Abstract
In glutaric aciduria type I, an autosomal recessive
disease of mitochondrial lysine, hydroxylysine and
tryptophan catabolism, striatal lesions are
characteristically induced by acute encephalopathic crises
during a finite period of brain development (age 3-36
months). The frequency of striatal injury is significantly
less in patients diagnosed as asymptomatic newborns by
newborn screening. Most previous studies have focused on
the onset and mechanism of striatal injury, whereas little
is known about neuroradiological abnormalities in
pre-symptomatically diagnosed patients and about dynamic
changes of extrastriatal abnormalities. Thus, the major aim
of the present retrospective study was to improve our
understanding of striatal and extrastriatal abnormalities
in affected individuals including those diagnosed by
newborn screening. To this end, we systematically analysed
magnetic resonance imagings (MRIs) in 38 patients with
glutaric aciduria type I diagnosed before or after the
manifestation of neurological symptoms. To identify brain
regions that are susceptible to cerebral injury during
acute encephalopathic crises, we compared the frequency of
magnetic resonance abnormalities in patients with and
without such crises. Major specific changes after
encephalopathic crises were found in the putamen (P <
0.001), nucleus caudatus (P < 0.001), globus pallidus (P =
0.012) and ventricles (P = 0.001). Analysis of empirical
cumulative distribution frequencies, however, demonstrated
that isolated pallidal abnormalities did not significantly
differ over time in both groups (P = 0.544) suggesting that
isolated pallidal abnormalities are not induced by acute
crises--in contrast to striatal abnormalities. The
manifestation of motor disability was associated with
signal abnormalities in putamen, caudate, pallidum and
ventricles. In addition, we found a large number of
extrastriatal abnormalities in patients with and without
preceding encephalophatic crises. These abnormalities
include widening of anterior temporal and sylvian CSF
spaces, pseudocysts, signal changes of substantia nigra,
nucleus dentatus, thalamus, tractus tegmentalis centralis
and supratentorial white matter as well as signs of delayed
maturation (myelination and gyral pattern). In contrast to
the striatum, extrastriatal abnormalities were variable and
could regress or even normalize with time. This includes
widening of sylvian fissures, delayed maturation, pallidal
signal changes and pseudocysts. Based on these results, we
hypothesize that neuroradiological abnormalities and
neurological symptoms in glutaric aciduria type I can be
explained by overlaying episodes of cerebral alterations
including maturational delay of the brain in utero, acute
striatal injury during a vulnerable period in infancy and
chronic progressive changes that may continue lifelong.
This may have widespread consequences for the
pathophysiological understanding of this disease, long-term
outcomes and therapeutic considerations.
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