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Original article
Joubert syndrome: neuroimaging findings in 110 patients in correlation with cognitive function and genetic cause
  1. Andrea Poretti1,2,
  2. Joseph Snow3,
  3. Angela C Summers3,
  4. Aylin Tekes1,
  5. Thierry A G M Huisman1,
  6. Nafi Aygun4,
  7. Kathryn A Carson5,6,
  8. Dan Doherty7,8,
  9. Melissa A Parisi9,
  10. Camilo Toro10,
  11. Deniz Yildirimli11,
  12. Meghana Vemulapalli12,
  13. Jim C Mullikin12,
  14. NISC Comparative Sequencing Program,
  15. Andrew R Cullinane11,13,
  16. Thierry Vilboux11,14,
  17. William A Gahl10,11,15,
  18. Meral Gunay-Aygun11,15,16
  1. 1Section 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. 2Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland, USA
  3. 3Intramural Research Program, Office of the Clinical Director, National Institute of Mental Health, National Institutes of Health (NIH), Bethesda, Maryland, USA
  4. 4Division of Neuroradiology, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  5. 5Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
  6. 6Division of General Internal Medicine, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  7. 7Department of Pediatrics, University of Washington, Seattle, Washington, USA
  8. 8Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA
  9. 9Intellectual and Developmental Disabilities Branch, National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA
  10. 10NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Maryland, USA
  11. 11Medical Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA
  12. 12NIH Intramural Sequencing Center, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA
  13. 13Department of Anatomy, Howard University College of Medicine, Washington District of Columbia, USA
  14. 14Inova Translational Medicine Institute, Falls Church, Virginia, USA
  15. 15Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA
  16. 16Department of Pediatrics and McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  1. Correspondence to Dr Andrea Poretti, Section of Pediatric Neuroradiology, Division of Pediatric Radiology, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins School of Medicine, Charlotte R. Bloomberg Children's Center, Sheikh Zayed Tower, Room 4174, 1800 Orleans Street, Baltimore, MD 21287-0842, USA; aporett1{at}jhmi.edu

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.

  • Joubert syndrome
  • Magnetic resonance imaging
  • Cerebellar malformation
  • Cognition
  • Ciliopathy

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Footnotes

  • Contributors AP and MG-A conceptualised and designed the study, interpreted the results of the statistical analysis. AP drafted the manuscript. MG-A is the principal investigator of the NIH research protocol under which the patients were evaluated, recruited the patients, performed clinical evaluations, analysed clinical, molecular and imaging data, established collaborations. AP, AT, TAGMH, NA and MG-A evaluated the MR images. ACS and JS performed neurocognitive testing and interpretation of the neurocognitive data. KAC performed statistical analysis. CT performed neurological examinations and helped conceptualise the data analysis. MV, JCM and the NISC Comparative Sequencing Program performed whole-exome sequencing. TV interpreted whole-exome data. DY and ARC performed DNA sequencing for Sanger confirmation. DD assisted in recruiting patients and molecular genetic diagnosis. MAP assisted in conceptualising the study, recruited patients and assisted in interpretation of results. WAG is the financially accountable investigator of the NIH protocol; all co-authors critically revised the manuscript and read and approved the final manuscript.

  • Funding This research was supported by the Intramural Research Programs of the National Human Genome Research Institute and the National Institute of Mental Health (NIMH), National Institutes of Health (NIH), Bethesda, Maryland, USA. KAC's work was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health through grant number 1UL1TR001079. DD's work was supported by the National Institute of Neurological Disorders and Stroke (NINDS) through grant number R01NS064077 and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health through grant number U54HD083091 (Genetics Core and Sub-project 6849).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval This study has been approved by the National Human Genome Research Institute, NIH, Institutional Review Board and conducted in accordance with the Declaration of Helsinki.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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