Maternal Phenylketonuria Collaborative Study (MPKUCS)—The 'outliers'

Abstract

Analysis of outcome data from 305 of the 414 offspring from the Maternal Phenylketonuria Collaborative Study (MPKUCS), plus 70 control offspring, revealed significant deficits in the IQ (intelligence quotient), as measured by the Wechsler Intelligence Scale for Children--Revised (WISC-R), when maternal metabolic control during pregnancy was delayed and/or inadequate. There were, however, 23 'outliers' (7.5% of the 305) in which the offspring's intellectual IQ was worse (n =10) or better (n =13) than expected. The aim of this study was to determine whether collection parameters were incomplete or whether these subjects were true biological variants influenced by other undetected factors or, perhaps, by modifier genes. Among the 10 offspring whose intellectual functioning was worse than expected, additional complications were uncovered that could explain the poor outcome. Four of the 13 offspring with higher than expected IQ had mothers with mild variants of PKU in which the insult to the fetus would not be expected to be as profound. For the other nine offspring whose intellectual performance was better than expected, there was no explanation, based on the parameters studied. We hypothesize that modifier genes will, at times, protect the fetus despite high maternal concentrations of phenylalanine. Not all offspring from the same (untreated) PKU mother may be similarly affected. Finding the source of these modifiers might effect the treatment of MPKU.

Phenylketonuria (PKU) – A Success Story

“…The concept of modifier genes has been explored for some time. In foetal alcohol syndrome (FAS), for example, certain modifier genes protect the foetus against ethanol toxicity (Hanley et al, 2004b).…”

Sindrome De Fenilquetonuria Materna, Un Nuevo Desafío Para Chile

“…El tratamiento es tan estricto como al inicio y requiere de un seguimiento multiprofesional que permita un resultado exitoso (14). Existen diferencias en cuanto al tratamiento en el periodo de recién nacido y en la PKUm (tabla 1 5.…”

What we know that could influence future treatment of phenylketonuria

“…As PAH is the principal determinant of phenylalanine (Phe) homeostasis in vivo (Donlon et al 2008), normal dietary Phe intake (nurture), in the presence of compromised activity, results in hyperphenylalaninaemia (HPA); this is the intermediate (metabolic) level of the variant phenotype. The discord between nature and nurture, if left untreated, can have a toxic effect (the distal-clinical phenotype), leading to impaired cognitive development and neurophysiological function in the patient, as well as affecting the next generation, where maternal PKU, a form of metabolic teratogenesis, can permanently harm the development of the fetus (Dent 1957;Hanley et al 2004;Lenke and Levy 1980;Scriver 1967).…”