Dynamic changes of striatal and extrastriatal abnormalities in glutaric aciduria type I

Brain. 2009 Jul;132(Pt 7):1764-82. doi: 10.1093/brain/awp112. Epub 2009 May 11.


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.

Publication types

  • Case Reports
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Adolescent
  • Adult
  • Age Factors
  • Aged
  • Amino Acid Metabolism, Inborn Errors / diagnosis
  • Amino Acid Metabolism, Inborn Errors / metabolism
  • Amino Acid Metabolism, Inborn Errors / pathology*
  • Atrophy
  • Basal Ganglia / pathology
  • Brain / pathology*
  • Brain Diseases, Metabolic, Inborn / diagnosis
  • Brain Diseases, Metabolic, Inborn / metabolism
  • Brain Diseases, Metabolic, Inborn / pathology*
  • Brain Mapping / methods
  • Cerebellum / pathology
  • Child
  • Child Development
  • Child, Preschool
  • Corpus Striatum / pathology
  • Disease Progression
  • Follow-Up Studies
  • Glutaryl-CoA Dehydrogenase / deficiency*
  • Humans
  • Infant
  • Infant, Newborn
  • Intellectual Disability / pathology
  • Magnetic Resonance Imaging
  • Middle Aged
  • Movement Disorders / etiology
  • Movement Disorders / pathology
  • Retrospective Studies
  • Young Adult


  • Glutaryl-CoA Dehydrogenase