Subcortical heterotopic gray matter brain malformations: Classification study of 107 individuals

Renske Oegema, A. James Barkovich, Grazia M.S. Mancini, Renzo Guerrini, William B. Dobyns

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


ObjectiveTo better evaluate the imaging spectrum of subcortical heterotopic gray matter brain malformations (subcortical heterotopia [SUBH]), we systematically reviewed neuroimaging and clinical data of 107 affected individuals.MethodsSUBH is defined as heterotopic gray matter, located within the white matter between the cortex and lateral ventricles. Four large brain malformation databases were searched for individuals with these malformations; data on imaging, clinical outcomes, and results of molecular testing were systematically reviewed and integrated with all previously published subtypes to create a single classification system.ResultsReview of the databases revealed 107 patients with SUBH, the large majority scanned during childhood (84%), including more than half before 4 years (59%). Although most individuals had cognitive or motor disability, 19% had normal development. Epilepsy was documented in 69%. Additional brain malformations were common and included abnormalities of the corpus callosum (65/102 [64%]), and, often, brainstem or cerebellum (47/106 [44%]). Extent of the heterotopic gray matter brain malformations (unilateral or bilateral) did not influence the presence or age at onset of seizures. Although genetic testing was not systematically performed in this group, the sporadic occurrence and frequent asymmetry suggests either postzygotic mutations or prenatal disruptive events. Several rare, bilateral forms are caused by mutations in genes associated with cell proliferation and polarity (EML1, TUBB, KATNB1, CENPJ, GPSM2).ConclusionThis study reveals a broad clinical and imaging spectrum of heterotopic malformations and provides a framework for their classification.

Original languageEnglish (US)
Pages (from-to)E1360-E1373
Issue number14
StatePublished - Oct 1 2019
Externally publishedYes

Bibliographical note

Funding Information:
R. Oegema was supported by an EMBO short-term fellowship and a Simonsfonds grant from the Dutch Society of Human Genetics. A. Barkovich reports no disclosures relevant to the manuscript. G. Mancini was supported by the Erasmus MC-Mrace grant project number 104673 and NWO/ZonMW Top grant number 91217045. R. Guerrini was supported by the European Union Seventh Framework Programme FP7/2007–2013 under the project DESIRE, grant agreement number 602531. W. Dobyns was supported by the National Institute of Neurologic Disorders and Stroke of the NIH under award numbers R01NS050375, R01NS058721, and R01NS092772. Go to for full disclosures.

Funding Information:
The Article Processing Charge was funded by Utrecht University.

Publisher Copyright:
© 2019 American Academy of Neurology.


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