A new survey of six Italian clinics found varying and inconsistent approaches for managing adult phenylketonuria (PKU), with insufficient PKU diet therapy and poor patient adherence to such eating plans.
Importantly, the survey also found especially poor compliance to the PKU diet among adolescent patients transitioning to adult treatment, putting these teenagers at risk for poor outcomes, such as cognitive impairment.
The survey findings support the implementation of a shared approach for managing PKU patients, focused on increasing compliance and adherence to treatment and on better follow-up strategies.
The study, “The management of phenylketonuria in adult patients in Italy: a survey of six specialist metabolic centers,” was published in the journal Current Medical Research and Opinion.
An inherited disorder, PKU is caused by a deficiency in the enzyme phenylalanine hydroxylase (PAH) that breaks down phenylalanine, an essential amino acid found in all dietary proteins.
The resulting phenylalanine accumulation in the blood leads to a host of serious health problems such as seizures, intellectual disabilities, and behavioral problems. Newborn screening and early treatment are recommended to prevent permanent cognitive impairment.
PKU patients are usually managed with a low phenylalanine diet that helps maintain phenylalanine levels within a normal range, specifically 120-600 micromoles per litre, or umol/L. Some individuals with PKU also benefit from treatment with tetrahydrobiopterin (BH4), an enzyme co-activator that stabilizes PAH and helps it break down phenylalanine.
However, poor compliance to the diet, particularly in adolescents transitioning from pediatric to adult treatment, may result in elevated phenylalanine levels and poor patient outcomes.
European guidelines recommend that all adults with PKU are followed at specialized metabolic centers throughout their lives, with monthly monitoring of phenylalanine levels and, depending on treatment compliance, annual visits to a healthcare professional. But little is known as to how PKU patients are managed across different centers.
Now, a group of six Italian experts sought to identify differences and similarities in care for PKU patients in their country. The team conducted a systematic literature review and a survey at their respective specialized clinics — all in Italy — to investigate the management of patients ages 16 and older with PKU.
Funding came from BioMarin Pharmaceutical, the maker of Kuvan (sapropterin dihydrochloride), an approved PKU therapy that mimics BH4.
The study focused on topics such as the adolescent transition to adult PKU treatment, BH4 therapy, follow-up care, and patient compliance.
“The overall aim of this study was to analyze and highlight similarities and differences in clinical care between centers, thus providing the basis for a more collaborative approach to maximize clinical management and match unmet needs, where identified,” the researchers wrote.
A total of 44 published studies were included in the final review. As some studies had overlapping populations, the researchers could not quantify the exact number of patients included, but they estimated that the numbers were between 3,890 and 5,037, with patients from across 17 countries.
The review found different management approaches across countries, with the greatest differences observed in the definition of PKU subtypes, the therapeutic levels of phenylalanine, follow-up practices, and in testing for BH4 responsiveness.
Additionally, about 35-50% of patients older than 16 found it very difficult or impossible to maintain strict adherence to diet therapy. This resulted in elevated blood phenylalanine levels in more than half of these individuals. In line with that, patients perceived diet therapy and the cognitive declines associated with high phenylalanine levels as the main factors impacting their quality of life.
Based on the literature review, the researchers recommended the adoption of European PKU management guidelines. These guidelines urge patients over age 12 to maintain phenylalanine levels in the 120-600 umol/L range. A cognitive evaluation is recommended for patients between the ages of 12 and 18 with poor dietary adherence and/or behavioral problems.
An “internal survey” also was administered, across the six Italian centers, to a total of 678 patients, ages 16 and older, receiving early treatment for PKU. These centers have multidisciplinary teams comprising specialists, pediatricians, dieticians, and psychologists, many of whom treat the same patients from infancy until they reach adulthood.
While the centers had differences in their multidisciplinary teams, this did not affect their patients’ loyalty to the center they visit or their adherence to therapy, the researchers noted.
The majority of centers had data pertaining to patient management from an early age. While most of these patients exhibited good dietary therapy compliance (90%) before the age of 14, the researchers estimated that the number of people abandoning treatment after that age increased to 30%.
The main reasons for non-compliance were the impact of diet therapy on quality of life and patient denial about the disease. These findings suggest that newer, less onerous therapies may improve patient compliance. The experts recommend modifying treatment and follow-up schedules to better monitor patients and accommodate the adolescent transition.
Dietary therapy was insufficient to treat many adults with PKU and was supplemented with BH4 treatment, for patients who were responsive to such therapy. Although all six clinics required patients to receive diet therapy, the use of BH4 treatment varied widely (0-30%). The clinics also had varied approaches and criteria for testing for BH4 responsiveness.
At all six centers, phenylalanine levels were maintained based on the European PKU management guidelines, with most having different target ranges and frequency of monitoring for pregnant PKU patients, who are at risk of exposing their babies to elevated levels of phenylalanine if not closely monitored.
When phenylalanine levels are elevated, patients may fail to perceive their cognitive impairment, the researchers found. Patients reported impaired concentration and focus, as well as anxiety, moodiness, and memory problems when phenylalanine levels were above 600 umol/L.
But most only recognized their neurocognitive impairments after phenylalanine levels were effectively treated and back within the normal range. Such reduced perceptions of symptoms may affect treatment compliance.
Changes such as leaving home and switching schools contributed to treatment non-compliance, as did social concerns, a denial of diagnosis, and a lack of communication with healthcare providers. The experts concluded that the adolescent transition to adult treatment should be a gradual process to improve disease management and compliance with the PKU diet and other therapies.
“Correct and standardized use of therapeutic options available to date is highly recommended to be implemented in all centers,” the investigators wrote.
“We highly recommend the creation of a network between centers and territories. The network will offer the opportunity to share experiences, be aligned and manage Italian patients homogeneously, and create the basis for effectively improving the lives of patients with PKU in Italy,” they concluded.