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1.
Mov Disord ; 39(2): 400-410, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38314870

RESUMO

BACKGROUND: Congenital mirror movements (CMM) is a rare neurodevelopmental disorder characterized by involuntary movements from one side of the body that mirror voluntary movements on the opposite side. To date, five genes have been associated with CMM, namely DCC, RAD51, NTN1, ARHGEF7, and DNAL4. OBJECTIVE: The aim of this study is to characterize the genetic landscape of CMM in a large group of 80 affected individuals. METHODS: We screened 80 individuals with CMM from 43 families for pathogenic variants in CMM genes. In large CMM families, we tested for presence of pathogenic variants in multiple affected and unaffected individuals. In addition, we evaluated the impact of three missense DCC variants on binding between DCC and Netrin-1 in vitro. RESULTS: Causal pathogenic/likely pathogenic variants were found in 35% of probands overall, and 70% with familial CMM. The most common causal gene was DCC, responsible for 28% of CMM probands and 80% of solved cases. RAD51, NTN1, and ARHGEF7 were rare causes of CMM, responsible for 2% each. Penetrance of CMM in DCC pathogenic variant carriers was 68% and higher in males than females (74% vs. 54%). The three tested missense variants (p.Ile164Thr; p.Asn176Ser; and p.Arg1343His) bind Netrin-1 similarly to wild type DCC. CONCLUSIONS: A genetic etiology can be identified in one third of CMM individuals, with DCC being the most common gene involved. Two thirds of CMM individuals were unsolved, highlighting that CMM is genetically heterogeneous and other CMM genes are yet to be discovered. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Discinesias , Transtornos dos Movimentos , Masculino , Feminino , Humanos , Netrina-1/genética , Receptor DCC/genética , Transtornos dos Movimentos/genética , Mutação de Sentido Incorreto/genética , Fatores de Troca de Nucleotídeo Guanina Rho/genética
2.
Brain ; 146(3): 873-879, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36256600

RESUMO

Memantine is an N-methyl-D-aspartate receptor antagonist, approved for dementia treatment. There is limited evidence of memantine showing benefit for paediatric neurodevelopmental phenotypes, but no randomized placebo-controlled trials in children with developmental and epileptic encephalopathy. In this randomized double-blind placebo-controlled crossover trial (Trial registration: https://clinicaltrials.gov/ct2/show/NCT03779672), patients with developmental and epileptic encephalopathy received memantine and placebo, each for a 6-week period separated by a 2-week washout phase. Electroencephalography, seizure diary, patient caregivers' global impression, serum inflammatory markers and neuropsychological evaluation were performed at baseline and after each treatment phase. The primary outcome measure was classification as a 'responder', defined as ≥2 of: >50% seizure frequency reduction, electroencephalography improvement, caregiver clinical impression improvement or clear neuropsychological testing improvement. Thirty-one patients (13 females) enrolled. Two patients withdrew prior to initiating medication and two (twins) had to be removed from analysis. Of the remaining 27 patients, nine (33%) were classified as responders to memantine versus two (7%) in the placebo group (P < 0.02). Electroencephalography improvement was seen in eight patients on memantine compared to two on placebo (P < 0.04). Seizure improvement was observed in eight patients on memantine and two on placebo (P < 0.04). Caregivers reported overall clinical improvement in 10 patients on memantine compared to seven on placebo (not significant). Statistical analysis of neuropsychological evaluation suggested improvements in symptoms of attention-deficit hyperactivity disorder and autism. Memantine is a safe and effective treatment for children with developmental and epileptic encephalopathy, having the potential to improve both seizure control and cognitive function.


