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1.
N Engl J Med ; 384(25): 2406-2417, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34161705

RESUMO

BACKGROUND: Autophagy is the major intracellular degradation route in mammalian cells. Systemic ablation of core autophagy-related (ATG) genes in mice leads to embryonic or perinatal lethality, and conditional models show neurodegeneration. Impaired autophagy has been associated with a range of complex human diseases, yet congenital autophagy disorders are rare. METHODS: We performed a genetic, clinical, and neuroimaging analysis involving five families. Mechanistic investigations were conducted with the use of patient-derived fibroblasts, skeletal muscle-biopsy specimens, mouse embryonic fibroblasts, and yeast. RESULTS: We found deleterious, recessive variants in human ATG7, a core autophagy-related gene encoding a protein that is indispensable to classical degradative autophagy. Twelve patients from five families with distinct ATG7 variants had complex neurodevelopmental disorders with brain, muscle, and endocrine involvement. Patients had abnormalities of the cerebellum and corpus callosum and various degrees of facial dysmorphism. These patients have survived with impaired autophagic flux arising from a diminishment or absence of ATG7 protein. Although autophagic sequestration was markedly reduced, evidence of basal autophagy was readily identified in fibroblasts and skeletal muscle with loss of ATG7. Complementation of different model systems by deleterious ATG7 variants resulted in poor or absent autophagic function as compared with the reintroduction of wild-type ATG7. CONCLUSIONS: We identified several patients with a neurodevelopmental disorder who have survived with a severe loss or complete absence of ATG7, an essential effector enzyme for autophagy without a known functional paralogue. (Funded by the Wellcome Centre for Mitochondrial Research and others.).


Assuntos
Anormalidades Múltiplas/genética , Ataxia/genética , Proteína 7 Relacionada à Autofagia/genética , Autofagia/genética , Deficiências do Desenvolvimento/genética , Mutação de Sentido Incorreto , Adolescente , Adulto , Autofagia/fisiologia , Proteína 7 Relacionada à Autofagia/fisiologia , Células Cultivadas , Cerebelo/anormalidades , Simulação por Computador , Face/anormalidades , Feminino , Fibroblastos , Genes Recessivos , Humanos , Lactente , Masculino , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Malformações do Sistema Nervoso/genética , Linhagem , Fenótipo
2.
Dev Med Child Neurol ; 66(2): 176-186, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37501281

RESUMO

AIM: To study long-term sequelae in children with Guillain-Barré syndrome (GBS). METHOD: This was a prospective observational study with children from two French tertiary centres. Data were from clinical and several standardized scales or questionnaires. RESULTS: Fifty-one patients were included with a median follow-up of 6 years 4 months (range 3-20 years) after the acute phase. The sequelae rate was 67% (95% confidence interval [CI] 53-78) and did not vary with time. Most children had minor sequelae (Guillain-Barré Syndrome Disability Score [GBSDS] = 1); only one was unable to run (GBSDS = 2). The most frequent complaints were paraesthesia (43%), pain (35%), and fatigue (31%). The neurological examination was abnormal in 18% of children, autonomy was compromised in 14%, and symptoms of depression occurred in 34%. The factors associated with late-onset sequelae were correlated with severity during the initial phase (i.e. initial GBSDS >4, odds ratio 6.6, 95% CI 1.8-33; p = 0.009). The predictive factors of more severe late-onset conditions were initial severity (p = 0.002) and sex (female patients; p = 0.01). INTERPRETATION: Two-thirds of children with GBS had late-onset sequelae following an episode, often minor, but sometimes with continuing effects on their everyday lives. Particularly affected were those who had severe GBS during the acute phase and who lost the ability to walk. WHAT THIS PAPER ADDS: Two-thirds of children with Guillain-Barré syndrome (GBS) had persistent sequelae. Sequelae were often minor, but daily repercussions of them were sometimes serious. Sequelae were significantly associated with severe GBS during the acute phase.


