PDF(Pubmed)
Abstract：
L-2-hydroxyglutaric aciduria (L-2-HGA) is a rare neurometabolic disorder characterized by accumulation of L2-hydroxyglutarate (L-2-HG) due to mutations in the L2HGDH gene. L-2-HGA patients have a significantly increased lifetime risk of central nervous system (CNS) tumors. Here, we present a 16-year-old girl with L-2-HGA who developed a tumor in the right cerebral hemisphere, which was discovered after left-sided neurological deficits of the patient. Histologically, the tumor had a high-grade diffuse glioma phenotype. DNA sequencing revealed the inactivating homozygous germline L2HGDH mutation as well as inactivating mutations in TP53, BCOR and NF1. Genome-wide DNA-methylation analysis was unable to classify the tumor with high confidence. More detailed analysis revealed that this tumor clustered amongst IDH-wildtype gliomas by methylation profiling and did not show the glioma CpG island methylator phenotype (G-CIMP) in contrast to IDH-mutant diffuse gliomas with accumulated levels of D-2-HG, the stereoisomer of L-2-HD. These findings were against all our expectations given the inhibitory potential of 2-HG on DNA-demethylation enzymes. Our final integrated histomolecular diagnosis of the tumor was diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype. Due to rapid tumor progression the patient died nine months after initial diagnosis. In this manuscript, we provide extensive molecular characterization of the tumor as well as a literature review focusing on oncogenetic considerations of L-2-HGA-associated CNS tumors.
摘要：
L-2-羟基戊二酸尿症（L-2-HGA）是一种罕见的神经代谢疾病，其特征是由于L2HGDH基因突变导致L2-羟基戊二酸酯（L-2-HG）积累。L-2-HGA患者发生中枢神经系统(CNS)肿瘤的终生风险显著增加。这里,我们介绍了一个患有L-2-HGA的16岁女孩，她在右脑半球发展了肿瘤，这是在患者左侧神经功能缺损后发现的。组织学上,肿瘤具有高级别弥漫性神经胶质瘤表型.DNA测序揭示了纯合种系L2HGDH突变的失活以及TP53，BCOR和NF1中的失活突变。全基因组DNA甲基化分析无法对肿瘤进行高置信度分类。更详细的分析显示，与具有D-2-HG积累水平的IDH突变型弥漫性神经胶质瘤相比，该肿瘤通过甲基化谱分析聚集在IDH野生型神经胶质瘤中，并且未显示出神经胶质瘤CpG岛甲基化物表型（G-CIMP）。L-2-HD的立体异构体。鉴于2-HG对DNA去甲基化酶的抑制潜力，这些发现与我们的所有期望背道而驰。我们对肿瘤的最终综合组织分子诊断是弥漫性小儿型高级别神经胶质瘤，H3-野生型和IDH-野生型。由于肿瘤进展迅速，患者在初步诊断后9个月死亡。在这份手稿中,我们提供了广泛的肿瘤分子特征,并对L-2-HGA相关CNS肿瘤的致癌因素进行了文献综述.