Assuntos
Epilepsia Generalizada , Memantina , Feminino , Humanos , Memantina/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Estudos Cross-Over , Resultado do Tratamento , Convulsões/tratamento farmacológico , Epilepsia Generalizada/tratamento farmacológico , Método Duplo-Cego
3.
Ann Neurol ; 89(3): 485-497, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33236446

RESUMO

OBJECTIVE: The study was undertaken to identify a monogenic cause of early onset, generalized dystonia. METHODS: Methods consisted of genome-wide linkage analysis, exome and Sanger sequencing, clinical neurological examination, brain magnetic resonance imaging, and protein expression studies in skin fibroblasts from patients. RESULTS: We identified a heterozygous variant, c.388G>A, p.Gly130Arg, in the eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2) gene, segregating with early onset isolated generalized dystonia in 5 patients of a Taiwanese family. EIF2AK2 sequencing in 191 unrelated patients with unexplained dystonia yielded 2 unrelated Caucasian patients with an identical heterozygous c.388G>A, p.Gly130Arg variant, occurring de novo in one case, another patient carrying a different heterozygous variant, c.413G>C, p.Gly138Ala, and one last patient, born from consanguineous parents, carrying a third, homozygous variant c.95A>C, p.Asn32Thr. These 3 missense variants are absent from gnomAD, and are located in functional domains of the encoded protein. In 3 patients, additional neurological manifestations were present, including intellectual disability and spasticity. EIF2AK2 encodes a kinase (protein kinase R [PKR]) that phosphorylates eukaryotic translation initiation factor 2 alpha (eIF2α), which orchestrates the cellular stress response. Our expression studies showed abnormally enhanced activation of the cellular stress response, monitored by PKR-mediated phosphorylation of eIF2α, in fibroblasts from patients with EIF2AK2 variants. Intriguingly, PKR can also be regulated by PRKRA (protein interferon-inducible double-stranded RNA-dependent protein kinase activator A), the product of another gene causing monogenic dystonia. INTERPRETATION: We identified EIF2AK2 variants implicated in early onset generalized dystonia, which can be dominantly or recessively inherited, or occur de novo. Our findings provide direct evidence for a key role of a dysfunctional eIF2α pathway in the pathogenesis of dystonia. ANN NEUROL 2021;89:485-497.


Assuntos
Distúrbios Distônicos/genética , Fibroblastos/metabolismo , eIF-2 Quinase/genética , Adolescente , Adulto , Idade de Início , Povo Asiático , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Distúrbios Distônicos/metabolismo , Distúrbios Distônicos/fisiopatologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Linhagem , População Branca , Sequenciamento do Exoma , Adulto Jovem , eIF-2 Quinase/metabolismo
4.
Epilepsia ; 63(9): 2350-2358, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35759339

RESUMO

OBJECTIVE: Hormonal therapy is a standard treatment for children with infantile spasms. However, the high doses given and long treatment duration expose patients to the risk of adrenal insufficiency (AI). This study aims to quantify the cumulative incidence of AI among children with infantile spasms treated with high-dose corticosteroids and/or adrenocorticotropic hormone. METHODS: A retrospective chart review of patients treated for infantile spasms was performed between January 2009 and March 2020 in one pediatric specialized hospital. Variables collected include patient and treatment characteristics, risk factors of AI, and adrenal function testing. Analysis included descriptive statistics such as incidence and bivariate analysis. RESULTS: Thirty-one patients were included and received a total of 33 courses of treatment (17 corticosteroids [prednisone/prednisolone], 12 adrenocorticotropic hormone, and four combined). Physiologic hydrocortisone replacement therapy with stress supplementation was received after 32 of 33 (97%) courses of treatment. Adrenal function was assessed in 32 of 33 (97%) and AI occurred in 25 of 33 (76%, 95% confidence interval = 58-89). No predictive factor of AI was identified after hormonal treatment. No drug regimen was found to be safe. The two patients who developed an acute adrenal crisis presented to the emergency room within the days (between 2 and 7) following weaning off of hormonal treatment. They were the youngest children of the cohort, and both received prednisolone. SIGNIFICANCE: Adrenal insufficiency is frequent and can potentially lead to an adrenal crisis in this population. This study highlights the necessity of hydrocortisone replacement therapy until AI has been excluded in a patient who has received hormonal therapy to treat infantile spasms. As such, routine laboratory assessment of adrenal function should be done in all patients.