Assuntos
Síndrome de Guillain-Barré , Humanos , Criança , Feminino , Síndrome de Guillain-Barré/complicações , Síndrome de Guillain-Barré/diagnóstico , Estudos Prospectivos , Progressão da Doença , Inquéritos e Questionários , Fadiga/complicações
3.
Dev Med Child Neurol ; 66(8): 1053-1061, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38263722

RESUMO

AIM: To compare the efficacy of intravenous clonazepam (CLZ) for the initial management of convulsive status epilepticus (CSE) in children as a function of the first-line in-hospital dose used. METHOD: This monocentric retrospective study included children who received a first dose of CLZ for CSE at Montpellier University Hospital, France, between January 2016 and June 2019. Data from medical records (clinical, treatment, course) were collected and compared as a function of the first CLZ dose used. RESULTS: Among the 310 children treated for CSE, 105 received at least one CLZ dose (median age 3 years; quartile 1-quartile 3 [Q1-Q3] = 1 years 2 months-6 years 6 months). Among these 105 patients, 24 (22%) received a dose less than 0.03 mg/kg (low dose) and 69 (65%) received a dose of at least 0.03 mg/kg (high dose). Seizure cessation rate was not different between the low- and high-dose groups (62.5% vs 76%; odds ratio 0.53, 95% confidence interval [CI] 0.19-1.44, p = 0.29). The administration of a second dose of CLZ was more frequent in the low- than the high-dose group (37.5% vs 16%; odds ratio 3.2, 95% CI 1.1-9.1, p = 0.04). INTERPRETATION: Our study did not find any difference in seizure termination rate as a function of CLZ dose in children with CSE. However, a second CLZ dose was more frequently needed in the group receiving low (less than 0.03 mg/kg) CLZ.


Assuntos
Administração Intravenosa , Anticonvulsivantes , Clonazepam , Estado Epiléptico , Humanos , Estado Epiléptico/tratamento farmacológico , Masculino , Feminino , Clonazepam/administração & dosagem , Estudos Retrospectivos , Pré-Escolar , Criança , Anticonvulsivantes/administração & dosagem , Lactente , Resultado do Tratamento , Relação Dose-Resposta a Droga
4.
J Med Genet ; 60(6): 578-586, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36319078

RESUMO

PURPOSE: In this study, we describe the phenotype and genotype of the largest cohort of patients with Joubert syndrome (JS) carrying pathogenic variants on one of the most frequent causative genes, CC2D2A. METHODS: We selected 53 patients with pathogenic variants on CC2D2A, compiled and analysed their clinical, neuroimaging and genetic information and compared it to previous literature. RESULTS: Developmental delay (motor and language) was nearly constant but patients had normal intellectual efficiency in 74% of cases (20/27 patients) and 68% followed mainstream schooling despite learning difficulties. Epilepsy was found in only 13% of cases. Only three patients had kidney cysts, only three had genuine retinal dystrophy and no subject had liver fibrosis or polydactyly. Brain MRIs showed typical signs of JS with rare additional features. Genotype-phenotype correlation findings demonstrate a homozygous truncating variant p.Arg950* linked to a more severe phenotype. CONCLUSION: This study contradicts previous literature stating an association between CC2D2A-related JS and ventriculomegaly. Our study implies that CC2D2A-related JS is linked to positive neurodevelopmental outcome and low rate of other organ defects except for homozygous pathogenic variant p.Arg950*. This information will help modulate patient follow-up and provide families with accurate genetic counselling.


Assuntos
Anormalidades Múltiplas , Anormalidades do Olho , Doenças Renais Císticas , Humanos , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Doenças Renais Císticas/diagnóstico , Doenças Renais Císticas/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Retina/diagnóstico por imagem , Retina/patologia , Proteínas do Citoesqueleto
5.
Int J Mol Sci ; 25(8)2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38673950

