Large neutral amino acids in the treatment of PKU: from theory to practice

Notwithstanding the success of the traditional dietary phenylalanine restriction treatment in phenylketonuria (PKU), the use of large neutral amino acid (LNAA) supplementation rather than phenylalanine restriction has been suggested. This treatment modality deserves attention as it might improve cognitive outcome and quality of life in patients with PKU. Following various theories about the pathogenesis of cognitive dysfunction in PKU, LNAA supplementation may have multiple treatment targets: a specific reduction in brain phenylalanine concentrations, a reduction in blood (and consequently brain) phenylalanine concentrations, an increase in brain neurotransmitter concentrations, and an increase in brain essential amino acid concentrations. These treatment targets imply different treatment regimes. This review summarizes the treatment targets and the treatment regimens of LNAA supplementation and discusses the differences in LNAA intake between the classical dietary phenylalanine-restricted diet and several LNAA treatment forms

PKU: food for thougt

In dit proefschrift worden verschillende aspecten van de stofwisselingsziekte fenylketonurie (PKU, afkorting van de Engelse term Phenylketonuria) besproken. Alvorens verder op deze ziekte in te gaan, volgt eerst een korte introductie over de stofwisseling. Ontelbare processen zorgen ervoor dat wij het eten dat wij binnenkrijgen kunnen omzetten in energie en in bouwstoff en voor het lichaam. Al die processen bij elkaar noemen we de stofwisseling. Enzymen vervullen een belangrijke rol bij de stofwisseling. Het zijn eiwitten die helpen bij het omzetten van de ene stof in de andere. Als een enzym niet goed werkt, kan de om te zetten stof niet goed worden afgebroken en ontstaat er een tekort aan de stof die bij de omzetting wordt gemaakt. Het voedsel dat wij innemen en dat in het lichaam moet worden verwerkt is grofweg in te delen in drie groepen: koolhydraten (afkomstig uit granen en suikers uit fruit en groente), vetten (uit boter, olie e.d.) en eiwitten. Een grote eiwitbron vormen vlees en andere dierlijke producten zoals melk, yoghurt en eieren, maar ook in granen en in groente en fruit komen eiwitten voor. Eiwitten zijn opgebouwd uit aminozuren. Als we eiwitten eten, worden deze gesplitst in het maag-darmkanaal tot losse aminozuren. De aminozuren worden vervolgens opgenomen in de bloedbaan, waarna ze voor drie verschillende doeleinden gebruikt kunnen worden: het lichaam kan er nieuwe eiwitten uit opbouwen, ze kunnen worden omgezet in andere stoff en of ze kunnen worden gebruikt als brandstof. De ziekte die in dit proefschrift wordt besproken is een ziekte waarbij de eiwitstofwisseling verstoord is; PKU. Bij deze ziekte werkt het enzym dat het aminozuur fenylalanine omzet in het aminozuur tyrosine niet. Hierdoor is de fenylalanineconcentratie in het bloed te hoog en is de tyrosineconcentratie aan de lage kant (zie fi guur 1). Het belangrijkste ziektekenmerk van PKU is dat patiënten een grote achterstand in de ontwikkeling hebben en verstandelijk gehandicapt raken. ... Zie: Samenvatting

Brain dysfunction in phenylketonuria: Is phenylalanine toxicity the only possible cause?

In phenylketonuria, mental retardation is prevented by a diet that severely restricts natural protein and is supplemented with a phenylalanine-free amino acid mixture. The result is an almost normal outcome, although some neuropsychological disturbances remain. The pathology underlying cognitive dysfunction in phenylketonuria is unknown, although it is clear that the high plasma concentrations of phenylalanine influence the blood-brain barrier transport of large neutral amino acids. The high plasma phenylalanine concentrations increase phenylalanine entry into brain and restrict the entry of other large neutral amino acids. In the literature, emphasis has been on high brain phenylalanine as the pathological substrate that causes mental retardation. Phenylalanine was found to interfere with different cerebral enzyme systems. However, apart from the neurotoxicity of phenylalanine, a deficiency of the other large neutral amino acids in brain may also be an important factor affecting cognitive function in phenylketonuria. Cerebral protein synthesis was found to be disturbed in a mouse model of phenylketonuria and could be caused by shortage of large neutral amino acids instead of high levels of phenylalanine. Therefore, in this review we emphasize the possibility of a different idea about the pathogenesis of mental dysfunction in phenylketonuria patients and the aim of treatment strategies. The aim of treatment in phenylketonuria might be to normalize cerebral concentrations of all large neutral amino acids rather than prevent high cerebral phenylalanine concentrations alone. In-depth studies are necessary to investigate the role of large neutral amino acid deficiencies in brain

Subtle Problems in Activities of Daily Living after a Transient Ischemic Attack or an Apparently Fully Recovered Non-disabling Stroke

Little is known about the effects on the performance of activities of daily living (ADL) and quality of life (QoL) of transient ischemic attack (TIA) or a nondisabling stroke (NDS) with a full recovery in 72 hours. The present study evaluated ADL performance and QoL, as well as symptoms of anxiety and depression, in patients at 1 and 6 months after a TIA or an NDS. Consecutive hospitalized TIA/NDS patients not requiring rehabilitation were assessed at 1 and 6 months after discharge from a hospital or emergency department. ADL performance was evaluated using the Assessment of Motor and Process Skills (AMPS), QoL was assessed with the Short Form 36 (SF-36), and depression and anxiety symptoms were assessed with the Hospital Anxiety and Depression Scale (HADS). A total of 45 patients completed the follow-up. At 1 month after TIA/NDS, all patients were independent in ADL performance but had AMPS and SF-36 scores below the norm. In addition, 12 patients (27%) had anxiety symptoms, and 9 patients (20%) had symptoms of depression. Although initially considered fully recovered, 23 patients (51%) required rehabilitation after the first follow-up. After 6 months, their AMPS, SF-36, and HADS scores were lower than those of the patients who did not require rehabilitation after the first screening. Half of the patients with a TIA or an NDS who were initially considered fully recovered exhibited ADL limitations, decreased QoL, and symptoms of anxiety or depression after 6 month

