Neurology Unit, St. Bassiano Hospital, Bassano del Grappa, Italy.
Neuroradiology Unit, University Hospital of Padua, Padua, Italy.
Eur J Neurol. 2024 Dec;31(12):e16508. doi: 10.1111/ene.16508. Epub 2024 Oct 4.
Phenylketonuria, the most common inherited metabolic disease, results from a deficiency of phenylalanine hydroxylase enzyme activity that causes high blood phenylalanine levels. Most adults do not adhere to the gold standard therapy: lifelong treatment with a low-phenylalanine diet. Elevated and fluctuating phenylalanine levels in untreated adults can cause white matter abnormalities, neurological symptoms, and cognitive dysfunction (executive function). Pegvaliase, a derivative of the phenylalanine ammonia-lyase enzyme, metabolizes phenylalanine to trans-cinnamic acid and ammonia, and is approved by the US Food and Drug Administration and European Medicines Agency for subcutaneous administration in adults with phenylketonuria and blood phenylalanine concentrations > 600 μmol/L. In clinical trials, it reduced blood phenylalanine, even in patients consuming an unrestricted diet. We report longitudinal results on the first three such adults, in whom phenylalanine levels were quantified monthly, starting 1 year before pegvaliase administration and continuing through achievement of a pegvaliase response (defined as six consecutive monthly blood phenylalanine concentrations < 360 μmol/L while consuming an unrestricted diet). Brain magnetic resonance imaging (MRI) and neuropsychological assessments were performed before starting therapy and after response was achieved. Our results show that all three patients had significantly reduced white matter hyperintensities on brain MRI and improved executive function on neuropsychological assessment, especially on the Paced Auditory Serial Addition Test, which is known to be very sensitive to white matter functioning. To the best of our knowledge, this is the first report of concomitant improvements in cognitive performance and white matter damage after a pharmacological intervention to normalize phenylalanine levels in adults with phenylketonuria consuming an unrestricted diet.
苯丙酮尿症是最常见的遗传性代谢疾病，由苯丙氨酸羟化酶活性缺乏引起，导致血液苯丙氨酸水平升高。大多数成年人无法坚持金标准治疗：终身接受低苯丙氨酸饮食治疗。未经治疗的成年人血液中苯丙氨酸水平升高和波动会导致白质异常、神经症状和认知功能障碍（执行功能）。培维利塞是苯丙氨酸氨解酶的衍生物，可将苯丙氨酸代谢为反式肉桂酸和氨，已被美国食品和药物管理局和欧洲药品管理局批准用于治疗血苯丙氨酸浓度>600μmol/L的成年苯丙酮尿症患者，给药途径为皮下注射。在临床试验中，即使在饮食不受限制的患者中，它也能降低血液苯丙氨酸水平。我们报告了首批 3 名此类成年人的纵向研究结果，他们在接受培维利塞治疗前 1 年开始每月定量检测血液苯丙氨酸水平，并在达到培维利塞应答（定义为连续 6 个月的每月血液苯丙氨酸浓度<360μmol/L，同时饮食不受限制）后继续检测。在开始治疗前和达到应答后，我们进行了脑磁共振成像（MRI）和神经心理学评估。我们的结果表明，所有 3 名患者的脑 MRI 上的白质高信号均显著减少，神经心理学评估中的执行功能得到改善，尤其是在听觉连续加法测试中，该测试对白质功能非常敏感。据我们所知，这是在饮食不受限制的苯丙酮尿症成年患者中进行药物干预以将苯丙氨酸水平正常化后，首次报告认知表现和白质损伤同时改善。
