Objective: The primary aim of this retrospective cohort study was to determine the association between the source of dietary protein intake and the sum of plasma concentration of large neutral amino acids (LNAA) in patients with Phenylketonuria (PKU). A secondary aim of the study was to examine the effect of dietary compliance on plasma concentration of LNAA. Methods: The analysis included combined participant data from two previous studies conducted at the Emory University School of Medicine. Subjects are males (n=34) and females (n=43) with PKU ages 4-50 years. A Student t-test was used to compare total combined plasma LNAA (excluding tryptophan and phenylalanine) by dietary compliance status (alpha=0.05). Correlation statistics were used to determine the association between the ratio of reported intact food protein to medical food protein on plasma levels of LNAA. Multiple regression analysis was used to examine the contribution of intact protein to medical food protein ratio and other variables to plasma LNAA. Results: The median ratio of intact protein to medical food protein reported was 0.354 (IQR: 0.188, 0.914). Median percent of PHE intake over the PHE intake recommendation was 31.64 (Interquartile range [IQR]; 7.44, 104.98). Plasma concentration of LNAA did not differ significantly between those with plasma PHE levels within the therapeutic range μmol/L (compliant; 611.7 μmol/L [n=19]) vs levels above the therapeutic range (non-compliant; 595.3 μmol/L [n=47]); p=0.613). There was an inverse marginal correlation between the ratio of intact protein to medical food protein and plasma concentration of LNAA for those who were compliant (r = -0.436, r = 0.1) although the association was not statistically significant (p=0.08). No correlation was found for patients who were non-compliant. Regression analysis revealed that plasma concentration of LNAA was not significantly affected by the ratio of intact protein to medical food protein ratio, age, or gender. Conclusions: Although not statistically significant, a negative trend was observed between plasma LNAA concentration and the intact protein to medical food protein ratio in patients compliant with the PHE prescription. This suggests that the ratio of intact dietary protein to protein coming from medical food, as reported by patient diet records, may promote increased plasma LNAA levels in the effective treatment of PKU. The majority of the sample (74%) were non-compliant with diet based on plasma PHE levels. Future studies are needed to determine the consequences of non-compliance by decreased intake of medical food protein or increased intake of intact protein on plasma LNAA concentration and downstream health effects.

Phenylketonuria (PKU) is an inherited metabolic disease that affects about one in 10,000 of the population worldwide. In the classical form of the condition, the hepatic enzyme phenylalanine hydroxlase is absent or much reduced. If untreated, severe or profound mental handicap customarily results due to the accumulation of dietary phenylalanine (phe) which is neurotoxic. The mechanism by which phe impairs growth in the immature nervous system is little understood, but myelin metabolism appears to be disturbed. Treatment is by reduction of phe in daily food intake. Treatment should ideally begin in the neonatal period if intellectual loss is to be avoided. However, the safe range of phe concentrations during treatment and the age at which treatment can be discontinued without further damage being inflicted are uncertain. The studies reported in this volume investigated neuropsychological outcomes of treatment control and cessation factors. In addition, the question of whether executive functions are especially vulnerable to elevated phe concentrations during treatment was addressed. Patient samples conformed to the practice adopted in the West of Scotland regional centre for the management of PKU of maintaining dietary treatment until age 10 or beyond. Almost exclusively, negative findings emerged. These suggested that, if control of phe intake conforms to current UK recommendations for the preschool and primary years, neither global nor specific intellectual deficit result. Furthermore, the data supported the view that cessation of treatment at 10 years of age does not have harmful consequences. These findings have direct implications for the formulation of clinical policy on the treatment of PKU, but it must be recognized that the history of the successful treatment of PKU and mass screening for the disease spans a mere three decades. Thus, treatment outcome research to date is based only on children and young adults. In future investigations, a life-span approach will be required before the issues raised in this thesis can be finally settled.

Articles and serials related to the thesis research bound in appendix / Includes bibliographical references / v, 217 leaves, [2] leaves of plates : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (M.D.)--University of Adelaide, Faculty of Medicine, 1984

Thesis (M.S.)--University of Wisconsin--Madison, 1983. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 55-64).

Phenylketonuria is a rare genetic disorder that causes cognitive impairment unless treated with a strict, protein-restricted diet. Due to the challenges of treatment adherence, caring for a child with PKU may affect parental wellbeing, and many children and adolescents have poor metabolic control. The overall aim of the thesis was to examine influences on parental wellbeing and treatment adherence. Paper 1 is a systematic literature review of the demographic and psychosocial influences on blood phenylalanine concentration for children and adolescents with PKU. The aim was to identify factors that were robustly linked with metabolic control and could potentially be used to inform clinical practice. Findings from 29 identified studies indicated that whilst a number of demographic and psychosocial factors were related to metabolic control, the most reproducible association was with child age. Quality assessment of the studies indicated some methodological limitations, and a paucity of research in some areas highlighted the need for further research. The limitations of the evidence-base, clinical implications, and directions for future research are discussed. Paper 2 presents an investigation of the psychological impact of parenting a child with PKU, the determinants of parental wellbeing, and the association between parental wellbeing and treatment adherence. Forty-six caregivers of children with PKU completed questionnaires examining psychological distress, parenting stress related to caring for a child with an illness, resilience, perceived social support, and child dependency. The proportion of blood phenylalanine concentrations within target range in the preceding year was used a measure of treatment adherence. Results showed that more than half of caregivers had clinical levels of psychological distress, which was predicted by their parenting stress and resilience. Whilst treatment adherence was not associated with parental distress, it was predicted by child age and caregiver perceived support from family. The limitations of the study, implications for clinical practice, and future research directions are discussed. Paper 3 provides a critical evaluation of Papers 1 and 2 and a personal reflection of the research process.

