Polymicrogyria

What Is Polymicrogyria?

Normally, the brain has a wrinkled and folded hemispheric structure, consisting of numerous ridges and indentations. The gyrus (or gyri) is a ridge(s) on the cerebral cortex. These gyri endow human and other mammalian brains with a larger cortical surface area within a smaller skull, which are critical for neuronal functions and cognitive activities. Abnormal alterations in the structure of gyri are closely related to various neurological diseases and disorders.

Polymicrogyria is a developmental malformation of the brain before birth caused by abnormal neuronal migration. It is one of the most common brain malformations characterized by an excessive number of small gyri (microgyri) or folds in the cerebral cortex. These abnormal microgyri can cause a series of specific neurological disorders according to the affecting subregions in the brain, such as bilateral frontal polymicrogyria, bilateral generalized polymicrogyria, bilateral frontoparietal polymicrogyria, etc.

Fig.1 Bilateral frontal polymicrogyria shown by magnetic resonance images. (Jansen, 2005)

Possible Causes of Polymicrogyria

As a kind of developmental disorder, polymicrogyria is thought to be caused by aberrant neuronal migration during pregnancy or cortical organization abnormalities in early fetal development. This may result from genetic factors, infections, and other environmental factors.

1. Genetic factors: polymicrogyria has been reported to associate with mutations or rearrangements of genetic material from multiple different chromosomes since neuronal migration is a complex process, such as: i) tubulin-related genes affect neuronal migration by participating in the construction of microtubules; ii) WDR62 gene mutation is related to microcephaly and multiple brain malformations; iii) ADGRG1 mutations associate with localized bilateral frontoparietal polymicrogyria, and so forth.
2. Viral infections: Cytomegalovirus prenatal infection and Zika virus infection recently have been reported to be linked to polymicrogyria.
3. Metabolic disorders: metabolic disorders, such as classic nonketotic hyperglycinemia, fumaric aciduria, glutaric acidemia type II, etc., also have been indicated to associate with polymicrogyria.
4. Environmental factors: polymicrogyria also may be caused by fetal hypoxia.

Important Proteins in Polymicrogyria Pathology

The exact pathological mechanism of polymicrogyria is still being explored. Polymicrogyria mainly results from the abnormalities of neuronal migration, an extremely complicated process involving a variety of regulatory proteins. Therefore, multiple proteins have been identified that exerted important roles in polymicrogyria pathology, which including but not limited to:

1. Tubulins: tubulins are a group of globular proteins and critical components of eukaryotic cytoskeleton microtubules, playing essential roles in neuron differentiation and neuronal migration. The abnormal tubulin expression or tubulin deficiency can lead to abnormal neuronal differentiation and the inability to migrate to where they are supposed to be. TUBA1A, TUBB2B, TUBB3 mutations have been identified as contributors in polymicrogyria.
2. G protein-coupled receptor 56 (GPR56): in neurogenesis, GPR56 is an important adhesion G-protein coupled receptor expressed in developing neural cells of the cerebral cortical ventricular. It regulates the development and lamination of the cerebral cortex by binding to collagen type III. Moreover, GPR56 exerts key action in multiple neurobiological pathways, including myelination, oligodendrocyte development, neuronal migration, and cortical formation. GPR56 encoding gene ADGRG1 is the direct cause of the human bilateral frontoparietal polymicrogyria.

Fig.2 GPR56 signaling in brain development. (Ganesh, 2020)

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References

1. Jansen, A.; Andermann, E. Genetics of the polymicrogyria syndromes. Journal of Medical Genetics. 42(5): 369-378.
2. Ganesh, R.A.; et al. GPR56: An adhesion GPCR involved in brain development, neurological disorders and cancer. Brain Research. 2020, 1747, 147055.