Assuntos
Insuficiência Adrenal , Espasmos Infantis , Corticosteroides/uso terapêutico , Insuficiência Adrenal/induzido quimicamente , Insuficiência Adrenal/tratamento farmacológico , Insuficiência Adrenal/epidemiologia , Hormônio Adrenocorticotrópico/uso terapêutico , Criança , Humanos , Hidrocortisona , Lactente , Prednisolona/uso terapêutico , Prednisona/uso terapêutico , Estudos Retrospectivos , Espasmos Infantis/induzido quimicamente , Espasmos Infantis/tratamento farmacológico
5.
Front Hum Neurosci ; 17: 1253529, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37964801

RESUMO

Introduction: Pediatric frontal and temporal lobe epilepsies (FLE, TLE) have been associated with language impairments and structural and functional brain alterations. However, there is no clear consensus regarding the specific patterns of cerebral reorganization of language networks in these patients. The current study aims at characterizing the cerebral language networks in children with FLE or TLE, and the association between brain network characteristics and cognitive abilities. Methods: Twenty (20) children with FLE or TLE aged between 6 and 18 years and 29 age- and sex-matched healthy controls underwent a neuropsychological evaluation and a simultaneous functional near-infrared spectroscopy and electroencephalography (fNIRS-EEG) recording at rest and during a receptive language task. EEG was used to identify potential subclinical seizures in patients. We removed these time intervals from the fNIRS signal to investigate language brain networks and not epileptogenic networks. Functional connectivity matrices on fNIRS oxy-hemoglobin concentration changes were computed using cross-correlations between all channels. Results and discussion: Group comparisons of residual matrices (=individual task-based matrix minus individual resting-state matrix) revealed significantly reduced connectivity within the left and between hemispheres, increased connectivity within the right hemisphere and higher right hemispheric local efficiency for the epilepsy group compared to the control group. The epilepsy group had significantly lower cognitive performance in all domains compared to their healthy peers. Epilepsy patients' local network efficiency in the left hemisphere was negatively associated with the estimated IQ (p = 0.014), suggesting that brain reorganization in response to FLE and TLE does not allow for an optimal cognitive development.

6.
J Child Neurol ; 38(5): 329-335, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-37225698

RESUMO

Parents of children with genetically determined leukoencephalopathies play a major role in their children's health care. We sought to gain a better understanding of their experience with the public health care system in Quebec, Canada, to obtain suggestions for improving their services, and to identify modifiable factors to improve their quality of life. We conducted interviews with 13 parents. Data was analyzed thematically. Five themes were identified: challenges of the diagnostic odyssey, limited access to services, excessive parental responsibilities, positive relationships with health care professionals as a facilitator of care, and benefits of a specialized leukodystrophy clinic. Parents felt like waiting for the diagnosis was extremely stressful, and they expressed their need for transparency during this period. They identified multiple gaps and barriers in the health care system, which burdened them with many responsibilities. Parents emphasized the importance of a positive relationship with their child's health care professionals. They also felt grateful for being followed at a specialized clinic as it improved the quality of care received.


Assuntos
Pais , Qualidade de Vida , Criança , Humanos , Atenção à Saúde , Canadá , Quebeque
7.
Front Neurol ; 13: 913652, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36324377

RESUMO

PLPHP (pyridoxal-phosphate homeostasis protein) deficiency is caused by biallelic pathogenic variants in PLPBP and is a rare cause of pyridoxine-responsive disorders. We describe three French-Canadian individuals with PLPHP deficiency, including one with unusual paroxysmal episodes lacking EEG correlation with a suspicious movement disorder, rarely reported in B6RDs. In addition, we review the clinical features and treatment responses of all 51 previously published individuals with PLPHP deficiency. Our case series underlines the importance of considering PLPBP mutations in individuals with partially B6-responsive seizures and highlights the presence of a founder effect in the French-Canadian population.

