We report an inborn error of metabolism caused by TKFC deficiency in two unrelated families. Rapid trio genome sequencing in family 1 and exome sequencing in family 2 excluded known genetic etiologies, and further variant analysis identified rare homozygous variants in TKFC. TKFC encodes a bifunctional enzyme involved in fructose metabolism through its glyceraldehyde kinase activity and in the generation of riboflavin cyclic 4',5'-phosphate (cyclic FMN) through an FMN lyase domain. The TKFC homozygous variants reported here are located within the FMN lyase domain. Functional assays in yeast support the deleterious effect of these variants on protein function. Shared phenotypes between affected individuals with TKFC deficiency include cataracts and developmental delay, associated with cerebellar hypoplasia in one case. Further complications observed in two affected individuals included liver dysfunction and microcytic anemia, while one had fatal cardiomyopathy with lactic acidosis following a febrile illness. We postulate that deficiency of TKFC causes disruption of endogenous fructose metabolism leading to generation of by-products that can cause cataract. In line with this, an affected individual had mildly elevated urinary galactitol, which has been linked to cataract development in the galactosemias. Further, in light of a previously reported role of TKFC in regulating innate antiviral immunity through suppression of MDA5, we speculate that deficiency of TKFC leads to impaired innate immunity in response to viral illness, which may explain the fatal illness observed in the most severely affected individual.

中文翻译：

---

TKFC编码Triokinase / FMN环化酶中的双等位基因变异与白内障和多系统疾病相关。

我们报告了两个不相关家庭中由TKFC缺乏引起的先天性代谢错误。家庭1中的快速三重基因组测序和家庭2中的外显子组测序排除了已知的遗传病因，进一步的变异分析确定了TKFC中罕见的纯合变异。TKFC编码一种双功能酶，通过其甘油醛激酶活性参与果糖代谢，并通过FMN裂解酶结构域参与核黄素环状4'，5'-磷酸（环状FMN）的生成。此处报道的TKFC纯合变体位于FMN裂解酶域内。酵母中的功能测定支持这些变体对蛋白质功能的有害作用。患有TKFC缺乏症的受影响个体之间共有的表型包括白内障和发育迟缓，其中1例与小脑发育不全有关。在两名受影响的个体中观察到的进一步并发症包括肝功能障碍和小细胞性贫血，而其中一名患有发热性疾病的致命性心肌病伴乳酸性酸中毒。我们假设TKFC的缺乏会引起内源性果糖代谢的破坏，从而导致产生可引起白内障的副产物。与此相符，患病个体的尿半乳糖醇轻度升高，这与半乳糖血症中的白内障发展有关。此外，鉴于先前报道的TKFC在通过抑制MDA5来调节先天抗病毒免疫中的作用，我们推测TKFC的缺乏会导致对病毒性疾病的响应，从而削弱先天性免疫力，这可能解释了在最严重感染者中观察到的致命疾病个人。