Phenylketonuria screening and management in southeastern Europe – survey results from 11 countries

This was the first study to assess the PKU screening and management characteristics in the region of southeastern Europe, involving 11 countries from the region with a cumulative population of approx. 52.5 mio. The included populations are thought to be ethnically and genetically very heterogeneous, which was reflected also by the variations of PKU incidences [15‐17]. Even within the same country large differences are reported; for instance, in Croatia, the incidence of PKU in the region “Hrvatsko Zagorje” is about 1/3.500, while in the region of “Dalmatia” only 1/15.500 [15]. The incidence of classical PKU is geographically scattered with significantly lower incidences in Serbia and Bulgaria [17, 18]. The reported PAH genotypes from the participating countries in different genetic studies are reflecting the heterogeneity of the populations but numerous historically documented migrations over the Balkan Peninsula were causing genetic similarity to other Caucasian populations [18‐24]. The incidences are not known for 4 countries without newborn screening, while only estimations were possible for Bosnia and Romania. Taking the birth rates in the 4 countries without screening and the PKU incidence of 1/10,000 the expected number of the PKU patients would be 10 per year. The number seems low but the many lost screening years in this region in the last 40 years are suggesting a much higher number of missed opportunities for the diagnosis and treatment of PKU.

The most disturbing fact shown by our survey was that the PKU newborn screening was not introduced in 4 of 11 countries (Albania, Kosovo, Macedonia, Montenegro), while in two other countries (Bulgaria, Romania) where it was introduced, over 10 % of newborns were not screened. Thus large parts of the region were falling behind the internationally established standards regarding the PKU screening [6, 8]. In the countries with non existing newborn screening none or very few patients with PKU were diagnosed. In the countries with implemented newborn screening, the total numbers of diagnosed PKU patients born before the implementation of the newborn screening were available, but were very low as compared to the expected number of PKU patients based on the PKU incidences.

The possibility of treatment was very limited in Kosovo, Albania and Macedonia because amino acids supplements and low protein food were not reimbursed, while patients in Bulgaria and Moldova were reported not to get any additional financial support for the low protein diet. The nutritional recommendations and target Phe values in blood could be hardly met without sufficient amounts of low-Phe protein substitutes and low protein food. The unavailability and high prices of the medical food would be a further important limitation for PKU treatment in these countries in case of successful consolidation of newborn screening throughout the region.

Almost half of the countries reported the use of the national PKU guidelines. Fundamentally they are based on several published recommendations and the management of the patients is very similar [13, 25]. Surprisingly a dietitian was a part of PKU team in only 4 countries and in other PKU centers the dietary plan was a responsibility of the physicians. Previous European surveys show that basic PKU team consists of a physician and a dietitian [11‐13], which was not shown to be a regular practice in the region of southeastern Europe. The quality of the dietary PKU management without a specialized dietitian may be insufficient. The multidisciplinary approach to include a dietitian is consistent with the requirements for minimum standards of care for PKU [9], which any European country should be encouraged to adopt.

The economic backgrounds of the participating countries were also very heterogeneous, four of 11 countries had GDP per capita under 10,000 USD and nine of 11 countries under 20,000 USD. Moldova with lowest GDP per capita maintained better standards of PKU screening and management as compared to some other countries with relatively 2 to 3-times higher GDP per capita. Financial situation seemed not to be the most important factor of the standard of the PKU screening and management, which we believe was an important and encouraging finding of the study.

The newly published proceedings of the PKU scientific review conference are providing one of the most comprehensive and up-to-date understandings of PKU available [8]. The preparation and publication of the proceedings perfectly coincides with fifty years anniversary of the Guthrie’s discovery and implementation of first newborn screening programs for PKU. In the 1970s the screening for PKU was mandatory in nearly all industrialized European countries [26]. PKU screening is a prerequisite for an early implementation of the phenylalanine-restricted diet, preventing and eliminating the severe neurological impairment typical for untreated PKU patients [5, 27]. Nevertheless, the people from many developing countries throughout the world are not taking a part in any of advances in the field of PKU of the last 50 years [28]. The report from year 2004 that outlined the status of neonatal screening for PKU has included 7 countries from southeastern Europe [29]. Moldova had no screening in year 2004 and Montenegro was a part of Serbian screening program [18, 29]. The breakup of former Yugoslavia after inter-ethnic wars resulted in newly established countries with limited resources. Consequently, the screening statistics is not significantly better after 10 years. Bosnia, Bulgaria, Croatia, Serbia and Slovenia continued or improved the screening program while other countries in the region with the exception of Romania did not implement the screening [30].

Sporadic reports from certain developing countries (e.g. Tunisia, Lebanon, Iran) without newborn PKU screening show PKU to be one of the most common preventable causes of mental retardation [28, 31‐33]. A significant group of mentally impaired patients is expected in Balkan Peninsula because of the late or absent introduction of the screening [30, 34]. Additionally the families miss the opportunity for genetic counseling without a proper diagnosis and maternal PKU is not prevented. Furthermore, some other studies are showing that the introduction of newborn screening in developing countries would clearly be a cost-effective decision [28, 35].

We firmly believe that implementation of basic standards of PKU management to the developing parts of the world should be among priorities when identifying future medical and research needs, while these efforts should be supported by relevant professional forums, patients’ organizations and also industry [9, 28]. One such emerging initiative is that by the E.S.PKU, which very recently proposed the need for recommendations for a minimum standard of care for PKU, also arguing for equal access to screening, treatment and monitoring throughout Europe [9].