A food pyramid for adult patients with phenylketonuria and a systematic review on the current evidences regarding the optimal dietary treatment of adult patients with PKU.

Early dietary treatment is mind-saving in patients with phenylketonuria. A "diet-for-life" is advocated, aimed to prevent effects of chronic exposure to hyperphenylalaninemia. While adherence to diet is significant during childhood as patients are followed-up at specialized metabolic centers, during adolescence and adulthood percentage of patients discontinuing diet and/or lost at follow-up is still high. The process of passing skills and responsibilities from pediatric team to adult team is defined "transition". The goal of transition clinics is to set up specific multidisciplinary care pathways and guarantee continuity of care and compliance of patients to care. In 2017, "The complete European guidelines on phenylketonuria" were published. These guidelines, however, do not provide an easy way to illustrate to adult patients how to follow correct dietary approach. The purpose of this review is to evaluate current evidence on optimum dietary treatment of adults with phenylketonuria and to provide food pyramid for this population. The pyramid built shows that carbohydrates should be consumed every day (3 portions), together with fruits and vegetables (5 portions), extra virgin olive oil, and calcium water (almost 1 L/day); weekly portions can include 150 g potatoes walnuts and hazelnuts (20 g). At top of pyramid, there are two pennants. The green means that, based on individual metabolic phenotype and daily phenylalanine tolerance, patients need personalized supplementation (specific phenylalanine free amino acid mixtures, vitamins and omega 3 fatty acids); the one red indicates foods that are banned from diet (aspartame and protein foods exceeding individual dietary phenylalanine tolerance).

Real-Time Multiscale Monitoring and Tailoring of Graphene Growth on Liquid Copper.

The synthesis of large, defect-free two-dimensional materials (2DMs) such as graphene is a major challenge toward industrial applications. Chemical vapor deposition (CVD) on liquid metal catalysts (LMCats) is a recently developed process for the fast synthesis of high-quality single crystals of 2DMs. However, up to now, the lack of in situ techniques enabling direct feedback on the growth has limited our understanding of the process dynamics and primarily led to empirical growth recipes. Thus, an in situ multiscale monitoring of the 2DMs structure, coupled with a real-time control of the growth parameters, is necessary for efficient synthesis. Here we report real-time monitoring of graphene growth on liquid copper (at 1370 K under atmospheric pressure CVD conditions) via four complementary in situ methods: synchrotron X-ray diffraction and reflectivity, Raman spectroscopy, and radiation-mode optical microscopy. This has allowed us to control graphene growth parameters such as shape, dispersion, and the hexagonal supra-organization with very high accuracy. Furthermore, the switch from continuous polycrystalline film to the growth of millimeter-sized defect-free single crystals could also be accomplished. The presented results have far-reaching consequences for studying and tailoring 2D material formation processes on LMCats under CVD growth conditions. Finally, the experimental observations are supported by multiscale modeling that has thrown light into the underlying mechanisms of graphene growth.

SLC25A19 deficiency and bilateral striatal necrosis with polyneuropathy: a new case and review of the literature.

OBJECTIVES: Biallelic mutations in the SLC25A19 gene impair the function of the thiamine mitochondrial carrier, leading to two distinct clinical phenotypes. Homozygosity for the c.530G > C mutation is invariably associated to Amish lethal microcephaly. The second phenotype, reported only in 8 patients homozygous for different non-Amish mutations (c.373G > A, c.580T > C, c.910G > A, c.869T > A, c.576G > C), is characterized by bilateral striatal necrosis and peripheral polyneuropathy. We report a new patient with the non-Amish SLC25A19 phenotype showing compound heterozygosity for the new variant c.673G > A and the known mutation c.373G > A. CASE PRESENTATION: The natural history of non-Amish SLC25A19 deficiency is characterized by acute episodes of fever-induced encephalopathy accompanied by isolated lactic acidosis and Leigh-like features at magnetic resonance imaging (MRI). Acute episodes are prevented by high-dose thiamine treatment (600 mg/day). As shown in the new case, both mild clinical signs and basal ganglia involvement can precede the acute encephalopathic onset of the disease, potentially allowing treatment anticipation and prevention of acute brain damage. Peripheral axonal neuropathy, observed in 7 out of 9 patients, is not improved by thiamine therapy. In two early treated patients, however, peripheral neuropathy did not occur even on long-term follow-up, suggesting a potential preventive role of treatment anticipation also at the peripheral level. CONCLUSIONS: Non-Amish SLC25A19 deficiency is an extra-rare cause of Leigh syndrome responsive to thiamine treatment. Ex adiuvantibus thiamine treatment is mandatory in any patient with Leigh-like features.