No description available.

Absence of functional phenylalanine hydroxylase results in phenylketonuria (PKU). Viable treatments remain few, expensive and secondary conditions such as osteopenia occur in most PKU patients. Objective 1: Given the recently described roles of gut microbes to aid host digestion, an orally administered genetically engineered probiotic as the delivery vehicle for enzyme replacement therapy was created. The engineered probiotic, pHENOMMenal, produced phenylalanine ammonia lyase with significant production of trans-cinnamate (phenylalanine cleavage product) in vitro and resulted in a reduction of 515 μM in blood phenylalanine when fed to PKU animals for 14 days (from 2307µM ± 264µM to 1792µM ± 261µM, n = 6, P < 0.05). The control probiotic produced no change in blood phenylalanine. Thus, pHENOMMenal treatment in PKU mice demonstrated engineered microbes could compensate for a metabolic deficiency of the host. Objective 2: Evaluate the PAHenu2 mouse model of PKU for a genetic discrepancy causing ocular enlargement and delayed development observed only after the PAHenu2 mutation was crossed to the C57BL/6J mouse. When compared to healthy littermates, ELISA indicated a consistent but insignificant decrease in plasma IGF-1 and an increase in ocular IGF-1 in PKU animals. SNP screening demonstrated a differential inheritance of IGF-1 alleles in healthy and PKU animals based on PAH allele inheritance. Ocular and developmental phenotypes in the PAHenu2 colony match those described in previous IGF-1 studies. Understanding the IGF-1 inheritance discrepancy will enable better osteopenia research using PAHenu2 mice and allow breeding of a healthier mouse colony for continued research. Collectively the results from this work describe a new therapeutic approach for treatment of PKU as well as a better understanding of the PAHenu2 mouse model to study this disease.

No description available.

<p>Phenylketonuria (PKU) is an inborn, metabolic disease affecting the enzyme phenylalanine hydroxylase, which converts phenylalanine to tyrosine. Since 1965, all Swedish patients are treated with a diet from the neonatal period, while patients without treatment become severely mentally retarded. This thesis presents a recent survey of intelligence, adjustment, and coping among Swedish patients with PKU aged 8-19 years. In Study I the patients’ blood phenylalanine level was in accordance with treatment norms and they were normal in terms of intelligence and adjustment. The next study was a comparison of adjustment between patients with PKU, patients with neurobehavioral disorders, and patients with obesity. A reference group with matched non-clinical children was included. In this comparison, patients with PKU did not differ from the healthy children. Patients with neurobehavioral disorders were the least adjusted, and patients with obesity differed from the reference group and from patients with PKU in some respects, indicating less work capacity and internalising problems. Study II was undertaken for methodological reasons and showed that the measure of adjustment was reliable and valid. Study III was an investigation of psychological mechanisms associated with adherence to the dietetic therapy in PKU. The results showed that parents’ problem-focused coping was the main factor behind good adherence. A marked transition to self-care was recommended to enhance the patients’ motivation to continue with the diet into adulthood. This thesis concludes that the good outcome among the Swedish patients is due to general improvement of the treatment, but a contributing factor can be the high and fairly equal standards of living in the Swedish society.</p>

Phenylketonuria (PKU) is an inborn, metabolic disease affecting the enzyme phenylalanine hydroxylase, which converts phenylalanine to tyrosine. Since 1965, all Swedish patients are treated with a diet from the neonatal period, while patients without treatment become severely mentally retarded. This thesis presents a recent survey of intelligence, adjustment, and coping among Swedish patients with PKU aged 8-19 years. In Study I the patients’ blood phenylalanine level was in accordance with treatment norms and they were normal in terms of intelligence and adjustment. The next study was a comparison of adjustment between patients with PKU, patients with neurobehavioral disorders, and patients with obesity. A reference group with matched non-clinical children was included. In this comparison, patients with PKU did not differ from the healthy children. Patients with neurobehavioral disorders were the least adjusted, and patients with obesity differed from the reference group and from patients with PKU in some respects, indicating less work capacity and internalising problems. Study II was undertaken for methodological reasons and showed that the measure of adjustment was reliable and valid. Study III was an investigation of psychological mechanisms associated with adherence to the dietetic therapy in PKU. The results showed that parents’ problem-focused coping was the main factor behind good adherence. A marked transition to self-care was recommended to enhance the patients’ motivation to continue with the diet into adulthood. This thesis concludes that the good outcome among the Swedish patients is due to general improvement of the treatment, but a contributing factor can be the high and fairly equal standards of living in the Swedish society.