RESUMO

Demyelinating Charcot-Marie-Tooth 4G (CMT4G) results from a recessive mutation in the 5'UTR region of the Hexokinase 1 (HK1) gene. HK participates in mitochondrial calcium homeostasis by binding to the Voltage-Dependent Anion Channel (VDAC), through its N-terminal porin-binding domain. Our hypothesis is that CMT4G mutation results in a broken interaction between mutant HK1 and VDAC, disturbing mitochondrial calcium homeostasis. We studied a cohort of 25 CMT4G patients recruited in the French gypsy population. The disease was characterized by a childhood onset, an intermediate demyelinating pattern, and a significant phenotype leading to becoming wheelchair-bound by the fifth decade of life. Co-IP and PLA studies indicated a strong decreased interaction between VDAC and HK1 in the patients' PBMCs and sural nerve. We observed that either wild-type HK1 expression or a peptide comprising the 15 aa of the N-terminal wild-type HK1 administration decreased mitochondrial calcium release in HEK293 cells. However, mutated CMT4G HK1 or the 15 aa of the mutated HK1 was unable to block mitochondrial calcium release. Taken together, these data show that the CMT4G-induced modification of the HK1 N-terminus disrupts HK1-VDAC interaction. This alters mitochondrial calcium buffering that has been shown to be critical for myelin sheath maintenance.


Assuntos
Cálcio , Doença de Charcot-Marie-Tooth , Hexoquinase , Mitocôndrias , Canal de Ânion 1 Dependente de Voltagem , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Regiões 5' não Traduzidas/genética , Cálcio/metabolismo , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/metabolismo , Células HEK293 , Hexoquinase/genética , Hexoquinase/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/genética , Mutação , Ligação Proteica , Canal de Ânion 1 Dependente de Voltagem/metabolismo , Canal de Ânion 1 Dependente de Voltagem/genética
6.
Eur J Neurol ; 30(9): 2828-2837, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37235686

RESUMO

BACKGROUND: Classical infantile-onset Pompe disease (IOPD) is the most severe form of Pompe disease. Enzyme replacement therapy (ERT) has significantly increased survival but only a few studies have reported long-term outcomes. METHODS: We retrospectively analyzed the outcomes of classical IOPD patients diagnosed in France between 2004 and 2020. RESULTS: Sixty-four patients were identified. At diagnosis (median age 4 months) all patients had cardiomyopathy and most had severe hypotonia (57 of 62 patients, 92%). ERT was initiated in 50 (78%) patients and stopped later due to being ineffective in 10 (21%). Thirty-seven (58%) patients died during follow-up, including all untreated and discontinued ERT patients, and 13 additional patients. Mortality was higher during the first 3 years of life and after the age of 12 years. Persistence of cardiomyopathy during follow-up and/or the presence of heart failure were highly associated with an increased risk of death. In contrast, cross-reactive immunologic material (CRIM)-negative status (n = 16, 26%) was unrelated to increased mortality, presumably because immunomodulation protocols prevent the emergence of high antibody titers to ERT. Besides survival, decreased ERT efficacy appeared after the age of 6 years, with a progressive decline in motor and pulmonary functions for most survivors. CONCLUSIONS: This study reports the long-term follow-up of one of the largest cohorts of classical IOPD patients and demonstrates high long-term mortality and morbidity rates with a secondary decline in muscular and respiratory functions. This decreased efficacy seems to be multifactorial, highlighting the importance of developing new therapeutic approaches targeting various aspects of pathogenesis.


Assuntos
Cardiomiopatias , Doença de Depósito de Glicogênio Tipo II , Humanos , Criança , Lactente , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Seguimentos , Estudos Retrospectivos , Terapia de Reposição de Enzimas/efeitos adversos , Terapia de Reposição de Enzimas/métodos
7.
Dev Med Child Neurol ; 65(2): 215-222, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-35765978

RESUMO

AIM: To compare paediatric patients with cerebral sinovenous thrombosis (CSVT) with and without head/neck infection to improve management of the condition. METHOD: We conducted a bicentric retrospective study of consecutive children (neonates excluded) with radiologically confirmed CSVT, comparing children with a concurrent head/neck infection and children with other causes. RESULTS: A total of 84 consecutive patients (46 males and 38 females) with a median age of 4 years 6 months (range 3 months-17 years 5 months) were included. Associated head/neck infection was identified in 65.4% of cases and represented the main identified CSVT aetiology. Children in the head/neck infection group displayed a milder clinical presentation and less extensive CSVT. Median time to complete recanalization was significantly shorter in this group (89 days [interquartile range 35-101] vs 112.5 days [interquartile range 83-177], p = 0.005). These findings were even more pronounced in the subgroup of patients with otogenic infection and no neurological sign. INTERPRETATION: As CSVT in the setting of an otogenic infection and no neurological sign seems to represent a milder condition with a shorter course, these results suggest adapting current recommendations: consider earlier control imaging in paediatric otogenic CSVT, and shorter anticoagulant treatment if recanalization is obtained. WHAT THIS PAPER ADDS: Children with cerebral sinovenous thrombosis related to head/neck infections have a milder clinical presentation. They also have a shorter recanalization time, especially if there is otogenic infection without neurological symptoms.


