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Unravelling the complex MRI pattern in glutaric aciduria type I using statistical models—a cohort study in 180 patients

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Background

Glutaric aciduria type I (GA-I) is a cerebral organic aciduria caused by inherited deficiency of glutaryl-CoA dehydrogenase and is characterized biochemically by an accumulation of putatively neurotoxic dicarboxylic metabolites. The majority of untreated patients develops a complex movement disorder with predominant dystonia during age 3–36 months. Magnetic resonance imaging (MRI) studies have demonstrated striatal and extrastriatal abnormalities.

Aims/methods

The major aim of this study was to elucidate the complex neuroradiological pattern of patients with GA-I and to associate the MRI findings with the severity of predominant neurological symptoms. In 180 patients, detailed information about the neurological presentation and brain region-specific MRI abnormalities were obtained via a standardized questionnaire.

Results

Patients with a movement disorder had more often MRI abnormalities in putamen, caudate, cortex, ventricles and external CSF spaces than patients without or with minor neurological symptoms. Putaminal MRI changes and strongly dilated ventricles were identified as the most reliable predictors of a movement disorder. In contrast, abnormalities in globus pallidus were not clearly associated with a movement disorder. Caudate and putamen as well as cortex, ventricles and external CSF spaces clearly collocalized on a two-dimensional map demonstrating statistical similarity and suggesting the same underlying pathomechanism.

Conclusions

This study demonstrates that complex statistical methods are useful to decipher the age-dependent and region-specific MRI patterns of rare neurometabolic diseases and that these methods are helpful to elucidate the clinical relevance of specific MRI findings.

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Abbreviations

FLAIR:

Fluid attenuated inversion recovery

GA-I:

Glutaric aciduria type I (OMIM #231670)

MD:

Movement disorder

MDS:

Multi-dimensional scaling

MRI:

Magnetic resonance imaging

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Acknowledgments

We are indebted to the patients and their families for their participation and trust. We thank the patient advocacy group “Glutarazidurie e.V.” (www.glutarazidurie.de) for excellent collaboration.

This study was supported by a grant from the “Kindness for Kids” Foundation, Munich, Germany to S. K. This is a private foundation focusing on stimulating research for children with rare diseases.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. SFG: Faculty of Applied Psychology, SRH University of Applied Sciences, Heidelberg, Germany

    Sven F. Garbade

  2. Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Children’s Hospital Heidelberg, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany

    Sven F. Garbade, Peter Burgard & Stefan Kölker

  3. Department of Biochemistry and Medical Genetics, Winnipeg Children’s Hospital, University of Manitoba, Winnipeg, MB, Canada

    Cheryl R. Greenberg

  4. Department of Nutrition and Metabolism, Children’s Hospital, Istanbul Medical Faculty, Istanbul, Turkey

    Mübeccel Demirkol & Gülden Gökçay

  5. Division of Inborn Errors of Metabolism, Department of Biochemistry and Molecular Genetics, Hospital Clinic and CIBERER, Barcelona, Spain

    Antonia Ribes

  6. Neuropediatrics Service, Hospital Sant Joan de Deu, Barcelona, Spain

    Jaume Campistol

  7. University Children’s Hospital, Padova, Italy

    Alberto B. Burlina

Authors
  1. Sven F. Garbade
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  2. Cheryl R. Greenberg
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  3. Mübeccel Demirkol
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  4. Gülden Gökçay
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  5. Antonia Ribes
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  6. Jaume Campistol
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  7. Alberto B. Burlina
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  8. Peter Burgard
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  9. Stefan Kölker
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Corresponding author

Correspondence to Stefan Kölker.

Additional information

Communicated by: Nicole Wolf

Electronic supplementary material

Below is the link to the electronic supplementary material.

Suppl. Fig. 1

Histogram of age of the GA-I study cohort. (JPEG 101 kb)

Suppl. Fig. 2

Multidimensional scaling of neuroradiological items using the minimum-spanning tree in a group of patients older than three years. The stress was 9.06%. Collocalization of pathologic MRI changes in ventricles, external CSF spaces and cortex, as well as in caudate and putamen indicate similarities in the underlying mechanisms. Globus pallidus, a white-matter rich grey matter structure, is located between caudate/putamen and white matter indicating that pallidal MRI changes may reflect putatively reversible white matter pathology or irreversible basal ganglia damage. Results are almost identical to an analysis of the whole study group (see Fig. 3). (JPEG 110 kb)

Suppl. Figs. 3–7

Age-dependent frequency and severity of MRI changes in putamen (Suppl. Fig. 3), caudate (Suppl. Fig. 4), white matter (Suppl. Fig. 5), pallidum (Suppl. Fig. 6), and thalamus (Suppl. Fig. 7) was depicted as spinograms. Striatal MRI abnormalities reflect an age-dependent window of vulnerability of this brain region during the youngest age group, whereas the frequency and severity of pallidal MRI changes were similar in all age groups. MRI abnormalities in the white showed some increase in older compared to younger age groups. MRI abnormalities in other brain regions such as thalamus were only rarely detected. (JPEG 94 kb)

Suppl. Table 1

(DOCX 15 kb)

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Garbade, S.F., Greenberg, C.R., Demirkol, M. et al. Unravelling the complex MRI pattern in glutaric aciduria type I using statistical models—a cohort study in 180 patients. J Inherit Metab Dis 37, 763–773 (2014). https://doi.org/10.1007/s10545-014-9676-9

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  • DOI: https://doi.org/10.1007/s10545-014-9676-9

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