Brain phenotyping in Moebius syndrome and other congenital facial weakness disorders by diffusion MRI morphometry
Authors: Sadeghi Neda , Hutchinson Elizabeth , Van Ryzin Carol , FitzGibbon Edmond J , Butman John A , Webb Bryn D , Facio Flavia , Brooks Brian P , Collins Francis S , Jabs Ethylin Wang , Engle Elizabeth C , Manoli Irini , Pierpaoli Carlo ,   Moebius Syndrome Research Consortium, Erazo Monica , Frempong Tamiesha , Hao Ke , Jabs Ethylin Wang , Naidich Thomas P , Rucker Janet C , Webb Bryn D , Zhang Zhongyang , Andrews Caroline , Barry Brenda J , DiGioia Silvio Alessandro , Engle Elizabeth , Hunter David G , MacKinnon Sarah E , Robson Caroline , Rose Matthew , Biesecker Barbara B , Bonnycastle Lori L , Brewer Carmen C , Brooks Brian P , Butman John A , Chien Wade W , Chines Peter S , Collins Francis S , Facio Flavia , Farrell Kathleen , FitzGibbon Edmond J , Gropman Andrea L , Hutchinson Elizabeth , Jain Mina S , King Kelly A , Lehky Tanya J , Lee Janice , Liberton Denise K , Manoli Irini , Narisu Narisu , Paul Scott M , Pierpaoli Carlo , Sadeghi Neda , Snow Joseph , Solomon Beth , Summers Angela , Swift Amy J , Toro Camilo , Thurm Audrey , Van Ryzin Carol , Zalewski Chris K 
Published: February 2020

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.