Brain phenotyping in Moebius syndrome and other congenital facial weakness disorders by diffusion MRI morphometry

Neda Sadeghi; Elizabeth Hutchinson; Carol Van Ryzin; Edmond J FitzGibbon; John A Butman; Bryn D Webb; Flavia Facio; Brian P Brooks; Francis S Collins; Ethylin Wang Jabs; Elizabeth C Engle; Irini Manoli; Carlo Pierpaoli; Moebius Syndrome Research Consortium

doi:10.1093/braincomms/fcaa014

Brain phenotyping in Moebius syndrome and other congenital facial weakness disorders by diffusion MRI morphometry

Brain Commun. 2020;2(1):fcaa014. doi: 10.1093/braincomms/fcaa014. Epub 2020 Feb 14.

Authors

Collaborators

Moebius Syndrome Research Consortium:
Monica Erazo⁶, Tamiesha Frempong¹⁰, Ke Hao^{6

11}, Ethylin Wang Jabs^{6

12

13}, Thomas P. Naidich¹⁴, Janet C. Rucker^{13

15}, Caroline Andrews^{16

17

18

19}, Brenda J. Barry^{16

17

18

19}, Silvio Alessandro DiGioia^{16

17

18}, Elizabeth Engle^{16

17

18

19

20

21

22

23}, David G. Hunter^{21

22}, Sarah E. MacKinnon²¹, Caroline Robson²⁴, Matthew Rose^{16

17

20

23

25}, Barbara B. Biesecker²⁶, Lori L. Bonnycastle²⁷, Carmen C. Brewer²⁸, Brian P. Brooks²⁹, John A. Butman³⁰, Wade W. Chien²⁸, Peter S. Chines²⁷, Francis S. Collins^{27

31}, Flavia Facio²⁷, Kathleen Farrell³², Edmond J. FitzGibbon²⁹, Andrea L. Gropman³³, Elizabeth Hutchinson³⁴, Mina S. Jain³², Kelly A. King²⁸, Tanya J. Lehky³⁵, Janice Lee³⁶, Denise K. Liberton³⁶, Irini Manoli²⁷, Narisu Narisu²⁷, Scott M. Paul³², Carlo Pierpaoli³⁴, Neda Sadeghi³⁴, Joseph Snow³⁷, Beth Solomon³², Angela Summers³⁷, Amy J. Swift²⁷, Camilo Toro³⁸, Audrey Thurm³⁹, Carol Van Ryzin²⁷, Chris K. Zalewski²⁸

Affiliations

¹ Quantitative Medical Imaging Section, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892, USA.
² Department of Biomedical Engineering, University of Arizona, Tucson, AZ 85719, USA.
³ Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁴ Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁵ Radiology & Imaging Sciences Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
⁶ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁷ Office of the Director, National Institutes of Health, Bethesda, MD 20892, USA.
⁸ Department of Neurology and Department of Ophthalmology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
⁹ Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
¹⁰ Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, New York
¹¹ Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York
¹² Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York
¹³ Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York
¹⁴ Departments of Radiology, Neurosurgery, and Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York
¹⁵ Department of Neurology, New York University School of Medicine, New York, New York
¹⁶ Department of Neurology, Boston Children’s Hospital, Boston, MA
¹⁷ F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA
¹⁸ Department of Neurology, Harvard Medical School, Boston, MA
¹⁹ Howard Hughes Medical Institute, Chevy Chase, MD
²⁰ Department of Pathology, Boston Children’s Hospital, Boston, MA
²¹ Department of Ophthalmology, Boston Children’s Hospital, Boston, MA
²² Department of Ophthalmology, Harvard Medical School, Boston, MA
²³ Medical Genetics Training Program, Harvard Medical School, Boston, MA
²⁴ Department of Radiology, Boston Children’s Hospital, Harvard Medical School, Boston, MA
²⁵ Department of Pathology, Brigham and Women’s Hospital, Boston, MA
²⁶ Social and Behavioral Research Branch, National Human Genome Research Institute, Bethesda, MD
²⁷ Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, Bethesda, MD
²⁸ Audiology Unit, Otolaryngology Branch, National Institute of Deafness and other Communications Disorders, Bethesda, MD
²⁹ Ophthalmic Genetics & Visual Function Branch, National Eye Institute, Bethesda, MD
³⁰ Radiology and Imaging Sciences, Clinical Research Center, Bethesda, MD
³¹ Office of the Director, National Institutes of Health, Bethesda, MD
³² Rehabilitation Medicine Department, Clinical Research Center, Bethesda, MD
³³ George Washington University and Children’s National Medical Center, Washington, DC
³⁴ Quantitative Medical Imaging Section, National Institute of Biomedical Imaging and Bioengineering, Bethesda, MD
³⁵ Electromyography Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD
³⁶ Office of the Clinical Director, National Institute of Dental and Craniofacial Research, Bethesda, MD
³⁷ Office of the Clinical Director, National Institute of Mental Health, Bethesda, MD
³⁸ NIH Undiagnosed Diseases Program, Common Fund, National Human Genome Research Institute, Bethesda, MD
³⁹ Pediatrics and Developmental Neuroscience Branch, National Institute of Mental Health, Bethesda, MD

Abstract

In this study, we used a novel imaging technique, DTI (diffusion tensor imaging)-driven tensor-based morphometry, to investigate brain anatomy in subjects diagnosed with Moebius syndrome (n = 21), other congenital facial weakness disorders (n = 9) and healthy controls (n = 15). First, we selected a subgroup of subjects who satisfied the minimum diagnostic criteria for Moebius syndrome with only mild additional neurological findings. Compared to controls, in this cohort, we found a small region of highly significant volumetric reduction in the paramedian pontine reticular formation and the medial longitudinal fasciculus, important structures for the initiation and coordination of conjugate horizontal gaze. Subsequently, we tested if volume measurements from this region could help differentiate individual subjects of the different cohorts that were included in our study. We found that this region allowed discriminating Moebius syndrome subjects from congenital facial weakness disorders and healthy controls with high sensitivity (94%) and specificity (89%). Interestingly, this region was normal in congenital facial weakness subjects with oculomotor deficits of myopathic origin, who would have been classified as Moebius on the basis of purely clinical diagnostic criteria, indicating a potential role for diffusion MRI morphometry for differential diagnosis in this condition. When the entire Moebius syndrome cohort was compared to healthy controls, in addition to this 'landmark' region, other areas of significantly reduced volume in the brainstem emerged, including the location of the nuclei and fibres of cranial nerve VI (abducens nerve), and fibres of cranial nerve VII (facial nerve), and a more rostral portion of the medial longitudinal fasciculus. The high sensitivity and specificity of DTI-driven tensor-based morphometry in reliably detecting very small areas of volumetric abnormality found in this study suggest broader applications of this analysis in personalized medicine to detect hypoplasia or atrophy of small pathways and/or brainstem nuclei in other neurological disorders.

Keywords: brainstem, DTI, DTBM, magnetic resonance imaging, quantitative.

Published by Oxford University Press on behalf of the Guarantors of Brain 2020. This work is written by US Government employees and is in the public domain in the US.

Abstract

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