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A structural basis for reading fluency: White matter defects in a genetic brain malformation

From Beth Israel Deaconess Medical Center and Harvard Medical School (B.S.C., K.A.A., A.B., D.H., D.A.), Boston, MA; University of Haifa (T.K.), Haifa, Israel; Brigham and Women's Hospital and Harvard Center for Neurodegeneration and Repair (T.L., S.W.), Boston; Harvard Graduate School of Education (K.C.), Cambridge, MA; Center for Reading and Language Research (M.B.), Tufts University, Medford, MA; and Children's Hospital Boston (C.A.W.), Harvard Medical School, Howard Hughes Medical Institute.

Address correspondence and reprint requests to Dr. Bernard S. Chang, Comprehensive Epilepsy Center, KS-457, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215 bchang{at}bidmc.harvard.edu

Background: Multiple lines of evidence have suggested that developmental dyslexia may be associated with abnormalities of neuronal migration or axonal connectivity. In patients with periventricular nodular heterotopia—a rare genetic brain malformation characterized by misplaced nodules of gray matter along the lateral ventricles—a specific and unexpected reading disability is present, despite normal intelligence. We sought to investigate the cognitive and structural brain bases of this phenomenon.

Methods: Ten adult subjects with heterotopia, 10 with dyslexia, and 10 normal controls were evaluated, using a battery of neuropsychometric measures. White matter integrity and fiber tract organization were examined in six heterotopia subjects, using diffusion tensor imaging methods.

Results: Subjects with heterotopia and those with developmental dyslexia shared a common behavioral profile, with specific deficits in reading fluency. Individuals with dyslexia seemed to have a more prominent phonological impairment than heterotopia subjects. Periventricular nodular heterotopia was associated with specific, focal disruptions in white matter microstructure and organization in the vicinity of gray matter nodules. The degree of white matter integrity correlated with reading fluency in this population.

Conclusions: We demonstrate that a genetic disorder of gray matter heterotopia shares behavioral characteristics with developmental dyslexia, and that focal white matter defects in this disorder may serve as the structural brain basis of this phenomenon. Our findings represent a potential model for the use of developmental brain malformations in the investigation of abnormal cognitive function.

Abbreviations: DTI = diffusion tensor imaging; FA = fractional anisotropy; PNH = periventricular nodular heterotopia; ROI = region of interest.

*These authors contributed equally to this work.

B.S.C. was supported by the National Institute of Neurological Disorders and Stroke of the NIH K23 grant NS049159). B.S.C. and T.K. were supported by an interfaculty initiative grant from the Mind-Brain-Behavior program of Harvard University. C.A.W. is an Investigator of the Howard Hughes Medical Institute.

Disclosure: The authors report no conflicts of interest.

Received May 2, 2007. Accepted in final form July 20, 2007.