Large Neutral Amino Acid Therapy Increases Tyrosine Levels in Adult Patients with Phenylketonuria: A Long-Term Study

Cazzorla, Chiara; Massa, Pamela; Polo, Giulia; Loro, Christian; Gueraldi, Daniela; Burlina, Alberto

doi:10.3390/nu11102541

Cited by 14 publications

(22 citation statements)

References 38 publications

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“…However, in all patients, Phe levels gradually raised during the following months as they went back to their previous dietary habits. This observation is in agreement with the data by Burlina and colleagues [26] which show a reduction of plasma Phe after the first 6-months of LNAAs supplementation but not after 12 months.…”

Section: Discussionsupporting

confidence: 94%

“…We also do not have data on the levels of neurotransmitter metabolites and we could not correlate the levels of plasma Phe and Tyr with the levels in the cerebrospinal fluid (CSF) nor the improvement of the psychological performance with the variation of neurotransmitters. We and others [26] suggest that the improvement of blood Tyr may be beneficial to attenuate the neurotransmitter imbalance in PKU, however we cannot exclude the opposite hypothesis, i.e., that a high dose of LNAAs may have a detrimental effect on Tyr transport across the BBB. Despite those limitations, these results add further evidence of the advantage of LNAAs supplementation in improving cognition and well-being in patients with PKU and poor metabolic control.…”

Section: Discussionmentioning

confidence: 66%

“…The study confirmed a 58% reduction of Phe from baseline and a significant raise of Tyr levels. Finally, a significant increase of Tyr levels was found after a 12-month period of LNAAs supplementation in 12 adult PKU patients [26].…”

Section: Introductionmentioning

confidence: 81%

“…In this study, we choose to monitor plasma Phe and Tyr levels over a long time-period (12 months) and patients were asked to keep their dietary habits unchanged during the trial in order to obtain Phe and Tyr measures as realistic as possible. Under these conditions, we choose to supplement with the highest dose of LNAAs used so far in clinical trials (0.8-1 g/kg/day) [21,26] with the hope to achieve the best competition between dietary Phe and LNAAs at the level of the intestinal LAT transporter. Unfortunately, the present study failed to show a reduction of plasma Phe levels over the long period.…”

Section: Discussionmentioning

confidence: 99%

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Large Neutral Amino Acids (LNAAs) Supplementation Improves Neuropsychological Performances in Adult Patients with Phenylketonuria

et al. 2020

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Phenylketonuria is an inborn error of phenylalanine (Phe) metabolism diagnosed by newborn screening and treated early with diet. Although diet prevents intellectual disability, patients often show impairment of executive functions, working memory, sustained attention, and cognitive flexibility. Large neutral amino acids (LNAAs) have been proposed as a dietary supplement for PKU adults. Few studies show that LNAAs may help in improving metabolic control as well as cognitive functions. In this study, 10 adult PKU patients with poor metabolic control were treated for 12 months with LNAAs (MovisCom, 0.8-1 g/kg/day) and underwent Phe and Tyrosine (Tyr) monitoring monthly. Neuropsychological assessment was performed at T0, T+3, and T+12 months by using the American Psychological General Well-Being Index, the Wisconsin Card Sorting Test, the Test of Attentional Performance, and the 9-Hole Peg Test. No change in plasma Phe levels was observed during LNAAs supplementation, while Tyr levels significantly improved during LNAAs supplementation (p = 0.03). Psychometric tests showed an improvement of distress and well-being rates, of executive functions, attention, and vigilance, whereas no difference was noted regarding hand dexterity. This study adds evidence of the advantage of LNAAs supplementation in improving cognitive functions and well-being in patients with PKU with poor metabolic control.Nutrients 2020, 12, 1092 2 of 12 almost normal neurological development [2]. However, although intelligence is within the normal range, patients with PKU often show executive function (EF) impairment compared to healthy controls [3] as well as deficit of working memory [4,5], inhibitory control [4,6,7], sustained attention [8], cognitive flexibility [7,9], verbal fluency [5,10], and planning [8,11,12].The disturbance of Phe metabolism causes the depletion of Tyr, a precursor of the neurotransmitter dopamine. In addition, Phe accumulates and competes with Tyr and tryptophan, a precursor of serotonin, to cross the blood-brain barrier (BBB). As a consequence, the main effect of this disorder on the nervous system is a deficiency of dopamine and serotonin neurotransmitters [13].The mainstay of PKU treatment is still a low protein diet, supplemented with Phe-free amino acid formulas and vitamins. However, this treatment is often complicated by psychological discomfort and reduced compliance to the diet after the first 4-5 years of life. Initial reports supported the possibility to loosen the diet during adulthood; however, as defects of executive functions and brain hypomyelination may occur in patients with poor metabolic control [14,15], a life-long dietary therapy is recommended. Hence, alternative therapies have been developed such as sapropterin (Kuvan, Biomarin) for PKU patients responsive to BH4, and enzyme substitution therapy (Pegvaliase, Biomarin) for adult patients. Gene therapy is under development.Large neutral amino acids (LNAAs) supplementation has been developed for PKU patients with a loosen diet and poor compliance to di...

