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1.
Nature ; 632(8024): 390-400, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39048830

RESUMO

Most cases of herpes simplex virus 1 (HSV-1) encephalitis (HSE) remain unexplained1,2. Here, we report on two unrelated people who had HSE as children and are homozygous for rare deleterious variants of TMEFF1, which encodes a cell membrane protein that is preferentially expressed by brain cortical neurons. TMEFF1 interacts with the cell-surface HSV-1 receptor NECTIN-1, impairing HSV-1 glycoprotein D- and NECTIN-1-mediated fusion of the virus and the cell membrane, blocking viral entry. Genetic TMEFF1 deficiency allows HSV-1 to rapidly enter cortical neurons that are either patient specific or derived from CRISPR-Cas9-engineered human pluripotent stem cells, thereby enhancing HSV-1 translocation to the nucleus and subsequent replication. This cellular phenotype can be rescued by pretreatment with type I interferon (IFN) or the expression of exogenous wild-type TMEFF1. Moreover, ectopic expression of full-length TMEFF1 or its amino-terminal extracellular domain, but not its carboxy-terminal intracellular domain, impairs HSV-1 entry into NECTIN-1-expressing cells other than neurons, increasing their resistance to HSV-1 infection. Human TMEFF1 is therefore a host restriction factor for HSV-1 entry into cortical neurons. Its constitutively high abundance in cortical neurons protects these cells from HSV-1 infection, whereas inherited TMEFF1 deficiency renders them susceptible to this virus and can therefore underlie HSE.


Assuntos
Encéfalo , Encefalite por Herpes Simples , Herpesvirus Humano 1 , Proteínas de Membrana , Internalização do Vírus , Animais , Feminino , Humanos , Masculino , Encéfalo/citologia , Encéfalo/metabolismo , Encéfalo/virologia , Encefalite por Herpes Simples/virologia , Encefalite por Herpes Simples/metabolismo , Herpesvirus Humano 1/patogenicidade , Herpesvirus Humano 1/fisiologia , Homozigoto , Interferon Tipo I/metabolismo , Interferon Tipo I/imunologia , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Nectinas/genética , Nectinas/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Neurônios/virologia , Células-Tronco Pluripotentes/citologia , Replicação Viral , Pré-Escolar , Adulto Jovem , Linhagem
2.
Lupus ; 33(4): 328-339, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38315109

RESUMO

OBJECTIVE: Juvenile systemic lupus erythematosus (j-SLE) is a rare chronic auto-immune disease involving several organs. Neuropsychiatric (NP) SLE (NPSLE) is frequent in j-SLE and associated with increased morbidity/mortality. Although NPSLE classification criteria exist, attributing NP features to j-SLE remains a major challenge. The study objective is to thoroughly describe j-NPSLE patients and assist in their diagnosis. METHODS: This is a 4-year retrospective monocentric study of j-SLE patients. NP events were attributed to j-SLE using standardised diagnostic criteria and multidisciplinary paediatric clinical expertise. Clinical features, brain magnetic resonance imaging (MRI)s and samples analysis including cerebrospinal fluid were assessed. A risk of j-NPSLE score was developed based on multivariable logistic regression analysis. RESULTS: Of 39 patients included, 44% were identified as having j-NPSLE. J-NPSLE diagnosis was established at the onset of j-SLE in 59% of patients. In addition to frequent kidney involvement (76%) and chilblains (65%), all j-NPSLE patients displayed psychiatric features: cognitive symptoms (82%), hallucinations (76%), depressed mood (35%), acute confused state (18%) and catatonia (12%). Neurological involvement was often mild and nonspecific, with headache (53%) in about half of the patients. The main features reported on brain MRI were nonspecific T2/FLAIR white matter hyperintensities (65%), and cerebral atrophy (88%). Upon immunosuppressive treatment, clinical improvement of NP features was observed in all j-NPSLE patients. The score developed to attribute j-NPSLE probability, guide further investigations and appropriate treatments is based on hallucinations, memory, sleep and renal involvement (Sensitivity: 0.95 Specificity: 0.85). Cerebrospinal fluid (CSF) neopterin assessment increases the score sensitivity and specificity. CONCLUSION: Physicians should carefully and systematically assess the presence of NP features at diagnosis and early stages of j-SLE. For j-NPSLE patients with predominant psychiatric features, a multidisciplinary collaboration, including psychiatrists, is essential for the diagnosis, management and follow-up.


