Long-term treatment of phenylketonuria with a new medical food containing large neutral amino acids

Concolino, Daniela; Mascaro, Italia; Moricca, Maria Teresa; Bonapace, Giuseppe; Matalon, Kimberlee Michals; Trapasso, J.; Radhakrishnan, Geetha L.; Ferrara, Carla; Matalon, Reuben; Strisciuglio, Pietro

doi:10.1038/ejcn.2016.166

Cited by 21 publications

(23 citation statements)

References 29 publications

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“…However, clinical measures of downstream LNAA metabolites (ie, respective keto‐acids, histamine from histidine, cysteine from methionine) in patients with PKU, combined with dietary intake and plasma concentrations, are needed to identify the mechanisms that maintain stable LNAA plasma levels relevant to diet patterns . Additionally, measuring flux across membrane barriers for cellular uptake could add further insight, particularly as studies have shown that prescribing LNAA supplements to patients with PKU may be an effective therapy due to competitive inhibition of PHE across both the gut and blood brain barriers.…”

Section: Discussionmentioning

confidence: 99%

“…Plasma P:T ratio, residuals 3 Table 2). When evaluating the full cohort with Kendall's tau, P:T ratio had significant inverse correlations with all plasma LNAA concentrations (P ≤ .028) except for isoleucine (τ = −0.166, P = .056).…”

Section: Lnaa Interaction With Plasma Phe Tyr and P:t Ratiomentioning

confidence: 99%

“…Plasma concentration of large neutral amino acids (LNAA) may also play an important role in the treatment of PKU, particularly with the presence of LNAA in prescription medical foods and with prescribed LNAA supplements becoming more prevalent as a treatment option. 3,4 Large neutral amino acids include the essential amino acids histidine, isoleucine, leucine, methionine, threonine, tryptophan, phenylalanine, and valine as well as the nonessential amino acid tyrosine. Consumption of supraphysiologic LNAA supplements as a part of treatment in PKU may increase blood LNAA levels and reduce PHE concentrations in the blood and brain.…”

Section: Introductionmentioning

confidence: 99%

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Large neutral amino acid status in association with P:T ratio and diet in adult and pediatric patients with phenylketonuria

et al. 2019

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Background Intake of large neutral amino acids (LNAA) may inhibit phenylalanine (PHE) transport across the blood brain barrier and assist with blood PHE control in patients with phenylketonuria (PKU). We evaluated the interrelationship between LNAA in plasma and diet on Phe:Tyr (P:T) ratio in patients with PKU and the influence of dietary factors on plasma LNAA markers. Methods Plasma amino acid values and 3‐day food record analysis from two studies (34 male/30 female; age 4.6‐47 years) were examined. For pediatrics (<18 years) and adults (≥18 years) the relationship between P:T ratio, plasma LNAA, and dietary intake patterns were investigated. Results Dietary factors influencing P:T ratio included intake of total protein (g/kg), medical food (MF) protein (g/kg, % below Rx), and LNAA (g) in the full cohort (P < .05). Associations were found between plasma valine and other dietary and plasma LNAA in pediatrics (P < .05) and plasma LNAA with dietary LNAA intake in adults (P = .019). Plasma P:T ratio was inversely associated with plasma LNAA concentrations in both age groups (P < .05). Aside from histidine in pediatrics (P = .024), plasma LNAA did not differ by having plasma PHE levels within or above the therapeutic range (120‐360 μmol/L). Plasma LNAA in both age groups was similar to reported healthy control values. Conclusion P:T ratio is significantly tied to dietary LNAA, adherence to MF Rx, and plasma LNAA concentrations. Additionally, P:T ratio and valine may be effective clinical proxies for determining LNAA metabolic balance and LNAA quality of the diet in patients with PKU.

