Brain Dysfunction In Phenylketonuria Research Articles

Large neutral amino acid supplementation as an alternative to the phenylalanine-restricted diet in adults with phenylketonuria: evidence from adult Pah-enu2 mice

Phenylketonuria treatment mainly consists of a phenylalanine-restricted diet but still results in suboptimal neuropsychological outcome, which is at least partly based on cerebral monoamine deficiencies, while, after childhood, treatment compliance decreases. Supplementation of large neutral amino acids (LNAAs) was previously demonstrated in young phenylketonuria mice to target all three biochemical disturbances underlying brain dysfunction in phenylketonuria. However, both its potential in adult phenylketonuria and the comparison with the phenylalanine-restricted diet remain to be established. To this purpose, several LNAA supplements were compared with a severe phenylalanine-restricted diet with respect to brain monoamine and amino acid concentrations in adult C57Bl/6 Pah-enu2 mice. Adult phenylketonuria mice received a phenylalanine-restricted diet, unrestricted diet supplemented with several combinations of LNAAs or AIN-93M control diet for 6 weeks. In addition, adult wild-type mice on AIN-93M diet served as controls. The severe phenylalanine-restricted diet in adult phenylketonuria mice significantly reduced plasma and brain phenylalanine and restored brain monoamine concentrations, while brain concentrations of most nonphenylalanine LNAAs remained subnormal. Supplementation of eight LNAAs was similarly effective as the severe phenylalanine-restricted diet to restore brain monoamines, while brain and plasma phenylalanine concentrations remained markedly elevated. These results provide biochemical support for the effectiveness of the severe phenylalanine-restricted diet and showed the possibilities of LNAA supplementation being equally effective to restore brain monoamines in adult phenylketonuria mice. Therefore, LNAA supplementation is a promising alternative treatment to phenylalanine restriction in adult phenylketonuria patients to further optimize neuropsychological functioning.

Therapeutic brain modulation with targeted large neutral amino acid supplements in the Pah-enu2 phenylketonuria mouse model

Phenylketonuria treatment consists mainly of a Phe-restricted diet, which leads to suboptimal neurocognitive and psychosocial outcomes. Supplementation of large neutral amino acids (LNAAs) has been suggested as an alternative dietary treatment strategy to optimize neurocognitive outcome in phenylketonuria and has been shown to influence 3 brain pathobiochemical mechanisms in phenylketonuria, but its optimal composition has not been established. In order to provide additional pathobiochemical insight and develop optimal LNAA treatment, several targeted LNAA supplements were investigated with respect to all 3 biochemical disturbances underlying brain dysfunction in phenylketonuria. Pah-enu2 (PKU) mice received 1 of 5 different LNAA-supplemented diets beginning at postnatal day 45. Control groups included phenylketonuria mice receiving an isonitrogenic and isocaloric high-protein diet or the AIN-93M diet, and wild-type mice receiving the AIN-93M diet. After 6 wk, brain and plasma amino acid profiles and brain monoaminergic neurotransmitter concentrations were measured. Brain Phe concentrations were most effectively reduced by supplementation of LNAAs, such as Leu and Ile, with a strong affinity for the LNAA transporter type 1. Brain non-Phe LNAAs could be restored on supplementation, but unbalanced LNAA supplementation further reduced brain concentrations of those LNAAs that were not (sufficiently) included in the LNAA supplement. To optimally ameliorate brain monoaminergic neurotransmitter concentrations, LNAA supplementation should include Tyr and Trp together with LNAAs that effectively reduce brain Phe concentrations. The requirement for Tyr supplementation is higher than it is for Trp, and the relative effect of brain Phe reduction is higher for serotonin than it is for dopamine and norepinephrine. The study shows that all 3 biochemical disturbances underlying brain dysfunction in phenylketonuria can be targeted by specific LNAA supplements. The study thus provides essential information for the development of optimal LNAA supplementation as an alternative dietary treatment strategy to optimize neurocognitive outcome in patients with phenylketonuria.

Impaired Neurotransmission in Early-treated Phenylketonuria Patients

Cerebral neurotransmitter (NT) deficiency has been suggested as a contributing factor in the pathophysiology of brain dysfunction in phenylketonuria (PKU), even in early-treated phenylketonuric patients. The study aimed to review dopamine and serotonin status in PKU, and the effect of the impaired neurotransmission. Several mechanisms are involved in the pathophysiology of PKU, primarily characterized by impaired dopamine and serotonin synthesis. These deficits are related to executive dysfunctions and social-emotional problems, respectively, in early treated patients. Blood phenylalanine is the main biomarker for treatment compliance follow-up, but further investigations and validation of peripheral biomarkers may be performed to monitor NT status. The development of new therapies is needed not only for decreasing blood and brain phenylalanine levels but also to improve NT syntheses.

