By Véronique Abadie, M.D.
In France, screening for phenylketonuria (PKU) started in 1966. In 1978, the Association Française pour le Dépistage et la Prévention des Handicaps de l’Enfant (AFDPHE) began systematic and coordinated screening and management of patients with phenylalanine hydroxylase (PAH) deficits or hypothyroidism. The association later added congenital adrenal hyperplasia and sickle cell disease to the list. The AFDPHE pays the financial costs of screening and of diet products for patients with PKU, handles technical questions regarding screening, and keeps tabs on children with PKU by means of a yearly questionnaire sent to physicians. The AFDPHE has a branch in each of the country’s 20 administrative regions that is responsible for operation of a PKU screening laboratory.
Initially, neonatal screening was done by the Guthrie method. In 1996 we began using an enzymatic test (Quantase TM) for screening, along with fluorimetry, to uncover patients with phenylalanine (Phe) levels exceeding 2.5 mg/dl (150 µmol/L). The PAH deficit phenotype is defined by the Phe level found in patients after they have received 500 mg a day of Phe for 4 days, with a tolerance for Phe levels of between 2 and 5 mg/dl (120-300 µmol/L). In the Paris region, all screened children are genotyped.
The PKU screening program expanded over the years, and by 1979 the program covered all infants born in France. Over the past 20 years the incidence of PKU has been quite stable, at 1 case for every 17,124 living births (44 new cases per year). Since PKU screening started, 11 children have been detected with a false negative test (sensitivity 99.1 percent), 1.7 percent had a cofactors deficiency, and 17 percent a non-PKU hyperphenylalaninemia (HPA) (<10 mg/dl, or 600 µmol/L on a normal diet). The proportion of moderate phenotypes varies from one region to another, being higher in the south than in the north of France. A precise proportion of moderate phenotypes is not available in the national database because phenotypic definition has varied over time. The age at which infant patients with PKU are placed on a diet has regularly decreased during the last 25 years, reaching a median of 14 days in 1996.
PKU Management During the First Years
Only children on a normal diet with a spontaneous Phe level of more than 10 mg/l are treated in our group. In a group of 202 children, 19 percent had a moderate phenotype (10 to 20 mg/dl on a normal diet and Phe tolerance >350 mg/J). The objective is to reduce the Phe plasma level to between 2 and 5 mg/dl. Testing for Phe levels is done weekly during the first 2 years, then fortnightly to the age of 5, then monthly until dietary restrictions are relaxed. Visits with a doctor, a dietician, and a psychologist occur monthly during the first year, then on a variable schedule, depending on Phe levels and family cooperation. Three times a year is the average during the strict diet period. Intellectual development is tested at 3 years of age (DQ, Brunet-Lésine), 6 years (WPPSI), 10 and 14 years (WISC), and 18 years (WAIS). One sibling undergoes an IQ test between 10 and 14 years of age. A nutritional assessment is performed every 2 years.
Age at Which Diet is Relaxed
Up until 1990, the standard approach was to relax the strict diet of patients with PKU at the age of 6. Since then, however, the standard has risen. The trend now is to leave children with PKU on a strict diet until they reach the age of 10. This change was based on international practice, especially in the United Kingdom (Smith, Beasley, Ades, 1991) and Germany (Schmidt, Mahle, Michel, et al., 1987). It was also based on national data showing that patients with PKU in France entered primary school at the same age (6 years) as the general population but entered secondary school at a later age (if born before 1979), compared with both children in the general population and children with PKU born after 1979. Children with PKU who entered secondary school without delay had been placed on a restricted diet at an earlier age (23.5 vs. 28.5 days) and had a higher age of diet discontinuation (8 vs. 6 years) compared with children with PKU who entered secondary school a year or more later than their peers in the general population.
Views on dietary treatment of adolescents and adults with PKU lack a consensus, but the majority of French investigators continue to think that there are more benefits than disadvantages to diet relaxation after 10 years of age. Phe levels are maintained at 20 ± 2 mg/dl, respecting the RDA for protein intakes (1 g/kg/day for children from 10 to 18 years old, and 0.75 g/kg/day thereafter). This allows children with moderate PKU to have a normal diet and allows children with classical PKU to increase their natural protein intake in order to have a normal lunch at school, except for meat and fish. Hypoprotein products and amino acid substitutes are still taken by the majority of patients with classical PKU, depending on their Phe tolerance, age, protein requirements, and appetite.
Children with PKU are clinically investigated at least once a year, especially females, in part to provide them with warnings about the problems caused by maternal PKU. Phe levels are measured two to four times a year, and school performance, social behavior, neurological health, and IQ are watched so that a stricter diet can be reinstituted, if necessary.
