Alireza Radmanesh

Over the past decade, advances in MRI techniques and molecular biology have revolutionized our understanding of brain malformations. During this time, classifications for developmental malformations of the cortex, or those of the midbrain and hindbrain, have undergone a few revisions in light of the evolving understanding of their molecular mechanisms.^1,2

In the early part of the past decade, much emphasis was placed on classifying genetic malformations based on the specific gene that was mutated. Therefore, authors grouped diseases from different mutations of the same gene together. For example, mutations of the GFAP gene associated with infantile macrocephaly and other mutations of GFAP associated with spinomedullary degeneration in adults were all classified as Alexander disease.

Despite the values of such classifications, many different genes involved in the same molecular pathway may cause a single clinical disorder. For example, Leigh syndrome could have many different genetic causes all of which result in defective oxidative metabolism and energy production.^3,4

On the other hand, different mutations of the same gene could cause different phenotypes (different diseases), because proteins have complex structures with different components participating in different molecular pathways. Therefore, different mutations affecting different structural components of a protein could affect very different pathways and lead to distinct phenotypes.

In addition to different mutations of the same gene, epigenetic factors and environmental factors likely modulate clinical phenotypes, further complicating this tangled web. Therefore, sooner or later neuroscientists will need to reclassify diseases by how each specific mutation or epigenetic modification affects the function of the metabolic pathway(s) involved.

The trend toward reclassifying diseases based on the affected metabolic pathways has been expeditiously on course over the past several years.

For example, the mammalian target of rapamycin (mTOR) pathway, with an increasingly recognized central controlling role in organism growth and homeostasis, has been the subject of extensive basic science and clinical research.⁵

Another example with tangible neuroimaging applications is the reelin signaling pathway. It is well known that a lack of RELN (a protein) leads to the clumping of cerebellar Purkinje cells (i.e. cerebellar dysplasia/hypoplasia), as well as cerebral lissencephaly or a simplified gyral pattern.^6,7 Mutations of other genes in the reelin signaling pathway, such as the very low-density lipoprotein receptor gene and the disabled gene, may cause similar impairments of neuronal migration and organization and result in similar malformations.^7-9

This digest features a few articles that showcase correlations of imaging features with genes, molecular pathways, or both. To understand brain formation and malformation, it is more important to understand molecular pathways and mechanisms than to understand (and memorize) specific genes. Neuroradiologists, among other neuroscientists, should be well aware of this fast-paced paradigm shift.

References

1. Di Donato N, Chiari S, Mirzaa GM, et al. Lissencephaly: expanded imaging and clinical classification. Am J Med Genet A 2017;173:1473–88.
2. Barkovich AJ, Millen KJ, Dobyns WB. A developmental and genetic classification for midbrain-hindbrain malformations. Brain 2009;132:3199–3230.
3. DiMauro S, Schon EA. Mitochondrial disorders in the nervous system. Annu Rev Neurosci 2008;31:91–123.
4. Gerards M, Sallevelt SC, Smeets HJ. Leigh syndrome: resolving the clinical and genetic heterogeneity paves the way for treatment options. Mol Genet Metab 2016;117:300–12.
5. Bockaert J, Marin P. mTOR in brain physiology and pathologies. Physiol Rev 2015;95:1157–87.
6. Miyata T, Ono Y, Okamoto M, et al. Migration, early axonogenesis, and Reelin-dependent layer-forming behavior of early/posterior-born Purkinje cells in the developing mouse lateral cerebellum. Neural Dev 2010;5:23.
7. Larouche M, Beffert U, Herz J, et al. The Reelin receptors Apoer2 and Vldlr coordinate the patterning of Purkinje cell topography in the developing mouse cerebellum. PLoS One 2008;3:e1653.
8. Boycott KM, Flavelle S, Bureau A, et al. Homozygous deletion of the very low density lipoprotein receptor gene causes autosomal recessive cerebellar hypoplasia with cerebral gyral simplification. Am J Hum Genet 2005;77:477–83.
9. Sekine K, Kawauchi T, Kubo K, et al. Reelin controls neuronal positioning by promoting cell-matrix adhesion via inside-out activation of integrin alpha5beta1. Neuron 2012;76:353–69.

Image from: Cizmeci MN, Lequin M, Lichtenbelt KD, et al. Characteristic MR imaging findings of the neonatal brain in RASopathies. AJNR Am J Neuroradiol 2018 April. [Epub ahead of print]