Brain dysfunction in phenylketonuria: Is phenylalanine toxicity the only possible cause?

Abstract

In phenylketonuria, mental retardation is prevented by a diet that severely restricts natural protein and is supplemented with a phenylalanine-free amino acid mixture. The result is an almost normal outcome, although some neuropsychological disturbances remain. The pathology underlying cognitive dysfunction in phenylketonuria is unknown, although it is clear that the high plasma concentrations of phenylalanine influence the blood-brain barrier transport of large neutral amino acids. The high plasma phenylalanine concentrations increase phenylalanine entry into brain and restrict the entry of other large neutral amino acids. In the literature, emphasis has been on high brain phenylalanine as the pathological substrate that causes mental retardation. Phenylalanine was found to interfere with different cerebral enzyme systems. However, apart from the neurotoxicity of phenylalanine, a deficiency of the other large neutral amino acids in brain may also be an important factor affecting cognitive function in phenylketonuria. Cerebral protein synthesis was found to be disturbed in a mouse model of phenylketonuria and could be caused by shortage of large neutral amino acids instead of high levels of phenylalanine. Therefore, in this review we emphasize the possibility of a different idea about the pathogenesis of mental dysfunction in phenylketonuria patients and the aim of treatment strategies. The aim of treatment in phenylketonuria might be to normalize cerebral concentrations of all large neutral amino acids rather than prevent high cerebral phenylalanine concentrations alone. In-depth studies are necessary to investigate the role of large neutral amino acid deficiencies in brain.

Experimental Evidence that Phenylalanine Provokes Oxidative Stress in Hippocampus and Cerebral Cortex of Developing Rats

“…Elevated blood concentrations of Phe also provoke reduced concentrations of the other large neutral amino acids (LNAA) probably because of a competition of these amino acids for the same transport L-type amino acid system (LAT1, SLC7A5) through the blood-brain barrier (Pratt 1980;Smith et al 1987;Pardridge 1998;Surtees and Blau 2000;van Spronsen et al 2009). Therefore, although the literature emphasizes Phe as the pathological toxic substrate that causes mental retardation, brain deficiency of other essential LNAA cannot be ruled out as an important contributor factor affecting brain development and functioning (van Spronsen et al 2009).…”

“…Therefore, although the literature emphasizes Phe as the pathological toxic substrate that causes mental retardation, brain deficiency of other essential LNAA cannot be ruled out as an important contributor factor affecting brain development and functioning (van Spronsen et al 2009). …”

Caracterización fenotípica y molecular de una familia colombiana con fenilcetonuria

“…La importancia de los programas de tamización neonatal es evidente, pues permiten la detección temprana de la enfermedad y logran un cometido crucial en la medicina actual: evitar que se instauren secuelas irreversibles de enfermedades que pudieron haber sido tratadas y controladas si se hubieran diagnosticado en el momento del nacimiento (21,22).…”

Resonancia magnética nuclear de encéfalo en pacientes con fenilcetonuria diagnosticada tardíamente

“…8,9 Hay evidencia que el exceso de fenilalanina altera el transporte de otros aminoácidos. 10 Algunos autores han propuesto que el exceso de fenilalanina afecta la viabilidad, la morfología y la excitabilidad neuronal. 3,[11][12][13][14] En modelos animales de fenilcetonuria se ha demostrado mielogénesis reducida, 15 disminución de la velocidad de conducción axonal así como disminución de la actividad de la Na+/ K+-ATPasa en las membranas sinápticas.…”