Assuntos
Lúpus Eritematoso Sistêmico , Vasculite Associada ao Lúpus do Sistema Nervoso Central , Humanos , Criança , Vasculite Associada ao Lúpus do Sistema Nervoso Central/patologia , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/patologia , Estudos Retrospectivos , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Imageamento por Ressonância Magnética/métodos , Alucinações/complicações , Alucinações/patologia
3.
Eur J Neurol ; 31(9): e16324, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38693756

RESUMO

Neuronal ceroid lipofuscinosis type 2 (CLN2) disease is a rare, lysosomal storage disorder that causes pediatric onset neurodegenerative disease. It is characterized by mutations in the TPP1 gene. Symptoms begin between 2 and 4 years of age with loss of previously acquired motor, cognitive, and language abilities. Cerliponase alfa, a recombinant human TPP1 enzyme, is the only approved therapy. We report the first presymptomatic cerliponase alfa intraventricular treatment in a familial case of CLN2 related to a classical TPP1 variant. Sister 1 presented with motor, cognitive, and language decline and progressive myoclonic epilepsy since the age of 3 years, evolved with severe diffuse encephalopathy, received no specific treatment, and died at 11 years. Sister 2 had a CLN2 presymptomatic diagnosis and has been treated with cerliponase since she was 12 months old. She is now 6 years 8 months and has no CLN2 symptom except one generalized seizure 1 year ago. No serious adverse event has occurred. Repeated Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition standardized index scores are heterogeneous in the extremely low to low average ranges. Mean length of utterances, a global index of sentence complexity, showed a delay, but a gradual improvement. The reported case enhances the major contribution of presymptomatic diagnosis and significant middle-term treatment benefit for patients with CLN2.


Assuntos
Aminopeptidases , Dipeptidil Peptidases e Tripeptidil Peptidases , Lipofuscinoses Ceroides Neuronais , Serina Proteases , Tripeptidil-Peptidase 1 , Humanos , Lipofuscinoses Ceroides Neuronais/genética , Lipofuscinoses Ceroides Neuronais/tratamento farmacológico , Lipofuscinoses Ceroides Neuronais/complicações , Dipeptidil Peptidases e Tripeptidil Peptidases/genética , Feminino , Serina Proteases/genética , Aminopeptidases/genética , Proteínas Recombinantes/uso terapêutico , Proteínas Recombinantes/administração & dosagem , Criança , Terapia Enzimática
4.
J Clin Immunol ; 43(6): 1436-1447, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37171742

RESUMO

The paradigm type I interferonopathy Aicardi-Goutières syndrome (AGS) is most typically characterized by severe neurological involvement. AGS is considered an immune-mediated disease, poorly responsive to conventional immunosuppression. Premised on a chronic enhancement of type I interferon signaling, JAK1/2 inhibition has been trialed in AGS, with clear improvements in cutaneous and systemic disease manifestations. Contrastingly, treatment efficacy at the level of the neurological system has been less conclusive. Here, we report our real-word approach study of JAK1/2 inhibition in 11 patients with AGS, providing extensive assessments of clinical and radiological status; interferon signaling, including in cerebrospinal fluid (CSF); and drug concentrations in blood and CSF. Over a median follow-up of 17 months, we observed a clear benefit of JAK1/2 inhibition on certain systemic features of AGS, and reproduced results reported using the AGS neurologic severity scale. In contrast, there was no change in other scales assessing neurological status; using the caregiver scale, only patient comfort, but no other domain of everyday-life care, was improved. Serious bacterial infections occurred in 4 out of the 11 patients. Overall, our data lead us to conclude that other approaches to treatment are urgently required for the neurologic features of AGS. We suggest that earlier diagnosis and adequate central nervous system penetration likely remain the major factors determining the efficacy of therapy in preventing irreversible brain damage, implying the importance of early and rapid genetic testing and the consideration of intrathecal drug delivery.


