There are some people living in the community with asymptomatic PKU and normal intelligence. Instances of PKU in which the symptoms are of adult onset are rare but of interest because of the entirely unexpected diagnosis. The few such cases reported and summarized by Kasim and colleagues, with a case of their own, developed a progressive spastic paraparesis, some with mild dementia. The phenylalanine levels were at values that reflect total or partial enzyme deficiency.
The finding of high levels of serum phenylalanine (above 15 mg/dL) and of phenylpyruvic acid in the blood, CSF, and urine is diagnostic of PKU. The level is normal at birth and rises only after the first few days. But screening by the Guthrie (ferric chloride) test will reliably identify the patient at risk. The addition of 3 to 5 drops of 10 percent ferric chloride to 1 mL of urine is a simple and informative test that was used at the neonates or child’s bedside in the past. It yields an emerald-green color that reaches peak intensity in 3 to 4 min and fades in 20 to 40 min. In contrast, the green-brown color in the urine of patients with histidinemia is permanent. In maple syrup urine disease, the ferric chloride test gives a navy-blue color; propionic and methylmalonic acidemia and either ketones or salicylates in the urine yield a purple color.
The fundamental biochemical abnormality is a deficiency of the hepatic enzyme PA hydroxylase; the failure of conversion of PA to tyrosine results in the excretion of phenylpyruvic acid by affected individuals. The precise step that is faulty in the complex phenylalanine hydroxylating reaction is still unknown.
Pathologic examination shows poor staining of myelin in the cerebral hemispheres. This can be visualized by MRI in untreated children. Another instructive feature is that the pigmented nuclei (substantia nigra, locus ceruleus, dorsal vagal motor) fail to acquire dark coloration because of a block in the production of neuromelanin. Reduction in size of cortical neurons and their dendritic arborizations is said to be demonstrable in some cases.
Treatment If instituted in infancy, diets low but not totally lacking in PA can improve intellectual development (blood level should be maintained at 5 to 10 mg/dL). Careful dietary management may result in completely normal intellectual development. Once the neurologic picture unfolds, diet has little or no effect on the mental status but may improve behavior. Prolonged dietary treatment has many untoward effects and should be supervised by physicians and nutritionists experienced in its use; if too restricted, it may retard growth. This is particularly important, as it has been shown that intellectual impairment is greatest among children who were the earliest to abandon their diets, permitting the PA concentration to rise above 15 mg/dL, and least in children who maintained dietary control the longest (Holtzman et al). Continued dietary treatment is probably necessary, but the degree of restriction of PA may be relaxed once the nervous system is fully developed. The precise degree of allowed restriction of dietary PA restriction is not known but many children, having been raised on a low PA diet, will have little or no difficulty in maintaining the restrictions into adulthood.
With the widespread screening for PKU and the initiation of dietary control during early postnatal life, this metabolic brain disease has virtually disappeared in the New England states. Treated women who reach childbearing age should be particularly careful about dietary restriction, because high levels of phenylalanine are harmful to the normal fetus. Mild cases of PKU have been successfully treated with the cofactor tetrahydrobiopterin (Muntau et al).
The late forms of maple syrup urine disease, and hydroxyprolinemia evolve in much the same fashion as PKU and raise similar problems in diagnosis and therapy. Histidinemia can be detected by screening but is now considered a benign biochemical variant.