RESUMEN
Congenital fixed dilated pupils (congenital mydriasis) is characterized by hypoplasia or aplasia of the iris muscles, with absence of iris between the collarette and pupillary border, creating a scalloped pupillary margin. This condition has been reported in a multisystemic smooth muscle cell dysfunction syndrome, combined with congenital patent ductus arteriosus, cerebrovascular disease (Moya-moya-like), coronary artery disease, thoracic aorta aneurysm, and dysfunction of smooth muscle cells in organs throughout the body. All affected individuals carry a p.R179H heterozygous mutation in the ACTA2 gene. We add to the ophthalmologic involvement with 3 more patients. Congenital fixed dilated pupils is a rare condition and should alert ophthalmologists to the possibility of the coexistence of systemic life-threatening disorders.
Asunto(s)
Actinas/genética , Músculo Liso/patología , Enfermedades Musculares/patología , Trastornos de la Pupila/genética , Trastornos de la Pupila/patología , Adolescente , Femenino , Humanos , Imagen por Resonancia Magnética , Enfermedades Musculares/complicaciones , Enfermedades Musculares/genética , Trastornos de la Pupila/complicaciones , Adulto JovenRESUMEN
This study estimated ASD prevalence in a cohort of 3-year-old very preterm children (N = 55) and investigated the usefulness of parent-reported ASD screeners and the ADOS-2. 12.7% received an ASD diagnosis by clinical judgment based on DSM-5 criteria. An additional 14.5% were classified as having a broader-autism-phenotype outcome. Sensitivity values for the screeners were poor, whereas specificity values ranged from poor to excellent. The ADOS-2 identified all children with ASD and had a fair specificity. These findings confirm the elevated ASD prevalence made by previous studies with preterm children but also highlight the challenges of successfully identifying ASD in this at-risk group. Caution is warranted when interpreting results of ASD instruments with the currently available cut-off scores and algorithms, especially when developmental challenges are present.
Asunto(s)
Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/epidemiología , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Recien Nacido Extremadamente Prematuro/fisiología , Algoritmos , Trastorno del Espectro Autista/psicología , Preescolar , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recien Nacido Extremadamente Prematuro/psicología , Recién Nacido , Masculino , Prevalencia , Estudios Prospectivos , Factores de RiesgoRESUMEN
Mitochondrial DNA (mtDNA) has been suggested to drive immune system activation, but the induction of interferon signaling by mtDNA has not been demonstrated in a Mendelian mitochondrial disease. We initially ascertained two patients, one with a purely neurological phenotype and one with features suggestive of systemic sclerosis in a syndromic context, and found them both to demonstrate enhanced interferon-stimulated gene (ISG) expression in blood. We determined each to harbor a previously described de novo dominant-negative heterozygous mutation in ATAD3A, encoding ATPase family AAA domain-containing protein 3A (ATAD3A). We identified five further patients with mutations in ATAD3A and recorded up-regulated ISG expression and interferon α protein in four of them. Knockdown of ATAD3A in THP-1 cells resulted in increased interferon signaling, mediated by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Enhanced interferon signaling was abrogated in THP-1 cells and patient fibroblasts depleted of mtDNA. Thus, mutations in the mitochondrial membrane protein ATAD3A define a novel type I interferonopathy.
Asunto(s)
ATPasas Asociadas con Actividades Celulares Diversas/genética , Interferones/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas Mitocondriales/genética , Mutación , Nucleotidiltransferasas/metabolismo , ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , Niño , Preescolar , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Femenino , Genes Dominantes , Humanos , Interferones/genética , Masculino , Proteínas Mitocondriales/metabolismo , Nucleotidiltransferasas/genética , Esclerodermia Sistémica/genética , Esclerodermia Sistémica/patología , Transducción de Señal , Células THP-1 , Adulto JovenRESUMEN
Voltage-gated calcium channels have an important role in neurotransmission. Aberrations affecting genes encoding the alpha subunit of these channels have been associated with epilepsy and neuropsychiatric disorders such as autism or schizophrenia. Here we report three patients with a genomic aberration affecting the CACNA2D1 gene encoding the α2δ subunit of these voltage-gated calcium channels. All three patients present with epilepsy and intellectual disability pinpointing the CACNA2D1 gene as an interesting candidate gene for these clinical features. Besides these characteristics, patient 2 also presents with obesity with hyperinsulinism, which is very likely to be caused by deletion of the CD36 gene.
Asunto(s)
Canales de Calcio/genética , Aberraciones Cromosómicas , Epilepsia/diagnóstico , Epilepsia/genética , Estudios de Asociación Genética , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Adolescente , Hibridación Genómica Comparativa , Femenino , Humanos , Hibridación Fluorescente in Situ , LactanteRESUMEN
Warburg Micro Syndrome is a rare, autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornia, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism. We have found five new mutations in the RAB3GAP1 gene in seven patients with suspected Micro Syndrome from families with Turkish, Palestinian, Danish, and Guatemalan backgrounds. A thorough clinical investigation of the patients has allowed the delineation of symptoms that are consistently present in the patients and may aid the differential diagnosis of Micro Syndrome for patients in the future. All patients had postnatal microcephaly, micropthalmia, microcornia, bilateral congenital cataracts, short palpebral fissures, optic atrophy, severe mental retardation, and congenital hypotonia with subsequent spasticity. Only one patient had microcephaly at birth, highlighting the fact that congenital microcephaly is not a consistent feature of Micro syndrome. Analysis of the brain magnetic resonance imagings (MRIs) revealed a consistent pattern of polymicrogyria in the frontal and parietal lobes, wide sylvian fissures, a thin hypoplastic corpus callosum, and increased subdural spaces. All patients were homozygous for the mutations detected and all mutations were predicted to result in a truncated RAB3GAP1 protein. The analysis of nine polymorphic markers flanking the RAB3GAP1 gene showed that the mutation c.1410C>A (p.Tyr470X), for which a Danish patient was homozygous, occurred on a haplotype that is shared by the unrelated heterozygous parents of the patient. This suggests a possible founder effect for this mutation in the Danish population.