By Forrester Cockburn, M.D.
Phenylketonuria (PKU—meaning persistent hyperphenylalaninemia >240 µmol/L, a relative tyrosine deficiency, and excretion of an excess of phenylketones) occurs in approximately 1 in 10,000 births in the United Kingdom (Smith, Cook, Beasley, 1991; Smith, 1985). Except for the 1 to 2 percent with defective metabolism of tetrahydrobiopterin, infants with PKU have a recessively inherited deficiency in the hepatic enzyme phenylalanine hydroxylase (PAH) due to a large number of sequence variations at the PAH gene (Tyfield, Stephenson, Cockburn, et al., 1997).
Screening of neonates using capillary blood obtained between 5 and 21 days after birth and early treatment with a diet low in phenylalanine (Phe) produced the virtual disappearance of children with a mental handicap because of PKU in the United Kingdom between 1964 and 1970. In 1993, a working group convened by the Medical Research Council (MRC) of the United Kingdom reviewed current knowledge on PAH deficiency (Medical Research Council, 1993), and a set of recommendations on the dietary management of PKU evolved from that review (Recommendations, 1993). The MRC report noted that the intellectual status of early-treated subjects was not as good as had been expected. Subtle but global intellectual impairments were to a substantial degree occurring in the preschool years and were closely linked with the character of Phe control in the preschool years and to a lesser extent in the pre-adolescent years. In addition, the performance of executive tasks appeared to depend on control of Phe. The appearance of neurological deterioration in older individuals with PKU and changes in myelin structure shown by magnetic resonance imaging (MRI) emphasized the need to appraise existing treatment protocols for PKU (Smith, Beasley, Ades, 1990; Smith, Beasley, Wolff, et al., 1988; Welsh, Pennington, Ozonoff, et al., 1990; Villasana, Butler, Williams, et al., 1989; Thompson, Smith, Brenton, et al., 1990; Thompson, Smith, Kendall, et al., 1991; Bick, Fahrendorf, Ludolph, et al., 1991).
Levels of Blood Phe at Which Treatment is Initiated and Maintenance Levels During Treatment
Screening of neonates for PKU must be conducted soon after birth so that diagnosis and treatment can begin with a minimum of delay—certainly by 20 days of age. Diagnostic investigation should include an assessment of protein intake, quantitative measurement of plasma amino acids, and separation of infants with defective biopterin metabolism. All infants whose blood Phe concentrations exceed 600 µmol/L, and who have a normal or low plasma tyrosine and an otherwise normal plasma amino acid profile while receiving a normal protein intake (2 to 3g/kg/day), should receive a low Phe diet immediately. Infants whose blood Phe concentrations remain between 400 and 600 µmol/L for more than a few days should also be given dietary treatment. The diet should contain a protein substitute which is Phe-free (or at least very low in Phe) and otherwise nutritionally complete, with a composition sufficient to provide 100 to 120 mg/kg/day of tyrosine and an amino acid intake of at least 3g/kg/day in children younger than 2 years of age. In children 2 years of age and older, the intake of amino acids should be maintained at a level of 2g/kg/day. The protein substitute should be given as evenly as possible over a 24-hour period (Cockburn, Clark, 1996). If Phe concentrations exceed 900 µmol/L at the time of diagnosis, natural forms of milk should be excluded long enough to ensure a rapid fall in blood Phe concentration to below 600 µmol/L. Concentrations of Phe are likely to fall at a rate of 300 to 600 µmol/L/day. Daily monitoring of blood Phe should be conducted in order to ascertain individual protein requirements (usually between 60 and 110 mg/kg/day) and to prevent Phe deficiency. Phe readings made at a standard time (ideally, early morning, when concentrations are likely to be at their peak) should be conducted at least weekly. The aim is to keep Phe concentrations between 120 and 360 µmol/L. Biochemical monitoring should continue on a weekly basis up to at least 4 years of age. After 4 years of age, monitoring can be done every 2 weeks. Phe intake should be adjusted to produce therapeutic blood Phe levels.
The overall nutrient intake, body growth, feeding pattern, and general health of patients with PKU should be reviewed every 2 to 3 months in infancy, every 3 to 4 months up to school age, and every 6 months thereafter. In subjects with mild PKU, treatment should be withdrawn only if intake of natural protein reaches optimum requirements for their age while blood Phe concentrations remain below 400 µmol/L. Low protein diets and protein low tests are not recommended. Feeding strategies should aim to have children responsible for their own diet and the consequent blood test results by school age. The aim should be to maintain strict control of Phe levels as long as possible.
Age at Dietary Relaxation and Discontinuation
An upper limit of 480 µmol/L may be acceptable in children of school age. It becomes increasingly difficult to maintain strict control of Phe blood levels in older children, but every effort should be made to hold Phe concentrations no higher than 700 µmol/L. Adolescent and young adult patients should be made aware of the evidence that, even at that level of Phe concentration, the performance of decision-making tasks may improve if Phe levels are reduced.
