Enzyme: phenylalanine hydroxylase (chr 12q, autosomal recessive)
Untreated, leads to severe brain damanage with mental retardation. Other clinical features in untreated patients include fair pigmentation for ethnicity, eczema, a musty odor, microcephaly, autistic behaviors, and hand movements. Neurologic signs include seizures (26%), spasticity, hyperreflexia, and tremors.
Untreated biopterin-deficient hyperphenylalaninemia also produces mental retardation but, in addition, has severe neurologic disease beginning in infancy. There are bulbar abnormalities, alterations in mental status and tone, seizures, progressive microcephaly, and movement disorders
White matter disease is prominent in phenylketonuria - including areas of demyelination and gliosis. In gray matter there is neuronal loss, reduced size of neurons, and decreased dendritic processes on Purkinje cells. In the biopterin-deficient hyperphenylalaninemias, white matter changes also occur; in addition there may be diffuse atrophy and (in dihydropteridine reductase deficiency) basal ganglia calcifications.
MRI in treated patients reveals increased signal on T2 images with decreased signal on T1 images, most prominently in parieto-occipital and periventricular white matter, with severe cases also involving more frontal areas. Although these changes do not correlate with IQ, there may be correlation with quality of dietary control and blood phenylalanine level at time of imaging, and the changes may be reversible with improved dietary control. The changes are present even in children under optimal dietary control.
Neurophysiology: Maturation of EEG patterns is delayed. Sensory NCVs and SSEPs are delayed. Latencies of VEPs and ABRs are prolonged.
Phe-restricted diet in classical PKU. BH4 supplementation can normalize Phe levels in mild hyperPhe. BH4 deficiency treated with supplementation of L-dopa, 5-OH-tryptophan, tetrahydrobiopterin, and folinic acid (and Phe-restricted diet in DHPR deficiency).
In treated PKY, prognosis is usually good, with normal intelligence. The severity of decrease in IQ score correlates with duration off diet and age at discontinuation of diet, with the poorest performance seen in children off diet at less than 6 years old. However, even patients treated early and well will have mild executive impairment. When assessed by their teachers, children with phenylketonuria are more likely to be rated as having more deviant behavior (mannerisms, anxiety, hyperactivity, and less social). Adolescents and adults show more depression, dependency, low frustration tolerance, and low self-esteem, and are prone to social withdrawal. Some of these abnormalities may correlate with duration off diet and may respond to dietary phenylalanine restriction.
The prognosis of biopterin-deficient hyperphenylalaninemia can be poor.