Animal models of brain dysfunction in phenylketonuria

Phenylketonuria (PKU) is a metabolic disorder that results in significant brain dysfunction if untreated. Although phenylalanine restricted diets instituted at birth have clearly improved PKU outcomes, neuropsychological deficits and neurological changes still represent substantial problems. The specific mechanisms by which Phe affects the brains of individuals with PKU are yet fully determined. The use of animal models in PKU research significantly broadens the possibilities for investigating these mechanisms. This report presents an overview of findings from animal studies on the mechanisms of Phe action in the PKU brain, discussing the importance of changes in protein synthesis, transport of large neutral amino acids across the blood–brain barrier, synthesis of monoamine neurotransmitters, activity of glutamate receptors, animal behavior, and translation of animal behavioral data to patients with PKU. This report shows that great progress has been made in past years and demonstrates the importance of further animal research to understand the neuropathological mechanisms underlying brain dysfunction in PKU. A better understanding of these mechanisms will guide the development of optimal treatment strategies for PKU.

L-phenylalanine selectively depresses currents at glutamatergic excitatory synapses.

To explore the hypothesis that L-phenylalanine (L-Phe) depresses glutamatergic synaptic transmission and thus contributes to brain dysfunction in phenylketonuria (PKU), the effects of L-Phe on spontaneous and miniature excitatory postsynaptic currents (s/mEPSCs) in rat and mouse hippocampal and cerebrocortical cultured neurons were studied using the patch-clamp technique. L-Phe depressed the amplitude and frequency of both N-methyl-D-aspartate (NMDA) and non-NMDA components of glutamate receptor (GluR) s/mEPSCs. The IC(50) of L-Phe to inhibit non-NMDAR mEPSC frequency was 0.98 +/- 0.13 mM, a brain concentration seen in classical PKU. In contrast, D-Phe had a significantly smaller effect, whereas L-leucine, an amino acid that competes with L-Phe for brain transporter, had no effect on mEPSCs. Unlike GluR s/mEPSCs, GABA receptor mIPSCs were not attenuated by L-Phe. A high extracellular concentration of glycine prevented the attenuation by L-Phe of NMDAR current, activated by exogenous agonist, and of NMDAR s/mEPSC amplitude, but not of NMDAR s/mEPSC frequency. On the other hand, L-Phe significantly depressed non-NMDAR current activated by low but not high concentrations of exogenous agonists. Glycine-independent attenuation of NMDAR s/mEPSC frequency suggests decreased presynaptic glutamate release caused by L-Phe, whereas decreased amplitudes of NMDAR and non-NMDAR s/mEPSCs are consistent with competition of L-Phe for the glycine- and glutamate-binding sites of NMDARs and non-NMDARs, respectively. The finding that GluR activity is significantly depressed at conditions characteristic of classical PKU indicates a potentially important contribution of impaired GluR function to PKU-related mental retardation and provides important insights into the potential physiological consequences of impaired GluR function.

Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria.

Large neutral amino acids (LNAAs), including phenylalanine (Phe), compete for transport across the blood-brain barrier (BBB) via the L-type amino acid carrier. Accordingly, elevated plasma Phe impairs brain uptake of other LNAAs in patients with phenylketonuria (PKU). Direct effects of elevated brain Phe and depleted LNAAs are probably major causes for disturbed brain development and function in PKU. Competition for the carrier might conversely be put to use to lower Phe influx when the plasma concentrations of all other LNAAs are increased. This hypothesis was tested by measuring brain Phe in patients with PKU by quantitative 1H magnetic resonance spectroscopy during an oral Phe challenge with and without additional supplementation with all other LNAAs. Baseline plasma Phe was approximately 1,000 micromol/l and brain Phe was approximately 250 micromol/l in both series. Without LNAA supplementation, brain Phe increased to approximately 400 micromol/l after the oral Phe load. Electroencephalogram (EEG) spectral analysis revealed acutely disturbed brain activity. With concurrent LNAA supplementation, Phe influx was completely blocked and there was no slowing of EEG activity. These results are relevant for further characterization of the LNAA carrier and of the pathophysiology underlying brain dysfunction in PKU and for treatment of patients with PKU, as brain function might be improved by continued LNAA supplementation.

Pattern reversal visual evoked potentials in phenylketonuria

The pathogenesis of brain dysfunction in phenylketonuria (PKU) is still under investigation. Hyperphenylalaninaemia results in increased turnover of myelin. In order to demonstrate the derangement of myelinization in PKU we studied the visual evoked potentials (VEP) in 14 PKU patients and in 20 normal subjects. VEP findings were correlated with the metabolic control of the disease and with the electroencephalographic findings. VEP were more sensitive than the EEG in detecting a neurological dysfunction. VEP are influenced by dietary control and are normal only in children with good metabolic control.