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Hyperphenylalaninemias are an important group of metabolic disorders that present mainly as chronic encephalopathy. Severe hyperphenylalaninemia leading to phenylketonuria (PKU) has a very distinct role in the field of inherited metabolic disorders: PKU is the first genetic disease that could be treated exclusively by dietary manipulation and that could be entirely prevented by universal newborn screening and presymptomatic dietary intervention. This has had a huge impact on pediatric medicine, on the evolution of neonatal mass screening, and on the concept of gene-environment interaction. Genetic defects associated with hyperphenylalaninemia can now be regarded as a strong risk factor for neurodisability, but their outcome is more determined by the degree of metabolic control than by genetic variability.

Clinical Presentation

There is a continuous clinical spectrum of severity that ranges from malformation and mental retardation to asymptomatic mild hyperphenylalaninemia. Symptoms depend on the extent and ontogenetic timing of an organism’s exposure to elevated phenylalanine concentrations. The phenylalanine pool is a function of dietary phenylalanine intake and residual capacity for catabolism.

Intrauterine exposure of an unborn child to elevated phenylalanine concentrations due to maternal hyperphenylalaninemia can disrupt embryo-fetal development. This syndrome, called maternal phenylketonuria (mPKU), has been consistently observed with maternal hyperphenylalaninemia above 20 mg/dL (1200 μmol/L) and includes intrauterine dystrophy; facial dysmorphism resembling fetal alcohol syndrome; microcephaly and mental retardation; and malformations, especially of the heart and great vessels.1,2 The risk for mPKU increases when maternal plasma phenylalanine concentrations rise above 10 mg/dL (600 μmol/L). The relatively low threshold for embryo-fetal toxicity can be explained by an increased vulnerability of the unborn child and an at least one-and-a-half-fold materno-fetal transplacental concentrative gradient.3

In contrast, children who suffer from severe postnatal hyperphenylalaninemia do not show any symptoms at birth: fetal phenylalanine accumulation is effectively prevented by transplacental clearance. Affected children may become lethargic or appear irritable and have feeding difficulties during the first weeks of life, but this does not usually prompt evaluation and diagnosis. In early infancy, they can develop a peculiar mousy smell due to the excretion of phenylacetic acid, and approximately one third will develop an eczematoid rash or infantile spasms.4,5 A clinical diagnosis of phenylketonuria (PKU) is usually only made in the second half of the first year of life or later, after seizures or delayed psychomotor development lead to further biochemical investigation. At this time, affected infants appear less dark pigmented than their unaffected siblings and present with microcephaly due to decreased brain growth, which is reflected by cortical atrophy on brain imaging. They majority have behavioral disturbances such as restlessness, anxiety, aggression, repetitive behavior, and sleep disturbance.

Approximately 90% of individuals with untreated PKU will have severe mental disability, with intelligence quotients (IQ) under 30 on psychometric assessment.6 Up to 10% of untreated individuals with severe hyperphenylalaninemia escape the phenylketonuria phenotype. It has been hypothesized that their brain may have ...

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