Elsevier

Molecular Genetics and Metabolism

Volume 92, Issues 1–2, September–October 2007, Pages 63-70
Molecular Genetics and Metabolism

Phenylalanine blood levels and clinical outcomes in phenylketonuria: A systematic literature review and meta-analysis

https://doi.org/10.1016/j.ymgme.2007.05.006Get rights and content

Abstract

Blood phenylalanine (Phe) levels provide a practical and reliable method for the diagnosis and monitoring of metabolic status in patients with phenylketonuria (PKU). To assess the reliability of blood Phe levels as a predictive biomarker of clinical outcomes in the development of treatments for PKU, a systematic literature review and meta-analysis of published trials of PKU, which included Phe level and neurological and dietary compliance outcome measures, was conducted. Within-study correlations between Phe level and intelligence quotient (IQ) were extracted from 40 studies. Significant, proportional correlations were found during critical periods (from 0 to 12 years of age) for early-treated patients with PKU (r = −0.35; 95% confidence interval [CI]: −0.44 to −0.27), where each 100 μmol/l increase in Phe predicted a 1.3- to 3.1-point reduction in IQ. Similar significant correlations were observed between IQ and mean lifetime Phe level for early-treated patients (r = 0.34; 95% CI: −0.42 to −0.25), where each 100 μmol/l increase in Phe predicted a 1.9- to 4.1-point reduction in IQ. Moderate correlations were found between concurrent Phe level and IQ for early-treated patients. In conclusion, these results confirm a significant correlation between blood Phe level and IQ in patients with PKU, and support the use of Phe as a predictive biomarker for IQ in clinical trials.

Introduction

Phenylketonuria (PKU)1 is an autosomal, recessive disorder involving mutations in the phenylalanine (Phe) hydroxylase gene, which inhibits the normal metabolism of Phe, an amino acid found in all proteins [1]. As a result, Phe cannot be converted to tyrosine and accumulates in the blood and other tissues [2].

Based on blood Phe levels, individuals affected with PKU are classified as having classic PKU (blood Phe: >1200 μmol/l), mild PKU (blood Phe: 600–1200 μmol/l) or non-PKU hyperphenylalaninemia (blood Phe: 120–599 μmol/l) [3]. More than half of patients affected have one of the milder clinical phenotypes [4]. The incidence of PKU varies considerably worldwide, with the highest rates seen in Ireland (approximately 1:4500) [5] and Eastern Europe (approximate rates for Estonia, Hungary and Latvia: 1:6000 [6], 1:9000 [7], [8] and 1:8700 [9], respectively) and the lowest in Finland, Japan and Thailand (approximate rates: 1:100,000 [10], 1:108,000 [11] and 1:212,000 [12], respectively). With an incidence of approximately 1:10,000 in North America, it is estimated that more than 350 children in this continent are diagnosed with PKU each year and require lifelong treatment [13].

Untreated PKU is associated with severe mental retardation (IQ < 30), seizures, severe behavioral difficulties and other symptoms [14], [15], [16]. Detection through neonatal screening programs and early initiation of treatment prevent the most severe neurological consequences of the disorder [17], [18], [19]. The only treatment currently available involves lifelong dietary measures [20], the continuation of which confers substantial health benefits to patients in adult life. Indeed, patients who maintain Phe-restrictive diets throughout childhood and into adolescence reported reduced rates of eczema, asthma, mental disorders, headache, hyperactivity and hypoactivity, compared with those who discontinue [21].

The PKU diet is highly restrictive, prohibiting the consumption of meat, fish, dairy products, nuts, beans and other protein-containing foods [22]. Measured amounts of fruits and vegetables are permitted in addition to special low-protein (low Phe) products [22]. A supplemental formula is required to provide the other essential amino acids, but has a strong taste and odor that many patients find unpalatable [23]. As a result, management of PKU is burdensome for both patients and their families, and adherence is a major medical problem [24], [25], [26], [27].

Researchers in industry and academic centers began trials recently to assess potential therapies, including enzyme, amino acid or co-factor supplements, such as 6R-BH4 (sapropterin dihydrochloride). Study endpoints for these and other trials need to be determined. The present analysis was conducted to assess the use of blood Phe as a predictive biomarker for clinical outcomes in patients with PKU, based on an assessment of the global relationship between blood Phe and intelligence quotient (IQ).

Section snippets

Methods

A systematic review was performed using established best methods [28], [29] to identify studies published between January 1980 and February 2004 that assessed Phe levels and neurological outcomes in patients with any clinical phenotype of PKU (classic/mild PKU or hyperphenylalaninemia). This process included developing a protocol in which objectives were stated, study sources and eligibility criteria were determined prospectively, key data elements were identified, and a preliminary analysis

Results

Searches yielded a total of 1153 citations. Of these, a total of 228 studies were accepted for inclusion in the database. Of these, 64 parent studies with 48 kin studies (publications describing preliminary results, subgroup results, other outcomes, or duplicate publications on the same patient population) reported within-study correlations of blood Phe and neurological outcomes (IQ, brain magnetic resonance imaging, or neuropsychological function measures) or provided sufficient individual

Discussion

This systematic review and meta-analysis has documented a quantitative proportional relationship between Phe level and IQ. Each 100 μmol/l increase in Phe (assessed by mean IDC during the critical childhood period or lifetime through 18 years) predicted a 1.3- to 3.9-point decrease in IQ for early-treated patients with PKU, over a Phe range from 394 to 750 μmol/l. A correlation was also found between concurrent Phe level and IQ for early-treated patients with PKU, in which each 100 μmol/l increase

Acknowledgments

The authors thank MetaWorks Inc. for their assistance with the literature review and statistical analysis, and Dr. Hannah Wills for editorial support. Support for the meta-analysis was provided by BioMarin Pharmaceutical Inc.

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