Early diagnosis, a protein-free diet, and treatment with a cofactor called BH4 enable normal development for patients with this disease. A project currently being carried out between Hospital Clínic and Hospital Sant Joan de Déu aims to better understand phenylketonuria, expand therapeutic options, and improve patients’ quality of life.
A project funded by La Marató de TV3, led by Dr. Josep M. Grau from the research group on muscle and mitochondrial function at IDIBAPS and Hospital Clínic, and developed in parallel with Hospital Sant Joan de Déu, studies various cardiovascular, cerebral, metabolic, and gut microbiota parameters in patients with phenylketonuria to better understand the pathophysiology of the disease and offer more therapeutic options.
Phenylketonuria is a rare disorder that affects protein metabolism. It is hereditary and caused by the lack of the enzyme that breaks down the amino acid phenylalanine into tyrosine. This causes phenylalanine to accumulate, creating toxicity primarily in the brain, and on the other hand, there are insufficient amounts of tyrosine. As a consequence, damage occurs to the central nervous system (CNS), which can lead to severe neurocognitive disabilities. Currently, in Catalonia, neonatal screening is performed through the heel prick blood test, which allows the diagnosis of more than 20 diseases, including phenylketonuria. A prick in this area of the newborn’s foot allows a few drops of blood to be extracted, facilitating diagnosis.
The prevalence of this condition worldwide is between 1 and 5 per 10,000 live births. Patients diagnosed early, meaning at birth, who follow the appropriate protein-free diet, avoiding meat, fish, eggs, etc., and respond to treatment, can achieve normal neurological development, meaning their intellectual capacity is not affected. The administered drug is called BH4, a chemical compound that partially converts phenylalanine into tyrosine. Patients who respond to this treatment do not need to follow such a strict diet. Besides the diet, they receive amino acids in the form of supplements.
A person diagnosed late, for example, at 10-12 years old, will not have normal neurocognitive development. These patients often present various symptoms such as developmental delay, intellectual disability, psychological disorders, behavioral issues, and neurological problems such as seizures. The molecular mechanisms that cause these issues are being studied, which is why this project involving two centers has been launched, including most patients in Catalonia. It represents a sample of 150 patients from Hospital Sant Joan de Déu, where they are diagnosed and treated from infancy and undergo clinical evaluations using blood, stool, and urine samples compared to a control group. Later, when they reach adulthood, they continue their follow-up and undergo a multidimensional assessment at Hospital Clínic analyzing a group of more than 80 cases. Patients with higher phenylalanine levels will be followed longitudinally for 18 months.
This is a multidisciplinary project involving various medical specialties due to its multidimensional nature. A dietary and cardiovascular assessment is performed, including ultrasound scans of the arteries, as these patients are at higher cardiovascular risk and may develop atherosclerotic plaques at a young age. A detailed dietary record is kept, along with an evaluation of body composition, among other tests. Neurologically, patients undergo an innovative study that includes functional brain MRI to analyze connections between different brain areas. The profiles of affected individuals are compared with those of healthy individuals, followed by a complex neuropsychological test. Gut microbiota is also studied, as it has been observed that siblings with the same disease, enzyme deficiency, and diet, but with similar phenylalanine levels, can have different clinical outcomes. It is possible that microbiota plays a significant role in these differences. Finally, mitochondrial function is analyzed. Mitochondria are organelles in cells responsible for providing energy. The study focuses on oxidative stress in this organelle, an imbalance that can cause toxic effects on the cell. This phenomenon seems to be related to premature aging and neurological and cardiovascular diseases.
The goal of this project is to identify certain patterns that are key in brain connectivity, cardiovascular risk, microbiota diversity, and oxidative stress, and help advance research in rare diseases such as phenylketonuria.
Information documented by: Dr. Josep M. Grau from the muscle and mitochondrial function research group at IDIBAPS and Hospital Clínic.
Source: www.clinicbarcelona.org