Metabolic control during the neonatal period in phenylketonuria:associations with childhood IQ

Background In phenylketonuria, treatment and subsequent lowering of phenylalanine levels usually occur within the first month of life. This study investigated whether different indicators of metabolic control during the neonatal period were associated with IQ during late childhood/early adolescence. Methods Overall phenylalanine concentration during the first month of life (total "area under the curve"), proportion of phenylalanine concentrations above upper target level (360 mu mol/L) and proportion below lower target level (120 mu mol/L) during this period, diagnostic phenylalanine levels, number of days until phenylalanine levels were 360 mu mol/L during the first month of life negatively correlated with IQ in late childhood/early adolescence. Separately, phenylalanine concentrations during different periods within the first month of life (0-10 days, 11-20 days, 21-30 days) were negatively correlated with later IQ as well, but correlation strengths did not differ significantly. No further significant associations were found. Conclusions In phenylketonuria, achievement of target-range phenylalanine levels during the neonatal period is important for cognition later in life, also when compared to other indicators of metabolic control. Impact In phenylketonuria, it remains unclear during which age periods or developmental stages metabolic control is most important for later cognitive outcomes. Phenylalanine levels during the neonatal period were clearly and negatively related to later IQ, whereas no significant associations were observed for other indices of metabolic control. This emphasizes the relative importance of this period for cognitive development in phenylketonuria. No further distinctions were observed in strength of associations with later IQ between different indicators of metabolic control during the neonatal period. Thus, achievement of good metabolic control within 1 month after birth appears "safe" with respect to later cognitive outcomes

Leitlinienerstellung bei fetalen Alkoholspektrumstörungen

Das Ziel der vorliegenden Arbeit ist es, Leitlinienprozesse der FASD-Diagnostik in einen historischen Kontext zu setzen und Limitierungen sowie Möglichkeiten der Optimierung vorzustellen. Verantwortlich für die Vielzahl an Diagnosesystemen sind viele variable Parameter, bestehende offene Fragestellungen sowie insgesamt die Komplexität der FASD. Bis heute liegt der Fokus der Diagnostik wesentlich auf den äußerlich sichtbaren Veränderungen, anstatt auf den ZNS-Kriterien, obwohl diese die größere Alltagsrelevanz haben. Zur Optimierung der Diagnostik sollte zukünftig der Fokus vermehrt auf die ZNS-Veränderungen gerichtet werden. Hilfreich hierfür ist die Forschung an spezifischen neuropsychologischen Profilen, an zuverlässigen Nachweismarkern für eine intrauterine Alkoholexposition und ein größeres Verständnis im Bereich der Kausalzusammenhänge zwischen einer solchen Alkoholexposition und möglichen Veränderungen. Insgesamt ist eine Einigung auf international allgemeingültige Diagnosekriterien anzustreben

Kinetics of phenylalanine transport at the human blood-brain barrier investiagted in vivo

77

Brain imaging and proton magnetic resonance spectroscopy in patients with phenylketonuria.

Magnetic resonance imaging studies in patients with phenylketonuria (PKU) revealed white matter alterations that correlated to most recent blood phenylalanine (Phe) concentrations as well as to brain Phe concentrations measured by magnetic resonance spectroscopy. The clinical significance of these changes is unknown. Magnetic resonance imaging data thus have no impact on therapeutic recommendations for adolescents and adults with PKU. Kinetic investigations of patients by magnetic resonance spectroscopy showed differences in brain Phe concentrations despite similar blood Phe levels. These were influenced by interindividual variations of blood-brain barrier Phe transport constants and by variations of the individual brain Phe consumption rate. Blood-brain barrier Phe transport characteristics as well as brain Phe consumption rates thus seem to be causative factors for the individual outcome in PKU

Tackling frontal lobe-related functions in PKU through functional brain imaging: a Stroop task in adult patients.

BACKGROUND: Profound mental retardation in phenylketonuria (PKU) can be prevented by a low phenylalanine (Phe) diet. However, even patients treated early have inconsistently shown deficits in several frontal lobe-related neuropsychological tasks such as the widely accepted Stroop task. The goal of this study was to investigate whether adult patients exhibit altered brain activation in Stroop-related locations in comparison to healthy controls and if an acute increase in blood Phe levels in patients has an effect on activation patterns. METHODS: Seventeen male, early-treated patients with classic PKU (mean ± SD age: 31.0 ± 5.2 years) and 15 male healthy controls (32.1 ± 6.4 years) were compared using a color-word matching Stroop task in a functional magnetic resonance imaging (fMRI) study at 3T. Participants were scanned twice, and an oral Phe load (100 mg/kg body weight) was administered to patients prior to one of the fMRI sessions (placebo-controlled). Activity in brain regions that are known to be involved in Stroop tasks was assessed. RESULTS: PKU patients exhibited poorer accuracy in incongruent trials. Reaction times were not significantly different. There were no consistent differences in BOLD activations in Stroop-associated brain regions. The oral Phe administration had no significant effect on brain activity. CONCLUSIONS: Neither a generally slower task performance nor distinctively altered functioning of brain networks involved in a task representing a subset of dopamine-dependent executive functions could be proven. Decreased accuracy and inconsistent findings in posterior areas necessitate further study of frontal-lobe functioning in PKU patients in larger study samples

Normal clinical outcome in untreated subjects with mild hyperphenylalaninemia.

ABSTRACT There is international consensus that patients with phenylalanine (Phe) levels 600 microM do. Clinical outcome of patients showing Phe levels between 360 and 600 microM in serum on a free nutrition has so far only been assessed in a small number of cases. Therefore, different recommendations exist for patients with mild hyperphenylalaninemia. We investigated in a nationwide study 31 adolescent and adult patients who persistently displayed serum Phe levels between 360 and 600 microM on a normal nutrition with a corresponding genotype. Because of limited accuracy of measurements, Phe levels should be looked on as an approximation, but not as an absolute limit in every instance. In addition to serum Phe levels, the assessment program consisted of comprehensive psychological testing, magnetic resonance imaging of the head, (1)H magnetic resonance spectroscopy, and genotyping. We found a normal intellectual (intelligence quotient, 103 +/- 15; range, 79-138) and educational (school performance and job career) outcome in these subjects as compared with healthy control subjects (intelligence quotient, 104 +/- 11; range, 80-135). Magnetic resonance imaging revealed no changes of cerebral white matter in any patient, and (1)H magnetic resonance spectroscopy revealed brain Phe levels below the limit of detection (<200 microM). In the absence of any demonstrable effect, dietary treatment is unlikely to be of value in patients with mild hyperphenylalaninemia and serum Phe levels <600 microM on a free nutrition, and should no longer be recommended. Because of a possible late-onset phenylketonuria, Phe levels of untreated patients should be monitored carefully at least during the first year of life. Nevertheless, problems of maternal phenylketonuria should still be taken into account