四氢生物terin代谢缺陷的基因型谱:在单一墨西哥参考中心的经验

辛西娅Fernandez-Lainez ^{1 *}，玛赛拉Vela-Amieva¹， 米格尔·安吉尔Á。ALCANTARA-ORTIGOZA ²，伊莎贝尔Ibarra-Gonzalez^3.， 阿里阿德纳González-del Ángel ²，莉莉安娜Fernandez-Hernandez²， 莎拉Guillen-Lopez¹， 莉兹白Lopez-Mejia¹， Itzel Carrillo-Nieto¹而且 莫伊塞斯O。Fiesco-Roa ^4、5

• ¹墨西哥国家研究所新陈代谢和Tamiz误差实验室Pediatría
• ²分子实验室Biología，国家研究所Pediatría, Secretaría de Salud，墨西哥
• ^3.Unidad de Genética de la Nutrición, Instituto de investigation aciones Biomédicas, UNAM。、墨西哥
• ⁴墨西哥实验室Citogenética，国家研究所Pediatría (México)
• ⁵Maestría墨西哥国立大学教授Médicas y de la Salud。、墨西哥

背景。由苯丙氨酸羟化酶(PAH)缺乏症或四氢生物嘌呤缺乏症(BH4D)引起的高苯丙氨酸血症(HPA)的蝶呤谱图或分子分析在低收入或中等收入国家(包括墨西哥)并不总是可用，这限制了有关BH4D患者表型和基因型特征的信息。目标。报道在墨西哥单一代谢参考中心就诊的具有正常PAH基因型的无关联的墨西哥HPA儿童BH4D的基因型和临床表现。方法。对14例HPA患者的PTS、QDPR和PCBD1基因进行了自动Sanger测序。通过硅蛋白模型来评估错义变异对蛋白质结构的预测影响。结果和讨论。在我们的HPA队列中，BH4D的患病率很高(9.8%，N=14/142)。PTS (N=7/14例)、QDPR (N=6/14例)和PCBD1 (N=1/14例)基因中存在临床相关双等位基因型。 Four novel QDPR variants [c.714dup or p.(Leu239Thrfs*44), c.106-1G>T or p.(?), c.214G>T or p.(Gly72*), and c.187_189dup or p.(Gln63dup)] were identified. In silico protein modeling of six missense variants of PTS [p.(Thr67Met), p.(Glu81Ala), and p.(Tyr113Cys)], QDPR [p.(Cys161Phe) and p.(Pro172Leu)], and PCBD1 [p.(Glu97Lys)] supports their pathogenicity. Progressive neurological symptoms (mainly intellectual and motor impairment and even death in 4 patients) were noted in all patients with biallelic QDPR genotypes and in 5/7 patients bearing biallelic PTS genotypes. The single homozygous PCBD1 p.(Glu97Lys) patient remains asymptomatic. Conclusion. A higher proportion of BH4D (9.8 vs. 1-2% worldwide), attributable to a heterogeneous mutational spectrum and wide clinical presentation, was noted in our Mexican HPA cohort, with the PTS-related HPA disorder being the most frequent. Sequencing-based assays could be a reliable approach for diagnosing BH4D in our population.