Untreated PKU Patients without Intellectual Disability: What Do They Teach Us?

Phenylketonuria (PKU) management is aimed at preventing neurocognitive and psychosocial dysfunction by keeping plasma phenylalanine concentrations within the recommended target range. It can be questioned, however, whether universal plasma phenylalanine target levels would result in optimal neurocognitive outcomes for all patients, as similar plasma phenylalanine concentrations do not seem to have the same consequences to the brain for each PKU individual. To better understand the inter-individual differences in brain vulnerability to high plasma phenylalanine concentrations, we aimed to identify untreated and/or late-diagnosed PKU patients with near-normal outcome, despite high plasma phenylalanine concentrations, who are still alive. In total, we identified 16 such cases. While intellectual functioning in these patients was relatively unaffected, they often did present other neurological, psychological, and behavioral problems. Thereby, these "unusual" PKU patients show that the classical symptomatology of untreated or late-treated PKU may have to be rewritten. Moreover, these cases show that a lack of intellectual dysfunction despite high plasma phenylalanine concentrations does not necessarily imply that these high phenylalanine concentrations have not been toxic to the brain. Also, these cases may suggest that different mechanisms are involved in PKU pathophysiology, of which the relative importance seems to differ between patients and possibly also with increasing age. Further research should aim to better distinguish PKU patients with respect to their cerebral effects to high plasma phenylalanine concentrations.

Finding the fertile woman with phenylketonuria.

This review highlights two groups of women with phenylketonuria (PKU) who are at risk of producing offspring with maternal phenylketonuria (MPKU) embryopathy: (I) those not yet diagnosed; (II) those lost to follow-up. The world literature is reviewed, including that published from the International MPKU Collaborative Study (MPKUCS) and evidence is presented to support our hypothesis that at least 10% of subjects with untreated "classical PKU" will have relatively normal intellectual function and that a significantly higher percentage of the less severe "variants" (who make up approximately 50% of the total) will have IQ's measured within the normal range. The offspring of the females with these PKU variants, however, are not as fortunate-most suffering profound damage in-utero if the pregnant woman is not treated. However, the offspring of the mildest variant (untreated) "non-PKU mild hyperphenylalaninemia (MHP)" - blood phenylalanine 200-600 micromol/L - appear to be unaffected. This latter variant makes up 10-15% of the total. Many of these women, born before neonatal screening began in the jurisdiction of their birth, are unaware of their disease. Others, whose diet was discontinued in childhood, may not remember why they were on special diets. Our literature review has revealed reports, since 1990, of 60 women with previously undiagnosed PKU, most with relatively normal intellectual function, who produced 119 offspring, virtually all profoundly damaged. It is pointed out that the recent trend, in industrialized countries, of delayed child-bearing may be a factor. Reports are presented from various jurisdictions showing that up to 10% of known women with PKU in the reproductive age group have been lost to follow-up. "Selective Prenatal Screening or Case-Finding" for fertile women with PKU is recommended and a template is presented.

Can untreated PKU patients escape from intellectual disability? A systematic review.

BACKGROUND: Phenylketonuria (PKU) is often considered as the classical example of a genetic disorder in which severe symptoms can nowadays successfully be prevented by early diagnosis and treatment. In contrast, untreated or late-treated PKU is known to result in severe intellectual disability, seizures, and behavioral disturbances. Rarely, however, untreated or late-diagnosed PKU patients with high plasma phenylalanine concentrations have been reported to escape from intellectual disability. The present study aimed to review published cases of such PKU patients. METHODS: To this purpose, we conducted a literature search in PubMed and EMBASE up to 8th of September 2017 to identify cases with 1) PKU diagnosis and start of treatment after 7 years of age; 2) untreated plasma phenylalanine concentrations ≥1200 µmol/l; and 3) IQ ≥80. Literature search, checking reference lists, selection of articles, and extraction of data were performed by two independent researchers. RESULTS: In total, we identified 59 published cases of patients with late-diagnosed PKU and unexpected favorable outcome who met the inclusion criteria. Although all investigated patients had intellectual functioning within the normal range, at least 19 showed other neurological, psychological, and/or behavioral symptoms. CONCLUSIONS: Based on the present findings, the classical symptomatology of untreated or late-treated PKU may need to be rewritten, not only in the sense that intellectual dysfunction is not obligatory, but also in the sense that intellectual functioning does not (re)present the full picture of brain damage due to high plasma phenylalanine concentrations. Further identification of such patients and additional analyses are necessary to better understand these differences between PKU patients.

Newborn screening in Canada - Are we out of step?

