPRETATION: HD-EEG and MEG can map interictal ripples and their propagation onset (virtual ROZ). Noninvasively mapping the ripple onset may augment epilepsy surgery planning and improve surgical outcome of children with MRE. ANN NEUROL 2021;89:911-925.


Asunto(s)
Mapeo Encefálico/métodos , Epilepsia Refractaria/diagnóstico por imagen , Epilepsia Refractaria/cirugía , Electrocorticografía/métodos , Adolescente , Niño , Preescolar , Femenino , Humanos , Magnetoencefalografía , Masculino , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Resultado del Tratamiento
20.
J Child Neurol ; 36(13-14): 1200-1209, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-33624531

RESUMEN

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare inborn metabolic disorder caused by the functional impairment of SSADH (encoded by the ALDH5A1 gene), an enzyme essential for metabolism of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). In SSADHD, pathologic accumulation of GABA and its metabolite γ-hydroxybutyrate (GHB) results in broad spectrum encephalopathy including developmental delay, ataxia, seizures, and a heightened risk of sudden unexpected death in epilepsy (SUDEP). Proof-of-concept systemic SSADH restoration via enzyme replacement therapy increased survival of SSADH knockout mice, suggesting that SSADH restoration might be a viable intervention for SSADHD. However, before testing enzyme replacement therapy or gene therapy in patients, we must consider its safety and feasibility in the context of early brain development and unique SSADHD pathophysiology. Specifically, a profound use-dependent downregulation of GABAA receptors in SSADHD indicates a risk that any sudden SSADH restoration might diminish GABAergic tone and provoke seizures. In addition, the tight developmental regulation of GABA circuit plasticity might limit the age window when SSADH restoration is accomplished safely. Moreover, given SSADH expressions are cell type-specific, targeted instead of global restoration might be necessary. We therefore describe 3 key parameters for the clinical readiness of SSADH restoration: (1) rate, (2) timing, and (3) cell type specificity. Our work focuses on the construction of a novel SSADHD mouse model that allows "on-demand" SSADH restoration for the systematic investigation of these key parameters. We aim to understand the impacts of specific SSADH restoration protocols on brain physiology, accelerating bench-to-bedside development of enzyme replacement therapy or gene therapy for SSADHD patients.

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