Assuntos
Trombose dos Seios Intracranianos , Trombose Venosa , Criança , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Fatores de Risco , Trombose dos Seios Intracranianos/complicações , Trombose dos Seios Intracranianos/diagnóstico por imagem , Trombose/complicações
8.
Neuropediatrics ; 53(3): 182-187, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35297028

RESUMO

INTRODUCTION: Among the hereditary motor and sensory neuropathies (HMSN), demyelinating forms are the best characterized, with a clear predominance of CMT1A. The axonal and intermediate forms are less described. The aim of this study is to report the genetic diagnosis of Charcot-Marie-Tooth (CMT) according to the nerve conduction velocity (NCV) findings in a pediatric population. METHODS: We retrospectively described a population of HMSN children with a confirmed genetic diagnosis of demyelinated, intermediate, or axonal forms. We compared the results of the genetic analyses with those of motor NCV in median nerve according to whether they were below 25 m/s (demyelinating group); between 25 and 45 m/s (intermediate group), or above 45 m/s (axonal group). RESULTS: Among the 143 children with an HMSN, 107 had a genetic diagnosis of which 61 had an electromyogram. On NCV findings: seven (11%) pertain to the axonal group, 20 (32%) to the intermediate group, and 34 (55%) to the demyelinating group. When NCV was above 45 m/s, CMT2A was the predominant genetic diagnosis (70%) when NCV were below 25 m/s, CMT1A was the predominant genetic diagnosis (71%). Intermediate NCV findings group was the more heterogeneous with seven genetic CMT subgroups (60% CMT1A, CMT1B, CMT1X, CMT2A, CMT2N, CMT4G). CONCLUSION: Taking NCV values between 25 and 45 m/s to define an intermediate group of CMT in children leads to the inclusion of non-typically "intermediate", especially CMT1A. We emphasize the broad spectrum of NCV in CMT1A that justified the systematic search of PMP22 duplication/deletion screening before next generation sequencing panel.


Assuntos
Doença de Charcot-Marie-Tooth , Neuropatia Hereditária Motora e Sensorial , Doença de Charcot-Marie-Tooth/diagnóstico , Doença de Charcot-Marie-Tooth/genética , Criança , Testes Genéticos , Neuropatia Hereditária Motora e Sensorial/diagnóstico , Neuropatia Hereditária Motora e Sensorial/genética , Humanos , Condução Nervosa , Estudos Retrospectivos
9.
Eur Heart J ; 42(20): 1976-1984, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-33748842

RESUMO

AIMS: To estimate the effect of prophylactic angiotensin-converting enzyme inhibitors (ACEi) on survival in Duchenne muscular dystrophy (DMD). METHODS AND RESULTS: We analysed the data from the French multicentre DMD Heart Registry (ClinicalTrials.gov: NCT03443115). We estimated the association between the prophylactic prescription of ACEi and event-free survival in 668 patients aged 8 to 13 years, with normal left ventricular function, using (i) a Cox model with intervention as a time-dependent covariate, (ii) a propensity-based analysis comparing ACEi treatment vs. no treatment, and (iii) a set of sensitivity analyses. The study outcomes were overall survival and hospitalizations for heart failure (HF) or acute respiratory failure. Among the 668 patients included in the DMD Heart Registry, 576 (mean age 6.1 ± 2.8 years) were eligible for this study, of whom 390 were treated with ACEi prophylactically. Death occurred in 53 patients (13.5%) who were and 60 patients (32.3%) who were not treated prophylactically with ACEi, respectively. In a Cox model with intervention as a time-dependent variable, the hazard ratio (HR) associated with ACEi treatment was 0.49 [95% confidence interval (CI) 0.34-0.72] and 0.47 (95% CI 0.31-0.17) for overall mortality after adjustment for baseline variables. In the propensity-based analysis, 278 patients were included in the treatment group and 834 in the control group, with 18.5% and 30.4% 12-year estimated probability of death, respectively. ACEi were associated with a lower risk of death (HR 0.39; 95% CI 0.17-0.92) and hospitalization for HF (HR 0.16; 95% CI 0.04-0.62). All other sensitivity analyses yielded similar results. CONCLUSION: Prophylactic ACEi treatment in DMD was associated with a significantly higher overall survival and lower rates of hospitalization for HF.


