Brain phenotyping in Moebius syndrome and other congenital facial weakness disorders by diffusion MRI morphometry Neda Sadeghi, 1 Elizabeth Hutchinson, 1,2 Carol Van Ryzin, 3 Edmond J. FitzGibbon, 4 John A. Butman, 5 Bryn D. Webb, 6 Flavia Facio, 3 Brian P. Brooks, 4 Francis S. Collins, 3,7 Ethylin Wang Jabs, 6 Elizabeth C. Engle, 8,9 Irini Manoli, 3 Carlo Pierpaoli 1 and Moebius Syndrome Research Consortium* 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 ¼ 21), other congenital facial weakness disorders (n ¼ 9) and healthy controls (n ¼ 15). First, we selected a subgroup of subjects who satisfied the minimum diagnostic criteria for Moebius syn- drome with only mild additional neurological findings. Compared to controls, in this cohort, we found a small region of highly sig- nificant volumetric reduction in the paramedian pontine reticular formation and the medial longitudinal fasciculus, important struc- tures 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 re- gion 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 oculo- motor 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 vol- ume 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 sug- gest broader applications of this analysis in personalized medicine to detect hypoplasia or atrophy of small pathways and/or brain- stem nuclei in other neurological disorders. 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 Received August 21, 2019. Revised December 20, 2019. Accepted January 13, 2020. Advance Access publication February 14, 2020 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. B BR AIN COMMUNICATIONS AIN COMMUNICATIONS doi:10.1093/braincomms/fcaa014 BRAIN COMMUNICATIONS 2020: Page 1 of 16 | 1 Downloaded from https://academic.oup.com/braincomms/article/2/1/fcaa014/5736127 by guest on 15 February 2022