Assuntos
Doenças Autoimunes do Sistema Nervoso , Malformações do Sistema Nervoso , Humanos , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/tratamento farmacológico , Doenças Autoimunes do Sistema Nervoso/genética , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/tratamento farmacológico , Malformações do Sistema Nervoso/genética , Transdução de Sinais , Testes Genéticos
5.
Eur J Neurol ; 30(7): 2051-2061, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37046408

RESUMO

BACKGROUND AND PURPOSE: Stroke-like episodes (SLEs) are defined as acute onset of neurological symptoms mimicking a stroke and radiological lesions non-congruent to vascular territory. We aimed to analyze the acute clinical and radiological features of SLEs to determine their pathophysiology. METHODS: We performed a monocenter retrospective analysis of 120 SLEs in 60 children over a 20-year period. Inclusion criteria were compatible clinical symptoms and stroke-like lesions on brain magnetic resonance imaging (MRI; performed for all 120 events) with focal hyperintensity on diffusion-weighted imaging in a non-vascular territory. RESULTS: Three groups were identified: children with mitochondrial diseases (n = 22) involving mitochondrial DNA mutations (55%) or nuclear DNA mutations (45%); those with other metabolic diseases or epilepsy disorders (n = 22); and those in whom no etiology was found despite extensive investigations (n = 16). Age at first SLE was younger in the group with metabolic or epilepsy disorders (18 months vs. 128 months; p < 0.0001) and an infectious trigger was more frequent (69% vs. 20%; p = 0.0001). Seizures occurred in 75% of episodes, revealing 50% episodes of SLEs and mainly leading to status epilepticus (90%). Of the 120 MRI scans confirming the diagnosis, 28 were performed within a short and strict 48-h period and were further analyzed to better understand the underlying mechanisms. The scans showed primary cortical hyperintensity (n = 28/28) with decreased apparent diffusion coefficient in 52% of cases. Systematic hyperperfusion was found on spin labeling sequences when available (n = 18/18). CONCLUSION: Clinical and radiological results support the existence of a vicious circle based on two main mechanisms: energy deficit and neuronal hyperexcitability at the origin of SLE.


Assuntos
Epilepsia , Acidente Vascular Cerebral , Criança , Humanos , Lactente , Encéfalo/patologia , Epilepsia/complicações , Imageamento por Ressonância Magnética , Estudos Retrospectivos , Acidente Vascular Cerebral/etiologia , Pré-Escolar
6.
Brain ; 145(10): 3374-3382, 2022 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-35714222

RESUMO

Claudin-5 is the most enriched tight junction protein at the blood-brain barrier. Perturbations in its levels of expression have been observed across numerous neurological and neuropsychiatric conditions; however, pathogenic variants in the coding sequence of the gene have never been reported previously. Here, we report the identification of a novel de novo mutation (c.178G>A) in the CLDN5 gene in two unrelated cases of alternating hemiplegia with microcephaly. This mutation (G60R) lies within the first extracellular loop of claudin-5 and based on protein modelling and sequence alignment, we predicted it would modify claudin-5 to become an anion-selective junctional component as opposed to a purely barrier-forming protein. Generation of stably transfected cell lines expressing wild-type or G60R claudin-5 showed that the tight junctions could still form in the presence of the G60R mutation but that the barrier against small molecules was clearly attenuated and displayed higher Cl- ion permeability and lower Na+ permeability. While this study strongly suggests that CLDN5 associated alternating hemiplegia is a channelopathy, it is also the first study to identify the conversion of the blood-brain barrier to an anion-selective channel mediated by a dominant acting variant in CLDN5.


Assuntos
Barreira Hematoencefálica , Junções Íntimas , Humanos , Barreira Hematoencefálica/metabolismo , Claudina-5/genética , Claudina-5/metabolismo , Junções Íntimas/metabolismo , Proteínas de Junções Íntimas/metabolismo , Ânions/metabolismo , Mutação/genética
7.
Eur J Pediatr ; 182(6): 2615-2624, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36947244

