Andrea Poretti1,2, Joseph Snow3, Angela C Summers3, Aylin Tekes1, Thierry A G M Huisman1, Nafi Aygun4, Kathryn A Carson5,6, Dan Doherty7,8, Melissa A Parisi9, Camilo Toro10, Deniz Yildirimli11, Meghana Vemulapalli12, Jim C Mullikin12, Andrew R Cullinane11,13, Thierry Vilboux11,14, William A Gahl10,11,15, Meral Gunay-Aygun11,15,16. 1. Section of Pediatric Neuroradiology, Division of Pediatric Radiology, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 2. Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland, USA. 3. Intramural Research Program, Office of the Clinical Director, National Institute of Mental Health, National Institutes of Health (NIH), Bethesda, Maryland, USA. 4. Division of Neuroradiology, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 5. Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA. 6. Division of General Internal Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 7. Department of Pediatrics, University of Washington, Seattle, Washington, USA. 8. Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA. 9. Intellectual and Developmental Disabilities Branch, National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA. 10. NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Maryland, USA. 11. Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA. 12. NIH Intramural Sequencing Center, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA. 13. Department of Anatomy, Howard University College of Medicine, Washington District of Columbia, USA. 14. Inova Translational Medicine Institute, Falls Church, Virginia, USA. 15. Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA. 16. Department of Pediatrics and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Abstract
BACKGROUND: Joubert syndrome is a clinically and genetically heterogeneous ciliopathy. Neuroimaging findings have not been systematically evaluated in a large cohort of patients with Joubert syndrome in correlation with molecular genetic cause and cognitive function. METHODS: Brain MRI of 110 patients with Joubert syndrome was included in this study. A comprehensive evaluation of brain MRI studies for infratentorial and supratentorial morphological abnormalities was performed. Genetic cause was identified by whole-exome sequencing, and cognitive functions were assessed with age-appropriate neurocognitive tests in a subset of patients. RESULTS: The cerebellar hemispheres were enlarged in 18% of the patients, mimicking macrocerebellum. The posterior fossa was enlarged in 42% of the patients, resembling Dandy-Walker malformation. Abnormalities of the brainstem, such as protuberance at the ventral contour of the midbrain, were present in 66% of the patients. Abnormalities of the supratentorial brain were present in approximately one-third of the patients, most commonly malrotation of the hippocampi. Mild ventriculomegaly, which typically did not require shunting, was present in 23% of the patients. No correlation between neuroimaging findings and molecular genetic cause was apparent. A novel predictor of outcome was identified; the more severe the degree of vermis hypoplasia, the worse the neurodevelopmental outcome was. CONCLUSIONS: The spectrum of neuroimaging findings in Joubert syndrome is wide. Neuroimaging does not predict the genetic cause, but may predict the neurodevelopmental outcome. A high degree of vermis hypoplasia correlates with worse neurodevelopmental outcome. This finding is important for prognostic counselling in Joubert syndrome. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
BACKGROUND:Joubert syndrome is a clinically and genetically heterogeneous ciliopathy. Neuroimaging findings have not been systematically evaluated in a large cohort of patients with Joubert syndrome in correlation with molecular genetic cause and cognitive function. METHODS: Brain MRI of 110 patients with Joubert syndrome was included in this study. A comprehensive evaluation of brain MRI studies for infratentorial and supratentorial morphological abnormalities was performed. Genetic cause was identified by whole-exome sequencing, and cognitive functions were assessed with age-appropriate neurocognitive tests in a subset of patients. RESULTS: The cerebellar hemispheres were enlarged in 18% of the patients, mimicking macrocerebellum. The posterior fossa was enlarged in 42% of the patients, resembling Dandy-Walker malformation. Abnormalities of the brainstem, such as protuberance at the ventral contour of the midbrain, were present in 66% of the patients. Abnormalities of the supratentorial brain were present in approximately one-third of the patients, most commonly malrotation of the hippocampi. Mild ventriculomegaly, which typically did not require shunting, was present in 23% of the patients. No correlation between neuroimaging findings and molecular genetic cause was apparent. A novel predictor of outcome was identified; the more severe the degree of vermis hypoplasia, the worse the neurodevelopmental outcome was. CONCLUSIONS: The spectrum of neuroimaging findings in Joubert syndrome is wide. Neuroimaging does not predict the genetic cause, but may predict the neurodevelopmental outcome. A high degree of vermis hypoplasia correlates with worse neurodevelopmental outcome. This finding is important for prognostic counselling in Joubert syndrome. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
Entities:
Keywords:
Cerebellar malformation; Ciliopathy; Cognition; Joubert syndrome; Magnetic resonance imaging
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