BACKGROUND Phenylketonuria (PKU) is an autosomal recessive disease caused by mutations in the PAH gene, resulting in deficiency of phenylalanine hydroxylase (PAH), an enzyme that converts phenylalanine (Phe) to tyrosine (Tyr). The purpose of this study was to capture real-world data associated with managing PKU under current standard of care and to characterize a representative population for a planned gene therapy trial. METHODS A retrospective chart review was conducted at two U.S. clinics for individuals 10-40 years old diagnosed with PKU-related hyperphenylalaninemia (HPA). Demographics, medical history, treatments and blood Phe data were collected from electronic medical records spanning a five-year period ending in November 2017. RESULTS 152 patients were enrolled (65.8% had classical PKU). Although >95% of patients were prescribed a Phe-restricted diet, blood Phe concentrations remained substantially elevated, particularly in patients diagnosed with classical PKU. As the Phe threshold was lowered (Phe < 600, 360, 120 or 30 μmol/L), the number of patients with consecutive lab values below the threshold decreased, suggesting that many patients' Phe levels are inadequately controlled. 62.5% of patients were reported as having a history of at least one neuropsychiatric comorbidity, and adults were more likely than adolescents (69.5% vs. 54.3%). 92 of 98 PAH genotypes collected were distinct mutations; the 6 null-null genotypes were associated with classical PKU. Overall the demographics and clinical data were consistent across both sites. CONCLUSION Despite dietary restrictions, mean Phe concentrations were > 360 μmol/L (a level considered well-controlled based on current U.S. treatment guidelines) for mild, moderate, and classical PKU patients. There remains an unmet need for therapies to control Phe concentrations.

中文翻译：

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对两个专科诊所治疗的苯丙酮尿​​症 (PKU) 和高苯丙氨酸血症患者的 5 年回顾性分析。


背景苯丙酮尿症（PKU）是一种常染色体隐性遗传病，由PAH基因突变引起，导致苯丙氨酸羟化酶（PAH）缺乏，苯丙氨酸羟化酶是一种将苯丙氨酸（Phe）转化为酪氨酸（Tyr）的酶。本研究的目的是获取与在当前护理标准下管理 PKU 相关的真实世界数据，并为计划中的基因治疗试验描述代表性人群的特征。方法 对美国两家诊所诊断患有 PKU 相关高苯丙氨酸血症 (HPA) 的 10-40 岁个体进行回顾性图表审查。人口统计、病史、治疗和血液 Phe 数据是从截至 2017 年 11 月的五年期间的电子病历中收集的。 结果 纳入了 152 名患者（65.8% 患有经典 PKU）。尽管超过 95% 的患者接受了限制 Phe 的饮食，但血液 Phe 浓度仍然大幅升高，特别是在诊断为经典 PKU 的患者中。随着Phe阈值降低（Phe<600、360、120或30μmol/L），连续实验室值低于阈值的患者数量减少，表明许多患者的Phe水平控制不充分。据报告，62.5% 的患者有至少一种神经精神合并症史，成人比青少年更有可能（69.5% vs. 54.3%）。收集的 98 个 PAH 基因型中有 92 个是不同的突变； 6 个 null-null 基因型与经典 PKU 相关。总体而言，两个地点的人口统计数据和临床数据是一致的。结论 尽管存在饮食限制，但轻度、中度和典型 PKU 患者的平均 Phe 浓度仍 > 360 μmol/L（根据美国现行治疗指南，该水平被认为是良好控制的水平）。 对于控制 Phe 浓度的疗法的需求仍然未得到满足。