Assuntos
Insuficiência Cardíaca , Distrofia Muscular de Duchenne , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Criança , Pré-Escolar , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/prevenção & controle , Humanos , Distrofia Muscular de Duchenne/tratamento farmacológico , Sistema de Registros , Resultado do Tratamento , Função Ventricular Esquerda
10.
Am J Hum Genet ; 102(5): 744-759, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29656859

RESUMO

RORα, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy. Consistent with the human and mouse data, disruption of the D. rerio ortholog, roraa, causes significant reduction in the size of the developing cerebellum. Systematic in vivo complementation studies showed that, whereas wild-type human RORA mRNA could complement the cerebellar pathology, missense variants had two distinct pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect according to their localization in the ligand-binding or DNA-binding domains, respectively. This dichotomous direction of effect is likely relevant to the phenotype in humans: individuals with loss-of-function variants leading to haploinsufficiency show ID with autistic features, while individuals with de novo dominant toxic variants present with ID, ataxia, and cerebellar atrophy. Our combined genetic and functional data highlight the complex mutational landscape at the human RORA locus and suggest that dual mutational effects likely determine phenotypic outcome.


Assuntos
Transtorno Autístico/genética , Ataxia Cerebelar/genética , Genes Dominantes , Deficiência Intelectual/genética , Mutação de Sentido Incorreto/genética , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Adolescente , Adulto , Idoso de 80 Anos ou mais , Alelos , Animais , Transtorno Autístico/complicações , Encéfalo/patologia , Ataxia Cerebelar/complicações , Criança , Pré-Escolar , Variações do Número de Cópias de DNA/genética , Modelos Animais de Doenças , Feminino , Teste de Complementação Genética , Humanos , Deficiência Intelectual/complicações , Larva/genética , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Células de Purkinje/metabolismo , Células de Purkinje/patologia , Síndrome , Peixe-Zebra/genética
11.
Int J Mol Sci ; 22(23)2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34884796

RESUMO

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting following repeated muscle damage and inadequate regeneration. Impaired myogenesis and differentiation play a major role in DMD as well as intracellular calcium (Ca2+) mishandling. Ca2+ release from the sarcoplasmic reticulum is mostly mediated by the type 1 ryanodine receptor (RYR1) that is required for skeletal muscle differentiation in animals. The study objective was to determine whether altered RYR1-mediated Ca2+ release contributes to myogenic differentiation impairment in DMD patients. The comparison of primary cultured myoblasts from six boys with DMD and five healthy controls highlighted delayed myoblast differentiation in DMD. Silencing RYR1 expression using specific si-RNA in a healthy control induced a similar delayed differentiation. In DMD myotubes, resting intracellular Ca2+ concentration was increased, but RYR1-mediated Ca2+ release was not changed compared with control myotubes. Incubation with the RYR-calstabin interaction stabilizer S107 decreased resting Ca2+ concentration in DMD myotubes to control values and improved calstabin1 binding to the RYR1 complex. S107 also improved myogenic differentiation in DMD. Furthermore, intracellular Ca2+ concentration was correlated with endomysial fibrosis, which is the only myopathologic parameter associated with poor motor outcome in patients with DMD. This suggested a potential relationship between RYR1 dysfunction and motor impairment. Our study highlights RYR1-mediated Ca2+ leakage in human DMD myotubes and its key role in myogenic differentiation impairment. RYR1 stabilization may be an interesting adjunctive therapeutic strategy in DMD.