Protein metabolism in adult patients with phenylketonuria

Objective: Protein intake recommendations in phenylketonuria (PKU) are frequently the subject of discussion. For healthy adults, the recommended daily allowance (RDA) is 0.8 g . kg(-1) . d(-1), which is generally lower than that observed in the general Western population. We investigated whether whole-body protein metabolism in patients with PKU is comparable to that of healthy controls at a RDA rate of protein intake. Methods: Six adult patients with well-controlled PKU and six healthy subjects of comparable age, height, and weight were studied using a primed continuous infusion of [1-C-13] -valine for 8 h after an overnight fast before and during frequent meals. Normal protein was given to controls, whereas patients with PKU received a combination of an amino acid mixture and natural protein. Results: No significant differences were observed between patients with PKU and controls in preprandial and prandial rates of valine appearance and oxidation and protein breakdown, protein synthesis, and net protein balance. Feeding resulted in a significant (P <0.01) decrease in protein breakdown (PKU: 94 +/- 15 mu mol . kg(-1) . h(-1) preprandial to 49 +/- 10 mu mol . kg(-1) . h(-1) prandial; controls: 97 +/- 10 mu mol . kg(-1) . h(-1) preprandial to 55 +/- 10 mu mol . kg(-1) . h(-1) prandial), whereas no effects were observed in protein synthesis (PKU: 77 +/- 10 mu mol . kg(-1) . h(-1) preprandial to 73 +/- 7 mu mol . kg(-1) . h(-1) prandial; controls: 76 +/- 8 mu mol . kg(-1) . h(-1) preprandial to 71 +/- 5 mu mol . kg(-1) . h(-1) prandial). Net protein balance increased from negative prandial to positive preprandial values (PKU: -17 +/- 6 mu mol . kg(-1) . h(-1), preprandial to +23 +/- 8 mu mol kg(-1) . h(-1) prandial; controls: -21 +/- 4 mu mol . kg(-1) . h(-1) preprandial to + 16 +/- 9 mu mol . kg(-1) . h(-1) prandial). Conclusion: Whole-body protein metabolism in adult patients with PKU is fully comparable to that in healthy controls at the RDA level of protein intake. (C) 2007 Elsevier Inc. All rights reserved

Diurnal variations in blood phenylalanine of PKU infants under different feeding regimes

In phenylketonuria (PKU) patients, diurnal fluctuations of blood phenylalanine (Phe) are different from healthy individuals. Until now this pattern has been studied in PKU patients over one year of age. Objective: The aim of this observational study was to investigate diurnal patterns in PKU infants under one year of age receiving both the natural protein and Phe-free formula at the same time or in an alternating feeding scheme. Methods: In 7 PEW infants (aged 3-8 months), diurnal variations in blood Phe concentrations were recorded: on day A they received natural protein and Phe-free formula combined in each feeding; on day B they received these in an alternating feeding scheme. The number of feedings, total protein, and energy intake was similar on both study days. Blood samples were taken before each feeding. Results: The means (+/- SD) of the difference between the individual minimum and maximum blood Phe concentrations were 81(+/- 50) mu mol/L and 104(+/- 26) mu mol/L on days A and B, respectively (n.s.). Fifty and 30% of the samples were below target range for age (120 mu mol/L), while only 3% and 6% were above target range (360 mu mol/L) on days A and B respectively (n.s.). Conclusion: Both feeding regimes, i.e. the natural protein and Phe-free formula combined in each feeding or alternating, resulted in comparable diurnal fluctuations of blood Phe concentrations. (C) 2011 Elsevier Inc. All rights reserved

Isolated elevated serum transaminases leading to the diagnosis of asymptomatic Pompe disease

An asymptomatic boy, aged 1.5 years, was referred with presumed liver disease because of persistently increased transaminase. Ultimately Pompe disease was confirmed, without specific abnormalities in muscle biopsy. This case demonstrates that increased transaminases do not always suggest liver disease. It is hard to determine prognosis and to decide whether enzyme replacement therapy should be started in asymptomatic patients with Pompe disease

Adult Patients with Well-Controlled Phenylketonuria Tolerate Incidental Additional Intake of Phenylalanine

Background/Aims: In patients with phenylketonuria (PKU), target ranges of blood phenylalanine (Phe) concentrations have been tightened in order to improve long-term outcomes. We investigated day-to-day and week-to-week variations in blood Phe concentration and the effect of an additional Phe load. Methods: We performed a longitudinal study in 6 adult PKU patients. The study was divided in five 7-day periods: 1 period without any intervention (period I) and 4 periods with a Phe load on day 3 equivalent to 100% (periods II and III) and to 200% (periods IV and V) of each patient's individual daily Phe intake. Phe loading was given as encapsulated L-Phe. Blood spots to measure blood Phe concentration were taken each morning before breakfast in all periods. Results: Day-to-day and week-to-week blood Phe concentrations varied considerably with and without intervention in Phe intake. Equal loads of Phe did not result in comparable effects in blood Phe concentrations in all patients. In periods II-IV, mean blood Phe concentrations of days 1-3 (pre-load) were not significantly different from days 4-7 (post-load). The 200% load resulted in a significantly larger variation. Conclusion: These results showed that patients with well-controlled PKU can incidentally tolerate 100% - and in some cases 200% - of their normal daily Phe intake. Copyright (C) 2011 S. Karger AG, Base