Eye Exam May Help Assess PKU Severity, Study Suggests

Eye Exam May Help Assess PKU Severity, Study Suggests
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The thickness of the retinal nerve fiber layer, or RNFL — a light-sensitive tissue layer of the eye — correlates with the levels of the amino acid phenylalanine and with cognitive function in people with phenylketonuria (PKU), a study reports.

These findings suggest the potential of a non-invasive eye exam to help assess the level of neural damage in PKU.

The study, “Retinal nerve fibre layer thickness associates with phenylketonuria control and cognition,” was published in the Journal of Medical Genetics.

PKU is caused by mutations in the PAH gene, which carries the instructions to make an enzyme that converts phenylalanine into another amino acid called tyrosine. (Amino acids are the building blocks of proteins). Mutations in this gene increase the amount of phenylalanine in the blood to toxic levels, which causes cognitive problems and other complications in people with PKU.

While a low-protein diet that limits foods high in phenylalanine has therapeutic benefits, the optimal levels of the essential amino acid are still under debate.

In addition, easily accessible and non-invasive biomarkers are missing to monitor the neural damage in PKU patients.

Here, a team led by researchers at the Poznan University of Medical Sciences, in Poland, tested the potential of using the thickness of the RNFL — assessed during a non-invasive eye exam — as a biomarker for monitoring phenylalanine levels and patients’ cognition.

A precise imaging technique called optical coherence tomography (OCT) provided high-resolution, 3D images of the eye.

In total, 15 patients (mean age 15.2 years) with PKU diagnosed through newborn screening underwent a standard eye exam, which showed no abnormalities. This was followed by an OCT of the retina.

From the OCT images, the researchers specifically used four quadrants — temporal, superior, nasal, and inferior — to evaluate the thickness of the RNFL.

In turn, the participants’ cognition was accessed by a well-trained practitioner using the Wechsler Adult Intelligence Scale or the revised Wechsler Intelligence Scale for Children; both are measures of perceptual and fluid reasoning, spatial processing, and visual–motor integration. The lifetime phenylalanine concentration for each patient was measured using dry blood spots, which were routinely provided.

On average, the participants’ RNFL had a thickness of 103.8 micrometers (mcm), which is similar to the measurements recorded in a previous study in healthy young adults. The mean overall IQ was 105.1, with similar results in verbal and performance scores.

The average blood level of phenylalanine over time was 7.1 mg/dL. A mean of 43.9% of the phenylalanine measurements spiked above 6 mg/dL, while 23.7% were above 10 mg/dL. Notably, 6 mg/dL and 10 mg/dL are the two phenylanaline levels’ limits recommended in the U.S. and Europe.

The RNFL thickness correlated significantly with the IQ full score and with verbal IQ. The association was even stronger when analyzing the inferior quadrant separately.

In addition, the concentration of phenylalanine over time showed a significant negative correlation with RNFL thickness. That means that lower levels of phenylalanine were linked with thicker RNFL.

Although no correlation was found between phenylalanine values over time and IQ scores, a lower verbal IQ was associated with a higher percentage of spikes above 6 and 10 mg/dL.

A statistical analysis demonstrated that the total RNFL thickness was independently associated with verbal IQ and with average phenylalanine concentration, demonstrating the potential of using this measure to monitor PKU progression.

Overall, these findings show “for the first time that RNFL thickness is a correlate of IQ and time-weighted average blood Phe [phenylalanine] concentration in PKU,” the researchers wrote.

“We are convinced that prospective studies on larger PKU groups with serial RNFL measurements are warranted to verify the value of RNFL as a neuromarker in PKU,” they concluded.

Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York.
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José holds a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.

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Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York.
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