Lissencephaly: Expanded imaging and clinical classification

Nataliya Di Donato, Sara Chiari, Ghayda M. Mirzaa, Kimberly Aldinger, Elena Parrini, Carissa Olds, A. James Barkovich, Renzo Guerrini, William B. Dobyns

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Lissencephaly (“smooth brain,” LIS) is a malformation of cortical development associated with deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. The LIS spectrum includes agyria, pachygyria, and subcortical band heterotopia. Our first classification of LIS and subcortical band heterotopia (SBH) was developed to distinguish between the first two genetic causes of LIS—LIS1 (PAFAH1B1) and DCX. However, progress in molecular genetics has led to identification of 19 LIS-associated genes, leaving the existing classification system insufficient to distinguish the increasingly diverse patterns of LIS. To address this challenge, we reviewed clinical, imaging and molecular data on 188 patients with LIS-SBH ascertained during the last 5 years, and reviewed selected archival data on another ∼1,400 patients. Using these data plus published reports, we constructed a new imaging based classification system with 21 recognizable patterns that reliably predict the most likely causative genes. These patterns do not correlate consistently with the clinical outcome, leading us to also develop a new scale useful for predicting clinical severity and outcome. Taken together, our work provides new tools that should prove useful for clinical management and genetic counselling of patients with LIS-SBH (imaging and severity based classifications), and guidance for prioritizing and interpreting genetic testing results (imaging based- classification).

Original languageEnglish (US)
Pages (from-to)1473-1488
Number of pages16
JournalAmerican Journal of Medical Genetics, Part A
Volume173
Issue number6
DOIs
StatePublished - Jun 2017
Externally publishedYes

Bibliographical note

Funding Information:
We wish to thank the many patients and their families, as well as the many physicians and genetic counselors who referred them for their important contributions to research over more than 30 years. Research reported in this publication was supported by the Deutsche Forschungsgemeinschaft (German Research Foundation, to N.DD), the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health under award numbers P01NS039404, R01NS050375, 1R01NS058721, and 1R01NS092772 (toW.B.D.), the National Institute of Health under the award number K08 NS092898 (to GMM), and by the EU Seventh Framework Program under the project DESIRE grant agreement N602531, and E-RareJTC2011 (to R.G.). None of the authors have any competing interests. The content is solely the responsibility of the authors, and does not necessarily represent the official views of the National Institutes of Health. The funding sources had no role in the design and conduct of the study, collection, management, analysis and interpretation of the data, preparation, review or approval of the manuscript, or decision to submit the manuscript for publication.

Keywords

  • agyria
  • classification
  • lissencephaly
  • pachygyria
  • subcortical band heterotopia
  • tubulinopathy

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