Unchanged MRI of myelin in adolescents with PKU supplied with non‐phe essential amino acids after dietary relaxation

Hc, Lou; Toft, P; Andresen, Jente; Mikkelsen, I.; Olsen, B. R.; Guldberg, Per; Güttler, Flemming

doi:10.1111/j.1651-2227.1994.tb13025.x

Cited by 13 publications

(6 citation statements)

References 9 publications

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“…Studies that have evaluated LNAA in PKU patients [26,27] are relevant; however, they failed to show any clear advantage in terms of a reduction in brain Phe concentrations. A four-week study performed with 16 classical PKU patients on a strict daily food diary identified a trend toward lower plasma Phe levels with LNAA supplementation, suggesting that LNAA supplementation may be beneficial in patients who are unable to comply with PKU medical products [28].…”

Section: Discussionmentioning

confidence: 99%

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

Cazzorla¹,

Massa²,

Polo³

et al. 2019

Nutrients

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The standard treatment for phenylketonuria (PKU) is a lifelong low-phenylalanine (Phe) diet, supplemented with Phe-free protein substitutes; however, adult patients often show poor adherence to therapy. Alternative treatment options include the use of large neutral amino acids (LNAA). The aim of this study was to determine the Phe, tyrosine (Tyr), and Phe/Tyr ratio in a cohort of sub-optimally controlled adult patients with classical PKU treated with a new LNAA formulation. Twelve patients received a Phe-restricted diet plus a slow-release LNAA product taken three times per day, at a dose of 1 g/kg body weight (mean 0.8 ± 0.24 g/kg/day), over a 12-month period. The product is in a microgranulated formulation, which incorporates all amino acids and uses sodium alginate as a hydrophilic carrier to prolong its release. This LNAA formulation provides up to 80% of the total protein requirement, with the rest of the protein supplied by natural food. Patients had fortnightly measurements of Phe and Tyr levels over a 12-month period after the introduction of LNAA. All patients completed the 12-month treatment period. Overall, adherence to the new LNAA tablets was very good compared with a previous amino acid mixture, for which taste was a major complaint by patients. Phe levels remained unchanged (p = 0.0522), and Tyr levels increased (p = 0.0195). Consequently, the Phe/Tyr ratio decreased significantly (p < 0.05) in the majority of patients treated. In conclusion, LNAA treatment increases Tyr levels in sub-optimally controlled adult PKU patients, while offering the potential to improve their adherence to treatment.

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Section: Discussionmentioning

confidence: 99%

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

Cazzorla¹,

Massa²,

Polo³

et al. 2019

Nutrients

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“…Interestingly, some white matter lesions have been reported to resolve after resumption of the special diet [Thompson et al, 1993], suggesting that the insult to myelin can be reversed. However, this has not been shown to occur in every case [McCombe et al, 1992;Lou et al, 1994].…”

Section: Neuropathologymentioning

confidence: 95%

Pathophysiology of phenylketonuria

Dyer¹

1999

Ment. Retard. Dev. Disabil. Res. Rev.

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The brain is the organ primarily affected by elevated phenylalanine (Phe) in the disease phenylketonuria (PKU). The hallmark neuropathology of both the untreated and treated PKU brains is hypomyelination or demyelination or both. Because cognitive deficits are present in untreated and treated individuals, the link between the observed neuropathology and cognitive deficits is important to ascertain. Two current models of the molecular events underlying the cognitive deficits are presented. The first model is based on the hypothesis that cognitive deficits in individuals with PKU result from a deficiency of the neurotransmitter dopamine. Decreased levels of tyrosine in the PKU brain are believed to cause the low levels of dopamine. The possible connections between reduced dopamine levels and the observed myelin deficits are presented. However, as discussed, the link between the two remains elusive. The second model is based on the hypothesis that the primary insult to the PKU brain is loss of myelin and that this secondarily leads to neuronal dysfunction. The function of myelin is reviewed, including evidence showing that myelin and the axon communicate with one another to form a functional unit. Because the ability of the axon to conduct action potentials at normal speed is compromised when myelin is not formed or is lost, the latter model has the capacity to account for both abnormalities and cognitive deficits. Current studies characterizing the neuropathology of the recently developed genetic mouse model for PKU, the PAH enu2 mouse, are reviewed. Preliminary evidence is summarized that indicates that Phe specifically inhibits cholesterol metabolism in the oligodendrocyte, the cell that forms myelin in the brain. Finally, areas of future, high-priority research are outlined.

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“…Some literature suggests that the use of LNAA may be beneficial in adolescents and adults with elevated blood Phe who have relaxed or do not follow conventional dietary treatment recommendations [174,[178][179][180] or who were late diagnosed and previously untreated [181].…”

Section: Growth In Infants and Children And Weight In Adultsmentioning

confidence: 99%

Phenylketonuria Scientific Review Conference: State of the science and future research needs

Camp

Parisi

Acosta

et al. 2014

Molecular Genetics and Metabolism

218

157

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New developments in the treatment and management of phenylketonuria (PKU) as well as advances in molecular testing have emerged since the National Institutes of Health 2000 PKU Consensus Statement was released. An NIH State-of-the-Science Conference was convened in 2012 to address new findings, particularly the use of the medication sapropterin to treat some individuals with PKU, and to develop a research agenda. Prior to the 2012 conference, five working groups of experts and public members met over a 1-year period. The working groups addressed the following: long-term outcomes and management across the lifespan; PKU and pregnancy; diet control and management; pharmacologic interventions; and molecular testing, new technologies, and epidemiologic considerations. In a parallel and independent activity, an Evidence-based Practice Center supported by the Agency for Healthcare Research and Quality conducted a systematic review of adjuvant treatments for PKU; its conclusions were presented at the conference. The conference included the findings of the working groups, panel discussions from industry and international perspectives, and presentations on topics such as emerging treatments for PKU, transitioning to adult care, and the U.S. Food and Drug Administration regulatory perspective. Over 85 experts participated in the conference through information gathering and/or as presenters during the conference, and they reached several important conclusions. The most serious neurological impairments in PKU are preventable with current dietary treatment approaches. However, a variety of more subtle physical, cognitive, and behavioral consequences of even well-controlled PKU are now recognized. The best outcomes in maternal PKU occur when blood phenylalanine (Phe) concentrations are maintained between 120 and 360 μmol/L before and during pregnancy. The dietary management treatment goal for individuals with PKU is a blood Phe concentration between 120 and 360 μmol/L. The use of genotype information in the newborn period may yield valuable insights about the severity of the condition for infants diagnosed before maximal Phe levels are achieved. While emerging and established genotype-phenotype correlations may transform our understanding of PKU, establishing correlations with intellectual outcomes is more challenging. Regarding the use of sapropterin in PKU, there are significant gaps in predicting response to treatment; at least half of those with PKU will have either minimal or no response. A coordinated approach to PKU treatment improves long-term outcomes for those with PKU and facilitates the conduct of research to improve diagnosis and treatment. New drugs that are safe, efficacious, and impact a larger proportion of individuals with PKU are needed. However, it is imperative that treatment guidelines and the decision processes for determining access to treatments be tied to a solid evidence base with rigorous standards for robust and consistent data collection. The process that preceded the PKU State-of-the-Science Confe...

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Unchanged MRI of myelin in adolescents with PKU supplied with non‐phe essential amino acids after dietary relaxation

Cited by 13 publications

References 9 publications

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

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

Pathophysiology of phenylketonuria

Phenylketonuria Scientific Review Conference: State of the science and future research needs

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