RESUMO
Intellectual disability (ID) and autism spectrum disorder (ASD) are the most common neurodevelopmental disorders and are characterized by substantial impairment in intellectual and adaptive functioning, with their genetic and molecular basis remaining largely unknown. Here, we identify biallelic variants in the gene encoding one of the Elongator complex subunits, ELP2, in patients with ID and ASD. Modelling the variants in mice recapitulates the patient features, with brain imaging and tractography analysis revealing microcephaly, loss of white matter tract integrity and an aberrant functional connectome. We show that the Elp2 mutations negatively impact the activity of the complex and its function in translation via tRNA modification. Further, we elucidate that the mutations perturb protein homeostasis leading to impaired neurogenesis, myelin loss and neurodegeneration. Collectively, our data demonstrate an unexpected role for tRNA modification in the pathogenesis of monogenic ID and ASD and define Elp2 as a key regulator of brain development.
Assuntos
Transtorno do Espectro Autista/genética , Deficiência Intelectual/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação , Transtornos do Neurodesenvolvimento/genética , Transcriptoma/genética , Animais , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/fisiopatologia , Modelos Animais de Doenças , Epigênese Genética , Asseio Animal/fisiologia , Humanos , Deficiência Intelectual/metabolismo , Deficiência Intelectual/fisiopatologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/fisiopatologia , Fenótipo , Células Sf9 , SpodopteraRESUMO
Transient magnetic resonance imaging (MRI) hyperintensity of globus pallidi, thalami, dentate nuclei and cerebral peduncles has recently been described in a significant number of young children during treatment with vigabatrin for infantile spasms. We describe two children with infantile spasms treated with vigabatrin, investigated with consecutive MRI as well as magnetic resonance spectroscopy (MRS). Hyperintensity developed during high dose vigabatrin treatment and remitted totally after dose reduction in one case, and cessation in the other. Abnormalities on MRS, suggesting an increase in the glutamine-glutamate complex in the basal ganglia, were found in both cases while on vigabatrin treatment. These changes remitted in the first case after reduction of vigabatrin dose and when seizure free and with a normalized EEG, but persisted in the second case following cessation of vigabatrin without remission of seizure activity.
Assuntos
Doenças dos Gânglios da Base/induzido quimicamente , Encefalopatias Metabólicas/induzido quimicamente , Espasmos Infantis/tratamento farmacológico , Vigabatrina/efeitos adversos , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Doenças dos Gânglios da Base/patologia , Encefalopatias Metabólicas/patologia , Doença Crônica , Humanos , Lactente , Espectroscopia de Ressonância Magnética/métodos , Masculino , Espasmos Infantis/patologia , Vigabatrina/administração & dosagemRESUMO
UNLABELLED: A 5-week-old girl with inspiratory stridor is presented. No immediate cause of the stridor was found, but eventually a diagnosis of infantile hemangiopericytoma located in the rhinopharynx was made. After surgery all respiratory symptoms disappeared. CONCLUSION: Infantile hemangiopericytoma is a rare tumour of infancy and a very rare cause of inspiratory stridor in this age group. The mainstay of treatment is surgery. The overall prognosis is favourable but because of the unpredictable nature of the tumour, long-term follow-up is recommended.