Abstract：
Glutaric aciduria type II (GAII) is a heterogeneous genetic disorder affecting mitochondrial fatty acid, amino acid and choline oxidation. Clinical manifestations vary across the lifespan and onset may occur at any time from the early neonatal period to advanced adulthood. Historically, some patients, in particular those with late onset disease, have experienced significant benefit from riboflavin supplementation. GAII has been considered an autosomal recessive condition caused by pathogenic variants in the gene encoding electron-transfer flavoprotein ubiquinone-oxidoreductase (ETFDH) or in the genes encoding electron-transfer flavoprotein subunits A and B (ETFA and ETFB respectively). Variants in genes involved in riboflavin metabolism have also been reported. However, in some patients, molecular analysis has failed to reveal diagnostic molecular results. In this study, we report the outcome of molecular analysis in 28 Australian patients across the lifespan, 10 paediatric and 18 adult, who had a diagnosis of glutaric aciduria type II based on both clinical and biochemical parameters. Whole genome sequencing was performed on 26 of the patients and two neonatal onset patients had targeted sequencing of candidate genes. The two patients who had targeted sequencing had biallelic pathogenic variants (in ETFA and ETFDH). None of the 26 patients whose whole genome was sequenced had biallelic variants in any of the primary candidate genes. Interestingly, nine of these patients (34.6%) had a monoallelic pathogenic or likely pathogenic variant in a single primary candidate gene and one patient (3.9%) had a monoallelic pathogenic or likely pathogenic variant in two separate genes within the same pathway. The frequencies of the damaging variants within ETFDH and FAD transporter gene SLC25A32 were significantly higher than expected when compared to the corresponding allele frequencies in the general population. The remaining 16 patients (61.5%) had no pathogenic or likely pathogenic variants in the candidate genes. Ten (56%) of the 18 adult patients were taking the selective serotonin reuptake inhibitor antidepressant sertraline, which has been shown to produce a GAII phenotype, and another two adults (11%) were taking a serotonin-norepinephrine reuptake inhibitor antidepressant, venlafaxine or duloxetine, which have a mechanism of action overlapping that of sertraline. Riboflavin deficiency can also mimic both the clinical and biochemical phenotype of GAII. Several patients on these antidepressants showed an initial response to riboflavin but then that response waned. These results suggest that the GAII phenotype can result from a complex interaction between monoallelic variants and the cellular environment. Whole genome or targeted gene panel analysis may not provide a clear molecular diagnosis.
摘要：
戊二酸尿症II型（GAII）是一种影响线粒体脂肪酸的异质性遗传疾病，氨基酸和胆碱氧化。临床表现随寿命而变化，发病可能发生在从新生儿早期到成年晚期的任何时间。历史上,一些病人,特别是那些患有迟发性疾病的人，从补充核黄素中获得了显著的益处。GAII被认为是由编码电子转移黄素蛋白泛醌氧化还原酶（ETFDH）的基因或编码电子转移黄素蛋白亚基A和B（分别为ETFA和ETFB）的基因中的致病变体引起的常染色体隐性条件。还报道了与核黄素代谢有关的基因的变异。然而,在一些患者中，分子分析未能揭示诊断分子结果。在这项研究中,我们报告了28名澳大利亚患者的分子分析结果，10名儿科和18名成人，根据临床和生化参数诊断为II型戊二酸尿症。对26名患者进行了全基因组测序，两名新生儿发病患者对候选基因进行了靶向测序。具有靶向测序的两名患者具有双等位基因致病变体(在ETFA和ETFDH中)。全基因组测序的26名患者中没有一个在任何主要候选基因中具有双等位基因变体。有趣的是,其中9例(34.6%)在单个主要候选基因中具有单等位基因致病性或可能致病性变异,1例(3.9%)在同一途径中的两个不同基因中具有单等位基因致病性或可能致病性变异.当与普通人群中的相应等位基因频率相比时，ETFDH和FAD转运蛋白基因SLC25A32内的破坏性变体的频率显着高于预期。其余16例患者（61.5%）在候选基因中没有致病性或可能的致病性变异。18名成年患者中有10名（56％）正在服用选择性5-羟色胺再摄取抑制剂抗抑郁药舍曲林，已被证明会产生GAII表型，另外两名成年人（11%）正在服用5-羟色胺-去甲肾上腺素再摄取抑制剂抗抑郁药，文拉法辛或度洛西汀，具有与舍曲林重叠的作用机制。核黄素缺乏还可以模拟GAII的临床和生化表型。使用这些抗抑郁药的几名患者对核黄素有初始反应，但随后反应减弱。这些结果表明，GAII表型可能是由于单等位基因变体与细胞环境之间的复杂相互作用所致。全基因组或靶向基因组分析可能无法提供明确的分子诊断。
