Phenylalanine blood levels and clinical outcomes in phenylketonuria: A systematic literature review and meta-analysis
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.
References (68)
- et al.
Blood phenylalanine levels and intelligence of 10-year-old children with PKU in the National Collaborative Study
J. Am. Diet. Assoc.
(1988) - et al.
How practical are recommendations for dietary control in phenylketonuria?
Lancet
(2002) - et al.
Meta-analysis in clinical trials
Control Clin. Trials
(1986) - et al.
Plasma arachidonic acid and serum thromboxane B2 concentrations in phenylketonuric children negatively correlate with dietary compliance
Prostaglandins Leukot. Essent. Fatty Acids
(1997) - et al.
Sustained attention and inhibition of cognitive interference in treated phenylketonuria: associations with concurrent and lifetime phenylalanine concentrations
Neuropsychologia
(2002) - et al.
Age-related working memory impairments in children with prefrontal dysfunction associated with phenylketonuria
J. Int. Neuropsychol. Soc.
(2002) - et al.
Academic underachievement and attention-deficit/hyperactivity disorder: the negative impact of symptom severity on school performance
J. School Psychol.
(2002) - et al.
PAHdb: a locus-specific knowledgebase
Hum. Mutat.
(2000) Neurological aspects of adult phenylketonuria
Curr. Opin. Neurol.
(1998)- et al.
The hyperphenylalaninemias
Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria
N. Engl. J. Med.
Molecular analysis of PKU in Ireland
Acta Paediatr. Suppl.
Development of the phenylketonuria screening programme in Estonia
J. Med. Screen.
A longitudinal study of phenylketonuria based on the data of the Budapest Screening Center
Eur. J. Pediatr.
Experience based on 800,000 newborn screening tests of the Budapest Phenylketonuria Centre
Acta Paediatr. Hung
Newborn screening for PKU and congenital hypothyroidism in Latvia
Southeast Asian J. Trop. Med. Public Health
Phenylketonuria in a low incidence population: molecular characterisation of mutations in Finland
J. Med. Genet.
Follow-up study of a nation-wide neonatal metabolic screening program in Japan. A collaborative study group of neonatal screening for inborn errors of metabolism in Japan
Eur. J. Pediatr.
Phenylketonuria detected by the neonatal screening program in Thailand
Southeast Asian J. Trop. Med. Public Health
Hyperphenylalaninemia: phenylalanine hydroxylase deficiency
Phenylpyruvic oligophrenia
Arch. Neurol. Psychiatry
Phenylpyruvic oligophrenia (phenylketonuria)
Res. Publ. Assoc. Res. Nerv. Ment. Dis.
The variability in manifestations of untreated patients with phenylketonuria (phenylpyruvic aciduria)
Pediatrics
Effect of age at loss of dietary control on intellectual performance and behavior of children with phenylketonuria
N. Engl. J. Med.
Normal clinical outcome in untreated subjects with mild hyperphenylalaninemia
Pediatr. Res.
Phenylketonuria in adulthood: a collaborative study
J. Inherit. Metab. Dis.
Treating phenylketonuria by a phenylalanine-free diet
Prof. Care Mother Child
Acceptability of a new modular protein substitute for the dietary treatment of phenylketonuria
J. Inherit. Metab. Dis.
Comments on diet and compliance in phenylketonuria
Eur. J. Pediatr.
Maternal PKU: strategies for dietary treatment and monitoring compliance
Ann. N. Y. Acad. Sci.
Psychosocial factors in maternal phenylketonuria: women’s adherence to medical recommendations
Am. J. Public Health
Systematic reviews: synthesis of best evidence for clinical decisions
Ann. Intern. Med.
Cited by (250)
Pharmacodynamics, safety, tolerability and pharmacokinetics of a single oral dose of an engineered phenylalanine ammonia-lyase in patients with phenylketonuria
2023, Molecular Genetics and Metabolism ReportsNeuropsychiatric Function Improvement in Pediatric Patients with Phenylketonuria
2023, Journal of PediatricsNeuropsychological assessment of adults with phenylketonuria using the NIH toolbox
2023, Molecular Genetics and MetabolismPhenylketonuria and the brain
2023, Molecular Genetics and MetabolismMetabolic phenotyping in phenylketonuria reveals disease clustering independently of metabolic control
2023, Molecular Genetics and Metabolism