Common comorbidities associated with phenylketonuria (PKU) are highly elevated rates of aberrant behavior, ranging from relatively mild psychiatric disorders to extreme-even life-threatening—behavioral disturbances, such as aggression, disruption, pica, and self-injury. Typically, these clinically challenging problems have been treated through pharmacologic therapy, behavior modification, physical restraint, or some combination of the three. Reviews of the literature show that these interventions generally do not produce enduring and functionally meaningful effects.
Although behavior problems are common among persons with mental retardation, especially the more severe cases, examination of the literature indicates that disease etiology is usually not a major consideration in the development of clinical interventions. Nevertheless, the hyperphenylalaninemias present an excellent opportunity for designing treatments with high degrees of biological plausibility and etiological specificity. Not only may it be possible to treat such problems in persons with PKU, but these and other inborn errors of metabolism should provide models for designing therapies based on an understanding of specific disease pathogenesis.
Over the years, controlled experiments and case studies have found that the disordered behavior exhibited by persons with elevated blood phenylalanine (Phe) may be effectively managed by placing these individuals on a Phe-restricted diet. Such therapy may also be useful for those who have never been on a Phe-restricted diet, those with PKU who were identified early but removed from the diet in childhood, those treated late (Brown, Guest, 1998), and those with atypical or mild hyperphenylalaninemia. This literature, along with a great deal of corroborating evidence (dietary challenge, magnetic resonance imaging [MRI] results, free diet supplementation with amino acids, neurotransmitter regulation), was reviewed by Baumeister and Baumeister (1998). All the evidence, taken together, suggests that restricted-Phe dietary treatment and, perhaps, supplementation with other amino acids may be useful for treating behavioral disturbances in hyperphenylalaninemia.
As reported by Baumeister and Baumeister (1998), there appears to be a fairly close correlation between blood Phe concentrations and the occurrence of aberrant behavior. In the case of three patients, the investigators found that the correlations ranged from .64 (tantrum) to .71 (assault) and .96 (tantrum). For a fourth subject the correlation was also positive (face-slapping) but not statistically significant. In addition, when positive changes are observed, they are related to the length of time necessary for Phe blood levels to drop substantially. It is important to note that observed benefits are not necessarily conditional on attaining normal Phe levels. The range of blood Phe typically observed in studies with positive outcomes runs from 3 to 10 mg/dL.
Data from MRI studies also indicate that abnormalities (in white cerebral matter) are related to Phe concentration and that it takes at least 2 months of good dietary control to resolve such abnormalities. Nevertheless, it must be emphasized that the connection between changes in MRI results and behavioral disturbance is still unclear.
Although case studies and controlled experiments indicate that behavioral disturbances among patients with hyperphenylalaninemia often respond positively to the medical diet, there remains considerable variability both between and within individuals. In some cases, no improvement has been observed; in a few, symptoms have become more severe. In still other cases, the initial response is good, but then there is a relapse. The sources of this variability are uncertain, but degree of control over serum Phe is undoubtedly implicated. In addition, hyperphenylalaninemias are heterogeneous diseases, both phenotypically and genetically (Güttler, Azen, Guldberg, et al., 1999). Thus, mutational severity may be a critical determinant.
Recent studies (for example, Moats, Koch, Moseley, et al., 2000) indicate that brain Phe concentration is a more critical variable in management of patients with PKU than blood Phe. The correlation between blood and brain concentrations of Phe is, in general, not very high. All studies of dietary intervention in which behavioral and neurologic abnormalities have been targeted have measured blood levels of Phe. It could be that a better understanding of the effects of dietary management of behavioral and neurologic abnormalities would be achieved by measuring concentrations of Phe in the brain.
Virtually all intervention studies have focused on individuals with classical PKU. Nevertheless, as with other toxic agents, there is probably a dose-gradient relationship. A recent unpublished study has shown that two individuals with atypical PKU (Phe <12 mg/dL) who displayed disruptive behavior responded positively to dietary intervention to reduce Phe or dietary supplementation with the neurotransmitter precursors tryptophan and tyrosine.
Despite accumulating evidence that aberrant behavior among patients with hyperphenylalaninemia may be effectively treated with medical diet, several important considerations remain:
- The level of Phe restriction required to produce positive results.
- The extent to which free diet supplementation with amino acids can have positive effects.
- The relation of brain versus blood concentrations of Phe to clinical outcome.
- The generality of dietary effects across time, situation, and other indicators (e.g., seizures, motor control, socialization).
- The relation between changes in myelination and abnormalities in MRI and electroencephalographic findings.
- The applicability of Phe restrictions to atypical PKU.
- The serotonin and dopamine regulation of patients with PKU.
- The timing and degree of relaxation of diet.
- The advisability of Phe screening of adults with behavioral disorders who are not known to have PKU.
- The relative importance of the factors involved in dietary management (e.g., nutritional needs, family support, costs, variability of control).
- The relative importance of laboratory measures (e.g., plasma amino acids, urine pterins, albumin, CBC, ferritin, folate, and RBC indices).
- The relationship between phenylalanine hydroxylase (PAH) genotype, biochemical control, and outcome.
- The handling of methodological problems in most reported studies.
- Baumeister AA, Baumeister AA. Dietary treatment of destructive behavior associated with hyperphenylalaninemia. Clin Neuropharmacol 1998;21:18-27.
- Brown MCJ, Guest JF. Economic impact of feeding a phenylalanine restricted diet to adults with previously untreated phenylketonuria. J Intellect Disabil Res 1999;43:30-7.
- Güttler F, Azen C, Guldberg P, Romstad A, Hanley WB, Levy HL, et al. Relationship among genotype, biochemical phenotype, and cognitive performance in females with phenylalanine hydroxylase deficiency: report from the Maternal Phenylketonuria Collaborative Study. Pediatrics 1999;104:258-62.
- Moats RA, Koch R, Moseley K, Guldberg P, Güttler F, Boles RG, et al. Brain phenylalanine concentration in the management of adults with phenylketonuria. J Inherit Metab Dis