- Güttler F (1984) Phenylketonuria: 50 years since Folling's discovery and still expanding our
clinical and biochemical knowledge. Acta Paediatrica Scandinavica 73:705-716.
- Levy HL, Lobbregt D, Barnes PD, Poussaint TY (1996) Maternal phenylketonuria: magnetic
resonance imaging of the brain in offspring. Journal of Pediatrics 128:770-775.
- Yakovlev PI and Lecours A-R (1967) The myelogenetic cycles of regional maturation of the
brain. In A. Minkowski (Ed.), Regional Development of the Brain in Early Life (pp. 3-70). Oxford:
Blackwell Scientific Publications.
- Moore JK, Perazzo LM, Braun A (1995). Time course of axonal myelination in the human
brainstem auditory pathway. Hearing Research 87:21-31, 91:208-209.
2 - Maternal PKU
A low-phenylalanine diet is the treatment for the
majority of children with PKU. It was thought that this
diet could be discontinued after five to six years, after
the blood-brain barrier was mature enough to prevent
abnormal metabolites from entering neurons.
However, it has been found that women with PKU must
go back to a low-phenylalanine diet during pregnancy
to prevent brain damage in the developing fetus [1, 2].
Levy et al. (1996) emphasized the difference
between postnatal and prenatal exposure to high
levels of phenylalanine and its metabolites [2]. During
gestation abnormal metabolites generated by the
fetus are removed from the umbilical arteries and
excreted by the mother. After birth the process of
myelinization is affected leading to the hypoplasia of
myelin reported in many investigations of the brain in
PKU. In the infant with PKU full function is not
achieved in nerve tracts that normally mature after
birth and during the first two decades of life [3].
Hence PKU is primarily a postnatal disorder, and when
it leads to autism is of the disintegrative type. PKU
takes a progressive course with spasticity and
seizures developing during the first decade.
The effect of abnormal metabolites generated by a
mother with PKU on her developing child can on the
other hand be compared with prenatal exposure to
alcohol, cocaine, valproic acid, phenobarbital,
thalidomide, or any other teratogenic substance.
Levy et al. (1996) investigated MRI scans of five
children born to mothers with PKU who did not adhere
to a low-phenylalanine diet during pregnancy and
compared them with two brothers born to a mother
who did control her intake of phenylalanine during
pregnancy. The brain scans of these two brothers
appeared normal. Hypoplasia of the corpus callosum
was found in all of the children exposed to high levels
of phenylalanine during gestation. Thus, high levels
of phenylalanine and its abnormal metabolites had an
effect similar to that of prenatal exposure to alcohol, in
which hypoplasia of the corpus callosum is a frequent
finding.
Levy et al. (1996) cited evidence that maternal
rubella, maternal diabetes, and other metabolic
disorders as well as prenatal exposure to alcohol also
lead to abnormalities of the corpus callosum. They
cited studies showing that the corpus callosum
develops between 8 and 20 weeks of gestation [2].
The hypomyelination that occurs postnatally in PKU is
bilaterally symmetric and affects the nerve tracts that
develop and are myelinated during the first decade of
life. Yakovlev and Lecours (1967) found that the
auditory pathway is the earliest to be myelinated [3].
Moore et al. (1995) determined that myelination within
the auditory system takes place between 26 and 29
weeks of gestation [4]. Therefore, the auditory
system should become vulnerable at this stage of
development. Auditory nuclei like the inferior
colliculus remain vulnerable after birth because of
their high metabolic needs.
Other etiologic factors associated with autism can
all be detrimental in some circumstances to energy
metabolism in the auditory system, and the inferior
colliculus in particular. For the sake of learning which
brain systems are affected and how, these factors
should be investigated in experiments with laboratory
animals using the autoradiographic methods for blood
flow and deoxyglucose uptake in the brain. Enzymes
that produce neurotransmitters or membrane
receptors that respond to transmitter signals may be
the most important systems affected in the vulnerable
brain structures, without any signs of visible damage.
These need to be understood before effective and
safe pharmaceutical treatments can be devised or
tried.
- Güttler F (1984)
Phenylketonuria: 50 years
since Folling's discovery and
still expanding our clinical
and biochemical knowledge.
- Levy HL et al. (1996) Maternal
phenylketonuria: magnetic
resonance imaging of the
brain in offspring.
- Yakovlev PI & Lecours A-R
(1967) The myelogenetic
cycles of regional maturation
of the brain.
- Moore JK et al. (1995). Time
course of axonal myelination
in the human brainstem
auditory pathway.