Objectives: To retrospectively analyze the variation and characteristics of phenylalanine hydroxylase (PAH) gene, and to observe the long-term treatment effect and follow-up of newborns with PAH deficiency.
Methods: Clinical data, treatment and follow-up results of 198 patients with PAH deficiency diagnosed by newborn screening in Jinan from 1996 to 2021 were collected. The genetic analysis of 55 patients with PAH deficiency diagnosed by newborn screening in Jinan and 213 patients referred from the surrounding areas of Jinan were summarized. Gene variations were checked by a customized Panel gene detection method. Blood phenylalanine-concentration and physical development indicators including height and weight were regularly monitored. Intellectual development was assessed using a neuropsychological development scale for patients aged 0-6 years and academic performance, and brain injury in patients was assessed using brain magnetic resonance imaging.
Results: c.728G>A, c.158G>A, c.721C>T, c.1068C>A, c.611A>G variations were common in PAH gene. The genotype of c.158G>A variation is compound heterozygous variation, with mainly a mild hyperpheny-lalaninemia. 168 patients with PAH deficiency who were followed-up regularly had normal physical development without dwarfism or malnutrition. Among the 33 preschool patients who underwent mental development assessment, 2 were mentally retarded and the initial treatment age was older than 6 months. Nine patients with an average age of (17.13±2.42) years completed brain magnetic resonance imaging, one case was normal, and 8 cases were abnormal. There were patchy or patchy hyperintense foci near the bilateral lateral ventricles on T2WI, and the intellectual development was normal. Compared with the other eight patients, the blood phenylalanine concentration of the normal child was better and stably controlled within the ideal range.
Conclusions: c.728G>A, c.158G>A, c.721C>T, c.1068C>A, c.611A>G variations were common in PAH gene. After standardized treatment, most patients with PAH deficiency diagnosed by screening can obtain normal growth and intellectual development in adolescence, but there are different degrees of organic lesions in the cerebral white matter.
目的: 了解苯丙氨酸羟化酶（PAH）基因变异的特点，观察PAH缺乏症新生儿的长期治疗效果及随访情况。方法: 收集1996至2021年198例济南地区新生儿筛查确诊PAH缺乏症患者的临床资料及治疗随访结果，总结其中完善基因检测的55例及济南周边地区转诊的213例患者的基因分析结果。采用定制Panel检测基因变异，定期监测血苯丙氨酸浓度及患者身高、体重等体格发育指标，采用0~6岁儿童神经心理发育量表和学习成绩评估智力发育，颅脑磁共振成像检测评估患者脑损伤情况。结果: PAH基因以c.728G>A、c.158G>A、c.721C>T、c.1068C>A、c.611A>G变异多见；c.158G>A变异的基因型主要为复合杂合变异，以轻度高苯丙氨酸血症为主。随访期间，168例PAH缺乏症患者的体格发育均正常，无矮小及营养不良。33例学龄期前接受智能发育评估的患者中，2例智能发育落后，初始治疗年龄均超过6月龄。9例平均年龄为（17.13±2.42）岁的患者完成颅脑磁共振成像检查，结果正常1例，异常8例（以T2WI上双侧侧脑室旁小斑片状或片状高信号灶多见），智能发育均正常；结果正常的这例患者较其他8例患者的血苯丙氨酸浓度控制更佳。结论: PAH基因以c.728G>A、c.158G>A、c.721C>T、c.1068C>A、c.611A>G变异多见；经筛查确诊的PAH缺乏症患者规范治疗后，青少年期绝大部分能够获得正常的体格发育和智力发育，但脑白质存在不同程度的器质性病变。.
Keywords: Follow-up studies; Gene; Newborn screening; Phenylalanine hydroxylase deficiency; Prognosis.