RESUMEN
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.
Asunto(s)
Trastorno del Espectro Autista/genética , Discapacidad Intelectual/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Mutación , Trastornos del Neurodesarrollo/genética , Transcriptoma/genética , Animales , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/fisiopatología , Modelos Animales de Enfermedad , Epigénesis Genética , Aseo Animal/fisiología , Humanos , Discapacidad Intelectual/metabolismo , Discapacidad Intelectual/fisiopatología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Noqueados , Trastornos del Neurodesarrollo/metabolismo , Trastornos del Neurodesarrollo/fisiopatología , Fenotipo , Células Sf9 , SpodopteraRESUMEN
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.
Asunto(s)
Enfermedades de los Ganglios Basales/inducido químicamente , Encefalopatías Metabólicas/inducido químicamente , Espasmos Infantiles/tratamiento farmacológico , Vigabatrin/efectos adversos , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/efectos adversos , Enfermedades de los Ganglios Basales/patología , Encefalopatías Metabólicas/patología , Enfermedad Crónica , Humanos , Lactante , Espectroscopía de Resonancia Magnética/métodos , Masculino , Espasmos Infantiles/patología , Vigabatrin/administración & dosificaciónRESUMEN
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.