Tyrosine metabolism in health and disease: slow-release amino acids therapy improves tyrosine homeostasis in phenylketonuria.

OBJECTIVES: Phenylalanine (Phe) hydroxylase (PAH) deficiency leads to hyperphenylalaninemia (HPA) and tyrosine (Tyr) depletion. We investigated Tyr homeostasis in patients with PAH deficiency and the effect of a slow-release amino acids therapy in phenylketonuria (PKU). METHODS: We performed four complementary investigations: (1) Tyr concentrations were monitored in 114 patients (10.6 ± 11.9 years) with PKU on dietary treatment supplemented with traditional amino acid formulations (n=52, 1175 samples) or non-PKU HPA on a free diet (n=62, 430 samples); (2) Tyr metabolism in PKU was quantitatively evaluated in three patients by a simple Tyr oral loading test (100 mg/kg); (3) diurnal and (4) long-term Tyr concentrations were evaluated in 5 and 13 patients with PKU, respectively, who switched from traditional to slow-release amino acids therapy. RESULTS: 1) Tyr concentrations in the PKU population were subnormal and significantly lower than in non-PKU HPA (p<0.01); (2) the response to a Tyr loading test in PKU was normal, with basal Tyr concentrations reached within 12 h; (3) the diurnal metabolic profile in patients on slow-release amino acids therapy revealed higher morning fasting and nocturnal Tyr concentrations with respect to traditional therapy (p<0.01); (4) this picture was confirmed at follow-up, with normalization of morning fasting Tyr concentrations in patients on slow-release amino acids therapy (p<0.01) and unchanged Phe control (p=0.19). CONCLUSIONS: Slow-release amino acids therapy can improve Tyr homeostasis in PKU. If associated to optimized Phe control, such a metabolic goal may allow long-term clinical benefits in patients with PKU.

Impact of neonatal protein metabolism and nutrition on screening for phenylketonuria.

OBJECTIVES: Early blood phenylalanine (Phe) elevation after birth enables screening for and anticipation of the diagnosis of phenylketonuria. The differential impact of factors involved in this phenomenon, however, has not been elucidated. To solve this question, phenotype, genotype, dietary Phe intake, timing of blood collection, and Phe metabolism were retrospectively analyzed in 21 phenylketonuria newborns and prospectively in 1. PATIENTS AND METHODS: Patients were assigned to 1 of 4 classes of phenylalanine hydroxylase (PAH) deficiency (severe, moderate, mild, and benign) on the basis of their Phe tolerance. Phe ingested, tolerated, and released from endogenous catabolism was assessed. RESULTS: From birth to screening test, the amount of Phe tolerated ranged from 704 to 1620 mg, according to the class of PAH deficiency. The amount of Phe ingested ranged only from 204 to 405 mg, whereas the endogenous Phe breakdown ranged from 812 to 1534 mg, resulting in a rate of Phe catabolism ranging from 262 to 341 mg/day, regardless of the class of PAH deficiency. CONCLUSIONS: The high rate of protein catabolism is the main determinant of neonatal hyperphenylalaninemia. It is sufficient to turn to positive the screening test in severe and moderate PAH deficiency. In mild and benign PAH deficiency, the outcome of screening procedures can be substantially altered by the concurrence of genetic and peristaltic factors. These results imply that the value of blood Phe at the screening test is not fully predictive of the phenylketonuria phenotype, and strengthen concerns regarding the reliability of early screening procedures.