RESUMO

Influenza virus is generally characterized by fever, myalgia, and respiratory symptoms. Neurological entities have already been described, such as acute necrotizing encephalitis (ANE). We aimed to highlight the non-exceptional nature and explore the clinical spectrum and evolution of neurological features related to influenza virus in children. This monocentric observational study included patients under 18 years old, positive for influenza virus, between January 2017 and April 2019 in a pediatric university hospital. Patients were classified into two groups: those with or without a previous significant neurological or metabolic disorder. Two hundred eighty-nine children were identified with influenza infection. Thirty seven had a neurological manifestation: 14 patients who had previous significant neurological or metabolic disorder and 23 patients with no medical history. We identified several clinical patterns: 22 patients had seizures, 7 behavior disorders, 5 disturbances of consciousness, and 3 motor deficits. Four were diagnosed with a known influenza-associated neurological syndrome: 1 ANE, 1 cytotoxic lesion of the corpus callosum, 1 hemiconvulsion-hemiplegia-epilepsia syndrome, and 1 recurrent encephalitis in the context of a RANBP2 mutation. The neurological outcome was favorable in most cases. None of the patients with previous significant disorder retained sequalae or had a recurrence. Two patients had a fatal outcome, and both had a predisposing disorder. CONCLUSION: Various neurological manifestations can be associated with influenza virus. Certain entities led to a poor prognosis, but in most cases, symptoms improved within a few days. The severity of the neurological manifestations correlated with previous neurological or metabolic disorders. WHAT IS KNOWN: • Influenza viruses are well known pathogens with a seasonal epidemic evolution, particularly affecting children. These viruses cause acute fever with respiratory symptoms, associated with myalgia and headaches. Neurological presentation in influenza-virus infection is a well-established possibility as influenza virus is considered to be responsible for 27 to 36% of childhood encephalitis. Some specific and severe entity as acute necrotizing encephalitis, cytotoxic lesion of the corpus callosum, or Hemiconvulsion-hemiplegia-epilepsy syndrome are well described. WHAT IS NEW: • In a French monocentric cohort of 37 children with influenza-related neurologic manifestations, the majority of these manifestations, including seizure, drowsiness, motor deficiency, hallucination… are self limiting and do not lead to after-effects. In rare cases (4/37), they may reveal severe encephalitis requiring rapid and appropriate treatment. Otherwise, comparison of a group of 14 children with underlying neurological or metabolic disorder with a group of 23 children free of any significant disorder show that the severity of the neurological manifestations was largely related to previous neurological or metabolic disorders highlighting the importance of vaccination in this population.


Assuntos
Encefalite , Influenza Humana , Leucoencefalite Hemorrágica Aguda , Orthomyxoviridae , Criança , Humanos , Adolescente , Influenza Humana/complicações , Influenza Humana/diagnóstico , Influenza Humana/epidemiologia , Estudos Retrospectivos , Leucoencefalite Hemorrágica Aguda/complicações , Hemiplegia/complicações , Mialgia/complicações , Encefalite/complicações , Encefalite/diagnóstico , Convulsões/etiologia
8.
Euro Surveill ; 28(22)2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37261730

RESUMO

We report nine severe neonatal infections caused by a new variant of echovirus 11. All were male, eight were twins. At illness onset, they were 3-5 days-old and had severe sepsis and liver failure. This new variant, detected in France since April 2022, is still circulating and has caused more fatal neonatal enterovirus infections in 2022 and 2023 (8/496; 1.6%, seven associated with echovirus 11) compared with 2016 to 2021 (7/1,774; 0.4%). National and international alerts are warranted.


Assuntos
Doenças Transmissíveis , Infecções por Echovirus , Infecções por Enterovirus , Enterovirus , Recém-Nascido , Humanos , Masculino , Feminino , Infecções por Echovirus/diagnóstico , Infecções por Echovirus/epidemiologia , Enterovirus Humano B/genética , Infecções por Enterovirus/diagnóstico , Infecções por Enterovirus/epidemiologia , França/epidemiologia
9.
J Pediatr ; 247: 22-28.e2, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35577119

RESUMO

OBJECTIVE: To describe neurologic, radiologic and laboratory features in children with central nervous system (CNS) inflammatory disease complicating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. STUDY DESIGN: We focused on CNS inflammatory diseases in children referred from 12 hospitals in the Paris area to Necker-Sick Children Reference Centre. RESULTS: We identified 19 children who had a history of SARS-CoV-2 infection and manifest a variety of CNS inflammatory diseases: encephalopathy, cerebellar ataxia, acute disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, or optic neuritis. All patients had a history of SARS-CoV-2 exposure, and all tested positive for circulating antibodies against SARS-CoV-2. At the onset of the neurologic disease, SARS-CoV-2 PCR results (nasopharyngeal swabs) were positive in 8 children. Cerebrospinal fluid was abnormal in 58% (11/19) and magnetic resonance imaging was abnormal in 74% (14/19). We identified an autoantibody co-trigger in 4 children (myelin-oligodendrocyte and aquaporin 4 antibodies), representing 21% of the cases. No autoantibody was found in the 6 children whose CNS inflammation was accompanied by a multisystem inflammatory syndrome in children. Overall, 89% of patients (17/19) received anti-inflammatory treatment, primarily high-pulse methylprednisolone. All patients had a complete long-term recovery and, to date, no patient with autoantibodies presented with a relapse. CONCLUSIONS: SARS2-CoV-2 represents a new trigger of postinfectious CNS inflammatory diseases in children.


