Mutations in the PAH gene cause phenylketonuria. The PAH gene provides instructions for making an enzyme called phenylalanine hydroxylase. This enzyme converts the amino acid phenylalanine to other important compounds in the body. If gene mutations reduce the activity of phenylalanine hydroxylase, phenylalanine from the diet is not processed effectively. As a result, this amino acid can build up to toxic levels in the blood and other tissues.
Because nerve cells in the brain are particularly sensitive to phenylalanine levels, excessive amounts of this substance can cause brain damage. Classic PKU, the most severe form of the disorder, occurs when phenylalanine hydroxylase activity is severely reduced or absent.
People with untreated classic PKU have levels of phenylalanine high enough to cause severe brain damage and other serious health problems.
Mutations in the PAH gene that allow the enzyme to retain some activity result in milder versions of this condition, such as variant PKU or non-PKU hyperphenylalaninemia. Changes in other genes may influence the severity of PKU, but little is known about these additional genetic factors.
This condition is inherited in an autosomal recessive pattern , which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.
Genetics Home Reference has merged with MedlinePlus. Learn more. The information on this site should not be used as a substitute for professional medical care or advice. An amino acid, Phe is a building block of protein and is found in all proteins, most foods, and in some artificial sweeteners.
This is important because the damage caused by toxic levels of Phe in the first few years of life is irreversible. When treatment is begun early and rigorously adhered to, PKU affected children can expect normal development and lifespan.
Today the first line of therapy for PKU is often medical foods and a diet low in Phe. While currently there is no cure, in recent years new drug products have become available that can be used to better manage blood Phe levels. When an individual is untreated or poorly treated, Phe rises to high levels in the blood causing irreversible brain damage and neurological complications including IQ loss, memory loss, seizures, learning disabilities, and emotional problems.
Join us in our efforts to improve the lives of individuals with PKU by finding better treatments and find a cure. The gene defect for PKU is an autosomal recessive genetic defect. This means an affected person inherited two genetic defects for the disorder one from each parent. A person with one genetic defect for the disorder, is called a 'carrier' for PKU.
Carriers do not have symptoms of the disorder. The incidence of carriers in the general population is approximately one in fifty people, but the chance that two carriers will mate is only one in [2].
Carrier testing for PKU is available through several commercial testing companies. If you would like more information about genetic testing for PKU, speak with your doctor or a genetic counselor.
PKU affects between 1 in 10, and 1 in 20, depending on the country of origin. The incidence varies widely in different human populations from 1 in 4, births among the population of Ireland [3] to fewer than one in , births among the population of Finland [4].
Even higher levels have been reported in the Eastern Mediterranean region 1 in 4, in Turkey and 1 in 3, in the Islamic Republic of Iran [5].
The participation rate increased with the progression of the screening process in 8 studies [ 1 , 24 , 27 , 36 , 56 , 58 , 60 , 62 ]. Moreover, 6 studies reported the percentage of consanguineous marriages among the parents of newborns with PKU [ 1 , 13 , 16 , 17 , 21 , 50 ]. In the included studies, 2 stages were used to diagnose infants with classical PKU. A total of 19 studies reported the number of positive cases in the first stage of screening.
The phenylalanine cutoff point for separating positive cases and referrals for diagnostic testing ranged from 1. The highest recall rate in the first stage of screening was per , neonates in a study conducted in Russia [ 35 ]. In the diagnostic stage, the phenylalanine cutoff point for diagnosing classic PKU patients ranged from 1. Among the included studies, the highest prevalence was found in Turkey A subgroup estimation of the polled prevalence showed that the pooled prevalence of classic PKU in the included studies was 6.
The highest prevalence was seen in Eastern Mediterranean 9. Forest plot of pooled global prevalence of phenylketonuria. ES, estimated; CI, confidence interval. According to the results of mixed model, cutoff point selection had no effect on prevalence. The p value obtained from the likelihood ratio test in the mixed model test suggested that the random intercept model was appropriate. A meta-regression test was used to assess the effect of year, phenylalanine cutoff point, region, neonate age at screening, and screening level national or regional on heterogeneity.
Among the variables included in the model, only some WHO regions were significant. In the meta-regression model, the European region was selected as a reference.
In the Eastern Mediterranean region, the prevalence was 1. The pooled prevalence of the different regions is reported in Table 3. According to I 2 by region and overall, the studies had high heterogeneity Table 4. This systematic review aimed to investigate the worldwide prevalence of PKU and provided a general picture of its status. The results of this study demonstrate that the worldwide prevalence of the disease is 0. However, the meta-analysis revealed that the I 2 index, which indicates heterogeneity, was reported for all regions except Southeast Asia The uni- and multivariate models in the meta-regression showed that phenylalanine level, geographical area, neonate age at screening, screening level national or regional , after the control for year of study, did not change heterogeneity.
However, the differences in prevalence can be attributed to 2 factors: 1 variability of the factors affecting disease worldwide; and 2 differences in the methods used in the studies.
PKU is a c0ngenital genetic disease; thus, factors such as culture, customs, consanguineous marriage, and genetics are expected to affect its incidence but among included studies only 6 studies in Iran, Iraq, Turkey, and the United Arab Emirates [ 1 , 13 , 16 , 17 , 21 , 50 ] reported consanguineous marriages among parents of children with PKU.
