RESUMEN
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.
Asunto(s)
Adenosina Desaminasa/genética , Enfermedades Autoinmunes del Sistema Nervioso/genética , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Interferón Tipo I/metabolismo , Malformaciones del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/inmunología , Proteínas de Unión al ARN/genética , Adolescente , Adulto , Enfermedades Autoinmunes del Sistema Nervioso/diagnóstico por imagen , Biomarcadores/metabolismo , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Mutación , Malformaciones del Sistema Nervioso/diagnóstico por imagen , Fenotipo , Adulto JovenRESUMEN
BACKGROUND: Neonatal seizures are a risk factor for later epilepsy and their etiology is known to be implicated in the outcome but, little is known about this issue in the subgroup of seizures symptomatic of perinatal arterial ischemic stroke. The aim of this study was to describe the long term risk of epilepsy after electroencephalographic confirmed neonatal seizures symptomatic of perinatal arterial ischemic stroke. DESIGN/SUBJECT: Fifty-five patients with electroclinical ictal data, vascular territory confirmed by neuroimaging and a minimum follow up of 3.5 years were identified from a multi-centre prospective neonatal seizures registry. Primary outcome was occurrence of post-neonatal epilepsy. The association of outcome with family history of epilepsy, gender, location of the infarct, neonatal clinical and electroencephalogram data were also studied. RESULTS: During a mean follow up of 8 years and 5 months, 16.4% of the patients developed post neonatal epilepsy. The mean age at first post neonatal seizure was 4 years and 2 months (range 1-10 years and 6 months). Location of the infarct was the only statistically significant risk factor (p=0.001); epilepsy was more represented in males but the difference was not statistically significant. CONCLUSIONS: Neonatal seizures symptomatic of perinatal arterial ischemic stroke had lower risk and later onset of post-neonatal epilepsy, compared to seizures described in the setting of other perinatal brain insults. Our data have implications for counseling to the family at discharge from neonatal intensive care unit.
Asunto(s)
Isquemia Encefálica/epidemiología , Epilepsia/epidemiología , Convulsiones/epidemiología , Accidente Cerebrovascular/epidemiología , Edad de Inicio , Encéfalo/patología , Encéfalo/fisiopatología , Isquemia Encefálica/patología , Isquemia Encefálica/fisiopatología , Niño , Preescolar , Progresión de la Enfermedad , Electroencefalografía , Epilepsia/diagnóstico , Epilepsia/patología , Epilepsia/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Masculino , Pronóstico , Sistema de Registros , Estudios Retrospectivos , Riesgo , Convulsiones/patología , Convulsiones/fisiopatología , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/fisiopatologíaRESUMEN
Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutières syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials.
Asunto(s)
Adenosina Desaminasa/genética , Enfermedades Autoinmunes del Sistema Nervioso/diagnóstico , Enfermedades Autoinmunes del Sistema Nervioso/genética , ARN Helicasas DEAD-box/genética , Exodesoxirribonucleasas/genética , Proteínas de Unión al GTP Monoméricas/genética , Mutación , Malformaciones del Sistema Nervioso/diagnóstico , Malformaciones del Sistema Nervioso/genética , Fenotipo , Fosfoproteínas/genética , Ribonucleasa H/genética , Estudios de Asociación Genética , Genotipo , Humanos , Helicasa Inducida por Interferón IFIH1 , Interferones/sangre , Interferones/líquido cefalorraquídeo , Pterinas/líquido cefalorraquídeo , Proteína 1 que Contiene Dominios SAM y HDRESUMEN
We report on a 30-month-old baby girl with typical clinical features of WAGR syndrome. In addition, the patient showed bilateral preaxial polydactyly of the feet. Cytogenetic and fluorescent in situ hybridization (FISH) analyses identified a deletion, del(11)(p13p14.1), extending from 6.1 to 21.7 Mb in size. Although the simultaneous appearance of WAGR and polydactyly has been already described, to our knowledge this is the first case in which the characterization at the cytogenetic molecular level of a patient with these phenotypes is reported. These observations indicate that preaxial polydactyly may be another feature of the WAGR syndrome and suggest the existence of a related gene in the WAGR critical region or in its proximity.