Assuntos
COVID-19 , Autoanticorpos , COVID-19/complicações , Humanos , Glicoproteína Mielina-Oligodendrócito , Doenças Neuroinflamatórias , SARS-CoV-2 , Síndrome de Resposta Inflamatória Sistêmica
10.
Genet Med ; 23(1): 111-122, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32855533

RESUMO

PURPOSE: Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease with often unrecognized inherited forms. We sought to identify novel pathogenic variants associated with autosomal dominant inheritance of TAAD. METHODS: We analyzed exome sequencing data from 35 French TAAD families and performed next-generation sequencing capture panel of genes in 1114 unrelated TAAD patients. Functional effects of pathogenic variants identified were validated in cell, tissue, and mouse models. RESULTS: We identified five functional variants in THSD4 of which two heterozygous variants lead to a premature termination codon. THSD4 encodes ADAMTSL6 (member of the ADAMTS/L superfamily), a microfibril-associated protein that promotes fibrillin-1 matrix assembly. The THSD4 variants studied lead to haploinsufficiency or impaired assembly of fibrillin-1 microfibrils. Thsd4+/- mice showed progressive dilation of the thoracic aorta. Histologic examination of aortic samples from a patient carrying a THSD4 variant and from Thsd4+/- mice, revealed typical medial degeneration and diffuse disruption of extracellular matrix. CONCLUSION: These findings highlight the role of ADAMTSL6 in aortic physiology and TAAD pathogenesis. They will improve TAAD management and help develop new targeted therapies.


Assuntos
Aneurisma da Aorta Torácica , Dissecção Aórtica , Proteínas ADAM , Dissecção Aórtica/genética , Animais , Aneurisma da Aorta Torácica/genética , Exoma/genética , Fibrilina-1/genética , Humanos , Camundongos
11.
J Clin Apher ; 36(6): 823-830, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34469617

RESUMO

INTRODUCTION: Therapeutic plasma exchange (TPE) is acknowledged to be an effective treatment in life-threatening pediatric disorders. Apheresis for pediatric diseases has been poorly investigated, and most studies to date featured small numbers of patients and lacked control groups. The objective of the present study was to evaluate the tolerance of TPE in pediatric patients. MATERIALS AND METHODS: A retrospective cohort study via a web-based electronic case report form including pediatric patients referred for TPE between January 2005 and December 2014. RESULTS: A total of 78 patients (median [range] age: 9.8 [0.53-17.93]) and 731 TPE procedures were analyzed. The indications were antibody-mediated rejection (n = 33; 42%) and desensitization therapy (n = 5; 6%) after solid organ or hematopoietic stem cell transplantation, thrombotic microangiopathy (n = 17; 22%), pediatric inflammatory diseases (n = 16; 21%), kidney diseases (n = 6; 8%), and hyperviscosity syndrome (n = 1; 1%). On average, each patient underwent six procedures during the first session [range: 1-19]. In the 2 weeks following the start of a session, 72 patients (92%) presented a total of 311 adverse events (AEs) potentially related to TPE. The risk of AEs was not related to the indication for TPE, the intensity of care, venous access, plasma substitute use, or body weight. None of the deaths was related to the TPE. CONCLUSION: We studied one of the largest retrospective pediatric cohorts described to date. Our experience of TPE children's TPE feasibility concerned specific, life-threatening conditions and otherwise treatment-refractory diseases.


Assuntos
Cuidados Críticos/métodos , Troca Plasmática/métodos , Adolescente , Criança , Estudos de Viabilidade , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Inflamação/terapia , Unidades de Terapia Intensiva Pediátrica , Nefropatias/terapia , Masculino , Troca Plasmática/efeitos adversos , Estudos Retrospectivos , Microangiopatias Trombóticas/terapia , Resultado do Tratamento
12.
Euro Surveill ; 26(13)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33797390

