Brain uptake of 11C-methionine in phenylketonuria

Abstract

The brain uptake of 11C-methionine was studied in 26 children with classical phenylketonuria; one adult was used as a control. Labelled methionine uptake in brain was first measured during a low phenylalanine diet and again one week later after a load of phenylalanine. Ten children aged 1 to 30 months were studied twice at intervals of several months. In children having a phenylalaninemia less than or equal to 0.3 mumoles . ml-1, a decrease in methionine brain uptake was observed with increasing age, with the largest change occurring during the first year of life. After the phenylalanine load, a mean increase in phenylalaninemia by a factor of ten was accompanied by a mean decrease in brain methionine uptake by a factor of two while blood methionine remained unchanged. Brain activity curves increased with time for children younger than one year and having phenylalaninemia less than 0.6 mumoles . ml-1. After the age of 2 most patients had a decreasing curve regardless of the blood phenylalanine level. This study indicates that 11C-methionine brain uptake may be taken as an index of blood barrier permeability to essential amino acids, and of brain maturation. The results obtained suggest that an increase in phenylalaninemia to levels greater than 0.6 mumole . ml-1 induces a modification in brain uptake of amino acids, primarily during the first two years of life.

Cerebral protein synthesis in a genetic mouse model of phenylketonuria

“…The L- [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]leucine method is based on a compartmental model for the behavior of leucine in brain that includes bidirectional carrier-mediated transport of leucine at the bloodbrain barrier, an extracellular and multiple intracellular compartments in brain, and the possibility that unlabeled leucine from the breakdown of tissue protein can be reincorporated into tissue protein. The application of the model together with an appropriate experimental design, i.e., a pulse injection of a tracer dose of L-[1-14 C]leucine followed by a 60-min interval for clearance of the tracer from the blood and the brain, gives rise to Eq.…”

“…The radiolabeled tracer is [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]leucine, which is used in conjunction with quantitative autoradiography to achieve spatial localization of the labeled protein in the brain for the determination of rates of protein synthesis in discrete brain regions (17). The operational equation of the method is:…”

“…It has been hypothesized that an elevated plasma Phe concentration impedes entry of other neutral amino acids via the L-amino acid carrier at the bloodbrain barrier, and that reduced influx may limit their availability for incorporation into tissue protein (2). There is ample evidence for the effective competitive inhibition of the transport system in hyperphenylalaninemic patients with PKU (3)(4)(5). It is only by inference that cerebral protein synthesis rates appear to be affected.…”

Dietary Phenylalanine and Brain Function

“…The human brain is also known to be selectively vulnerable to hyperaminoacidemias based on the clinical findings in PKU (Scriver and Clow 1980). Moreover, studies using either brain scanning (Oldendorf et al 1971) or positron emission tomography (Comar et al 1981) have shown that the brain uptake of neutral amino acids such as methionine is greatly inhibited by increased blood concentrations of phenylalanine in humans. To test the hypothesis that the human BBB, like the rat BBB, has a neutral amino acid transport system with a very low Km (very high affinity) for neutral amino acids, the present studies were performed.…”

An Extracorporeal Hollow-Fiber Reactor for Phenylketonuria Using Immobilized Phenylalanine Ammonia Lyase

“…However, when they are small and hydrophilic enough, the toxic metabolites readily diffuse out of the deficient cells and may cause even more severe damage to the brain (or to other organs) than to the liver where they first accumulate. In phenylketonuria (PKU) and in other aminoacidopathies as well, the development of the neurological symptoms obligatorily involves the transit of a toxic substance via the blood circulation [5], It is therefore tempting to take advantage of these features for the elimination of the diffusing metabolites.…”