| Autor: |
Nabavi Nouri M; Division of Neurology, Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5A5, Canada.; Children's Health Research Institute, London Health Sciences Centre, London, ON N6A 5W9, Canada., Alandijani L; Division of Neurology, Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5A5, Canada., van Engelen K; Division of Genetics, Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5A5, Canada., Tole S; Division of Hematology and Oncology, Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5A5, Canada., Lalonde E; Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5A5, Canada., Balci TB; Children's Health Research Institute, London Health Sciences Centre, London, ON N6A 5W9, Canada.; Division of Genetics, Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5A5, Canada. |
| Abstrakt: |
Introduction : The NPRL3 gene is a critical component of the GATOR1 complex, which negatively regulates the mTORC1 pathway, essential for neurogenesis and brain development. Located on chromosome 16p13.3, NPRL3 is situated near the α-globin gene cluster. Haploinsufficiency of NPRL3 , either by deletion or a pathogenic variant, is associated with a variable phenotype of focal epilepsy, with or without malformations of cortical development, with known decreased penetrance. Case Description : This work details the diagnostic odyssey of a neurotypical 10-year-old boy who presented at age 2 with unusual nocturnal episodes and a history of microcytic anemia, as well as a review of the existing literature on NPRL3 -related epilepsy, with an emphasis on individuals with deletions who also present with α-thalassemia trait. The proband's episodes were mistaken for gastroesophageal reflux disease for several years. He had molecular testing for his α-thalassemia trait and was noted to carry a deletion encompassing the regulatory region of the α-thalassemia gene cluster. Following the onset of overt focal motor seizures, genetic testing revealed a heterozygous loss of NPRL3, within a 106 kb microdeletion on chromosome 16p13.3, inherited from his mother. This deletion encompassed the entire NPRL3 gene, which overlaps the regulatory region of the α-globin gene cluster, giving him the dual diagnosis of NPRL3 -related epilepsy and α-thalassemia trait. Brain imaging postprocessing showed left hippocampal sclerosis and mid-posterior para-hippocampal focal cortical dysplasia, leading to the consideration of epilepsy surgery. Conclusions : This case underscores the necessity of early and comprehensive genetic assessments in children with epilepsy accompanied by systemic features, even in the absence of a family history of epilepsy or a developmental delay. Recognizing phenotypic overlaps is crucial to avoid diagnostic delays. Our findings also highlight the impact of disruptions in regulatory regions in genetic disorders: any individual with full gene deletion of NPRL3 would have, at a minimum, α-thalassemia trait, due to the presence of the major regulatory element of α-globin genes overlapping the gene's introns. |