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Section: Discussionmentioning

confidence: 99%

Section: Lnaa Interaction With Plasma Phe Tyr and P:t Ratiomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Large neutral amino acid status in association with P:T ratio and diet in adult and pediatric patients with phenylketonuria

et al. 2019

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“…Hoeksma et al [ 22 ] demonstrated a significant negative correlation between plasma Phe concentration and cerebral protein synthesis in patients with PKU. This leads to development of new medical foods with higher concentrations of LNAA and fortification with vitamins and lutein, an antioxidant important for the development of the brain [ 23 ]. Studies in PAH enu2 mice provide support for the use of a variety of non-physiological amino acids to act as competitive inhibitors of brain transporters to reduce brain Phe concentrations with minimal impact on other down-stream intermediates [ 24 ].…”

Section: Large Neutral Amino Acid Supplementationmentioning

confidence: 99%

New Strategies for the Treatment of Phenylketonuria (PKU)

Strisciuglio¹,

Concolino

2014

Metabolites

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Phenylketonuria (PKU) was the first inherited metabolic disease in which dietary treatment was found to prevent the disease’s clinical features. Treatment of phenylketonuria remains difficult due to progressive decrease in adherence to diet and the presence of neurocognitive defects despite therapy. This review aims to summarize the current literature on new treatment strategies. Additions to treatment include new, more palatable foods based on glycomacropeptide that contains very limited amount of aromatic amino acids, the administration of large neutral amino acids to prevent phenylalanine entry into the brain or tetrahydropterina cofactor capable of increasing residual activity of phenylalanine hydroxylase. Moreover, human trials have recently been performed with subcutaneous administration of phenylalanine ammonia-lyase, and further efforts are underway to develop an oral therapy containing phenylanine ammonia-lyase. Gene therapy also seems to be a promising approach in the near future.

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“…A new medical food Phe LNAA fortified with Vitamin B 12 , biotin, docosahexaenoic acid (DHA), and lutein have been developed for the long‐term treatment of PKU (Concolino et al, ). Goda and Group () synthesized a modified gene sequence of bovine α‐casein replacing all the Phe with Tyr and expressed in E. coli for PKU patients.…”

Section: Introductionmentioning

confidence: 99%

Improvement, cloning, and expression of an in silico designed protein enriched with large neutral amino acids in Pichia pastoris for possible application in phenylketonuria

Appaiah

Vasu

2020

J Food Biochem

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Phenylketonuria (PKU) is an inborn disease caused by defective phenylalanine hydroxylase, which consequently results in the accumulation of phenylalanine in the brain leading to further complications. One of the promising approaches in dietary treatment is the supplementation of large neutral amino acid (LNAA). The LNAA compete with phenylalanine for the common L‐type LNAA transporter across the blood–brain barrier, and decrease phenylalanine levels in the brain. In this study, the earlier LNAA‐enriched protein model was improved (Protein Model‐66) and validated in silico. The reverse translated and codon‐optimized synthetic LNAA66 gene was cloned into pPICZαC and expressed in Pichia pastoris. The expressed protein was purified by His Select affinity chromatography. SDS‐PAGE and Western blotting analysis showed a band at an expected molecular weight of 12 kDa, confirming the expression of the modeled protein. To our knowledge, this is the first report showing the cloning and expression of an in silico designed LNAA‐enriched protein. Practical applications One of the promising dietary treatment of phenylketonuria (PKU) is the supplementation of large neutral amino acid (LNAA), wherein high levels of LNAA compete with phenylalanine for the same L‐type LNAA transporter, and consequently decrease phenylalanine accumulation in the brain, thereby decreasing neurological complications. For the first time, here, we are showing that an in silico designed and validated Protein Model‐66, rich in LNAA, can be successfully cloned and expressed in Pichia pastoris. The complete biochemical and structural characterization of this protein will give a clear insight into its potential application for PKU treatment. The protein can be potentially used as a supplement to treat PKU to those who are non‐adherent to the restricted, non‐palatable, and expensive diet. Furthermore, this novel and effective strategy of in silico designing, cloning and expression can be exploited to develop proteins for various applications of industrial, food, medical, and academic relevance.

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Long-term treatment of phenylketonuria with a new medical food containing large neutral amino acids

Cited by 21 publications

References 29 publications

Large neutral amino acid status in association with P:T ratio and diet in adult and pediatric patients with phenylketonuria

Large neutral amino acid status in association with P:T ratio and diet in adult and pediatric patients with phenylketonuria

New Strategies for the Treatment of Phenylketonuria (PKU)

Improvement, cloning, and expression of an in silico designed protein enriched with large neutral amino acids in Pichia pastoris for possible application in phenylketonuria

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