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Polymicrogyria

Polymicrogyria is an abnormally thick cortex due to multiple small gyri with atypical cortical lamination. People affected by polymicrogyria have many unusually small and excessive folding, gyri , in their brain compared to the average person. It can be a defect specific to a section of the brain or it can cover more than one region. Time of onset is not specifically identified but ranges in early and later stages in development of the brain before birth. Early stages include impaired proliferation and migration of neuroblasts, while later stages show disordered post-migration development. The symptoms experienced differ depending on what part of the brain is affected. There is no specific treatment to get rid of this condition, but there are medications that can control the side effects such a seizures, delayed development or weakened muscles as some of the noted effects.

History

Limited information was known about cerebral disorders until the development of modern technologies. Brain imaging and genetic sequencing greatly increased the information known about polymicrogyria within the past decade1. Understanding about development, classification and localization of the disorder have greatly improved1. For instance, localization of specific cortex regions affected by the disease was determined. This allowed for clinical symptoms of patients to be linked with localized cortex areas affected1. A gene that was identified to be a contributor to bilateral frontoparietal polymicrogyria was GPR56. This is the only gene that has been directly linked to the disease2.

Syndromes

Significant technological advances have been made in the past few decades that have allowed more extensive study of syndromes such as polymicrogyria. Research, imaging, and analysis has shown that distribution of polymicrogryia does not always appear to be random, and therefore revealed the different types of polymicrogyria. Bilateral Frontal Polymicrogyria (BFP) BFP appears to be a symmetrical polymicrogyria that extends anteriorly from the frontal poles to the posterior precentral gyrus, and inferiorly to the frontal operculum. Patients who had polymicrogyria distribution similar to this also experienced similar symptoms including delayed motor and language developments, spastic hemiparesis or quadriparesis, and forms of mild mental retardation. Bilateral Frontoparietal Polymicrogyria (BFPP) BFPP was one of the first discovered forms of polymicrogyria and was the form to have to have a gene identified that linked to the syndrome. This gene is called GPR56. Symmetrical distribution is also evident in this form, but more distinctly, patients with BFPP were found to have features that were found in no other bilateral polymicrogyria syndromes; atrophy of the cerebellum and brain stem, as well as bilateral white matter abnormalities. BFPP is characterized by estopia, global development delay, pyramidal signs, cerebral signs, and seizures. Estopia is also known as dysconjugate gaze, and is a common feature of severe static encephalopathy. This differentiates BFPP from the other bilatieral polymicrogyria syndromes.

Pathology

The pathogenesis of polymicrogyria is still being researched for understanding though it is historically heterogeneous. It results from both genetic and destructive events. While polymicrogyria is associated with genetic mutations, none of these are the sole cause of this abnormality. The cortical development of mammals requires specific cell functions that all involve microtubules, whether it is because of mitosis, specifically cell division, cell migration or neurite growth. Some mutations that affect the role of microtubules and are studied as possible contributors, but not causes, to polymicrogyria include TUBA1A and TUBB2B. TUBB2B mutations are known to contribute to polymicrogyria either with or without congenital fibrosis or the external ocular muscles, as well as bilateral perisylvian.

The gene GPR56 is a member of the adhesion G protein-coupled receptor family and is directly related to causing Bilateral Frontoparietal Polymicrogyria, (BFPP). Other genes in the G protein-coupled receptor family have effects with this condition as well such as the outer brain development, but not enough is known to carry out all the research properly so the main focus is starting with the specific GR56 gene within this category. This malformation of the brain is a result of numerous small gyri taking over the surface of the brain that should otherwise be normally convoluted. This gene is currently under studies to help identify and contribute to the knowledge about this condition. It is studied to provide information on the causes along with insight into the mechanisms of normal cortical development and the regional patterning of the cerebral cortex using magnetic resonance imagine, MRI. Specifically found to polymicrogyria due to mutation of this gene are myelination defects. GPR56 is observed to be important for myelinations due to a mutation in this gene results in reduced white matter volume and signal changes as shown in MRI’s. While the cellular roles of GPR56 in myelination remains unclear, this information will be used to further other studies done with this gene.

Diagnosis

The effects of Polymicrogyria (PMG) can either be focal or widespread. Although both can have physiological effects on the patient, it’s hard to determine PMG as the direct cause because it can be associated with other brain malformations. Most commonly, PMG is associated with Aicardi and Warburg Micro syndromes.2 These syndromes both have frontoparieto polymicrogyria as their anomalies. To ensure proper diagnosis, doctors thus can examine a patient through neuroimaging or neuropathological techniques.2

Pathologically, PMG is defined as “an abnormally thick cortex formed by the piling upon each other of many small gyri with a fused surface.” 3 To view these microscopic characteristics, Magnetic Resonance Imaging (MRI) is used. First physicians must distinguish between polymicrogyria and pachygyria. Pachygria leads to the development of broad and flat regions in the cortical area, which opposes the effect of PMG. Underneath a Computerized Tomography (CT scan) scan, these both appear similar in that the cerebral cortex appears thickened. However, Magnetic Resonance Imaging (MRI) with a T1 weighted inversion recovery will illustrate the gray-white junction that’s characterized by patients with PMG.2 An MRI is usually preferred over the CT scan because it has sub-mm resolution. The resolution displays the multiple folds within the cortical area, which is continuous with the neuropathology of an infected patient.

Gross examination exposes a pattern of many small gyri clumped together, which causes an irregularity in the brain surface.2 The cerebral cortex is also thinned out which in normal patients is six cell layers thick. As mentioned prior, the MRI of an infected patient shows what appears to be a thickening of the cortex. They appear to have a thickening cerebral cortex because of the tiny folds that aggregate together causing a more dense appearance. However gross analysis shows an infected patient can have as little as one to all six of these layers missing.2

References

Barkovich, A. James. "Current concepts of polymicrogyria." Neuroradiology 52.6 (2010): 479-487. Chang, Bernard, et al. "Polymicrogyria Overview. GeneReviews." (2007).

Jansen, A., and E. Andermann. "Genetics of the Polymicrogyria Syndromes." Journal of Medical Genetics. BMJ Group, n.d. Web.

Kato, Mitsuhiro. "Genotype-phenotype Correlation in Neuronal Migration Disorders." Journal of Medical Genetics. Neurogenesis, n.d. Web.

Singer, Kathleen, et al. "GPR56 and the developing cerebral cortex: cells, matrix, and neuronal migration." Molecular neurobiology 47.1 (2013): 186-196.

Squier, Waney, and Anna Jansen. "Polymicrogyria: pathology, fetal origins and mechanisms." Acta neuropathologica communications 2.1 (2014): 1.