Studies of the adverse effects of diet relaxation on IQ have failed to show any effect after the ages of 8 to 10 (Burgard, Bremer, Bührdel, et al., 1999). Moreover, in most studies arguing for prolongation of a restricted diet on the basis of IQ data, children who discontinue a strict diet early are also those who had the worst index of dietary control during the first years and those who had the lowest family IQ (Holtzman, Welcher, Mellits, 1975). In the Paris group, 31 children with classical PKU (who were treated for 5 years) had stable intellectual performance between 7 years of age and adulthood, either in mean or by pairs (IQ=102.6±16.2, 104.8±16 [WISC], and 101.8±14 [WAIS] at 7 to 8 years, 11 to 13 years, and 17 to 18 years, respectively).
The long-term effects of high Phe plasma levels are unknown. However, a comparison between French (relaxed diet) and German (strict diet) children showed that adverse effects of high Phe levels (20 mg) on neuropsychologic functions do not increase with time (Burgard, Rey, Rupp, et al., 1997). This study found lower reaction time in French children but decreasing differences with age between the two groups and no significant difference in reaction time in the adult groups. Similarly, an increase in the Phe level in children older than 10 years who were previously treated showed no midterm effects on neuropsychological tests, either after 3 months (Griffiths, Ward, Harvie, et al., 1998) or 3 years (Weglage, Pietsch, Denecke, et al., 1999). The educational and professional levels achieved by French adults with PKU who were treated for 8 years are similar to those of the general population and are consonant with their family socioeconomic levels (Farriaux, Dhondt, Paux, et al., 1997). An inquiry is in progress comparing the educational background, quality of social integration, and personal autonomy of adults with PKU whose diet was relaxed early with those of matched friends.
The French view regarding management of adolescents with PKU differs from other views, for two reasons. First, for the French, meals have great social value—thus, to be on a diet is felt as quite regrettable. Second, it is socially less easy in France than in the United States for people to accept those with handicaps. Our aim in PKU treatment is to reach the best balance between long-term protection of the intellectual abilities of patients and giving them the feeling that they can lead a normal life.
In France, the cost of one Guthrie test is 10 francs or US$2. Thus, it costs around 150,000 francs (US$30,000) to discover one infant with PKU, if we consider that screening uncovers 50 children out of 750,000 births per year. The annual cost of the PKU diet for one child from 10 to 14 years of age and from 15 to 21 years of age is 200,000 francs (US$40,000) and 250,000 francs (US$50,000), respectively. In other words, 10 additional years of treatment for one PKU child costs the same price as screening to find 15 children. Or, to put it another way, screening all of the country’s infants costs about the same as 10 more years of strict diet for fewer than four children with PKU.
In France, as in most developed countries, screening and management of children with PKU is a success. Ten years of close medical followup and strict diet allow satisfactory results. The long-term adverse effects of high Phe levels on cerebral functioning in adolescence and adulthood have to be evaluated more carefully and should be compared with the adverse nutritional and psychological effects of a prolonged strict diet. Our method of PKU treatment moderates the efficient but very constraining dietary treatment used in some other countries.
Other methods may be proposed in order to discover which adolescents with PKU are able to tolerate a higher-than-normal Phe plasma level. Measuring brain concentration of Phe may be a good tool for that purpose.
References
- Burgard P, Rey F, Rupp A, Abadie V, Rey J. Neuropsychologic functions of early treated patients with phenylketonuria, on and off diet: results of a cross-national and cross-sectional study. Pediatr Res 1997;41:368-74.
- Farriaux JP, Dhondt JL, Paux E, Debradander A. La dépèche (AFDPHE bulletin) 1997;24:1-6.
- Griffiths P, Ward N, Harvie A, Cockburn F. Neuropsychological outcome of experimental manipulation of phenylalanine intake in treated phenylketonuria. J Inherit Metab Dis1998;21:29-38.
- Holtzman NA, Welcher DW, Mellits ED. Termination of restricted diet in children with phenylketonuria: a randomized controlled study. New Engl J Med 1975;293:1121-4.
- Schmidt H, Mahle M, Michel U, Pietz J. Continuation vs discontinuation of low-phenylalanine diet in PKU adolescents. Eur J Pediatr 1987;146:A17-9.
- Smith I, Beasley MG, Ades AE. Effect on intelligence of relaxing the low phenylalanine diet in phenylketonuria. Arch Dis Child 1991;66:311-6.
- Weglage J, Pietsch M, Denecke J, Sprinz A, Feldmann R, Grenzebach M, et al. Regression of neuropsychological deficits in early-treated phenylketonurics during adolescence. J Inherit Metab Dis 1999;22:693-705.
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