RESUMEN
Early infantile epileptic encephalopathy 38 (EIEE38, MIM #617020) is caused by biallelic variants in ARV1, encoding a transmembrane protein of the endoplasmic reticulum with a pivotal role in glycosylphosphatidylinositol (GPI) biosynthesis. We ascertained seven new patients from six unrelated families harboring biallelic variants in ARV1, including five novel variants. Affected individuals showed psychomotor delay, hypotonia, early onset refractory seizures followed by regression and specific neuroimaging features. Flow cytometric analysis on patient fibroblasts showed a decrease in GPI-anchored proteins on the cell surface, supporting a lower residual activity of the mutant ARV1 as compared to the wildtype. A rescue assay through the transduction of lentivirus expressing wild type ARV1 cDNA effectively rescued these alterations. This study expands the clinical and molecular spectrum of the ARV1-related encephalopathy, confirming the essential role of ARV1 in GPI biosynthesis and brain function.
Asunto(s)
Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Proteínas de la Membrana/deficiencia , Fenotipo , Espasmos Infantiles/diagnóstico , Espasmos Infantiles/genética , Alelos , Sustitución de Aminoácidos , Encéfalo/anomalías , Proteínas Portadoras/genética , Análisis Mutacional de ADN , Facies , Femenino , Proteínas Ligadas a GPI/biosíntesis , Estudios de Asociación Genética/métodos , Glicosilfosfatidilinositoles/metabolismo , Humanos , Imagen por Resonancia Magnética , Masculino , Proteínas de la Membrana/genética , Mutación , Linaje , Embarazo , Diagnóstico Prenatal/métodos , Espasmos Infantiles/metabolismoRESUMEN
BACKGROUND: Of the fewer than 100 cases reported within the literature of constitutional deletions involving the long arm of chromosome 6, only five have been characterized using high-resolution microarray analysis. Reported 6q deletion patients show a high incidence of mental retardation, ear anomalies, hypotonia, and postnatal growth retardation. RESULTS: We report a 16-month-old male presenting with developmental delay and dysmorphic features who was found by array-based comparative genomic hybridization (aCGH) to have a ~2.16 Mb de novo deletion within chromosome band 6q16.1 that encompasses only two genes. Expression studies of the mouse homologue of one of the genes, the ephrin receptor 7 gene (EPHA7), have shown the gene functions during murine embryogenesis to form cortical domains, determine brain size and shape, and play a role in development of the central nervous system (CNS). DISCUSSION: Our results suggest that deletion of EPHA7 plays a role in the neurologic and dysmorphic features, including developmental delay, hypotonia, and ear malformations, observed in some 6q deletion patients.