RESUMO

BackgroundChildren have a low rate of COVID-19 and secondary severe multisystem inflammatory syndrome (MIS) but present a high prevalence of symptomatic seasonal coronavirus infections.AimWe tested if prior infections by seasonal coronaviruses (HCoV) NL63, HKU1, 229E or OC43 as assessed by serology, provide cross-protective immunity against SARS-CoV-2 infection.MethodsWe set a cross-sectional observational multicentric study in pauci- or asymptomatic children hospitalised in Paris during the first wave for reasons other than COVID (hospitalised children (HOS), n = 739) plus children presenting with MIS (n = 36). SARS-CoV-2 antibodies directed against the nucleoprotein (N) and S1 and S2 domains of the spike (S) proteins were monitored by an in-house luciferase immunoprecipitation system assay. We randomly selected 69 SARS-CoV-2-seropositive patients (including 15 with MIS) and 115 matched SARS-CoV-2-seronegative patients (controls (CTL)). We measured antibodies against SARS-CoV-2 and HCoV as evidence for prior corresponding infections and assessed if SARS-CoV-2 prevalence of infection and levels of antibody responses were shaped by prior seasonal coronavirus infections.ResultsPrevalence of HCoV infections were similar in HOS, MIS and CTL groups. Antibody levels against HCoV were not significantly different in the three groups and were not related to the level of SARS-CoV-2 antibodies in the HOS and MIS groups. SARS-CoV-2 antibody profiles were different between HOS and MIS children.ConclusionPrior infection by seasonal coronaviruses, as assessed by serology, does not interfere with SARS-CoV-2 infection and related MIS in children.


Assuntos
Anticorpos Antivirais/imunologia , COVID-19/imunologia , Coronavirus Humano OC43 , SARS-CoV-2/imunologia , Síndrome de Resposta Inflamatória Sistêmica , Adolescente , Anticorpos Antivirais/sangue , COVID-19/sangue , COVID-19/diagnóstico , Criança , Pré-Escolar , Estudos Transversais , Feminino , França/epidemiologia , Humanos , Lactente , Recém-Nascido , Masculino , Paris , Estações do Ano , Testes Sorológicos/métodos , Glicoproteína da Espícula de Coronavírus
13.
Genet Med ; 21(9): 2015-2024, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30739908

RESUMO

PURPOSE: Heritable thoracic aortic aneurysms and dissections (hTAAD) are life-threatening complications of well-known syndromic diseases or underdiagnosed nonsyndromic heritable forms (nshTAAD). Both have an autosomal dominant transmission and are genetically heterogeneous. Our objective was to describe the relevance of molecular diagnosis in these patients and the contribution of each gene in nshTAAD. METHODS: Two hundred twenty-six consecutive nshTAAD probands, either young (<45 years) sporadic or familial cases were included. A next-generation sequencing capture panel comprising 23 known disease-causing genes was performed. RESULTS: Class 4 or 5 variants were identified in 18% of the nshTAAD probands, while class 3 variants were found in 10% of them. The yield in familial cases was greater than in sporadic cases. SMAD3 and FBN1 genes were the major disease-causing genes. Unexpectedly, no premature termination codon variant was identified in the FBN1 gene. Furthermore, we report for the first time that aortic dissection or surgery occurred significantly more often and earlier in probands with a class 4 or 5 pathogenic variant. CONCLUSION: This study indicates that genetic screening using NGS is efficient in young and familial nshTAAD. The presence of a pathogenic variant has a possible predictive value, which needs to be further investigated because it may influence care.


Assuntos
Aneurisma da Aorta Torácica/genética , Dissecção Aórtica/genética , Fibrilina-1/genética , Proteína Smad3/genética , Adolescente , Adulto , Idoso , Dissecção Aórtica/diagnóstico , Dissecção Aórtica/fisiopatologia , Aneurisma da Aorta Torácica/diagnóstico , Criança , Códon sem Sentido/genética , Feminino , Predisposição Genética para Doença , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Patologia Molecular/métodos , Linhagem , Adulto Jovem
15.
J Med Genet ; 54(2): 100-103, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27582083