It is currently recommended in the United Kingdom that treatment be for life. Adults and adolescents with PKU require continued delivery of services in an appropriate setting. This requires the involvement of physicians with a special interest in metabolic disease who are linked to regional pediatric services; adult services should include frequent monitoring and dietetic advice (by mail and telephone) and the availability of specialists for outpatient followup and inpatient care.
Female subjects require counseling about the need for very strict dietary control before conception. Those who conceive when Phe concentrations are 900 µmol/L or more should be offered termination of pregnancy because of the high risk of infant malformation. Hyperphenylalanine poses some risk to brain growth and intellectual development even at levels below 900, and offers of detailed fetal ultrasound assessment and possible termination should be extended to patients with concentrations of 700 µmol/L or more. Because of positive amino acid gradients across the placenta, the fetus is exposed to higher concentrations of Phe than the mother is (Cockburn, Farquhar, Forfar, et al., 1972). Monitoring should be undertaken twice weekly, both in the period before conception and during pregnancy, aiming at values of 60 to 250 µmol/L. Effective contraception should be practiced until such control has been achieved.
Outcome of Long-Term Followup After Dietary Relaxation
Data from the German and U.S. collaborative studies, like United Kingdom studies of PKU, show that maintenance of lower plasma and blood Phe concentrations affects intelligence quotient (IQ) up to the ages of 8 to 10 years but probably not thereafter (Schmidt, Mahle, Michel, et al., 1987; Burgard, Bremer, Bührdel, et al., 1999; Holtzman, Welcher, Mellits, 1975; Smith, Beasley, Ades, 1991). Waisbren and colleagues have reviewed the neuropsychological functioning of treated phenylketonuric patients and found that impaired choice reaction times appear to be the only consistent finding in patients with greater concentrations of Phe in their blood (Waisbren, Brown, de Sonneville, et al., 1994). Specific executive function deficits can be demonstrated in younger patients with PKU (Welsh, Pennington, Ozonoff, et al., 1990; Diamond, 1994). In psychometric assessment of older treated patients with PKU, the results are in many ways ambiguous, but patients regularly give subjective reports of poor functioning during periods when their Phe concentrations are elevated (Griffiths, Paterson, Harvie, 1995; Weglage, Pietsch, Fünders, et al., 1996).
MRI scans have on occasion demonstrated the partial reversibility of an increase in Phe through the introduction of stricter dietary control (Cleary, Walter, Jenkins, et al., 1994). There is recent evidence that the genotypes of affected individuals might be useful in predicting the likelihood of intellectual changes in patients with hyperphenylalaninemia and PKU whose diet is relaxed after the age of 8 years (Greeves, Patterson, Carson, et al., 2000).
Deficiencies in Knowledge That Require Further Research
During the first 2 years after birth, the infant brain increases in weight from 350g to 1,200g. This growth is not caused by an increase in cell numbers but by formation of dendritic communication channels and myelination of neuronal axones. Inhibition of these processes, which are essential for early learning, can produce permanent deficits in adult brain function and could predispose to later degenerative disorders (Cockburn, 1999).
Feeding synthetic diets to normal infants during this critical period of brain growth increases the risk of an imbalanced supply of essential nutrients, and in infants with metabolic disorders like PKU, the risk is increased. There is evidence that "well-managed" children and infants with PKU have deficiencies of long chain polyunsaturated docosahexaenoic acid (DHA) (Galli, Agostoni, Masconi, et al., 1991; Sanjunjo, Perteagudo, Soriano, et al., 1994; Cockburn, Clark, Caine, et al., 1996). Deficient intake of DHA in the first weeks of life alters the fatty acid composition of the infant neuronal membrane phospholipids and, later, the visual and intellectual functions (Farquharson, Jamieson, Abbasi, et al., 1995; Birch, Garfield, Hoffman, et al., 2000).
Further research on the provision of a balanced nutrient intake during the critical early months is required not only for the fatty acids but also for other nutrients essential for neuronal growth and development. Growth of the fetal brain involves increases of cell numbers as well as cell and cell process migration, so maintenance of metabolic homeostasis and optimal nutrition during pregnancy are essential. In women with PKU during pre-pregnancy and pregnancy, strict control of Phe and tyrosine values reduces the risk of intellectual impairment in the infant (Smith, Glossop, Beasley, 1990).
A low Phe diet cannot substitute for the fine-tuning of Phe turnover normally exerted by hepatic PAH. It is particularly difficult to maintain Phe control in subjects with severe enzyme deficiency, in whom even a minor illness or a fall in energy intake may lead to an increase in Phe concentrations. Aiming at "normal" concentrations runs the risk of inducing Phe and tyrosine deficiency, which several lines of evidence suggest is harmful to both growth and brain development. It is clear that better therapeutic strategies may be needed if we are substantially to improve outcomes in subjects with PKU. Given the difficulties in implementing treatment, the human and financial costs, and concerns about neurologic progress and fetal outcome, PKU is a potential candidate for gene therapy. But even if molecular genetics ultimately provides a better form of treatment, we still need to evaluate and, where possible, improve our present dietary management strategies.
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