phenylketonuria samuel chan, jekaterina davydova phm142 fall 2015 instructor: dr. jeffrey henderson
TRANSCRIPT
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PhenylketonuriaSamuel Chan, Jekaterina Davydova
PHM142 Fall 2015Instructor: Dr. Jeffrey Henderson
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What is Phenylketonuria (PKU)?• Genetic disorder
• Most common inborn error of amino acid metabolism• Affect phenylalanine (Phe) metabolism
• Phenylketones in urine• Results in a hyperphenylalaninemia (HPA) phenotype
L-Phenylalanine chemical structure
Retrieved from http://www.mpbio.com/images/product-images/molecular-structure/02102623.png
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PKU Epidemiology• International Incidence
• Incidence in US is 1:15000• Less common in African-American descent 1:50000
• Incidence in Turkey 1:2600, in Scotland 1:5300• Incidence in Japan 1:125000, in Finland 1:100000
• No correlation with sex/gender
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Symptoms • If left undiagnosed or untreated initially :
• Intellectual disability• Delayed development• Neurological problems (ex. Seizures)• Eczema• Musty odour in urine and breath• Lighter skin and hair
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Pathophysiology - Genetic• Mutation in phenylalanine hydroxylase (PAH)
gene• Autosomal recessive on chromosome 12• Generally missense mutation
• Mutation related to tetrahydrobiopterin (BH4)• Autosomal recessive mutation in 1 of 5 proteins
• Guanosine triphosphate cyclohydrolase 1 (GTPCH)• 6-pyruvoyl-tetrahydrobiopterin synthase (PTPS)• Sepiapterin Reductase (SR)• Dihydropteridine reductase (DHPR)• Carbinolamine-4a-dehydratase (PCD) Irina et al.
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Pathophysiology - MetabolismOdour
Light skin
Schuck et al.
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Pathophysiology – Oxidative Stress• Stress induced by phenylketone metabolites• Impaired antioxidant enzyme activity
• Phenylpyruvic acid inhibits glucose-6-phosphate• Impair pentose monophosphate shunt
• High [Phe] impairs catalase, superoxide dismutase, glutathione peroxidase activity
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Pathophysiology - Neurotransmitter• Impaired neurotransmitter synthesis
• High [Phe] impair amino acid transport through blood brain barrier• Phe has high affinity for large neutral amino acid transporter• Phe out-competes other amino acids, including Tyr and Trp• Tyr and Trp are precursors for dopamine and serotonin respectively
• High [Phe] impair synthetic enzyme activity• Competitively inhibits tyrosine and tryptophan hydroxylase• Phe metabolites inhibit 5-hydroxytryptophan and dopa decarboxylase
• BH4 is an important co-factor for neurotransmitter synthesis
Retrieved from http://www.biomedcentral.com/1471-2148/4/24/figure/F1?highres=y
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Testing and Diagnosis • Made through newborn screening • Involves blood spot or heel prick test (Guthrie Test)• Levels of phenylalanine and tyrosine are measured
• if ratio is greater than 3 between the two PKU• Other tests to rule out possibility of other conditions which
increase phenylalanine levels
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Management of PKU• Aim to reduce phenylalanine levels• Phenylalanine levels depend on dietary intake • Mostly managed through diet which involves:
• elimination of high protein foods, such as milk, dairy products, meat, fish, chicken, eggs, beans, and nuts
• special phenylalanine-free formula which contains protein, vitamins, minerals and energy with no phenylalanine
• high consumption of fruits and vegetables• counting phenylalanine content in medium-rich foods
• Pregnant women who have PKU should be extra careful with their phenylalanine intake
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New Treatments for PKU
• Large neutral amino acids
• Enzyme replacement therapy
• Sapropterin Therapy• KuvanTM is available on market
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Summary Slide• Phenylketonuria is an inborn error of phenylalanine metabolism• Major symptoms include intellectual development and
neurological problems• Due to mutations in Phenylalanine Hydroxylase or BH4 deficiency
• Results in phenylalanine accumulation and production of phenylketones
• Oxidative stress and impaired neurotransmitter synthesis contribute to neurologic problems
• Main diagnostic is newborn screening• Management includes dietary restriction on phenylalanine intake• Pharmacology treatments include large neutral amino acid
supplements, enzyme replacement and Sapropterin therapy
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Reference• Cleary, M. A. (2011). Phenylketonuria. Paediatrics and Child Health, 21(2), 61-64.• Guldberg P, Henriksen K, Sipila I, et al. Phenylketonuria in a low incidence population: molecular
characterisation of mutations in Finland. Journal of Medical Genetics. 1995; 32: 976.• Hofman K, Steel G, Kazazian H, Valle D. Phenylketonura in U.S. blacks: molecular analysis of the
phenylalanine hydroxylase gene. American Journal of Human Genetics. 1991; 48: 791.• Ionova I, Vásquez J, Whisett J, et al. Deficient BH4 production via de novo and salvage pathways regulates
NO responses to cytokines in adult cardiac myoctes. American Journal of Physiology – Heart and Circulatory Physiology. 2008; 295: 2178-2187.
• Levy L, Milanowski A, Chakrapani A, et al. Efficacy of sapropterin dihydrochloride (tetrahydrobiopterin, 6R-BH4) for reduction of phenylalanine concentration in patients with phenylketonuria: a phase III randomized placebo-controlled study. Lancet 2007; 370: 504–10.
• Pietz J, Kreis R, Rupp A, et al. Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria. J Clin Invest 1999; 103: 1169–78.
• Réblová K, Kulhánek P, Fajkusová L. Computational study of missense mutations in phenylalanine hydroxylase. Journal of Molecular Modeling. 2015; 21:69-70.
• Sarkissian CN, Gamez A, Wang L, et al. Preclinical evaluation of multiple species of PEGylated recombinant phenylalanine ammonia lyase for the treatment of phenylketonuria. Proc Natl Acad Sci USA 2008; 52: 20894–99.
• Schuck P, Malgarin F, Cararo J, et al. Phenylketonura Physiology: on the Role of Metabolic Alterations. Aging and Disease. 2015; 6(5): 1-10.
• Shintaku H, Ohwada M. Long-term follow-up of tetrahydrobiopterin therapy in patients with tetrahydrobiopterin deficiency in japan. Brain & Development. 2013; 35: 406-410.