Assuntos
Desenvolvimento Muscular/fisiologia , Músculo Esquelético/crescimento & desenvolvimento , Distrofia Muscular de Duchenne/patologia , Mioblastos/citologia , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Cálcio/metabolismo , Sinalização do Cálcio/fisiologia , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Células Cultivadas , Criança , Pré-Escolar , Distrofina/metabolismo , Humanos , Masculino , Desenvolvimento Muscular/genética , Fibras Musculares Esqueléticas/patologia , Distrofia Muscular de Duchenne/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Retículo Sarcoplasmático/metabolismo , Proteínas de Ligação a Tacrolimo/metabolismo
12.
Ann Neurol ; 86(2): 181-192, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31177578

RESUMO

OBJECTIVE: Recent reports have described single individuals with neurodevelopmental disability (NDD) harboring heterozygous KCNQ3 de novo variants (DNVs). We sought to assess whether pathogenic variants in KCNQ3 cause NDD and to elucidate the associated phenotype and molecular mechanisms. METHODS: Patients with NDD and KCNQ3 DNVs were identified through an international collaboration. Phenotypes were characterized by clinical assessment, review of charts, electroencephalographic (EEG) recordings, and parental interview. Functional consequences of variants were analyzed in vitro by patch-clamp recording. RESULTS: Eleven patients were assessed. They had recurrent heterozygous DNVs in KCNQ3 affecting residues R230 (R230C, R230H, R230S) and R227 (R227Q). All patients exhibited global developmental delay within the first 2 years of life. Most (8/11, 73%) were nonverbal or had a few words only. All patients had autistic features, and autism spectrum disorder (ASD) was diagnosed in 5 of 11 (45%). EEGs performed before 10 years of age revealed frequent sleep-activated multifocal epileptiform discharges in 8 of 11 (73%). For 6 of 9 (67%) recorded between 1.5 and 6 years of age, spikes became near-continuous during sleep. Interestingly, most patients (9/11, 82%) did not have seizures, and no patient had seizures in the neonatal period. Voltage-clamp recordings of the mutant KCNQ3 channels revealed gain-of-function (GoF) effects. INTERPRETATION: Specific GoF variants in KCNQ3 cause NDD, ASD, and abundant sleep-activated spikes. This new phenotype contrasts both with self-limited neonatal epilepsy due to KCNQ3 partial loss of function, and with the neonatal or infantile onset epileptic encephalopathies due to KCNQ2 GoF. ANN NEUROL 2019;86:181-192.


Assuntos
Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Mutação com Ganho de Função/genética , Canal de Potássio KCNQ3/genética , Sequência de Aminoácidos , Criança , Pré-Escolar , Variação Genética/genética , Humanos , Canal de Potássio KCNQ3/química , Masculino , Estrutura Secundária de Proteína , Adulto Jovem
13.
Neuropediatrics ; 50(4): 244-247, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31170735

RESUMO

INTRODUCTION: Migraine is the most common neurological disorder and the third most common disease worldwide. However, the underlying mechanisms contributing to its development are not completely understood. Symptoms may arise from a combination of dilation-independent vascular events and neurogenic mechanisms interacting throughout the brain and within the trigeminovascular system in the meninges MATERIALS AND METHOD: We report here a case of a patient with a suspected familial hemiplegic migraine who presented an increased recurrence of events from one per month to one every other day. Three magnetic resonance imaging (MRI) acquisitions were performed after the appearance of a strong crisis which included a paresthesia and aphasia along with headaches. Two MRIs were performed close to the crisis, while the last one was done 1 month later. RESULTS: During the crisis, cerebral perfusion exhibits incoherent results. Blood velocity measurements highlight a strong phase lag between left internal carotid artery (ICA) and basilar artery and more importantly right ICA. After a month, parameters came back to standard values. CONCLUSION: The transitory nature of the observed modifications suggests a reversible alteration of the vascular tone of the ICA in patients with migraine. This alteration seems to follow recovery pattern of the patient.


