RESUMO
Heterozygous microdeletions of chromosome 15q13.3 (MIM: 612001) show incomplete penetrance and are associated with a highly variable phenotype that may include intellectual disability, epilepsy, facial dysmorphism and digit anomalies. Rare patients carrying homozygous deletions show more severe phenotypes including epileptic encephalopathy, hypotonia and poor growth. For years, CHRNA7 (MIM: 118511), was considered the candidate gene that could account for this syndrome. However, recent studies in mouse models have shown that OTUD7A/CEZANNE2 (MIM: 612024), which encodes for an ovarian tumor (OTU) deubiquitinase, should be considered the critical gene responsible for brain dysfunction. In this study, a patient presenting with severe global developmental delay, language impairment and epileptic encephalopathy was referred to our genetics center. Trio exome sequencing (tES) analysis identified a homozygous OTUD7A missense variant (NM_130901.2:c.697C>T), predicted to alter an ultraconserved amino acid, p.(Leu233Phe), lying within the OTU catalytic domain. Its subsequent segregation analysis revealed that the parents, presenting with learning disability, and brother were heterozygous carriers. Biochemical assays demonstrated that proteasome complex formation and function were significantly reduced in patient-derived fibroblasts and in OTUD7A knockout HAP1 cell line. We provide evidence that biallelic pathogenic OTUD7A variation is linked to early-onset epileptic encephalopathy and proteasome dysfunction.
Assuntos
Transtornos Cromossômicos/genética , Enzimas Desubiquitinantes/genética , Epilepsia/genética , Deficiência Intelectual/genética , Convulsões/genética , Animais , Deleção Cromossômica , Transtornos Cromossômicos/fisiopatologia , Cromossomos Humanos Par 15/genética , Epilepsia/fisiopatologia , Feminino , Heterozigoto , Homozigoto , Humanos , Deficiência Intelectual/patologia , Deficiência Intelectual/fisiopatologia , Masculino , Camundongos , Mutação de Sentido Incorreto/genética , Fenótipo , Convulsões/fisiopatologia , Sequenciamento do Exoma , Receptor Nicotínico de Acetilcolina alfa7/genéticaRESUMO
OBJECTIVES: Plummer-Vinson syndrome (PVS), also called Kelly-Paterson syndrome, is a rare cause of dysphagia in children. This syndrome associates single or multiple webs in the upper esophagus with frequent iron deficiency. METHODS: We reported 3 pediatric cases of PVS before analyzing all of the cases of PVS in children reported in the PubMed and EMBASE databases. RESULTS: Among 17 reported PVS cases in children, all of the patients experienced iron-deficiency anemia, and no immunological disease was reported. The male/female ratio was 1/1.9, and most cases were observed in adolescents. Conversely to adults, endoscopic dilation was often necessary because dysphagia resisted iron supplementation. A single dilation was usually sufficient. One case of pediatric PVS experienced esophageal cancer in adulthood. CONCLUSIONS: In the case of dysphagia in children, a swallow barium exploration with lateral incidence should look for PVS. Conversely to adults, an endoscopic dilation is frequently necessary to control dysphagia in children.
