Cerebellum Abnormalities, the 5th C in CHARGE Syndrome

Introduction and background: Children with CHARGE syndrome often have balance problems due to hypoplasia of the semicircular canals. Balance involves the complex task of integrating postural responses and multisensory (visual, labyrinthine from the semi-circular canals, and proprioceptive) feedback. The cerebellum plays an important role in coordination of movements and balance,but little is known about the effect of CHD7 mutations on cerebellum development and function. Recently, it was shown that loss ofChd7 resulted in decreased Fgf8 expression in mice. Combined lossof Chd7 and Fgf8 resulted in abnormal cerebellum development in mice. This prompted us to critically evaluate MRI scans of children with CHARGE syndrome for cerebellar defects.Methods: MRI scans of patients with a proven CHD7 mutation were collected and evaluated by an experienced neuroradiologist using a standard protocol. Only MRI scans that allowed are liable interpretation of the cerebellum, that is the presence of sagittal and axial images of the cerebellum, were included in this study (n = 20). MRI images of CHARGE patients were compared with images of age-matched controls. FGF8 was analyzed forvariants in the same 20 patients. Results: we found cerebellumab normalities in 55% of the 20 patients. Patients exhibited cerebellar vermis hypoplasia, varying from slight to pronounced hypoplasia (35%), and an anticlockwise rotated vermis (35%).Fluid-filled spaces surrounding the cerebellum appeared larger: a862 AMERICAN JOURNAL OF MEDICAL GENETICS PART Alarge foramen of Magendi and fourth ventricle (50%) and large subcerebellar cistern (25%) were seen. Two patients with vermishypoplasia exhibited broad gait or ataxia, consistent with defects that disrupt cerebellar function. Furthermore, 25% of the patients had foliation abnormalities, implying additional roles for CHD7 during the process of foliation. The presence or absence of cerebellum abnormalities could not be explained by the type of CHD7 mutation or by additional variants in FGF8.Conclusion: CHD7 plays a role in cerebellum development.Cerebellum defects are a clinical feature in CHARGE syndrome,being the 5th C after coloboma, choanal atresia, cranial nerve defects, and cardiac abnormalities. The involvement of the cerebellum may have important implications for among others posture and gait, and future studies are needed to explore theeffect on balance in CHARGE syndrome