Persons with genetic predisposition to PKU have normal mental development on this diet. Previously, it was thought safe to withdraw from the diet in the late teens or early twenties, after the central nervous system was fully developed; recent studies suggest some degree of relapse, and a continued phenylalanine-restricted diet is now recommended.PKU or hyperphenylalaninemia may also occur in persons without the PKU genotype. If the mother has the PKU genotype but has been treated so as to be asymptomatic, high levels of [phe] in the maternal blood circulation may affect the non-PKU fetus during gestation. Mothers successfully treated for PKU are advised to return to the [phe]-restricted diet during pregnancy.A small subset of patients with hyperphenylalaninemia shows an appropriate reduction in plasma phenylalanine levels with dietary restriction of this amino acid; however, these patients still develop progressive neurologic symptoms and seizures and usually die within the first 2 years of life ("malignant" hyperphenylalaninemia). These infants exhibit normal phenylalanine hydroxylase (PAH) enzymatic activity but have a deficiency in dihydropteridine reductase (DHPR), an enzyme required for the regeneration of tetrahydrobiopterin (THB or BH4), a cofactor of PAH.Less frequently, DHPR activity is normal but a defect in the biosynthesis of THB exists. In either case, dietary therapy corrects the hyperphenylalaninemia. However, THB is also a cofactor  for two other hydroxylation reactions required in the syntheses of neurotransmitters in the brain: the hydroxylation of tryptophan to 5-hydroxytryptophan and of tyrosine to L-dopa.
Pathophysiology
The etiology of RPON is still unknown and remains controversial - some scientists believe that RPON is a subtype of migraine, while others believe that it is a neuropathic disorder. As such, different potential etiologic mechanisms have been proposed based on case reports, including migrainous and neuropathic mechanisms. Yet, the renaming of RPON from OM indicates that the neuropathic cause may play a more important role than the migrainous cause in the pathophysiology of RPON. Migrainous mechanism
RPON was previously thought to be having a migrainous origin since it shares some common characteristics with migraine, and their only differences are the intensity and duration of headaches. Therefore, it was postulated that migraine caused ophthalmoplegia in RPON. However, the major argument against a migrainous origin is the long latency period between the onset of headache and ophthalmoplegia (up to 14 days), which is not consistent with a typical migraine. Nevertheless, several migrainous mechanisms have been proposed. Nerve compression
Compression mechanism is the first theory postulated regarding the pathophysiology of RPON. It is proposed that headache is caused by direct pressure on CNIII (compression neuropathy) within the cavernous sinus due to edema of the walls of the internal carotid artery (ICA) or posterior cerebral artery (PCA) during migraine episodes. Ischemia
Cavernous section of the ICA and a perforating vessel from the proximal PCA are responsible for supplying CNIII, CNIV, and CNVI. During migraine attacks, vasoconstriction of the ICA and PCA may lead to a reversible and ischemic breakdown of the blood-brain barrier.