A biochemical, genetic, and nutritional characterization of tetrahydrobiopterin responsiveness in patients with phenylketonuria 公开
Quirk, Meghan (2012)
Published
Abstract
In a subset of patients with phenylketonuria (PKU),
pharmacological doses of
tetrahydrobiopterin (BH4) work in conjunction with the mutated
phenylalanine
hydroxylase (PAH) enzyme to promote disposal of phenylalanine.
Current algorithms for
assessing BH4 responsiveness rely on acute change in blood
phenylalanine
concentrations as the only criterion for patient classification.
This approach inadequately
characterizes responses seen clinically.
We explore the use of a novel set of criteria to classify BH4
responsiveness in 58 patients
with PKU. "Definitive responders" experienced ≥15% decrease
in plasma phenylalanine
concentrations after one month of BH4 therapy and had substantial
improvements in
dietary phenylalanine tolerance (n=19). "Provisional responders"
also experienced an
initial ≥15% decrease in plasma phenylalanine concentrations,
but had limited
improvements in dietary phenylalanine tolerance (n=9). Patients
with <15% decrease in
plasma phenylalanine concentrations after one month of BH4 therapy
were classified as
"non-responders" (n=25), and patients lost to follow-up remained
unclassified (n=5).
Next, we explore the clinical utility of assessing PAH genotype
severity to classify BH4
response using a previously developed tool (assigned value sum).
While the majority of
definitive responders (17/19 patients) had genotypes with molecular
basis for
responsiveness, most of the provisional responders (7/9 patients)
had severe genotypes
indicative of a false-positive response. Furthermore, the
heterogeneity in genotype
severity within the non-responder group suggests that
false-negative classification may
have occurred. The simple genotype severity tool which was assessed
has the potential to
reveal misclassified patients and may have implication for
identifying candidates for BH4
therapy.
The potential response misclassification, however, could not be
attributed to overt or
divergent trends in dietary total protein, phenylalanine, and
medical food intake during
the first month of BH4 therapy. Pediatric definitive responders
reported consuming
significantly more dietary phenylalanine and less medical food than
the provisional
responders, further highlighting the phenotypic differences between
the two groups.
Thus, dichotomization of patients' acute plasma phenylalanine
response to BH4 therapy
is clinically insufficient. As demonstrated by our provisionally
responsive group, patients
can experience a marked decrease in plasma phenylalanine
concentrations, but not have
the added benefit of diet liberalization. A comprehensive approach
is necessary to
sufficiently characterize BH4 responsiveness in patients with
PKU.
Table of Contents
CHAPTER 1: INTRODUCTION
CHAPTER 2: THE BIOCHEMICAL, GENETIC, AND CLINICAL PRINCIPLES OF PHENYLKETONURIA
THE AFFECTED BIOCHEMICAL PATHWAY
Normal Phenylalanine Metabolism
Phenylalanine Metabolism in Patients with PKU
GENETIC BASIS OF PKU
DETECTION AND CLINICAL MANIFESTATIONS
PKU Screening and Differential Diagnosis
Clinical Manifestations of PKU
NUTRITION THERAPY
Low-Phenylalanine Diet
Medical Food
Monitoring Nutrition Therapy - Circulating Phenylalanine
Concentrations
Issues with Nutrition Therapy
CHAPTER 3: TETRAHYDROBIOPTERIN RESPONSIVENESS IN PATIENTS WITH PHENYLKETONURIA
MODES OF ACTION OF PHARMACOLOGICAL BH4
VARIABILITY OF PROTOCOLS ASSESSING BH4 RESPONSIVENESS
BH4 Doses Used in Responsiveness Protocols
Number of BH4 Doses Administered Prior to Classification
Use of a Phenylalanine Challenge
Dietary Regimen Prior to and During the Protocols
Duration of the Protocols
Timing and Frequency of Sample Collections
Definition of Responsiveness
CLINICAL OUTCOMES
Blood Phenylalanine Concentrations
Dietary Phenylalanine Tolerance and Medical Food Needs
LIMITATIONS OF THE CURRENT BH4 RESPONSE CLASSIFICATION APPROACHES
CHAPTER 4: USING CHANGE IN PLASMA PHENYLALANINE CONCENTRATIONS AND ABILITY TO LIBERALIZE DIET TO CLASSIFY RESPONSIVENESS TO TETRAHYDROBIOPTERIN THERAPY IN PATIENTS WITH PHENYLKETONURIA
ABSTRACT
4.1. INTRODUCTION
4.2. MATERIAL AND METHODS
4.2.1. Patient Eligibility
4.2.2. Responsiveness Classification Algorithm
4.2.3. Plasma and Blood Amino Acid Analysis
4.2.4. Dietary Intake and Diet Prescription
4.2.5. Statistical Analysis
4.3. RESULTS
4.3.1. Baseline Characteristics and Preliminary
Responsiveness Classification
4.3.2. BH4 Responsiveness: Diet Liberalization
4.3.3. Summary of Responsiveness Classification
4.4. DISCUSSION
CHAPTER 5: UTILITY OF PHENYLALANINE HYDROXYLASE GENOTYPE FOR TETRAHYDROBIOPTERIN RESPONSIVENESS CLASSIFICATION IN PATIENTS WITH PHENYLKETONURIA
ABSTRACT
5.1. INTRODUCTION
5.2. PATIENTS AND METHODS
5.2.1. Patients and Clinical BH4 Response
Classification
5.2.2. PAH Mutation Identification
5.2.3. Assessing PAH Genotype Severity Using Assigned Value (AV)
Sum
5.2.4. Assessment of Classification Approaches and Statistics
5.3. RESULTS
5.3.1. Summary of Identified Mutations
5.3.2. PAH Genotype AV Sum by BH4-Response Classification
5.3.3. Discordant BH4 Response Classification of Matching PAH
Genotypes
5.3.4. Ability of AV Sum to Predict BH4 Response
5.4. DISCUSSION
CHAPTER 6: DIETARY PROTEIN INTAKE OF PATIENTS WITH PHENYLKETONURIA DURING AN EXTENDED TETRAHYDROBIOPTERIN RESPONSE PROTOCOL
ABSTRACT
6.1. INTRODUCTION
6.2. PATIENTS AND METHODS
6.2.1. Patient Selection
6.2.2. Classification of BH4 Response
6.2.3. Assessment of Dietary Intake
6.2.4. Statistical Analysis
6.3. RESULTS
6.3.1. Analysis of All Patients
6.3.2. Pediatric Analysis
6.4. DISCUSSION
CHAPTER 7: SUMMARY OF RESULTS AND CONCLUSIONS
CAVEATS TO AND LIMITATIONS OF IMPLEMENTED BH4
CLASSIFICATION PROTOCOL
NEED FOR EXTERNAL VALIDATION
CLINICAL IMPLICATIONS FOR THE PKU POPULATION
CLINICAL IMPLICATIONS FOR BH4 BEYOND THE PAH PATHWAY
FUTURE DIRECTIONS
CONCLUSIONS
CITED LITERATURE
APPENDIX A: HETEROGENEITY OF PROTOCOLS
CLASSIFYING BH4 RESPONSIVENESS IN PATIENTS WITH PKU
APPENDIX B: SENSITIVITY ANALYSIS USING GENERAL LOGIT MODELS TO
EVALUATE PROTEIN INTAKE PRIOR TO BH4 RESPONSE CLASSIFICATION
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