A Pilot Study of FDG PET Findings in Patients With Phenylketonuria Before and After BH4 Supplementation
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 6
- 试验地点
- 1
- 主要终点
- Plasma Phenylalanine Level (mg/dl)
研究概览
简要总结
The aim of this pilot study is to determine if there are any changes in brain glucose metabolism in the gray matter of patients with Phenylketonuria (PKU) and whether administration of Sapropterin (KUVAN) therapy can improve such deficits.
详细描述
Phenylketonuria (PKU) is an autosomal recessive disorder resulting from a deficiency of phenylalanine hydroxylase, which converts phenylalanine to tyrosine. Phenylalanine hydroxylase is one of the three aromatic amino acid hydroxylases that utilizes tetrahydrobiopterin (BH4) as cofactor. The published reports indicate that there is altered energy metabolism in the brain of patients with PKU. Phenylalanine and its metabolites appear to impair several aspects of brain energetics including: (1) Inhibition of glucose uptake; (2) diminished glycosylation of cytoskeletal proteins; (3) Inhibition of pyruvate kinase; and (4) reduced flux through the glycolysis. Studies in vivo with magnetic resonance spectroscopy have demonstrated phenylalanine-responsive abnormalities in cerebral energy metabolism.
Positron Emission Tomography (PET) scanning with fluorodeoxyglucose (FDG-PET) is a non-invasive method that measures regional glucose metabolic rate with high resolution and absolute quantitation. To date this technology has been used only for single case reports or the investigation of white matter abnormalities in small numbers of patients with PKU.
The aim of this pilot study is to determine if there are any changes in brain glucose metabolism in the gray matter of patients with PKU and whether Sapropterin (KUVAN) can improve such deficits. This study will also elucidate the relationship between hyperphenylalaninemia, phenylalanine intake in diet, altered brain glucose handling and the neurocognitive profile of the patients with PKU before and after KUVAN therapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Males or females over the age of 18 years
- •Subject must be able to give independent informed consent
- •Girls must have a negative urine pregnancy test and must use an acceptable method of contraception, including abstinence, a barrier method (diaphragm or condom), Depo-Provera, or an oral contraceptive, for the duration of the study.
- •Subject must have a confirmed diagnosis of PKU
- •Subjects with Phenylalanine (Phe) levels over 10 mg/dL
- •Subjects naïve to KUVAN therapy or has not received KUVAN in the 6 months before screening
排除标准
- •Cognitive deficits resulting from physical trauma (e.g. subject with history of severe birth trauma).
- •Neurologic comorbidities including a history of a stroke or a seizure disorder.
- •Laboratory abnormalities that indicate clinically significant hepatic disease Aspartate aminotransferase (AST)> 2.0 times the upper limit of normal, Alanine transaminase (ALT) > 2.0 times the upper limit of normal, Prothrombin Time (PT) > 2.0 times the upper limit of normal, Partial Thromboplastin Time(PTT) > 2.0 times the upper limit of normal
- •Subjects using medications such as steroids, insulin and glucagons that may interfere with the results of PET scan.
- •Subjects using medications that inhibit folate metabolism such as methotrexate
- •Subjects using medications known to affect nitric oxide-mediated vasorelaxation.
- •Subjects using Levodopa
- •Treatment with KUVAN in the past 6 months before study entry.
- •Treatment with any investigational product in the last 90 days before study entry
研究组 & 干预措施
Sapropterin (KUVAN)
All subjects will receive Sapropterin (KUVAN) therapy at a dose of 20/mk/kg/day for four months.
干预措施: Sapropterin (Drug)
结局指标
主要结局
Plasma Phenylalanine Level (mg/dl)
时间窗: Measurements were obtained at the beginning and conclusion of each study period (baseline and 4 months)
Plasma phenylalanine level (mg/dl) served as the primary means of evaluating brain glucose metabolism before and after sapropterin (KUVAN) therapy. Blood tests for phenylalanine levels (Phe) were collected before and 4 months after sapropterin (KUVAN) therapy. All subjects received KUVAN at a dose of 20/mg/kg/day for four months. The goal was to estimate the change in blood glucose metabolism after treatment with Sapropterin (if any), with the hypothesis that treatment would decrease plasma Phe levels.
次要结局
- Hopkins Verbal Learning Test (HVLT) Total Recall(Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months))
- Hopkins Verbal Learning Test (HVLT) Delayed Recall(Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months))
- Paced Auditory Serial Addition Task (PASAT)(Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months))
- Symbol-Digit Modalities Test (SMTD)(Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months))
- Delis-Kaplan Executive Function System Verbal Fluency Subtest (D-KEFS)(Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months))
- Wechsler Adult Intelligence Scale (WAIS-IV)-Digit Span(Measures were obtained at the beginning and conclusion of each study period (baseline and 4 months))