Phenylalanine neurotoxicity

Eighty years after the discovery of PKU, the pathogenesis of brain dysfunction and the exact mechanisms of phenylalanine neurotoxicity have yet to be elucidated. Although there is a common agreement about the relationship between blood phenylalanine concentration and cognitive outcome in PKU, the concentration of phenylalanine... 

Phenylalanine neurotoxicity affects the brain and related structures during critical windows of growth and development. Periods of particularly rapid growth make neuronal cells especially vulnerable to excessive amounts of toxic factors (e.g., phenylalanine) or a lack of substances needed for an optimal development [41]. 

Phenylalanine neurotoxicity can be also discussed with regard to the impact of elevated phenylalanine concentrations on the oUgodendroglial enzyme, Phe-sensitive ATP-suUurylase. This enzyme is engaged in the synthesis of cerebrosul-... 

Structural manifestations of phenylalanine neurotoxicity include dysmyelination in the white matter of the brain, revealed with MRl as intense lesions and cortico-subcortical atrophy on T2-weighted images with specifically high-signal intensity in periventricular white matter. White matter abnormaUties may be explained by cytotoxic edema and dysmyelination changes with increase in free water trapped in myeUn sheaths [44]. The size and distribution of WMA vary between patients with locahzation in the white matter of temporal and occipital lobes as the most common areas affected [42] (Figs. 9.5 and 9.6). 

Infants with classic phenylketonuria (PKU) are normal at birth but if untreated show slow development, severe mental retardation, autistic symptoms, and loss of motor control. Children may have pale skin and white-blonde hair. The neurotoxic effects relate to high levels of phenylalanine and not to the phenylketones from which the name of the disease derives. Infants are routinely screened a few days after birth for blood phenylalanine level. Treatment consists of a life-long semisynthetic diet restricted in phenylalanine (smalt quantities are necessary because it is an essential amino acid). Aspartame (N-aspartyl-phenylalanine methyl ester), which is widely used as an artificial sweetener, must be strictly avoided by phenyiketonurics. 

Classic phenylketonuria (PKU) is due to deficiency of phenylalanine hydroxylase, which leads to brain damage due to the neurotoxic effects of accumulated Phe or its metabolites. 

Very little has been published about the neurotoxicity of artificial food colors, but Z-glutamic acid and aspartic acid are well-established neurotoxins. (Aspartame is rapidly hydrolyzed to release aspartic acid and two other neurotoxins, phenylalanine and methanol.) The two mixtures noted above synergistically inhibited the neurite outgrowth in mouse NB2a neuroblastoma cells to far greater extents than Z-glutamic acid and aspartame did alone without the addition of the artificial food colors. 

The typical symptoms of untreated individuals with PKU are the manifestation of the neurotoxic effect of phenylalanine on the central nervous system. A morphological change in the brain in patients with PKU affects both white and gray matter. Microcephaly, where the brain mass can be 80 % of that of a healthy individual, is characteristic feature for many untreated PKU patients [37]. This symptom is caused by myelin structure anomalies that result in a loss of myelin volume, disturbances in cortical neuronal development, diffuse cortical atrophy, and general abnormalities in protein synthesis [37, 39, 40]. 

Archibald and Tyree (1987) have demonstrated that Mn " in a pyrophosphate complex (probably Mn [pyrophosphate] 3) has the capacity to rapidly destroy the principal brain catecholamines and their precursor, dopa, oxidising them to a best useless and at worst toxic products. In the absence of Mn , oxidation of the neurotoxic 6-hydro-xydopamine to a stable coloured compound in the 02-containing reaction mixture took several minutes, while Mn accelerated this to completion in < 5 s. The observation thar phenylalanine and tyrosine were not oxidised by Mn " ", although their dihydroxy derivatives were, suggested that the site... 

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