Epilepsy in phenylketonuria: a complex dependence on serum phenylalanine levels.
OBJECTIVE
Phenylketonuria (PKU) is a disorder of phenylalanine (Phe) metabolism that frequently results in epilepsy if a low Phe diet was not implemented at birth. The mechanisms by which Phe affects the brain are poorly understood.


METHODS
Audiogenic seizures (AGS) were studied in female homozygous Pah(enu2) BTBR (PKU) mice.


RESULTS
Adult PKU mice, 18-20 weeks of age, in contrast to wild-type and heterozygous counterparts, exhibited a full range of AGS. Younger PKU mice, 5-7 weeks of age, had higher serum Phe levels (2.22 +/- 0.20 mM) in comparison with the adult animals (1.72 +/- 0.05 mM) and were not susceptible to AGS. Among adult mice, animals susceptible to AGS had significantly lower serum Phe levels (1.62 +/- 0.06 mM) in comparison with those resistant to AGS (1.86 +/- 0.07 mM). Susceptibility to AGS tended to increase in the afternoon when serum Phe concentration decreased in comparison to evening and morning. Normalization of serum Phe level by instituting a low Phe diet generally prevented susceptibility to AGS within 12 h. Although return to a standard diet raised Phe levels to hyperphenylalaninemic within 12 h in animals treated with a low Phe diet for 2 weeks, more than 7 weeks were needed for a complete resumption of AGS.


CONCLUSIONS
Transient decrease in Phe levels within hyperphenylalaninemic range may be a necessary condition for PKU-related seizures to occur. A low Phe diet prevents susceptibility to seizures, which can resume with the significant delay after termination of dietary treatment.
Martynyuk
Anatoly E
AE
Department of Anesthesiology, University of Florida, Gainesville, FL 32610-0254, USA. AMartynyuk@anest.ufl.edu
Ucar
Deniz A
DA
Yang
Dawn D
DD
Norman
Wendy M
WM
Carney
Paul R
PR
Dennis
Donn M
DM
Laipis
Philip J
PJ
D000161:Acoustic Stimulation; D000367:Age Factors; D000818:Animals; D002940:Circadian Rhythm; D004195:Disease Models, Animal; D004827:Epilepsy / Q000097:blood* / Q000175:diagnosis / Q000235:genetics; D020195:Epilepsy, Reflex / Q000097:blood* / Q000175:diagnosis / Q000235:genetics; D005260:Female; D005526:Food, Formulated; D020022:Genetic Predisposition to Disease; D051379:Mice; D008817:Mice, Mutant Strains; D010649:Phenylalanine / Q000008:administration & dosage / Q000097:blood* / Q000378:metabolism; D010661:Phenylketonurias / Q000097:blood* / Q000178:diet therapy / Q000235:genetics
D010649:Phenylalanine