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.
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 been ...