Brain Advance Access published online on November 20, 2009
Brain, doi:10.1093/brain/awp247
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Review Article |
A developmental and genetic classification for midbrain-hindbrain malformations
1 Department of Radiology, Department of Neurology, and Department of Pediatrics, University of California at San Francisco, San Francisco, CA, USA 2 Department of Human Genetics, University of Chicago, Chicago, IL, USA 3 Department of Neurology, University of Chicago, Chicago, IL, USA 4 Department of Pediatrics, University of Chicago, Chicago, IL, USA
Correspondence to:
Dr A. James Barkovich, Neuroradiology Room L371, University of California at San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143-0628, USA E-mail: Jim.Barkovich{at}radiology.ucsf.edu
Advances in neuroimaging, developmental biology and molecular genetics have increased the understanding of developmental disorders affecting the midbrain and hindbrain, both as isolated anomalies and as part of larger malformation syndromes. However, the understanding of these malformations and their relationships with other malformations, within the central nervous system and in the rest of the body, remains limited. A new classification system is proposed, based wherever possible, upon embryology and genetics. Proposed categories include: (i) malformations secondary to early anteroposterior and dorsoventral patterning defects, or to misspecification of mid-hindbrain germinal zones; (ii) malformations associated with later generalized developmental disorders that significantly affect the brainstem and cerebellum (and have a pathogenesis that is at least partly understood); (iii) localized brain malformations that significantly affect the brain stem and cerebellum (pathogenesis partly or largely understood, includes local proliferation, cell specification, migration and axonal guidance); and (iv) combined hypoplasia and atrophy of putative prenatal onset degenerative disorders. Pertinent embryology is discussed and the classification is justified. This classification will prove useful for both physicians who diagnose and treat patients with these disorders and for clinical scientists who wish to understand better the perturbations of developmental processes that produce them. Importantly, both the classification and its framework remain flexible enough to be easily modified when new embryologic processes are described or new malformations discovered.
Key Words: cerebellum; brain stem; malformations; development
Abbreviations: CDG, congenital disorders of glycosylation; FOXC1, Forkhead box C; GABA, gamma-aminobutyric acid; GPR, G protein-coupled receptor; JSRD, Joubert syndrome and related disorders; LCH, lissencephaly with cerebellar hypoplasia; MHB, midbrain-hindbrain boundary; OPHN, oligophrenin; PCH, pontocerebellar hypoplasias; Shh, sonic hedgehog signalling molecule
Received June 23, 2009. Revised August 4, 2009. Accepted August 21, 2009.