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Nature Genetics Jun 2012Megalencephaly-capillary malformation (MCAP) and megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndromes are sporadic overgrowth disorders associated...
Megalencephaly-capillary malformation (MCAP) and megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndromes are sporadic overgrowth disorders associated with markedly enlarged brain size and other recognizable features. We performed exome sequencing in 3 families with MCAP or MPPH, and our initial observations were confirmed in exomes from 7 individuals with MCAP and 174 control individuals, as well as in 40 additional subjects with megalencephaly, using a combination of Sanger sequencing, restriction enzyme assays and targeted deep sequencing. We identified de novo germline or postzygotic mutations in three core components of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway. These include 2 mutations in AKT3, 1 recurrent mutation in PIK3R2 in 11 unrelated families with MPPH and 15 mostly postzygotic mutations in PIK3CA in 23 individuals with MCAP and 1 with MPPH. Our data highlight the central role of PI3K-AKT signaling in vascular, limb and brain development and emphasize the power of massively parallel sequencing in a challenging context of phenotypic and genetic heterogeneity combined with postzygotic mosaicism.
Topics: Class I Phosphatidylinositol 3-Kinases; Exome; Germ-Line Mutation; Humans; Hydrocephalus; Malformations of Cortical Development; Megalencephaly; Mutation; Mutation, Missense; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Syndrome
PubMed: 22729224
DOI: 10.1038/ng.2331 -
Molecular Syndromology Sep 2016Malformations of cortical development (MCD) represent a major cause of developmental disabilities, severe epilepsy, and reproductive disadvantage. Genes that have been... (Review)
Review
Malformations of cortical development (MCD) represent a major cause of developmental disabilities, severe epilepsy, and reproductive disadvantage. Genes that have been associated to MCD are mainly involved in cell proliferation and specification, neuronal migration, and late cortical organization. Lissencephaly-pachygyria-severe band heterotopia are diffuse neuronal migration disorders causing severe global neurological impairment. Abnormalities of the , , , , , , , , and genes have been associated with these malformations. More recent studies have also established a relationship between lissencephaly, with or without associated microcephaly, corpus callosum dysgenesis as well as cerebellar hypoplasia, and at times, a morphological pattern consistent with polymicrogyria with mutations of several genes , , , , , and , regulating the synthesis and function of microtubule and centrosome key components and hence defined as tubulinopathies. MCD only affecting subsets of neurons, such as mild subcortical band heterotopia and periventricular heterotopia, have been associated with abnormalities of the , , and genes and cause neurological and cognitive impairment that vary from severe to mild deficits. Polymicrogyria results from abnormal late cortical organization and is inconstantly associated with abnormal neuronal migration. Localized polymicrogyria has been associated with anatomo-specific deficits, including disorders of language and higher cognition. Polymicrogyria is genetically heterogeneous, and only in a small minority of patients, a definite genetic cause has been identified. Megalencephaly with normal cortex or polymicrogyria by MRI imaging, hemimegalencephaly and focal cortical dysplasia can all result from mutations in genes of the PI3K-AKT-mTOR pathway. Postzygotic mutations have been described for most MCD and can be limited to the dysplastic tissue in the less diffuse forms.
PubMed: 27781032
DOI: 10.1159/000448639 -
AJNR. American Journal of Neuroradiology Nov 2022The presence of malformations of cortical development in patients with hereditary hemorrhagic telangiectasia has been reported on previous occasions. We evaluated a...
BACKGROUND AND PURPOSE
The presence of malformations of cortical development in patients with hereditary hemorrhagic telangiectasia has been reported on previous occasions. We evaluated a sample of adults with hereditary hemorrhagic telangiectasia for the presence of malformations of cortical development, spatial coincidence of malformations of cortical development and AVMs, and the coincidence of brain and pulmonary AVMs.
