Neonatal diagnosis is key in patients with phenylketonuria (PKU)

Early diagnosis, a protein-free diet and treatment with a cofactor called BH4 make it possible for patients with this disease to develop normally. A project being jointly developed by Hospital Clínic and Hospital Sant Joan de Déu aims to better understand phenylketonuria (PKU), increase therapeutic options, and improve patients’ quality of life.

A project funded by La Marató de TV3 (an annual television broadcast to raise funds for research into incurable diseases) and led by Dr Josep M. Grau from the Muscular and Mitochondrial Function Research Group at IDIBAPS and Hospital Clínic, developed together with Hospital Sant Joan de Déu, studies different cardiovascular, brain, metabolic and intestinal microbiota parameters in patients with PKU to better understand the pathophysiology of the disease, and to be able to offer more therapeutic options.

PKU is a rare disorder that affects protein metabolism. It is hereditary, and it is caused by a lack of the enzyme that breaks down the amino acid phenylalanine into tyrosine. This causes phenylalanine to accumulate and creates toxicity, especially in the brain. At the same time, the necessary quantities of tyrosine are not produced. This results in damage to the central nervous system (CNS), which can cause severe neurocognitive disabilities. Neonatal screening is currently carried out in Catalonia by means of the heel prick test. This test allows more than 20 diseases to be diagnosed, and fortunately phenylketonuria is one of them. A prick in the baby’s heel allows a few drops of blood to be extracted in order to diagnose various diseases.

The prevalence of this pathology is between 1 and 5 cases per 10,000 live births globally. Patients who are diagnosed early, meaning at birth, who follow the appropriate protein-free diet (consuming no meat, fish, eggs, etc.), and who respond to treatment, have normal neurological development and therefore their intellectual capacity is not affected. The drug administered is called BH4. It is a chemical compound that compensates somewhat for the lack of conversion of phenylalanine to tyrosine. Patients who respond to this treatment do not need to follow such a strict diet. In addition to the diet, amino acids are given in the form of supplements.

Someone given a late diagnosis, for example at 10-12 years of age, will not have normal neurocognitive development. These patients often present a variety of manifestations such as developmental delay, intellectual disability, psychological disturbances, behavioural problems and neurological problems such as seizures. This project was launched to study the molecular mechanisms that produce these manifestations. It involves two centres, and includes the majority of patients in Catalonia. It represents a sample of 150 patients from the Hospital Sant Joan de Déu, where they are diagnosed and receive treatment in infancy. They undergo a clinical assessment based on blood, stool and urine samples, which are compared to a control group. These patients continue to be monitored as adults and undergo a multidimensional assessment at Hospital Clínic, which analyses a group of more than 80 cases. Patients with higher phenylalanine levels will be followed up longitudinally for 18 months.

Because of its multidimensional nature, this is a multidisciplinary project that involves different medical specialities. A dietary and cardiovascular evaluation is carried out, including ultrasound scans of the arteries, because these patients are at increased risk of developing cardiovascular disease and atheromatous plaques at a very young age. A very detailed dietary log is made and an assessment of body composition is conducted, among other tests. At the neurological level, patients undergo a very innovative study that involves a functional brain resonance scan to study the connections between different parts of the brain.

The profiles of affected people are compared with those of healthy people, followed by a complex neuropsychological test. The gut microbiota is also studied, as it has been observed that siblings with the same disease and enzyme deficiency, the same diet, and similar phenylalanine levels, can be clinically different. It is possible that the microbiota plays a role in these differences. Finally, mitochondrial function is analysed. Mitochondria are the organelles in the cells that are responsible for providing them with energy. The oxidative stress of this organelle is being studied. This is an imbalance that can cause toxic effects in the cell. This phenomenon seems to be related to premature ageing, as well as neurological and cardiovascular pathology.

The aim of this project is to identify certain key patterns in brain connectivity, cardiovascular risk, microbiota diversity and oxidative stress, so that scientific research into minority diseases such as PKU can progress.

Documented information by: Dr. Josep M. Grau of the muscle and mitochondrial function research group of IDIBAPS and Hospital Clínic.