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

Objective: To better evaluate the imaging spectrum of subcortical heterotopic grey matter brain malformations (SUBH), we systematically reviewed neuroimaging and clinical data of 107 affected individuals.
Methods: SUBH 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 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.
Results: Review 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 and/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 HET (unilateral or bilateral) did not influence the presence or age of 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).
Conclusion: This study reveals a broad clinical and imaging spectrum of heterotopic malformations and provides a framework for their classification.