RESUMO

BACKGROUND: Marfan syndrome (MFS) is an autosomal-dominant connective tissue disorder usually associated with heterozygous mutations in the gene encoding fibrillin-1 (FBN1). Homozygous and compound heterozygous cases are rare events and have been associated with a clinical severe presentation. OBJECTIVES: Report unexpected findings of homozygosity and compound heterozygosity in the course of molecular diagnosis of heterozygous MFS and compare the findings with published cases. METHODS AND RESULTS: In the context of molecular diagnosis of heterozygous MFS, systematic sequencing of the FBN1 gene was performed in 2500 probands referred nationwide. 1400 probands carried a heterozygous mutation in this gene. Unexpectedly, among them four homozygous cases (0.29%) and five compound heterozygous cases (0.36%) were identified (total: 0.64%). Interestingly, none of these cases carried two premature termination codon mutations in the FBN1 gene. Clinical features for these carriers and their families were gathered and compared. There was a large spectrum of severity of the disease in probands carrying two mutated FBN1 alleles, but none of them presented extremely severe manifestations of MFS in any system compared with carriers of only one mutated FBN1 allele. This observation is not in line with the severe clinical features reported in the literature for four homozygous and three compound heterozygous probands. CONCLUSION: Homozygotes and compound heterozygotes were unexpectedly identified in the course of molecular diagnosis of MFS. Contrary to previous reports, the presence of two mutated alleles was not associated with severe forms of MFS. Although homozygosity and compound heterozygosity are rarely found in molecular diagnosis, they should not be overlooked, especially among consanguineous families. However, no predictive evaluation of severity should be provided.


Assuntos
Fibrilina-1/genética , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Patologia Molecular , Alelos , Códon sem Sentido , Feminino , Predisposição Genética para Doença , Testes Genéticos , Heterozigoto , Homozigoto , Humanos , Masculino , Síndrome de Marfan/patologia , Mutação de Sentido Incorreto/genética , Linhagem
16.
Hum Mol Genet ; 24(10): 2764-70, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25652400

RESUMO

Marfan syndrome is an autosomal dominant disorder mainly caused by mutations within FBN1 gene. The disease displays large variability in age of onset or severity and very poor phenotype/genotype correlations have been demonstrated. We investigated the hypothesis that phenotype severity could be related to the variable expression level of fibrillin-1 (FBN1) synthesized from the wild-type (WT) allele. Quantitative reverse-transcription and polymerase chain reaction was used to evaluate FBN1 levels in skin fibroblasts from 80 Marfan patients with premature termination codons and in skin fibroblasts from 80 controls. Results in controls showed a 3.9-fold variation in FBN1 mRNA synthesis level between subjects. A similar 4.4-fold variation was found in the Marfan population, but the mean level of FBN1 mRNA was a half of the control population. Differential allelic expression analysis in Marfan fibroblasts showed that over 90% of FBN1 mRNA was transcribed from the wild allele and the mutated allele was not detected. In the control population, independently of the expression level of FBN1, we observed steady-state equilibrium between the two allelic-mRNAs suggesting that FBN1 expression mainly depends on trans-acting regulators. Finally, we show that a low level of residual WT FBN1 mRNA accounts for a high risk of ectopia lentis and pectus abnormality and tends to increase the risk of aortic dilatation.


Assuntos
Síndrome de Marfan/genética , Proteínas dos Microfilamentos/genética , Adolescente , Adulto , Idoso , Alelos , Criança , Pré-Escolar , Códon sem Sentido , Ectopia do Cristalino/genética , Feminino , Fibrilina-1 , Fibrilinas , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Lactente , Recém-Nascido , Masculino , Síndrome de Marfan/diagnóstico , Pessoa de Meia-Idade , Adulto Jovem
17.
Am J Hum Genet ; 95(6): 736-43, 2014 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-25434006

RESUMO

Thoracic aortic aneurysm and dissection (TAAD) is an autosomal-dominant disorder with major life-threatening complications. The disease displays great genetic heterogeneity with some forms allelic to Marfan and Loeys-Dietz syndrome, and an important number of cases still remain unexplained at the molecular level. Through whole-exome sequencing of affected members in a large TAAD-affected family, we identified the c.472C>T (p.Arg158(∗)) nonsense mutation in MFAP5 encoding the extracellular matrix component MAGP-2. This protein interacts with elastin fibers and the microfibrillar network. Mutation screening of 403 additional probands identified an additional missense mutation of MFAP5 (c.62G>T [p.Trp21Leu]) segregating with the disease in a second family. Functional analyses performed on both affected individual's cells and in vitro models showed that these two mutations caused pure or partial haploinsufficiency. Thus, alteration of MAGP-2, a component of microfibrils and elastic fibers, appears as an initiating mechanism of inherited TAAD.


