In the following paper we explore the dilemma of treatment with phenylalanine-restricted diet in persons with phenylketonuria (PKU). There is still controversy, as can be found in most pediatric and internal medicine textbooks, as to when and if to stop the diet initiated at neonatal diagnosis. Some centers continue the diet until age 6 to 10 years, whereas others recommend treatment for life. In Israel the policy had been to discontinue diet at about 10 years.
Phenylketonuria was discovered in 1934, when a Norwegian mother brought her son and daughter, both of whom had mental retardation, to Professor Asbjorn Folling at the University of Oslo School of Medicine for a consultation (Guttler, 1984). In 1947, Jervis showed that the administration of phenylalanine to normal human patients without PKU led to a prompt rise in blood tyrosine, whereas no increase in blood tyrosine could be detected in patients with PKU, indicating both the normal pathway of phenylalanine metabolism and the metabolic error in PKU. Several years later this inborn error of the amino acid metabolism, caused by the deficiency of the liver enzyme phenylalanine hydroxylase (PAH), changed to become a preventable form of mental retardation when Bickel, Gerrard, and Hickmans (1954) published the results of dietary treatment. The work of Jervis and Bickel et al. was the incentive to later start the large field of investigations into the inborn errors of metabolism that became the basis for the understanding of a range of causes of mental retardation as well as the basis for studying the possibility for treatment and prevention.
In several further studies, researchers stressed the importance of diet for these patients, and a movement drive started in order to develop a diagnostic method to measure phenylalanine in the blood. Guthrie (1963) developed a bacterial “inhibition assay” that facilitated a sensitive, specific, inexpensive, and fast method for the determination of blood phenylalanine in large number of samples.
From 1964–1973 (Guttler, 1984), different types of PKU were found and worldwide neonatal screening started, resulting in early treatment and prevention of mental retardation. Whereas everyone can agree that treatment with phenylalanine (PHE) restricted diet must start as soon as possible (first 2 weeks of life), there is no agreement on when to stop or whether to even to continue a “diet for life.”
In Israel neonatal screening started in 1963, and the incidence of PKU was 1.04 per 10,000 live births (13 cases) in 1997. The PKU register at Chaim Sheba Medical Center has 250 cases registered, and 200 persons are followed regularly at the clinic.
The Division for the Mentally Retarded, Ministry of Labour and Social Affairs provided service in 1998 to 6,008 persons in 53 institutions/residential care facilities (government, private, and public, sized from 50 to 400 persons), and our recent survey in these institutions showed that there were 7 known persons with PKU.
In many countries the policy has been to keep children, found to have phenylketonuria at neonatal screening, on a PHE-restricted diet until their PHE level is no longer likely to affect brain development. Several investigators have found a deterioration in intellect once the diet is discontinued (Koch et al., 1996; Levy & Waisbren 1994; Potocnik & Widhalm, 1994), and many centers around the world are today recommending a “diet for life” (British Guidelines, 1993).
Koch et al. (1996) from Children's Hospital in Los Angeles followed a group of 43 persons, identified by neonatal screening, at an average age of 22 years. Nineteen had remained on dietary treatment (Group 1 treatment group) after being diagnosed at a mean age of 2.6 weeks, and 24 had discontinued the diet at an average age of 7.8 years (Group 2 untreated group). The individuals in the treatment group turned out substantially better on social and academic achievements. Their mean IQ was 104 (WAIS-R range = 74 to 123), 78% attended collage, 2 were married (1 had a child), none were on Social Security or welfare general relief, and none had been arrested. In the untreated group, the mean IQ of the individuals was 92 (range = 69 to 116), 28% attended college, 15 were employed, 5 were on welfare, 1 was mentally ill, 6 were married, and 5 were in relationships (they had a total of 9 children). A third group of 19 individuals from that center was diagnosed at an average age of 2.7 years, and at follow-up their mean IQ was 83 (range = 55 to 108), 10% attended college, 1 was married, and 3 were in relationships (and had a total of 10 children), 5 were on welfare, and 1 had been arrested for pedophilia. These findings, with the limitations of the small number studied, seem to support the conclusion that it is best to continue the diet into adulthood.
Positive effects have also been reported in late-diagnosed individuals with PKU (Holmgren, Blomquist, & Samuelson, 1980; Koch et al., 1999), resulting in marked progress in mental capacity. Providing a PHE-restricted diet, even to these individuals, can benefit not only the individual, but also society, because the diet prevents the need for residential care or makes residential care less burdensome for the caretakers.
Very few investigators have (Harper & Reid, 1987; ,Williams, 1998) have dealt with the PHE-restricted diet treatment of patients with PKU born before the introduction of neonatal screening and neonatal institution of the diet, in spite of an increased life expectancy of people with untreated phenylketonuria (Jancar, 1998) and the economic benefits to society (Brown & Guest, 1999).
In a recent study conducted in England, Fitzgerald et al. (2000) presented five case histories of providing PHE-restricted diet in previously untreated persons. Four out of the 5 individuals had considerable benefits in the areas of concentration, alertness, mood, irritability, and adaptive behavior.
We would, therefore, recommend a debate on this issue. We have now reviewed our policy in Israel for this population and recommend the diet for life. We have also embarked on a careful review of all known cases in order to treat these persons with diet and thereby increase their quality of life.
Authors:Joav Merrick, MD, DMSc, Professor, Medical Director, Division for the Mentally Retarded, Ministry of Labour and Social Affairs, Box 1260, Il-91012 Jerusalem, Israel (email@example.com). Shoshana Aspler, RN, Chief Nurse, Medical Clinic, Kfar Nachman, IL-43100 Raanana, Israel. Gerard Schwarz, MD, Medical Director, National PKU Clinic, Chaim Sheba Medical Center, Ministry of Health and Sackler School of Medicine, Tel Aviv University, IL-52621 Tel Hashomer, Israel.