Carbonell Elizabeth, Stenton Sarah L, Ganesh Vijay S, Ma Jialan, VanNoy Grace E, Pais Lynn, Gaitanis John N, O'Leary Melanie C, Rehm Heidi L, O'Donnell-Luria Anne
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
HGG Adv. 2025 Apr 10;6(2):100419. doi: 10.1016/j.xhgg.2025.100419. Epub 2025 Feb 21.
Bi-allelic variants in GLUL, encoding glutamine synthetase and responsible for the conversion of glutamate to glutamine, are associated with a severe recessive disease due to glutamine deficiency. A dominant disease mechanism was recently reported in nine females, all with a de novo single-nucleotide variant within the start codon or the 5' UTR of GLUL that truncates 17 amino acids of the protein product, including its critical N-terminal degron sequence. This truncation results in a disorder of abnormal glutamine synthetase stability and manifests as a phenotype of severe developmental and epileptic encephalopathy. Here, we report the first male with a pathogenic de novo variant in the same critical region of GLUL, with a phenotype of refractory focal and generalized seizures, as well as developmental delays. We provide a detailed description of the disease course and treatment response.
编码谷氨酰胺合成酶并负责将谷氨酸转化为谷氨酰胺的GLUL基因双等位基因变异，与因谷氨酰胺缺乏导致的严重隐性疾病相关。最近有报道称，在9名女性中发现了一种显性疾病机制，她们均在GLUL基因的起始密码子或5'非翻译区内有一个新生的单核苷酸变异，该变异导致蛋白质产物截短17个氨基酸，包括其关键的N端降解子序列。这种截短导致异常谷氨酰胺合成酶稳定性紊乱，并表现为严重发育性和癫痫性脑病的表型。在此，我们报告了首例在GLUL基因同一关键区域有致病性新生变异的男性患者，其表现为难治性局灶性和全身性癫痫发作以及发育迟缓的表型。我们提供了疾病病程和治疗反应的详细描述。
