Impact of sapropterin (tetrahydrobiopterin, BH4) treatment, with and without diet liberalization, on monoamine status and quality of life in a phenylketonuria (PKU) cohort Público

Abstract

Background: Phenylketonuria is an autosomal recessive inborn error of metabolism characterized by impaired phenylalanine hydroxylase activity. To prevent neurological disability caused by high neurotoxic phenylalanine (Phe) concentrations, a strict low Phe, medical food (formula) based diet from infancy is required. Sapropterin is a pharmaceutical for treating PKU that can lower blood Phe and increase dietary Phe tolerance. Objective: To evaluate
sapropterin's effect on urinary monoamine neurotransmitter concentrations and whether subsequent diet liberalization improves QOL outcomes. Methods: 58 PKU subjects were asked to provide an overnight 12 hour urine sample, diet record, and plasma amino acid blood draw for 5 study visits: Baseline, 1 month after initiating sapropterin, then 4, 8, and 12 months. Those above age 10 were asked to complete a self-report QOL questionnaire. Responders ( ≥ 15% decline in plasma Phe the first month) continued taking sapropterin and were identified after 3 month diet challenge as "definitive" or "provisional" dependent on increases in Phe tolerance. Sapropterin nonresponders identified at one month remained on their standard PKU diet
regimen. Urinary monoamines, analyzed in ratio to creatinine. Data was analyzed with linear regression techniques in SPSS 19.0 while controlling for age. Results: Provisional responders had significantly lower epinephrine than the other two groups ( P=.018). At one month, homovanil ic acid (HVA) had significantly increased in the study cohort ( P=.015). When control ing for sapropterin response category, HVA increase was significant only for
nonresponders ( P=.016) but not sustained longterm. 5-hydroxyindole acetic acid (5HIAA) for definitive responders had a modest decline over 1 year ( P=.019). Plasma Phe and formula protein were strongly associated with longterm monoamine outcomes ( P<.0001). No other significant variations to monoamines occurred. All three sapropterin response groups had significant improvement in longterm subscores measuring impact of PKU on life quality
(nonresponder P=.05, provisional P=.01, definitive P<.0001). Definitive responders had longterm improvement in subscores measuring satisfaction with life and health management ( P=.001). Both provisional and definitive groups experienced longterm improvement in total QOL scores ( P=.001, P=.028). For definitive responders, QOL improvement associated most strongly with increases to dietary Phe tolerance ( P=.005). Conclusions: Sapropterin has potential to improve dopamine metabolism in PKU, though plasma Phe control and dietary management remain critical to patient health. Lessening dietary restriction when possible improves patient satisfaction and overall QOL, while PKU's impact on life quality improved for all long-term study participants.

Table of Contents

CHAPTER 1: INTRODUCTION ........................................................................................................... 1
Focus of Investigation .................................................................................................................. 1
Central Hypothesis ....................................................................................................................... 2
Objective and Specific Aims ......................................................................................................... 2
Specific Aim 1 ........................................................................................................................... 2
Specific Aim 2 ........................................................................................................................... 3
Background and Significance ....................................................................................................... 3
Sapropterin as treatment for PKU ........................................................................................... 5
Phenylketonuria and impaired monoamine metabolism ........................................................ 7
Quality of Life issues in PKU ....................................................................................................... 12
Investigative intent and theoretical mechanisms by which sapropterin can improve monoamine dysfunction and QOL in PKU... 15
CHAPTER 2: METHODS ................................................................................................................... 17
Protocol approval and oversight ................................................................................................ 17
Recruitment, informed consent, and adverse event management .......................................... 18
Recruitment of probands ....................................................................................................... 18
Recruitment of controls ......................................................................................................... 19
Informed consent and authorization ..................................................................................... 20
Facilities and Resources ......................................................................................................... 21
Protection and management of patient information and study data ................................... 23
Study Design .......................................................................................................................... 24
EGC protocol for following patients on BH4 and determining response status ........................ 27
General management of all patients initiating sapropterin .................................................. 27
Evaluating BH4 response based on change in plasma Phe concentration ............................ 28
Response specific detailed patient management .................................................................. 30
Characteristics and management of provisional and definitive responder classes .............. 33
Study visit procedures................................................................................................................ 34
Study visit 1 ............................................................................................................................ 34
Study visits 2-4 for PKU patients ............................................................................................ 36
Study visit 5 for PKU patients ................................................................................................. 37

Data collection and biological sample handling ........................................................................ 38
Demographic and health information ................................................................................... 38
Quality of Life ......................................................................................................................... 39
Collection, storage, and analysis of biological samples ......................................................... 40
Chromatography analysis of urine monoamine analytes ...................................................... 41
Data reporting and management .............................................................................................. 43
Statistical analysis ...................................................................................................................... 45
General statistical approach .................................................................................................. 45
CHAPTER 3: THE EFFECT OF SAPROPTERIN ON URINARY MONOAMINE METABOLITES IN PHENYLKETONURIA............ 49
CHAPTER 4: QUALITY OF LIFE OUTCOMES FOR PHENYLKETONURIA PATIENTS PROVIDED SAPROPTERIN DIHYDROCHLORIDE (TETRAHYDROBIOPTERIN, BH4) WITH AND WITHOUT INCREASES TO DIETARY PHENYLALANINE TOLERANCE ................................................................. 76
CHAPTER 5: INTENT-TO-TREAT DIVISION OF PHENYLKETONURIA PATIENTS PROVIDED SAPROPTERIN INTO THREE DISTINCT CLINICAL MANAGEMENT GROUPS ..................................... 99
CHAPTER 6: CONCLUSIONS AND DISCUSSION ............................................................................. 110
REFERENCES ................................................................................................................................ 130

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Health Sciences, Nutrition Biology, Neuroscience Health Sciences, General
Palabra Clave	dopamine serotonin monoamine phenylalanine PKU sapropterin catecholamine tetrahydrobiopterin quality of life BH4 Phenylketonuria neurotransmitters
Committee Chair / Thesis Advisor	Singh, Rani H, Emory University
Committee Members	Cubells, Joseph F, Emory University Jinnah, Hyder A, Emory University Gletsu, Nana, Emory University Ramakrishnan, Usha, Emory University

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