Assuntos
Artéria Carótida Interna/diagnóstico por imagem , Circulação Cerebrovascular/fisiologia , Imageamento por Ressonância Magnética/métodos , Transtornos de Enxaqueca/diagnóstico por imagem , Adolescente , Feminino , Humanos
14.
Hum Mutat ; 39(1): 140-151, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29034544

RESUMO

Hereditary spastic paraplegia (HSP) is an inherited disorder of the central nervous system mainly characterized by gradual spasticity and weakness of the lower limbs. SPG56 is a rare autosomal recessive early onset complicated form of HSP caused by mutations in CYP2U1. The CYP2U1 enzyme was shown to catalyze the hydroxylation of arachidonic acid. Here, we report two further SPG56 families carrying three novel CYP2U1 missense variants and the development of an in vitro biochemical assay to determine the pathogenicity of missense variants of uncertain clinical significance. We compared spectroscopic, enzymatic, and structural (from a 3D model) characteristics of the over expressed wild-type or mutated CYP2U1 in HEK293T cells. Our findings demonstrated that most of the tested missense variants in CYP2U1 were functionally inactive because of a loss of proper heme binding or destabilization of the protein structure. We also showed that functional data do not necessarily correlate with in silico predictions of variants pathogenicity, using different bioinformatic phenotype prediction tools. Our results therefore highlight the importance to use biological tools, such as the enzymatic test set up in this study, to evaluate the effects of newly identified variants in clinical settings.


Assuntos
Família 2 do Citocromo P450/genética , Família 2 do Citocromo P450/metabolismo , Mutação de Sentido Incorreto , Paraplegia Espástica Hereditária/enzimologia , Paraplegia Espástica Hereditária/genética , Alelos , Substituição de Aminoácidos , Família 2 do Citocromo P450/química , Análise Mutacional de DNA , Ativação Enzimática , Expressão Gênica , Estudos de Associação Genética , Células HEK293 , Humanos , Modelos Moleculares , Oxirredução , Fenótipo , Conformação Proteica , Paraplegia Espástica Hereditária/diagnóstico
15.
Hum Mol Genet ; 24(14): 3948-55, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-25901006

RESUMO

Mitochondrial complex I (CI) deficiencies are causing debilitating neurological diseases, among which, the Leber Hereditary Optic Neuropathy and Leigh Syndrome are the most frequent. Here, we describe the first germinal pathogenic mutation in the NDUFA13/GRIM19 gene encoding a CI subunit, in two sisters with early onset hypotonia, dyskinesia and sensorial deficiencies, including a severe optic neuropathy. Biochemical analysis revealed a drastic decrease in CI enzymatic activity in patient muscle biopsies, and reduction of CI-driven respiration in fibroblasts, while the activities of complex II, III and IV were hardly affected. Western blots disclosed that the abundances of NDUFA13 protein, CI holoenzyme and super complexes were drastically reduced in mitochondrial fractions, a situation that was reproduced by silencing NDUFA13 in control cells. Thus, we established here a correlation between the first mutation yet identified in the NDUFA13 gene, which induces CI instability and a severe but slowly evolving clinical presentation affecting the central nervous system.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Discinesias/genética , Complexo I de Transporte de Elétrons/deficiência , Doenças Mitocondriais/genética , Hipotonia Muscular/genética , NADH NADPH Oxirredutases/genética , Proteínas Reguladoras de Apoptose/metabolismo , Criança , Pré-Escolar , Complexo I de Transporte de Elétrons/genética , Feminino , Seguimentos , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Mutação , NADH NADPH Oxirredutases/metabolismo , Fases de Leitura Aberta , Linhagem
16.
Neuropediatrics ; 48(3): 166-184, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28561207

RESUMO

We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64-25.71) compared with controls (median: 0.93, IQR: 0.57-1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context.


Assuntos
Adenosina Desaminase/genética , Doenças Autoimunes do Sistema Nervoso/genética , Doenças Autoimunes do Sistema Nervoso/imunologia , Interferon Tipo I/metabolismo , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/imunologia , Proteínas de Ligação a RNA/genética , Adolescente , Adulto , Doenças Autoimunes do Sistema Nervoso/diagnóstico por imagem , Biomarcadores/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Mutação , Malformações do Sistema Nervoso/diagnóstico por imagem , Fenótipo , Adulto Jovem
17.
PLoS Genet ; 10(9): e1004580, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25188300

RESUMO

SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Transtornos Cognitivos/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Estudos de Casos e Controles , Criança , Cognição/fisiologia , Variações do Número de Cópias de DNA/genética , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Neurônios/fisiologia , Sinapses/genética
18.
Am J Med Genet A ; 170(7): 1895-8, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27103084

