A Pilot Study of Fluorodeoxyglucose Positron Emission Tomography Findings in Patients with Phenylketonuria before and during Sapropterin Supplementation
1
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Background and Purpose PET scanning with fluorodeoxyglucose (FDG-PET) is a non-invasive method that measures regional glucose metabolic rate. Phenylalanine (Phe) and its metabolites appear to impair several aspects of brain energy metabolism. 1) To evaluate brain glucose metabolism with FDG-PET imaging in phenylketonuria (PKU) patients before and 4 months after sapropterin therapy; 2) to evaluate neurodevelopmental changes, blood Phe levels and dietary Phe tolerance before and after sapropterin therapy; 3) to generate pilot data to assess the feasibility of evaluating brain glucose metabolism with FDG-PET imaging and to explore potential trends resulting from the administration of sapropterin therapy. Methods We enrolled 5 subjects, ranged in age from 22 years to 51 years, with PKU. Subjects underwent FDG-PET brain imaging, blood tests for Phe and tyrosine levels, and neurocognitive evaluations before and 4 months after sapropterin therapy (20 mg/kg/day). All subjects’ Phe and tyrosine levels were monitored once a week during the study. Subjects kept 3 day diet records that allow calculation of Phe intake. Results None of the subjects responded to sapropterin therapy based on 30% decrease in blood Phe level. The data show that glucose metabolism appeared depressed in the cerebellum and left parietal cortex while it was increased in the frontal and anterior cingulate cortices in all five subjects. In response to sapropterin therapy, relative glucose metabolism showed significant increases in left Broca’s and right superior lateral temporal cortices. Interestingly, there was corresponding enhanced performance in a phonemic fluency test performed during pre- and postneurocognitive evaluation. Conclusions Further studies with a larger sample size are needed to confirm the above changesin both sapropterin non-responsive and responsive PKU patients.
Abstract
Background and Purpose PET scanning with fluorodeoxyglucose (FDG-PET) is a non-invasive method that measures regional glucose metabolic rate. Phenylalanine (Phe) and its metabolites appear to impair several aspects of brain energy metabolism. 1) To evaluate brain glucose metabolism with FDG-PET imaging in phenylketonuria (PKU) patients before and 4 months after sapropterin therapy; 2) to evaluate neurodevelopmental changes, blood Phe levels and dietary Phe tolerance before and after sapropterin therapy; 3) to generate pilot data to assess the feasibility of evaluating brain glucose metabolism with FDG-PET imaging and to explore potential trends resulting from the administration of sapropterin therapy. Methods We enrolled 5 subjects, ranged in age from 22 years to 51 years, with PKU. Subjects underwent FDG-PET brain imaging, blood tests for Phe and tyrosine levels, and neurocognitive evaluations before and 4 months after sapropterin therapy (20 mg/kg/day). All subjects’ Phe and tyrosine levels were monitored once a week during the study. Subjects kept 3 day diet records that allow calculation of Phe intake. Results None of the subjects responded to sapropterin therapy based on 30% decrease in blood Phe level. The data show that glucose metabolism appeared depressed in the cerebellum and left parietal cortex while it was increased in the frontal and anterior cingulate cortices in all five subjects. In response to sapropterin therapy, relative glucose metabolism showed significant increases in left Broca’s and right superior lateral temporal cortices. Interestingly, there was corresponding enhanced performance in a phonemic fluency test performed during pre- and postneurocognitive evaluation. Conclusions Further studies with a larger sample size are needed to confirm the above changesin both sapropterin non-responsive and responsive PKU patients.
참고문헌 (17)
- Scriver CR, "Hyperphenylalaninemia: phenylalanine hydroxylase deficiency, In The Metabolic and Molecular Bases of Inherited Disease", pp.1667~1709 (2001), McGraw-Hill
- Waisbren SE, "Phenylalanine blood levels and clinical outcomes in phenylketonuria: a systematic literature review and meta-analysis", Molecular Genetics and Metabolism, 92, pp.63~70 (2007)
- de Groot MJ, "Pathogenesis of cognitive dysfunction in phenylketonuria: review of hypotheses", Molecular Genetics and Metabolism, 99(Suppl 1), pp.S86~S89 (2010)
- Landvogt C, "Reduced cerebral fluoro-L-dopamine uptake in adult patients suffering from phenylketonuria", Journal of Cerebral Blood Flow & Metabolism, 28, pp.824~831 (2008)
- Rech VC, "Inhibition of the mitochondrial respiratory chain by phenylalanine in rat cerebral cortex", Neurochemical Research, 27, pp.353~357 (2002)
- Pietz J, "Cerebral energy metabolism in phenylketonuria: findings by quantitative In vivo 31P MR spectroscopy", Pediatric Research, 53, pp.654~662 (2003)
- Wasserstein MP, "Cerebral glucose metabolism in adults with early treated classic phenylketonuria", Molecular Genetics and Metabolism, 87, pp.272~277 (2006)
- Hennermann JB, "Long-term treatment with tetrahydrobiopterin increases phenylalanine tolerance in children with severe phenotype of phenylketonuria", Molecular Genetics and Metabolism, 86(Suppl 1), pp.S86~S90 (2005)
- Matalon R, "Response of patients with phenylketonuria in the US to tetrahydrobiopterin", Molecular Genetics and Metabolism, 86(Suppl 1), pp.S17~S21 (2005)
- Muntau AC, "Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria", The New England Journal of Medicine, 347, pp.2122~2132 (2002)
- Alavi A, "Regional cerebral glucose metabolism in aging and senile dementia as determined by 18F-deoxyglucose and positron emission tomography", Experimental Brain Research, (Suppl 5), pp.187~195 (1982)
- Sestini S, "The new FDG brain revolution: the neurovascular unit and the default network", European Journal of Nuclear Medicine and Molecular Imaging, 37, pp.913~916 (2010)
- Koshimura K, "Enhancement of dopamine release in vivo from the rat striatum by dialytic perfusion of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin", Journal of Neurochemistry, 54, pp.1391~1397 (1990)
- Mataga N, "6R-tetrahydrobiopterin perfusion enhances dopamine, serotonin, and glutamate outputs in dialysate from rat striatum and frontal cortex", Brain Research, 551, pp.64~71 (1991)
- Koshimura K, "Dopamine-releasing action of 6RL- erythro-tetrahydrobiopterin: analysis of its action site using sepiapterin", Journal of Neurochemistry, 63, pp.649~654 (1994)
- 김혜림, "Maintenance of cellular tetrahydrobiopterin homeostasis", BMB Reports, 43(9), pp.584~592 (2010), 생화학분자생물학회
- Sanayama Y, "Experimental evidence that phenylalanine is strongly associated to oxidative stress in adolescents and adults with phenylketonuria", Molecular Genetics and Metabolism, 103, pp.220~225 (2011)