Purpose

Biallelic CAD variants underlie CAD deficiency (or early infantile epileptic encephalopathy-50, [EIEE-50]), an error of pyrimidine de novo biosynthesis amenable to treatment via the uridine salvage pathway. We further define the genotype and phenotype with a focus on treatment.

Methods

Retrospective case series of 20 patients.

Results

Our study confirms CAD deficiency as a progressive EIEE with recurrent status epilepticus, loss of skills, and dyserythropoietic anemia. We further refine the phenotype by reporting a movement disorder as a frequent feature, and add that milder courses with isolated developmental delay/intellectual disability can occur as well as onset with neonatal seizures. With no biomarker available, the diagnosis relies on genetic testing and functional validation in patient-derived fibroblasts. Underlying pathogenic variants are often rated as variants of unknown significance, which could lead to underrecognition of this treatable disorder. Supplementation with uridine, uridine monophosphate, or uridine triacetate in ten patients was safe and led to significant clinical improvement in most patients.

Conclusion

We advise a trial with uridine (monophosphate) in all patients with developmental delay/intellectual disability, epilepsy, and anemia; all patients with status epilepticus; and all patients with neonatal seizures until (genetically) proven otherwise or proven unsuccessful after 6 months. CAD deficiency might represent a condition for genetic newborn screening.

中文翻译：

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扩大 CAD 缺乏症的临床和遗传谱：一种可通过补充尿苷治疗的癫痫性脑病。

目的

双等位基因CAD变异是 CAD 缺陷（或早期婴儿癫痫性脑病 50，[EIEE-50]）的基础，这是一种嘧啶从头生物合成的错误，可通过尿苷补救途径进行治疗。我们进一步定义基因型和表型，重点是治疗。

方法

20 例患者的回顾性病例系列。

结果

我们的研究证实 CAD 缺陷是一种进行性 EIEE，伴有反复发作的癫痫持续状态、技能丧失和红细胞生成异常性贫血。我们通过将运动障碍报告为常见特征来进一步细化表型，并补充说，可能会发生具有孤立性发育迟缓/智力残疾的轻度病程以及新生儿癫痫发作。由于没有可用的生物标志物，诊断依赖于患者来源的成纤维细胞的基因检测和功能验证。潜在的致病变异通常被评为意义不明的变异，这可能导致对这种可治疗疾病的认识不足。在 10 名患者中补充尿苷、单磷酸尿苷或三乙酸尿苷是安全的，并导致大多数患者的临床显着改善。

结论

我们建议对所有患有发育迟缓/智力残疾、癫痫和贫血的患者进行尿苷（单磷酸盐）试验；所有癫痫持续状态患者；和所有新生儿癫痫发作的患者，直到（基因）证明其他情况或在 6 个月后证明不成功。CAD缺陷可能代表遗传新生儿筛查的条件。