RESUMO

Anophthalmia and microphthalmia are the most severe malformations of the eye, referring to a congenital absence, and a reduced size of the eyeball respectively. More than 20 genes have been shown to be mutated in patients with syndromic and non-syndromic forms of anophthalmia-microphthalmia. In a recent study combining autozygome and exome analysis, a homozygous loss of function mutation in TENM3 (previously named ODZ3) was reported in two siblings with isolated bilateral colobomatous microphthalmia from a consanguineous Saudi family. Herein, we report a third patient (not related to the previously reported family) with bilateral colobomatous microphthalmia and developmental delay in whom genetic studies identified a homozygous TENM3 splicing mutation c.2968-2A>T (p.Val990Cysfs*13). This report supports the association of TENM3 mutations with colobomatous microphthalmia and expands the phenotypic spectrum associated with mutations in this gene. © 2016 Wiley Periodicals, Inc.


Assuntos
Encefalopatias Metabólicas Congênitas/genética , Coloboma/genética , Opacidade da Córnea/genética , Deficiências do Desenvolvimento/genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Proteínas de Membrana/genética , Microcefalia/genética , Microftalmia/genética , Proteínas do Tecido Nervoso/genética , Processamento Alternativo/genética , Encefalopatias Metabólicas Congênitas/fisiopatologia , Criança , Coloboma/fisiopatologia , Opacidade da Córnea/fisiopatologia , Deficiências do Desenvolvimento/fisiopatologia , Homozigoto , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Microcefalia/fisiopatologia , Microftalmia/fisiopatologia , Mutação
19.
J Neuroradiol ; 43(3): 176-85, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27126632

RESUMO

Hereditary ataxias are a heterogeneous group of neurodegenerative disorders, characterized by cerebellar ataxia as the main clinical feature, and a large spectrum of neurological-associated symptoms and possible multi-organ affection. Image-based approaches to hereditary ataxias in childhood have already been proposed. The aim of this review is to yield the main reports of neuroimaging patterns and diagnostic algorithms and compare them with the results from our study of 23 young patients addressed for ataxia, with subsequent genetic or metabolic diagnosis.


Assuntos
Encéfalo/diagnóstico por imagem , Ataxia Cerebelar/diagnóstico por imagem , Neuroimagem/métodos , Degenerações Espinocerebelares/diagnóstico por imagem , Encéfalo/patologia , Ataxia Cerebelar/genética , Ataxia Cerebelar/patologia , Criança , Diagnóstico por Computador/métodos , Humanos , Degenerações Espinocerebelares/genética , Degenerações Espinocerebelares/patologia
20.
Hum Mol Genet ; 21(17): 3910-7, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22678059

RESUMO

E2F1 deletion leads to increased mitochondrial number and function, increased body temperature in response to cold and increased resistance to fatigue with exercise. Since E2f1-/- mice show increased muscle performance, we examined the effect of E2f1 genetic inactivation in the mdx background, a mouse model of Duchenne muscular dystrophy (DMD). E2f1-/-;mdx mice demonstrated a strong reduction of physiopathological signs of DMD, including preservation of muscle structure, decreased inflammatory profile, increased utrophin expression, resulting in better endurance and muscle contractile parameters, comparable to normal mdx mice. E2f1 deficiency in the mdx genetic background increased the oxidative metabolic gene program, mitochondrial activity and improved muscle functions. Interestingly, we observed increased E2F1 protein levels in DMD patients, suggesting that E2F1 might represent a promising target for the treatment of DMD.


Assuntos
Fator de Transcrição E2F1/deficiência , Músculos/metabolismo , Músculos/fisiopatologia , Distrofia Muscular Animal/fisiopatologia , Distrofia Muscular de Duchenne/patologia , Distrofia Muscular de Duchenne/fisiopatologia , Adolescente , Animais , Estudos de Casos e Controles , Criança , Pré-Escolar , Modelos Animais de Doenças , Fator de Transcrição E2F1/genética , Fator de Transcrição E2F1/metabolismo , Feminino , Regulação da Expressão Gênica , Inativação Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos mdx , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Músculos/patologia , Distrofia Muscular Animal/genética , Distrofia Muscular Animal/patologia , Distrofia Muscular de Duchenne/genética , Oxirredução
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