Polymicrogyria and deletion 22q11.2 syndrome: Window to the etiology of a common cortical malformation

Università di Pisa, Pisa, Tuscany, Italy
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 11/2006; 140(22):2416-25. DOI: 10.1002/ajmg.a.31443
Source: PubMed


Several brain malformations have been described in rare patients with the deletion 22q11.2 syndrome (DEL22q11) including agenesis of the corpus callosum, pachygyria or polymicrogyria (PMG), cerebellar anomalies and meningomyelocele, with PMG reported most frequently. In view of our interest in the causes of PMG, we reviewed clinical data including brain-imaging studies on 21 patients with PMG associated with deletion 22q11.2 and another 11 from the literature. We found that the cortical malformation consists of perisylvian PMG of variable severity and frequent asymmetry with a striking predisposition for the right hemisphere (P = 0.008). This and other observations suggest that the PMG may be a sequela of abnormal embryonic vascular development rather than a primary brain malformation. We also noted mild cerebellar hypoplasia or mega-cisterna magna in 8 of 24 patients. Although this was not the focus of the present study, mild cerebellar anomalies are probably the most common brain malformation associated with DEL22q11.

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Available from: Shehla Mohammed
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    • "PMG has been described pathologically in patients with deletions in 22Q11 and MRI has shown cerebral atrophy and loss of white matter volume [4,79]. It is likely that the abnormal embryonic vascular development in this condition is associated with hypoperfusion which leads to malformation, rather than any independent gene effect on cortical development [80]. "
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    ABSTRACT: Polymicrogyria (PMG) is a complex cortical malformation which has so far defied any mechanistic or genetic explanation. Adopting a broad definition of an abnormally folded or festooned cerebral cortical neuronal ribbon, this review addresses the literature on PMG and the mechanisms of its development, as derived from the neuropathological study of many cases of human PMG, a large proportion in fetal life. This reveals the several processes which appear to be involved in the early stages of formation of polymicrogyric cortex. The most consistent feature of developing PMG is disruption of the brain surface with pial defects, over-migration of cells, thickening and reduplication of the pial collagen layers and increased leptomeningeal vascularity. Evidence from animal models is consistent with our observations and supports the notion that disturbance in the formation of the leptomeninges or loss of their normal signalling functions are potent contributors to cortical malformation. Other mechanisms which may lead to PMG include premature folding of the neuronal band, abnormal fusion of adjacent gyri and laminar necrosis of the developing cortex. The observation of PMG in association with other and better understood forms of brain malformation, such as cobblestone cortex, suggests mechanistic pathways for some forms of PMG. The role of altered physical properties of the thickened leptomeninges in exerting mechanical constraints on the developing cortex is also considered. Electronic supplementary material The online version of this article (doi:10.1186/s40478-014-0080-3) contains supplementary material, which is available to authorized users.
    Full-text · Article · Jul 2014
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    • "Early on, e.g., in the prenatal or neonatal periods, few CNS anomalies would be clinically detectable, apart from neonatal hypocalcemic seizures. Rare, clinically important anomalies reported include neuronal migration abnormalities, such as polymicrogyria and periventricular nodular heterotopia identifiable on structural MRI, and, even rarer, neural tube defects (Kiehl et al. 2009; Robin et al. 2006). In contrast, from infancy onward developmental delays are commonly observed (Gerdes et al. 2001; Roizen et al. 2007; Swillen et al. 1999). "
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    ABSTRACT: 22q11.2 Deletion syndrome has become an important model for understanding the pathophysiology of neurodevelopmental conditions, particularly schizophrenia which develops in about 20-25% of individuals with a chromosome 22q11.2 microdeletion. From the initial discovery of the syndrome, associated developmental delays made it clear that changes in brain development were a key part of the expression. Once patients were followed through childhood into adult years, further neurobehavioural phenotypes became apparent, including a changing cognitive profile, anxiety disorders and seizure diathesis. The variability of expression is as wide as for the myriad physical features associated with the syndrome, with the addition of evolving phenotype over the developmental trajectory. Notably, variability appears unrelated to length of the associated deletion. Several mouse models of the deletion have been engineered and are beginning to reveal potential molecular mechanisms for the cognitive and behavioural phenotypes observable in animals. Both animal and human studies hold great promise for further discoveries relevant to neurodevelopment and associated cognitive, behavioural and psychiatric disorders.
    Full-text · Article · May 2011 · Behavior Genetics
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    • "Cavum septum pellucidum cavum vergae Chow et al. 1999 van Amelsvoort et al., 2001 Shashi et al., 2004 Polymicrogyria Sztriha et al., 2004 Robin et al. 2006 White matter hyperintensities Chow et al., 1999 van Amelsvoort et al., 2001 Volumetric abnormalities "
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    ABSTRACT: Over the last fifteen years it has become established that 22q11.2 deletion syndrome (22q11DS) is a true genetic risk factor for schizophrenia. Carriers of deletions in chromosome 22q11.2 develop schizophrenia at rate of 25-30% and such deletions account for as many as 1-2% of cases of sporadic schizophrenia in the general population. Access to a relatively homogeneous population of individuals that suffer from schizophrenia as the result of a shared etiological factor and the potential to generate etiologically valid mouse models provides an immense opportunity to better understand the pathobiology of this disease. In this review we survey the clinical literature associated with the 22q11.2 microdeletions with a focus on neuroanatomical changes. Then, we highlight results from work modeling this structural mutation in animals. The key biological pathways disrupted by the mutation are discussed and how these changes impact the structure and function of neural circuits is described.
    Full-text · Article · Oct 2010 · International journal of developmental neuroscience: the official journal of the International Society for Developmental Neuroscience
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