Worldwide, phenylketonuria (PKU) is seen to affect about 6 of every 100,000 babies born, with the highest frequency being reported in Turkey and Iran, according to a review study based on newborn screening data.
Higher PKU rates were observed in countries and regions known to have more consanguineous marriages — families formed by individuals who are closely related. However, no potential association could be made due to the low number of studies reporting consanguineous marriage among parents of newborns with PKU.
The researchers suggested that this type of information should be recorded in PKU screening programs.
The study, “Global prevalence of classic phenylketonuria based on Neonatal Screening Program Data: systematic review and meta-analysis,” was published in the journal Clinical and Experimental Pediatrics.
PKU is caused by mutations in the PAH gene, which contains the instructions for producing an enzyme called phenylalanine hydroxylase (PAH). PAH is responsible for converting phenylalanine — an essential amino acid obtained through the diet — into another amino acid, tyrosine. (Amino acids are the building blocks of proteins.)
PAH mutations result in lower levels of PAH activity, leading to the toxic buildup of phenylalanine systemwide, and mainly damaging to the brain. Depending on PAH’s activity and resulting phenylalanine levels, PKU may be classic (severe), moderate, or mild. When classic, phenylalanine levels are higher than 20 mg/dL.
PKU’s early detection through newborn screening is crucial to managing the disease — with approaches such as a carefully controlled, low-phenylalanine diet — that may prevent further brain damage and intellectual disability.
The disease is inherited in a recessive way, meaning that a baby must inherit disease-causing PAH mutations from both parents to develop the disease. For this reason, consanguineous marriage is a notable risk factor for PKU, as it increases the chances a baby acquiring a mutated gene from each parent.
Numerous studies on PKU frequency have shown that it varies among races, ethnic groups, and geographic regions. Evidence also suggests that countries with higher rates of consanguineous marriages have a higher PKU incidence.
However, no study to date has systematically analyzed the global occurrence of PKU or compared its frequency across regions and countries.
Researchers at Kerman University of Medical Sciences, in Iran, set out to estimate the worldwide occurrence of classic PKU by systematically reviewing published studies based on PKU newborn screening.
The team searched for relevant studies in five databases in October 2018, and inclusion criteria included PKU screening, through a laboratory test, in the first 28 days of a baby’s life.
A total of 53 studies, conducted from 1964 through 2017 and involving more than 119 million newborns, were included in the systematic review, and 46 of these studies were used to estimate classic PKU global occurrence.
Results showed that longest screening study took place in France (over 35 years), while the largest screening population study was done in China (35.79 million newborns over 30 years). Only six studies reported the percentages of consanguineous marriages among parents of newborns with PKU, which varied from 45% in Turkey to 100% in Iraq.
The phenylalanine cutoff value for diagnosing classic PKU patients also ranged from 1.65 mg/dL to 20 mg/dL; the latter level used in 22 of these studies.
Notably, the highest PKU frequencies were reported in Turkey (38.13 per 100,000 newborns) and Iran (21.28 per 100,000 newborns), while the lowest were found in Thailand (0.3 per 100,000 newborns) and Taiwan (0.44 per 100,000 newborns).
Based on these data, the researchers estimated that the overall worldwide occurrence of classic PKU was 6.002 per 100,000 live births. Importantly, a high variability existed within the worldwide PKU prevalence, which may be due “to differences in the number of consanguineous marriages among the different regions, phenylalanine cutoff points, and sample sizes,” the researchers wrote.
Among World Health Organization defined regions, the highest prevalence was seen in the Eastern Mediterranean (9.83 per 100,000 newborns) area, followed by Europe (8.11 per 100,000 newborns), the Americas (5.32 per 100,000 newborns), the Western Pacific (2.94 per 100,000 newborns), and Southeast Asia (0.32 per 100,000 newborns).
Further analysis, using Europe as the reference, showed that the Eastern Mediterranean region had a higher PKU frequency, but this difference was not statistically significant. The Western Pacific and Southeast Asia had significantly lower PKU frequencies than those in Europe.
“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,” the researchers wrote.
The team highlighted that its study could not assess whether differences in consanguineous marriage rates contributed to the distinct PKU frequencies seen across countries and areas.
“Thus, we suggest that consanguineous marriages be recorded and reported in screening programs designed to identify patients with PKU and other congenital metabolic diseases,” the researchers wrote.