Nutritional Status in Phenylketonuria

Study Overview
=================
Brief Summary
-----------------
In the era of Phenylketonuria (PKU) newborn screening, early diagnosis in the neonatal period and prompt treatment institution has protected patients from developing severe and irreversible mental retardation. The main objective of the treatment is to prevent a chronic elevation of blood Phe concentrations, which together with reduced tyrosine concentrations may increase the risk of neurologic damage. In order to achieve this purpose, the mainstay of treatment is a special diet characterized by a natural protein restriction, supplemented with protein substitutes and special low protein foods. The requirement to optimize growth and body composition, usually result in dietary prescriptions that are high in carbohydrate (>60% of energy intake), to promote anabolism, considering the synthetic properties of this special diet. Some studies have described a high risk of developing overweight and obesity. Although there is a tendency for a higher incidence in females, it seems that the prevalence in PKU patients follows the same trend as the general population. However, there are limited studies published so far and no longitudinal studies are available describing current practice and its impact on the prevalence of overweight and obesity; neither its consequences in terms of metabolic syndrome or cardiometabolic markers. Recently, sapropterin dihydrochloride, which is the synthetic form of Phenylalanine Hydroxylase cofactor, is available in Portugal for patients with PKU. In practice, the sapropterin treated patients increase their natural protein intake, minimizing the synthetic characteristics of the diet. While there is a need for patient re-education about the practicalities of meeting their nutritional needs, scientific evidence about the nutritional status impact of diet liberalization is inadequate. This study aims to test the following hypothesis: Global nutritional status is not significantly affected in patients with PKU under exclusive dietary treatment. There is a trend for increased rates of overweight and obesity in patients with PKU from 2009 and we consider this will continue to increase. The start of sapropterin treatment allows a higher natural protein intake in patients with PKU that significantly targets nutritional status in at least one of its components (anthropometry, body composition or biochemistry).

Detailed Description
-----------------
At the Centro Hospitalar do Porto (Reference Centre for the treatment of Inherited Metabolic Diseases) the annual nutritional status evaluation routinely generates data on anthropometry, body composition, blood pressure, nutritional intake and clinical biochemistry. Since 2009, all this information is recorded for all the patients with PKU under follow-up. For the purpose of this project, data will be collected, from 2009 until 2018, using a minimum of 5 annual nutritional status evaluations per patient. The project will be able to compare the longitudinal evolution of nutritional status in exclusively diet treated patients (period between 2009 and 2014) with a subgroup of patients already under sapropterin treatment in the period between 2015 and 2018. Genotype is available for all patients with PKU under follow-up at Centro Hospitalar do Porto. However, the decision for starting sapropterin treatment was based on the results from a sapropterin-loading test protocol, approved in 2014 by the Portuguese Society of Metabolic Disorders (not published). For every PKU patient under follow-up at Centro Hospitalar do Porto, the information about nutritional intake is recorded in a special file that contains all the diet details collected in every appointment. In that way, for the purpose of the annual nutritional status evaluation, every PKU patient is submitted to anthropometric and body composition evaluations, blood pressure assessment and blood samples collection for completing the hematological and biochemical measurements. Also in the same day, at the nutrition appointment, a dietary assessment is done, in order to allow further nutrition adjustments when needed. This approach allows us to know the precise nutritional ingestion in the period before all the measurements. Data will be collected from patient databases or patient records. In the period between 2009 and 2014 there are no treatments or interventions to which the patients can be randomly assigned, as no specific treatment is the focus of the project. In the period between 2015 and 2018, patients will be divided in two groups based on treatment modalities: diet-treated only or sapropterin treatment. However, their assignment in each group does not have any influence of the project itself. The inclusion in one of the two groups will be decided based on the results of the sapropterin loading test done previously within the clinical routine protocol. Patients will be identified only by a number and only medical data will be collected. No directly or indirectly nominative data will be collected and data will be anonymous.

Official Title
-----------------
Trends in Nutritional Status of Patients With Phenylketonuria

Conditions
-----------------
Phenylketonurias

Intervention / Treatment
-----------------
* Other: Diet
* Drug: Sapropterin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of PKU. With all the clinical data available since 2009. Have completed the annual routine nutritional status evaluation in the periods 2009/2010, 2011/2012, 2013/2014, 2015/2016 and 2017/2018. Maintaining a follow-up at Centro Hospitalar do Porto. Exclusion Criteria: Lost of follow-up. Not have completed at least one full evaluation in each time period: 2009/2010, 2011/2012, 2013/2014, 2015/2016 and 2017/2018. Any other chronic medical condition which may affect diet or nutritional status.

Ages Eligible for Study
-----------------
Minimum Age: 3 Years

Sexes Eligible for Study
-----------------
All

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Diet-treated<br>Patients with Phenylketonuria under dietary treatment. | Other: Diet<br>* A specific dietary treatment for patients with Phenylketonuria.<br>* Other names: Dietary treatment;|
| Sapropterin-treated<br>Patients with Phenylketonuria under sapropterin treatment. | Drug: Sapropterin<br>* A pharmacological treatment for patients with Phenylketonuria, used alone or in combination with dietary treatment.<br>* Other names: Tetrahydrobiopterin;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overweight and obesity prevalence | To determine the prevalence of overweight and obesity. | 2009-2018 | 
| Overweight and obesity incidence | To determine the incidence of overweight and obesity. | 2009-2018 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metabolic syndrome prevalence | To determine the change of the prevalence of metabolic syndrome in patients. | 2009-2018 | 
| Metabolic syndrome incidence | To determine the incidence of metabolic syndrome in patients. | 2009-2018 | 
| Body composition using bioelectrical impedance analysis | To describe the body composition evolution (fat mass, fat-free mass and phase angle) throughout the 10 years of the study. | 2009-2018 | 
| Metabolic control (blood phenylalanine concentration) | To describe the evolution of metabolic control in patients. | 2009-2018 | 
| Metabolic control (blood phenylalanine concentration) and sapropterin | To describe the evolution of metabolic control (blood phenylalanine concentrations) in patients under sapropterin treatment during the period between 2015 and 2018. | 2015-2018 | 
| Phenylalanine intake and sapropterin | To understand the impact of sapropterin treatment on phenylalanine intake (mg of phenylalanine/day) during the period between 2015 and 2018. | 2015-2018 |