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

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Large Neutral Amino Acids (LNAAs) Supplementation Improves Neuropsychological Performances in Adult Patients with Phenylketonuria

et al. 2020

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“…Furthermore, palatability was another negative issue raised by patients [ 15 ]. Alternative strategies include the use of large neutral amino acids (LNAAs) [ 16 , 17 ], glycomacropeptide (GMP) [ 18 ], and pharmacological treatments such as sapropterin dihydrochloride (BH4) [ 19 ] and phenylalanine ammonia lyase enzyme (PEG-PAL) [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

The Impact of a Slow-Release Large Neutral Amino Acids Supplement on Treatment Adherence in Adult Patients with Phenylketonuria

et al. 2020

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The gold standard treatment for phenylketonuria (PKU) is a lifelong low-phenylalanine (Phe) diet supplemented with Phe-free protein substitutes. Adherence to therapy becomes difficult after childhood. Supplementing with large neutral amino acids (LNAAs) has been proposed as an alternative medication to Phe-free protein substitutes (i.e., amino acid mixtures). The aim of this study was to evaluate adherence to therapy and quality of life (QoL) in a cohort of sub-optimally controlled adult PKU patients treated with a new LNAA formulation. Twelve patients were enrolled in a 12-month-trial of slow-release LNAAs (1g/kg/day) plus a Phe-restricted diet. Medication adherence was measured with the Morisky Green Levine Medication Adherence Scale; the QoL was measured using the phenylketonuria-quality of life (PKU-QoL) questionnaire. Phe, tyrosine (Tyr) levels, and Phe/Tyr ratios were measured fortnightly. Before treatment, 3/12 patients self-reported a ‘medium’ adherence to medication and 9/12 reported a low adherence; 60% of patients reported a full adherence over the past four weeks. After 12 months of LNAA treatment, all patients self-reported a high adherence to medication, with 96% reporting a full adherence. Phe levels remained unchanged, while Tyr levels increased in most patients. The Phy/Tyr ratio decreased. All patients had a significant improvement in the QoL. LNAAs may give patients a further opportunity to improve medication adherence and, consequently, their QoL.

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Oral administration of phenylalanine molecularly imprinted polymer (MIP) benefits PKU mouse model

Torab

Jafari‐Sabet

Najafizadeh

et al. 2022

J of Inher Metab Disea

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Phenylketonuria (PKU) is a rare genetic disorder caused by a defect in the metabolism of phenylalanine (Phe). Currently, the most commonly used treatment for PKU is dietary Phe restriction. Problems associated with Phe restricted diets include lack of universal availability, high treatment costs, and reduced adherence to continued treatment with age and finally the development of psychological and neurological problems in a significant proportion of patients despite early start of treatment. One possible approach to decreasing blood Phe level, is inhibition of GI tract absorption of this amino acid. We had previously shown that a Phe selective molecularly imprinted polymer was able to bind Phe in the GI tract and attenuate its plasma concentration. In this work, we used different orally administered Phe selective molecularly imprinted polymer doses in a PKU mouse model to further study the effects of this treatment on biochemical profile and cognitive function in test animals. Treatments started 21 days postnatally. After 3 weeks, brain and plasma amino acid profiles and brain monoaminergic neurotransmitter concentrations were measured. Behavioral profile was also evaluated. Treatment with 2% and 5% Phe selective molecularly imprinted polymer significantly reduced levels of blood Phe in PKU model animals (46% and 48% respectively) meanwhile levels of other amino acids remained unchanged. Brain dopamine concentrations in hippocampus was effectively restored by supplementation of Phe selective molecularly imprinted polymer. Finally, polymer treatment improved locomotor dysfunction in PKU model animals. Our data suggest that the Phe selective molecularly imprinted polymer can be a new candidate for treatment of PKU patients. Take home message: Orally administered Phenylalanine Selective Molecularly Imprinted Polymer is able to inhibit absorption of phenylalanine from the GI tract and may offer a new treatment, in conjunction with dietary restriction, for PKU patients.

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Large Neutral Amino Acid Therapy Increases Tyrosine Levels in Adult Patients with Phenylketonuria: A Long-Term Study

Cited by 14 publications

References 38 publications

Large Neutral Amino Acids (LNAAs) Supplementation Improves Neuropsychological Performances in Adult Patients with Phenylketonuria

Large Neutral Amino Acids (LNAAs) Supplementation Improves Neuropsychological Performances in Adult Patients with Phenylketonuria

The Impact of a Slow-Release Large Neutral Amino Acids Supplement on Treatment Adherence in Adult Patients with Phenylketonuria

Oral administration of phenylalanine molecularly imprinted polymer (MIP) benefits PKU mouse model

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