8.
Epileptic Disord ; 24(6): 1087-1094, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36190316

RESUMO

Objective: We aimed to clarify the pathophysiology of epilepsy involving seizures with apparently generalized onset, progressing to focal ictal rhythm through stereotactic EEG (SEEG) implantation, recording, stimulation and high-frequency oscillation (HFO) analysis. Methods: We identified two patients with seizures with bilateral electrographic onset evolving to focal ictal rhythm, who underwent SEEG implantation. Patients had pre-surgical epilepsy work-up, including prolonged video scalp EEG, brain MRI, PET, ictal/interictal SPECT, MEG, and EEG-fMRI prior to SEEG implantation. Results: Both patients had childhood-onset seizures involving behavioural arrest and left versive head and eye deviation, evolving to bilateral tonic-clonic convulsions. Seizures were electrographically preceded by diffuse, bilateral 3-Hz activity resembling absence seizures. Both had suspected focal lesions based on neuroimaging, including 3T MRI and voxel-based post-processing in one patient. Electrode stimulation did not elicit any habitual electroclinical seizures. HFO analysis showed bilateral focal regions with high fast-ripple rates. Significance: "Generalized-to-focal" seizures may occur due to a diffuse, bilateral epileptic network, however, both patients showed ictal evolution from a generalized pattern to a single dominant focus which may explain why the focal aspect of their seizures had a consistent clinical semiology. Patients such as these may have a unique form of generalized epilepsy, but focal/multifocal cerebral abnormalities are also a possibility.


Assuntos
Epilepsias Parciais , Epilepsia Tipo Ausência , Epilepsia Generalizada , Criança , Eletroencefalografia/métodos , Epilepsias Parciais/diagnóstico , Epilepsias Parciais/cirurgia , Humanos , Convulsões/diagnóstico , Convulsões/cirurgia
9.
J Child Neurol ; 37(4): 237-245, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34986037

RESUMO

Parents of children with genetically determined leukoencephalopathies play a major role in their children's health care. Because of the COVID-19 pandemic, many health care services were suspended, delayed or delivered remotely with telemedicine. We sought to explore the experience of parents of children with genetically determined leukoencephalopathies during the pandemic given the adapted health care services. We conducted semistructured interviews with 13 parents of 13 affected children. Three main themes were identified using thematic analysis: perceived impact of COVID-19 on health care services, benefits and challenges of telemedicine, and expectations of health care after the pandemic. Parents perceived a loss/delay in health care services while having a positive response to telemedicine. Parents wished telemedicine would remain in their care after the pandemic. This is the first study assessing the impact of COVID-19 on health care services in this population. Our results suggest that parents experience a higher level of stress owing to the shortage of services and the children's vulnerability.


Assuntos
COVID-19 , Leucoencefalopatias , Telemedicina , Criança , Humanos , Leucoencefalopatias/epidemiologia , Pandemias , Pais
10.
J Neurosurg Pediatr ; 29(1): 74-82, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34624842

RESUMO

OBJECTIVE: In an attempt to improve postsurgical seizure outcomes for poorly defined cases (PDCs) of pediatric focal epilepsy (i.e., those that are not visible or well defined on 3T MRI), the authors modified their presurgical evaluation strategy. Instead of relying on concordance between video-electroencephalography and 3T MRI and using functional imaging and intracranial recording in select cases, the authors systematically used a multimodal, 3-tiered investigation protocol that also involved new collaborations between their hospital, the Montreal Children's Hospital, and the Montreal Neurological Institute. In this study, the authors examined how their new strategy has impacted postsurgical outcomes. They hypothesized that it would improve postsurgical seizure outcomes, with the added benefit of identifying a subset of tests contributing the most. METHODS: Chart review was performed for children with PDCs who underwent resection following the new strategy (i.e., new protocol [NP]), and for the same number who underwent treatment previously (i.e., preprotocol [PP]); ≥ 1-year follow-up was required for inclusion. Well-defined, multifocal, and diffuse hemispheric cases were excluded. Preoperative demographics and clinical characteristics, resection volumes, and pathology, as well as seizure outcomes (Engel class Ia vs > Ia) at 1 year postsurgery and last follow-up were reviewed. RESULTS: Twenty-two consecutive NP patients were compared with 22 PP patients. There was no difference between the two groups for resection volumes, pathology, or preoperative characteristics, except that the NP group underwent more presurgical evaluation tests (p < 0.001). At 1 year postsurgery, 20 of 22 NP patients and 10 of 22 PP patients were seizure free (OR 11.81, 95% CI 2.00-69.68; p = 0.006). Magnetoencephalography and PET/MRI were associated with improved postsurgical seizure outcomes, but both were highly correlated with the protocol group (i.e., independent test effects could not be demonstrated). CONCLUSIONS: A new presurgical evaluation strategy for children with PDCs of focal epilepsy led to improved postsurgical seizure freedom. No individual presurgical evaluation test was independently associated with improved outcome, suggesting that it may be the combined systematic protocol and new interinstitutional collaborations that makes the difference rather than any individual test.


