Supplementation with large neutral amino acids (LNAAs) improves cognitive function and overall well-being in adults with phenylketonuria (PKU) who poorly adhered to their dietary regimen, a study suggests.
The study, “Large Neutral Amino Acids (LNAAs) Supplementation Improves Neuropsychological Performances in Adult Patients with Phenylketonuria,” was published in the journal Nutrients.
PKU is caused by mutations in the PAH gene, which provides the instructions for making an enzyme that converts the amino acid phenylalanine into another amino acid, tyrosine. (Amino acids are the building blocks of proteins).
Mutations in this gene significantly increase the amount of phenylalanine in the blood and lower the concentration of other amino acids, some of which are needed in the brain to produce neurotransmitters — the chemical messengers used by nerve cells to communicate.
While early dietary interventions can largely prevent brain damage and aid in normal brain development, people with PKU still experience deficits in executive function — a set of cognitive skills that help in setting goals and getting things done in daily life — compared with healthy individuals. This is often due to poor compliance to a low protein diet.
Supplementation with LNAAs, a set of amino acids transported to the brain via the same transporter as phenylalanine, has been suggested for PKU patients who follow a less strict diet or who do not adhere to their diets.
This approach increases the amount of these amino acids in circulation, which compete with phenylalanine to enter the brain. The result is a reduction in phenylalanine levels in the brain, an increase in other LNAAs, and a greater production of essential neurotransmitters.
While some studies have examined the effect of LNAAs supplementation in PKU patients, most greatly differed in their treatment duration, doses used, and goals. As a result, only a few studies report reductions in phenylalanine levels and improvements in executive functions.
In the new study, a team in Italy examined the effects of long-term supplementation with high-dose LNAAs in adults with PKU recruited at the Federico II University Hospital.
Eligible participants had received early dietary intervention, and had a form of PKU that required dietary treatment and amino acid supplementation, but had a history of poor metabolic control in the year before enrollment.
The study included 10 adults, ages 18 to 32 years, six of whom were women and seven had classic PKU — phenylalanine levels at diagnosis higher than 1200 micromol/L and phenylalanine tolerance (the highest phenylalanine intake able to keep its blood levels within the safe range) up to 350 mg/day.
They received LNAAs at daily doses ranging from 0.8 to 1 gram per kg of body weight, divided in three daily doses at main meals. This LNAA formulation was taken for one year and completely replaced their prior amino acid and vitamin supplementation, but patients were still required to continue their diet without changing food habits.
Each month, patients were assessed for phenylalanine and tyrosine levels in the blood. They also underwent neuropsychological assessments before initiating the supplements (baseline), at three months, and then after one year. These included measures of perceived quality of life, executive functions, alertness, concentration, and finger dexterity (skills).
Over the course of the study, blood phenylalanine levels did not change with the LNAAs supplementation — except for one patient whose compliance to dietary treatment worsened. Tyrosine levels increased significantly in nine participants, and the ratio of phenylalanine over tyrosine also declined significantly in five patients.
“Considering the PKU patients as a group, [tyrosine] levels significantly improved during LNAAs supplementation,” the researchers wrote.
Before initiating the supplementation, six patients reported a positive well-being. The others had either borderline-mild distress or severe distress. After three months on LNAAs, all patients reported improvements in quality of life, which were maintained until the end of the study, although the benefit was not statistically significant.
Improvements were more evident among those with prior distress, which evolved to either mild distress or to a positive well-being.
Similar findings were seen for measures of executive function, alertness, and concentration, which significantly increased from baseline to month three and were maintained throughout the study. But no significant differences in dexterity were observed.
Overall, the findings suggest “an improvement of distress and well-being rates, of executive functions, sustained attention, and vigilance,” the researchers wrote.
Since phenylalanine levels did not change over time, the improvements are likely due to an increase in the amount of LNAAs reaching the brain, including those needed to produce neurotransmitters, the researchers said.
“In future studies, it would be interesting to correlate plasma [blood] amino acids and neurotransmitter metabolites with clinical data and to assess whether the cessation of LNAAs treatment would cause a decline of [neuropsychological] scores after initial improvements,” they added.
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