Therefore, a lack of information about the prevalence of PKU in many countries in which consanguineous marriage is prevalent and a lack of reporting consanguineous marriage status in parents of children with PKU in many studies prevented us from controlling the effect of this variable on prevalence. The next important determinant of prevalence is study performance; factors such as diagnostic tests, cutoff point, and sample size can affect the pooled prevalence in prevalence studies.
However, in the mixed model test, there was no significant relationship between cutoff point and disease prevalence, which might have been due to the effect of the confounding variables.
However, the difference was noticeable when the cutoff point differed in the same population and within the same country. For example, in 3 studies conducted during — in Fars province Iran , a different cutoff point was found. Habib et al. Furthermore, in the study of Karamifar et al. Sample size is the other factor involved in the difference in prevalence among studies. In a meta-analysis, the pooled prevalence is estimated according to the sample size, and larger studies have greater impact on prevalence.
Thus, although studies conducted in the Eastern Mediterranean region reported higher prevalence than those in the Western Pacific region, since most studies in the latter had a larger sample size and the weighted sample size in that region was Although this study addressed an important concern in genetic diseases, its findings may not be highly accurate, as there were many sources of heterogeneity in the reviewed studies that could have affected their pooled prevalence.
Moreover, some heterogeneous sources might not have been identified. However, the standardization of study methods can partly solve this problem. One of the limitations of this study was the failure to report consanguineous marriage in parents of newborns with PKU. Thus, it was not possible to answer the following question:.
Is the difference in PKU prevalence among different countries due to differences in the number of consanguineous marriages? Thus, we suggest that consanguineous marriages be recorded and reported in screening programs designed to identify patients with PKU and other congenital metabolic diseases. In conclusion, all relevant studies conducted in — were included in this review.
The highest PKU prevalence was observed in Turkey This difference in the prevalence may be due to differences in the number of consanguineous marriages among the different regions, phenylalanine cutoff points, and sample sizes. The authors thank Moslem Taheri for his advice for extraction, Razieh Zahedi for her advice for the meta-analysis, Maryam Nazemzadeh for professional English editing. Question: What is the global prevalence of classic phenylketonuria based on Neonatal Screening Program Data?
Finding: The overall worldwide prevalence of the disease is 6. Meaning: This difference in the prevalence may be due to differences in the number of consanguineous marriages among the different regions, phenylalanine cutoff points, and sample sizes. No potential conflicts of interest relevant to this article are reported. National Center for Biotechnology Information , U.
Journal List Clin Exp Pediatr v. Clin Exp Pediatr. Published online Feb 6. Author information Article notes Copyright and License information Disclaimer. Corresponding author: Farzaneh Zolala, PhD. This article has been cited by other articles in PMC. Abstract Phenylketonuria is a disease caused by congenital defects in phenylalanine metabolism that leads to irreversible nerve cell damage.
Open in a separate window. Introduction Genetic and congenital abnormalities are the most important causes of death and malformation in the first month of life [ 1 ]. Inclusion criteria All original articles that directly reported PKU prevalence based on newborn screening of populations were included.
Data collection The title, abstract, and keywords of every identified article were carefully scanned and relevant articles were selected by title or abstract review. Data extraction and management Two reviewers HSH. Assessment of methodological quality Article quality was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for studies that reported prevalence data.
Risk of bias Risk of bias was assessed using the risk of bias tool for studies measuring disease prevalence designed and developed by Hoy et al. Data analysis The data were analyzed using Stata ver. Results 1. Study selection After a comprehensive search, 1, relevant articles were identified, duplicates were removed.
Risk of bias In the bias assessment, 7 studies scored below 6 high risk and were excluded from the meta-analysis; thus, the pooled global prevalence was estimated without them [ 11 - 13 , 21 - 24 ]. Study characteristics In this section, the systematic review results are presented based on different characteristics, including region, test, and participant characteristics. Region characteristics The included studies — are presented in Table 1.
Table 1. Description of studies included in the study. Article did not report prevalence of PKU. Test characteristics In the included studies, 2 stages were used to diagnose infants with classical PKU. Screening tests A total of 19 studies reported the number of positive cases in the first stage of screening.
Diagnostic tests In the diagnostic stage, the phenylalanine cutoff point for diagnosing classic PKU patients ranged from 1. Pooled global prevalence of classic PKU Among the included studies, the highest prevalence was found in Turkey Statistical analysis According to the results of mixed model, cutoff point selection had no effect on prevalence. Autosomal recessive inheritance pattern To have an autosomal recessive disorder, you inherit two mutated genes, one from each parent.
Share on: Facebook Twitter. Show references National Library of Medicine. Genetics Home Reference. Accessed Oct. National Organization for Rare Disorders. Learning about phenylketonuria PKU. National Human Genome Research Institute.
Phenylketonuria PKU. Merck Manual Professional Version. Bodamer OA. Overview of phenylketonuria. Singh RH, et al. Recommendations for nutritional management of phenylalanine hydroxylase deficiency.
Genetics in Medicine. Zeratsky KA expert opinion. Mayo Clinic, Rochester, Minn.
0コメント