No description available.

No description available.

Thesis (Ph. D.)--University of Washington, 2002. / Vita. Includes bibliographical references (leaves 122-137).

Phenylketonuria (PKU) and related forms of non-PKU hyperphenylalaninemias (HPA) result from deficiencies in phenylalanine hydroxylase (PAH), the hepatic enzyme that catalyses the conversion of phenylalanine (phe) to tyrosine (tyr). Patients are characterised by a metabolic phenotype comprising elevated levels of phe and some of its metabolites, notably phenyllactate (PLA), phenylacetate (PAA) and phenylpyruvate (PPA), in both tissue and body fluids. Treatment from birth with low-phe diet largely prevents the severe mental retardation that is its major consequence. / Mechanisms underlying the pathophysiology of PKU are still not fully understood; to this end, the availability of an orthologous animal model is relevant. A number of N-ethyl-N-nitrosourea (ENU) mutagenized mouse strains have become available. I report a new heteorallelic strain, developed by crossing female ENU1 (with mild non-PKU HPA) with a male ENU2/+ carrier of a 'severe' PKU-causing allele. I describe the new hybrid ENU1/2 strain and compare it with control (BTBR/Pas), ENU1, ENU2 and the heterozygous counterparts. The ENU1, ENU1/2 and ENU2 strains display mild, moderate and severe phenotypes, respectively, relative to the control and heterozygous counterparts. / I describe a novel method using negative ion chemical ionization gas chromatography/mass spectrometry (NICI-GC/MS) to measure the concentration of PLA, PAA and PPA in the brain of normal and mutant mice. Although elevated moderately in HPA and more so in PKU mice, concentrations of these metabolites are not sufficient to explain impaired brain function; however phe is present in brain at levels associated with harm. / Finally, I describe a new modality for treatment of HPA, compatible with better human compliance: it involves enzyme substitution with non-absorbable and protected phenylalanine ammonia lyase (PAL) in the intestinal lumen, to convert L-phenylalanine to the harmless metabolites (trans-cinnamic acid and trace ammonia). PAL, taken orally, substitutes for the deficient PAH enzyme and depletes body pools of excess phe. I describe an efficient recombinant approach to produce PAL enzyme. I also provide proofs of both pharmacologic and physiologic principles by testing PAL in the orthologous mutant mouse strains with HPA. The findings encourage further development of PAL for oral use as an ancillary treatment of human PKU.

No description available.

Thesis (Ph. D.)--Washington State University, December 2008. / Title from PDF title page (viewed on July 10, 2009). "School of Molecular Biosciences." Includes bibliographical references.

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

No description available.

Thesis (PH. D.)--University of Michigan, 1937. / Caption title: Comparative studies of the metabolism of the amino acids. VII. Experimental alcaptonuria in the white rat, by Evangeline Papageorge and Howard B. Lewis. "Reprinted from the Journal of biological chemistry, vol. 123, no. 1 ... 1938." Bibliography: p. 219-220. Also issued in print.