Harvey Levy1, Diana Lamppu2, Vera Anastosoaie3, Jennifer L Baker4, Kevin DiBona3, Sarah Hawthorne3, Jessica Lindenberger4, Deborah Kinch2, Albert Seymour2, Mark McIlduff5, Sharon Watling5, Jerry Vockley6. 1. Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. 2. Homology Medicines, Inc., Bedford, MA, USA. 3. Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA. 4. Division Medical Genetics, Department of Pediatrics, University of Pittsburgh School of Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA. 5. Boston Biomedical Associates, LLC, Marlborough, MA, USA. 6. Division Medical Genetics, Department of Pediatrics, University of Pittsburgh School of Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA. Electronic address: gerard.vockley@chp.edu.
Abstract
BACKGROUND: Phenylketonuria (PKU) is an autosomal recessive disease caused by mutations in the PAH gene, resulting in deficiency of phenylalanine hydroxylase (PAH), an enzyme that converts phenylalanine (Phe) to tyrosine (Tyr). The purpose of this study was to capture real-world data associated with managing PKU under current standard of care and to characterize a representative population for a planned gene therapy trial. METHODS: A retrospective chart review was conducted at two U.S. clinics for individuals 10-40 years old diagnosed with PKU-related hyperphenylalaninemia (HPA). Demographics, medical history, treatments and blood Phe data were collected from electronic medical records spanning a five-year period ending in November 2017. RESULTS: 152 patients were enrolled (65.8% had classical PKU). Although >95% of patients were prescribed a Phe-restricted diet, blood Phe concentrations remained substantially elevated, particularly in patients diagnosed with classical PKU. As the Phe threshold was lowered (Phe < 600, 360, 120 or 30 μmol/L), the number of patients with consecutive lab values below the threshold decreased, suggesting that many patients' Phe levels are inadequately controlled. 62.5% of patients were reported as having a history of at least one neuropsychiatric comorbidity, and adults were more likely than adolescents (69.5% vs. 54.3%). 92 of 98 PAH genotypes collected were distinct mutations; the 6 null-null genotypes were associated with classical PKU. Overall the demographics and clinical data were consistent across both sites. CONCLUSION: Despite dietary restrictions, mean Phe concentrations were > 360 μmol/L (a level considered well-controlled based on current U.S. treatment guidelines) for mild, moderate, and classical PKU patients. There remains an unmet need for therapies to control Phe concentrations.
BACKGROUND:Phenylketonuria (PKU) is an autosomal recessive disease caused by mutations in the PAH gene, resulting in deficiency of phenylalanine hydroxylase (PAH), an enzyme that converts phenylalanine (Phe) to tyrosine (Tyr). The purpose of this study was to capture real-world data associated with managing PKU under current standard of care and to characterize a representative population for a planned gene therapy trial. METHODS: A retrospective chart review was conducted at two U.S. clinics for individuals 10-40 years old diagnosed with PKU-related hyperphenylalaninemia (HPA). Demographics, medical history, treatments and blood Phe data were collected from electronic medical records spanning a five-year period ending in November 2017. RESULTS: 152 patients were enrolled (65.8% had classical PKU). Although >95% of patients were prescribed a Phe-restricted diet, blood Phe concentrations remained substantially elevated, particularly in patients diagnosed with classical PKU. As the Phe threshold was lowered (Phe < 600, 360, 120 or 30 μmol/L), the number of patients with consecutive lab values below the threshold decreased, suggesting that many patients' Phe levels are inadequately controlled. 62.5% of patients were reported as having a history of at least one neuropsychiatric comorbidity, and adults were more likely than adolescents (69.5% vs. 54.3%). 92 of 98 PAH genotypes collected were distinct mutations; the 6 null-null genotypes were associated with classical PKU. Overall the demographics and clinical data were consistent across both sites. CONCLUSION: Despite dietary restrictions, mean Phe concentrations were > 360 μmol/L (a level considered well-controlled based on current U.S. treatment guidelines) for mild, moderate, and classical PKUpatients. There remains an unmet need for therapies to control Phe concentrations.
Authors: Erik A Koppes; Bethany K Redel; Marie A Johnson; Kristen J Skvorak; Lina Ghaloul-Gonzalez; Megan E Yates; Dale W Lewis; Susanne M Gollin; Yijen L Wu; Shawn E Christ; Martine Yerle; Angela Leshinski; Lee D Spate; Joshua A Benne; Stephanie L Murphy; Melissa S Samuel; Eric M Walters; Sarah A Hansen; Kevin D Wells; Uta Lichter-Konecki; Robert A Wagner; Joseph T Newsome; Steven F Dobrowolski; Jerry Vockley; Randall S Prather; Robert D Nicholls Journal: JCI Insight Date: 2020-10-15