Assuntos
Técnicas de Diagnóstico Neurológico , Epilepsias Parciais/cirurgia , Neurocirurgia/métodos , Cirurgia Assistida por Computador/métodos , Criança , Pré-Escolar , Eletrofisiologia/métodos , Epilepsias Parciais/complicações , Feminino , Humanos , Masculino , Imagem Multimodal/métodos , Neuroimagem/métodos , Convulsões/etiologia , Convulsões/cirurgia , Resultado do Tratamento
11.
JIMD Rep ; 45: 57-63, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30349987

RESUMO

Ethylmalonic encephalopathy (EE) is caused by mutations in the ETHE1 gene. ETHE1 is vital for the catabolism of hydrogen sulfide (H2S). Patients with pathogenic mutations in ETHE1 have markedly increased thiosulfate, which is a reliable index of H2S levels. Accumulation of H2S is thought to cause the characteristic metabolic derangement found in EE. Recently introduced treatment strategies in EE, such as combined use of metronidazole (MNZ) and N-acetylcysteine (NAC), are aimed at lowering chronic H2S load. Experience with treatment strategies directed against acute episodes of metabolic decompensation (e.g., hemodialysis) is limited. Here we present an unusually mild, molecularly confirmed, case of EE in a 19-year-old male on chronic treatment with MNZ and NAC. During an acute episode of metabolic decompensation, we employed continuous renal replacement therapy (CRRT) to regain metabolic control. On continuous treatment with NAC and MNZ during the months preceding the acute event, plasma thiosulfate levels ranged from 1.6 to 4 µg/mL (reference range up to 2 µg/mL) and had a mean value of 2.5 µg/mL. During the acute decompensation, thiosulfate levels were 6.7 µg/mL, with hyperlactatemia and perturbed organic acid, acylglycine, and acylcarnitine profiles. CRRT decreased thiosulfate within 24 h to 1.4 µg/mL. Following discontinuation of CRRT, mean thiosulfate levels were 3.2 µg/mL (range, 2.4-3.7 µg/mL) accompanied by clinical improvement with metabolic stabilization of blood gas, acylcarnitine, organic acid, and acylglycine profiles. In conclusion, CRRT may help to regain metabolic control in patients with EE who have an acute metabolic decompensation on chronic treatment with NAC and MNZ.

12.
Pediatr Neurol ; 84: 21-26, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29859719

RESUMO

BACKGROUND: We attempted to characterize the health-related quality of life in patients with genetically determined leukoencephalopathies as it relates to the severity of clinical features and the presence or absence of a precise molecular diagnosis. METHODS: Health-related quality of life was assessed using the Pediatric Quality of Life Inventory model (Pediatric Quality of Life Inventory 4.0 Self- and Proxy-reports) on 59 patients diagnosed with genetically determined leukoencephalopathies. In total, 38 male and 21 female patients ranging from one to 32 years of age (mean nine years), as well as their parents, completed the Pediatric Quality of Life Inventory health-related quality of life measures. In addition, participants completed detailed standardized clinical assessments or questionnaires. The correlation between health-related quality of life results and the severity of the clinical features, as well as the presence or absence of a molecular diagnosis, were analyzed. RESULTS: Patients with more severe clinical features showed statistically significant lower total Pediatric Quality of Life Inventory scores. More specifically, lower health-related quality of life was noted in children with sialorrhea, gastrostomy, and dystonia and in children who use a wheelchair. CONCLUSIONS: Patients with more severe clinical features experience a lower quality of life. Our study further highlights the importance of addressing both physical and psychosocial issues and discussing perception of quality of life with both parents and children. A larger multicenter prospective study will be needed to further define the burden of these diseases and to identify modifiable factors.


Assuntos
Leucoencefalopatias , Qualidade de Vida , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Leucoencefalopatias/genética , Leucoencefalopatias/fisiopatologia , Leucoencefalopatias/psicologia , Masculino , Qualidade de Vida/psicologia , Índice de Gravidade de Doença , Adulto Jovem
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