Maternal Phenylketonuria: Long-term Outcomes in Offspring and Post-pregnancy Maternal Characteristics

Abstract

Maternal phenylketonuria (MPKU) is a well-recognized complication of PKU and one of the most potent teratogenic syndromes of pregnancy. Virtually all offspring from untreated pregnancies in women with classic PKU have intellectual disabilities and microcephaly. Congenital heart disease and intrauterine growth retardation occur many times more often than expected in the general population. Control of maternal blood phenylalanine during pregnancy prevents most if not all of these complications. Previous studies demonstrated the benefits of treatment in terms of birth parameters and early development. In this study, physical examinations, a medical history, and neuropsychological evaluation were obtained in 47 children from 24 mothers with PKU who received treatment during pregnancy. Mothers were interviewed and administered an abbreviated IQ test. Associations between maternal factors and offspring outcomes were also analyzed.The 21 male and 26 female offspring ranged in age from 1 month to 26 years with 21 (62%) over 6 years. Results indicated mean intercanthal distances above the 70th percentile. Microcephaly was present in 19% of offspring, with head circumference below the third percentile. None of the offspring had cardiac anomalies. Mean offspring IQ was 94 ± 19, with 12% performing in the range of intellectual disability (IQ < 70). Among children >5 years of age, 25% had learning disabilities, 31% had attention deficit hyperactivity disorder (ADHD), 22% were on ADHD medication, and 34% had a diagnosis of anxiety and/or depression. Among the 24 mothers, 12 reported following the diet for PKU. Only one woman on diet had a blood phenylalanine concentration <360 μmol/L (recommended range) and the majority had indications of poor nutritional status. Mean maternal Full Scale IQ was 94 ± 16 (range = 61-117), with 25% performing in the borderline intellectual range (IQ < 85). Verbal IQ was significantly lower than Performance IQ (p = 0.01, CI 2.7, 16.1). On the self-report Beck Depression Inventory, Second Edition, 25% received scores indicating mild to moderate depression, and on the Beck Anxiety Inventory, 46% reported mild to moderate anxiety. Offspring IQ correlated with maternal metabolic control during pregnancy (r = 0.51), maternal IQ (r = -0.62), and socioeconomic position (r = -0.48). Offspring with ADHD, learning disabilities, or emotional disturbances were more likely to have mothers with anxiety and/or depression. To ensure optimal offspring outcomes, healthcare providers need to assess maternal nutrition, blood phenylalanine concentrations, cognitive abilities, and socioeconomic position. Interventions can then be initiated that reduce psychosocial stressors and enhance adherence to diet and positive parenting, which in turn can lead to better cognitive functioning, behavior, and emotional well-being in their children.

Ten years of specialized adult care for phenylketonuria – a single-centre experience

“…Importantly, these documented cases of maternal PKU syndrome might not be representative of the entire scope of maternal PKU syndrome even in our cohort. Since clinically normal infants from PKU mothers are not routinely followed up so far, the incidence of mild forms may be underestimated [ 27 ].…”

Inhibiting neutral amino acid transport for the treatment of phenylketonuria

“…In addition, even stricter control of Phe intake is of crucial importance for women who become pregnant, since elevated Phe levels are highly teratogenic to the developing fetus (11). This regimen is very difficult, and, consequently, the frequency of newborns with neurocognitive defects remains unacceptably high (12). Therefore, there is a significant unmet medical need for therapies that can at least partially restore Phe homeostasis and bring free Phe toward more normal levels.…”

Amino acid disorders

“…During pregnancy, females with PKU should maintain phenylalanine levels <360 µmol/L (6 mg/dL) since higher levels are associated with teratogenic effects such as microcephaly, congenital heart defects, IUGR, intellectual disability and other poor outcomes (11).…”