Phenylketonuria (PKU) is an inborn error of phenylalanine (PA) metabolism that occurs once in approximately seven thousand to one in fifteen thousand live births (Bickel et al, 1981; Elsas and Acosta, 1994). PKU is inherited as an autosomal recessive disorder and occurs in all ethnic groups (Eisensmith and Woo, 1992; Eisensmith et al, 1992). One in fifty people is a heterozygous carrier of this disease (Pietz, 1998). PKU is caused by a deficiency or absence of hepatic phenylalanine hydroxylase (PAH; Enzyme commission 188.8.131.52), which converts PA, an essential amino acid in humans, to tyrosine (Jervis, 1953; Hsia, 1966; Guttler et al, 1987). The ...view middle of the document...
The treatment of PKU individuals involves the reduction of blood PA by restricting dietary PA during the first month of life (Bickel et al, 1954). The diet of PKU individuals must provide enough PA to promote normal growth and development without allowing the level of PA in the blood to become exceedingly high (Scriver et al, 1989; Brenner et al, 1996). Generally, the PKU diet does not allow consumption of foods from animal origin (meat, fist, poultry, milk, and eggs) (Matalon and Michals, 1991). Food products that are low or free in PA and provide adequate amounts of tyrosine are used (Wendel et al, 1990; Whitehead, 1987). Optimal ranges for blood PA levels vary among treatment centers, but, most centers recommend that approximately 120-600 mol/L (> 10 mg/dL) of blood PA is sufficient to avoid neurological or behavioral problems associated with PKU (Matalon and Michals, 1991). In the past, the low PA diet was often discontinued at six years of age, since it was thought that the majority of brain development was complete by this age. However, recent evidence has shown that a loss of dietary PA control correlates with a decline in school performance and increased behavioral problems. Hence, it is now recommended that diet therapy for individuals with PKU continue indefinitely (Holtzman et al, 1986; Michals et al, 1988; Azen et al, 1991).
Phenylketonuria and Brain Dysfunction
Brain dysfunction in individuals with PKU is a major problem (Lenke and Levy, 1988). The exact mechanism by which elevated levels of circulating PA exerts its deleterious effects on the developing brain has not been fully elucidated. It is not clear as to why only the central nervous system but not other tissues are drastically affected in PKU (Barashnev et al, 1982). It is also not well understood why specific periods of brain development are more affected by high PA levels. Since PAH is not present in brain, the brain dysfunction that occurs in PKU individuals must be produced by a chemical(s) outside the central nervous system which then crosses the blood-brain barrier and enters the brain (Levy, 1987; Kudo and Boyd, 1990; Hanley and Clarke, 1987). The most common neuropathological finding in the brain of PKU individuals is reduction of brain lipids, in particular, myelin (Alvord et al, 1950; Shah et al, 1972; Pietz, 1998). It is conceivable that this reduction in brain myelin may be the primary cause of brain dysfunction observed in PKU. Therefore, studies that investigate the role of brain lipids, specifically, myelin, may provide the key for understanding the genesis of brain dysfunction in PKU.
Phenylketonuria and Brain Lipids
Brain development is a sequential anatomical process characterized by specific well-defined “stages” of growth and development (Dobbing 1971 Gottlieb et al, 1977; Albers, 1985). The brain is most vulnerable to exogenous and endogenous factor when it passes through its most rapid phase of growth (Gottlieb et al, 1977; Dobbing 1971;...