OBJECTIVES: To review the status of universal newborn screening programs in Canada. METHODS: A brief questionnaire (seven questions) was circulated to one key individual in each province (n=10) and territory (n=3). These individuals were usually physicians or clinical biochemists closely involved in the diagnosis and treatment of genetic metabolic diseases. RESULTS: Universal newborn screening is under provincial jurisdiction. The number of diseases screened for varies and ranges from three to 28. Nine provinces/territories have a central computerized system for tracking initially positive cases. Only five provinces/territories have adequate personnel and resources for follow-up and treatment. Treatment costs are only partially covered in most jurisdictions. Only five provinces/territories have formal advisory committees with official mandates. Expensive, restricted access treatment products for adults with inherited metabolic diseases are only fully available in six provinces/territories. There is very limited access to these products in an additional four provinces/territories. To date, specific informed consent for newborn screening is not required in any province or territory. CONCLUSIONS: Canada is far behind the rest of the developed (and some 'emerging') countries of the world in the field of universal newborn screening. New strategies for advocating expanded screening, follow-up and (long-term) payment of treatment costs on behalf of the potentially affected infants and their families must be devised, and such initiatives should include participation from the new Public Health Agency of Canada.

Impact of the phenylalanine hydroxylase gene on maternal phenylketonuria outcome.

OBJECTIVE: The aim of the present study was to examine to what extent maternal and offspring phenylalanine hydroxylase (PAH) genotypes in conjunction with maternal IQ and dietary control during pregnancy are related to cognitive development in offspring of women with phenylketonuria (PKU). METHODS: PAH gene mutations were determined in 196 maternal PKU subjects and their offspring. The women were grouped according to PAH genotype, which predicts the metabolic phenotype (severe PKU, mild PKU, and mild hyperphenylalaninemia [MHP]). IQ was determined in both the mothers (Wechsler Adult Intelligence Scale-Revised at >18 years) and their children (Wechsler Intelligence Scale for Children-Revised at > or = 6-7 years of age). RESULTS: According to PAH genotypes, 62% of the women exhibited severe PKU, 19% exhibited mild PKU, and 19% exhibited MHP. Maternal IQ increased, and the assigned phenylalanine (Phe) levels decreased with decreasing severity of PAH genotype. In offspring of mild maternal PKU, multiple regression analysis showed offspring IQ to be significantly related to maternal IQ but not to Phe exposure during pregnancy, which was <750 micromol/L in all cases of mild PKU. In offspring of mothers with severe PKU and average Phe exposure during pregnancy of 360 to 750 micromol/L, multiple regression analysis revealed both maternal IQ and Phe exposure to be significant predictors of offspring IQ. When average Phe exposure was <360 micromol/L, cognitive development was normal (mean IQ: 105), whereas an average Phe exposure of >750 micromol/L severely depressed offspring IQ (mean IQ: 56) in this group regardless of maternal IQ. It could not be documented that the offspring PAH genotype affects cognitive development. CONCLUSION: Female individuals with severe PKU should be offered a diet for a lifetime. If good metabolic control is established, then women with PKU will have children with IQ scores that are not influenced by their disease.

Pregnancy experiences in the woman with mild hyperphenylalaninemia.

OBJECTIVE: A major issue in maternal phenylketonuria (MPKU) has been whether maternal non-PKU mild hyperphenylalaninemia (MHP) is teratogenic. Such untreated pregnancies and their outcomes are presented on this report. METHODS: Enrolled pregnancies in which the untreated prepregnancy assigned phenylalanine level (APL) was no more than 600 micro mol/L were included in the Maternal PKU Collaborative Study and were followed according to protocol. RESULTS: Forty-eight enrolled women with non-PKU MHP had mean APL 408 +/- 114 micromol/L. They had a total of 58 pregnancies that resulted in live births. Fifty were untreated. Maternal phenylalanine (Phe) levels in the untreated pregnancies decreased during pregnancy for average Phe exposure of 270 +/- 84 micromol/L, virtually identical to the level of 269 +/- 136 micromol/L in the 8 treated pregnancies. Birth measurements in the 50 offspring from untreated pregnancies were within normal limits with z scores of -0.25 for weight, 0.28 for length, and -0.63 for head circumference, although birth head circumference was negatively correlated with maternal APL (r = -0.30). Only 1 offspring had congenital heart disease. Offspring IQ was 102 +/- 15 compared with 96 +/- 14 in the mothers with untreated pregnancies and with 109 +/- 21 in control offspring. CONCLUSION: Maternal non-PKU MHP no more than 600 micromol/L does not require dietary therapy. The naturally lower Phe level during pregnancy seems to protect against teratogenesis.