Assuntos
Aneurisma da Aorta Torácica/genética , Dissecção Aórtica/genética , Proteínas Contráteis/genética , Glicoproteínas/genética , Haploinsuficiência/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Substituição de Aminoácidos , Dissecção Aórtica/fisiopatologia , Aneurisma da Aorta Torácica/fisiopatologia , Criança , Códon sem Sentido , Proteínas Contráteis/metabolismo , Exoma/genética , Feminino , Fibroblastos , Glicoproteínas/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Masculino , Pessoa de Meia-Idade , Linhagem , Análise de Sequência de DNA
18.
J Pediatr Hematol Oncol ; 38(7): 497-502, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27548334

RESUMO

Iron overload is an ineluctable complication in chronically transfused children warranting accurate assessment to avoid related morbidity. We investigated longitudinally the relationships between ferritin levels and hepatic and cardiac T2* magnetic resonance imaging (MRI) in a cohort of chronically transfused children receiving chelation therapy. Thirty children with sickle cell anemia (SCA) and 7 with thalassemia major (TM) chelated similarly by deferasirox were analyzed. Sex ratio, age, median duration of transfusion programs (5 y; range, 2 to 14 y), median transfusion iron intake 0.54 mg/kg/d (range, 0.27 to 0.74 mg/kg/d), and median ferritin level (1550 mg/L; range, 184 to 6204 mg/L) were comparable in TM and SCA. A significant relation was found between ferritin level and transfusion iron intake (P<0.001) despite chelation therapy. Analysis of 73 hepatic T2* MRI performed yearly demonstrated severe hepatic iron overload (≥14 mg/g) in 38.3% cases and a strong relationship between serum ferritin level and liver iron content both in SCA and TM (P<0.001). Analysis of 55 cardiac T2* MRI measurements found no cardiac overload in patients with SCA. Cardiac iron overload was moderate in 4 cases and severe in 1 case of TM. In almost half the cases, ferritin trend correctly predicted hepatic iron trend, both in patients with SCA and TM but failed to predict cardiac iron trend, notably in TM patients. Despite chelation therapy, iron burden in chronically transfused patients remains a threat. Ferritin levels are associated with liver iron overload in chelated children with SCA and TM, but iron burden should be best monitored with MRI whenever the setting allows it.


Assuntos
Anemia Falciforme/terapia , Transfusão de Sangue , Terapia por Quelação , Ferritinas/sangue , Sobrecarga de Ferro/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Talassemia beta/terapia , Adolescente , Anemia Falciforme/sangue , Criança , Pré-Escolar , Feminino , Coração/diagnóstico por imagem , Humanos , Sobrecarga de Ferro/sangue , Fígado/diagnóstico por imagem , Masculino , Talassemia beta/sangue
19.
Euro Surveill ; 21(46)2016 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-27918268

RESUMO

We report 59 cases of severe paediatric conditions linked with enterovirus (EV)-A71 and EV-D68 in France between May and October 2016. Fifty-two children had severe neurological symptoms. EV sequence-based typing for 42 cases revealed EV-A71 in 21 (18 subgenotype C1, detected for the first time in France) and EV-D68 in eight. Clinicians should be encouraged to obtain stool and respiratory specimens from patients presenting with severe neurological disorders for EV detection and characterisation.


Assuntos
Coinfecção/virologia , Enterovirus Humano A/isolamento & purificação , Enterovirus Humano D/isolamento & purificação , Infecções por Enterovirus/epidemiologia , Tipagem Molecular , Doenças do Sistema Nervoso/virologia , Infecções Respiratórias/diagnóstico , Adolescente , Criança , Pré-Escolar , Coinfecção/epidemiologia , Enterovirus Humano A/genética , Enterovirus Humano D/genética , Infecções por Enterovirus/diagnóstico , Infecções por Enterovirus/virologia , Feminino , França/epidemiologia , Genótipo , Hospitalização/estatística & dados numéricos , Humanos , Lactente , Masculino , Doenças do Sistema Nervoso/complicações , Filogenia , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/virologia , Vigilância de Evento Sentinela , Análise de Sequência de DNA , Índice de Gravidade de Doença
20.
Pediatr Infect Dis J ; 43(8): e282-e284, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38753997

RESUMO

A 13-year-old boy was admitted with severe meningococcal meningitis. Immunologic workup revealed a properdin deficiency, and genetic sequencing of CFP identified a novel, private and predicted pathogenic variant in exon 8. The patient received broad immunizations and penicillin prophylaxis. Children with invasive meningococcal disease should be tested for complement deficiency.


Assuntos
Meningite Meningocócica , Properdina , Humanos , Masculino , Meningite Meningocócica/diagnóstico , Adolescente , Properdina/deficiência , Properdina/genética , Neisseria meningitidis/genética
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