The Effectiveness of Kuvan in Amish PKU Patients

Summary

The purpose of this study is to determine if Amish patients with PKU show responsiveness after a high dose, prolonged Saproterin trial. The population of interest has a high frequency of a specific splice site mutation, the 1066-11G\>A mutation. This splice site mutation activates a cryptic splice site resulting in an in frame insertion of 9 nucleotides preceding exon 11. This leads to protein conformational changes and abrogation of function. Previous studies of this genotype have indicated \<1% residual activity of the PAH enzyme and an insignificant responsiveness to Saproterin. However, in this specific study Phe levels were evaluated only over 24 hours after a single-dose BH4 challenge at the standard dose of 20mg/kg. Based on new clinical information, the investigators hypothesize that if given a prolonged trial of Saproterin at a higher dose, Amish patients with PKU, specifically those homozygous for the c.1066-11G\>A mutation, will have a significant reduction in Phe levels or an increase in Phe tolerance and/or improvement in executive functioning and quality of life.

Timeline

Start

2018-01-22

Primary completion

2018-11-20

Completion

2019-01-01

Publications

• Background Wang H, Nye L, Puffenberger E, Morton H. Phenylalanine hydroxylase deficiency exhibits mutation heterogeneity in two large old order Amish settlements. Am J Med Genet A. 2007 Aug 15;143A(16):1938-40. doi: 10.1002/ajmg.a.31852. No abstract available.
• Background Dobrowolski SF, Heintz C, Miller T, Ellingson C, Ellingson C, Ozer I, Gokcay G, Baykal T, Thony B, Demirkol M, Blau N. Molecular genetics and impact of residual in vitro phenylalanine hydroxylase activity on tetrahydrobiopterin responsiveness in Turkish PKU population. Mol Genet Metab. 2011 Feb;102(2):116-21. doi: 10.1016/j.ymgme.2010.11.158. Epub 2010 Nov 18.
• Background Dworniczak B, Aulehla-Scholz C, Kalaydjieva L, Bartholome K, Grudda K, Horst J. Aberrant splicing of phenylalanine hydroxylase mRNA: the major cause for phenylketonuria in parts of southern Europe. Genomics. 1991 Oct;11(2):242-6. doi: 10.1016/0888-7543(91)90129-3.
• Background Karacic I, Meili D, Sarnavka V, Heintz C, Thony B, Ramadza DP, Fumic K, Mardesic D, Baric I, Blau N. Genotype-predicted tetrahydrobiopterin (BH4)-responsiveness and molecular genetics in Croatian patients with phenylalanine hydroxylase (PAH) deficiency. Mol Genet Metab. 2009 Jul;97(3):165-71. doi: 10.1016/j.ymgme.2009.03.009. Epub 2009 Apr 1.
• Background Zurfluh MR, Zschocke J, Lindner M, Feillet F, Chery C, Burlina A, Stevens RC, Thony B, Blau N. Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Hum Mutat. 2008 Jan;29(1):167-75. doi: 10.1002/humu.20637.
• Background Keil S, Anjema K, van Spronsen FJ, Lambruschini N, Burlina A, Belanger-Quintana A, Couce ML, Feillet F, Cerone R, Lotz-Havla AS, Muntau AC, Bosch AM, Meli CA, Billette de Villemeur T, Kern I, Riva E, Giovannini M, Damaj L, Leuzzi V, Blau N. Long-term follow-up and outcome of phenylketonuria patients on sapropterin: a retrospective study. Pediatrics. 2013 Jun;131(6):e1881-8. doi: 10.1542/peds.2012-3291. Epub 2013 May 20.
• Background Waisbren S, White DA. Screening for cognitive and social-emotional problems in individuals with PKU: tools for use in the metabolic clinic. Mol Genet Metab. 2010;99 Suppl 1:S96-9. doi: 10.1016/j.ymgme.2009.10.006.
• Background Regnault A, Burlina A, Cunningham A, Bettiol E, Moreau-Stucker F, Benmedjahed K, Bosch AM. Development and psychometric validation of measures to assess the impact of phenylketonuria and its dietary treatment on patients' and parents' quality of life: the phenylketonuria - quality of life (PKU-QOL) questionnaires. Orphanet J Rare Dis. 2015 May 10;10:59. doi: 10.1186/s13023-015-0261-6.

Drugs

Indications