MATERIALS AND METHODS
A total of 141 patients 18 years of age or older who were referred to the Augusta University hereditary hemorrhagic telangiectasia clinic and underwent brain MR imaging between January 19, 2018, and December 3, 2020, were identified. MR imaging examinations were reviewed retrospectively by 2 experienced neuroradiologists, and the presence of malformations of cortical development and AVMs was confirmed by consensus. Demographic and clinical information was collected for each case, including age, sex, hereditary hemorrhagic telangiectasia status by the Curacao Criteria, mutation type, presence of malformations of cortical development, presence of brain AVMs, presence of pulmonary AVMs, and a history of seizures or learning disabilities.
RESULTS
Five of 141 (3.5%) patients with hereditary hemorrhagic telangiectasia had malformations of cortical development. Two of the 5 patients with polymicrogyria also had closed-lip schizencephaly. One of the patients had a porencephalic cavity partially lined with heterotopic GM. The incidence of spatially coincident polymicrogyria and brain AVMs was 40% (2/5 cases). Of the patients with hereditary hemorrhagic telangiectasia and malformations of cortical development, 4/5 (80%) had pulmonary AVMs and 2/5 (40%) had brain AVMs.
CONCLUSIONS
To our knowledge, we are the first group to report the presence of schizencephaly in patients with hereditary hemorrhagic telangiectasia. The presence of schizencephaly and porencephaly lends support to the hypothesis of regional in utero cerebral hypoxic events as the etiology of malformations of cortical development in hereditary hemorrhagic telangiectasia.
Topics: Adult; Humans; Adolescent; Telangiectasia, Hereditary Hemorrhagic; Schizencephaly; Polymicrogyria; Retrospective Studies; Arteriovenous Malformations
PubMed: 36265891
DOI: 10.3174/ajnr.A7677 -
AJNR. American Journal of Neuroradiology Nov 2018
Topics: Humans; Polymicrogyria; Pyramidal Tracts
PubMed: 30287457
DOI: 10.3174/ajnr.A5822 -
Biomedical Journal Oct 2021GPR56/ADGRG1 is a versatile adhesion G protein-coupled receptor important in the physiological functions of the central and peripheral nervous systems, reproductive... (Review)
Review
GPR56/ADGRG1 is a versatile adhesion G protein-coupled receptor important in the physiological functions of the central and peripheral nervous systems, reproductive system, muscle hypertrophy, immune regulation, and hematopoietic stem cell generation. By contrast, aberrant expression or deregulated functions of GPR56 have been implicated in diverse pathological processes, including bilateral frontoparietal polymicrogyria, depression, and tumorigenesis. In this review article, we summarize and discuss the current understandings of the role of GPR56 in health and disease.
Topics: Cell Transformation, Neoplastic; Depression; Humans; Malformations of Cortical Development; Receptors, G-Protein-Coupled
PubMed: 34654683
DOI: 10.1016/j.bj.2021.04.012 -
American Journal of Medical Genetics.... Dec 2018Oculocerebrocutaneous syndrome (OCCS) is a rare disorder characterized primarily by congenital skin, eye, and brain anomalies. The most distinctive findings are... (Review)
Review
Oculocerebrocutaneous syndrome (OCCS) is a rare disorder characterized primarily by congenital skin, eye, and brain anomalies. The most distinctive findings are hypoplastic or aplastic skin defects; pedunculated, typically hamartomatous, or nodular skin appendages; cystic microphthalmia; and a combination of forebrain anomalies and a specific mid-hindbrain malformation. Based on a review of 40 patients with OCCS, existing clinical criteria have been revised. Because of the asymmetric and patchy distribution of features, lack of recurrence in families, male preponderance and completely skewed X-inactivation in one female, OCCS is hypothesized to result from postzygotic mosaic variants in an X-linked gene. Whole exome and genome sequencing on blood DNA in two patients failed to identify pathogenic variants so far. In view of the overlapping features, in particular of the brain, of OCCS and Aicardi syndrome, both may be pathogenetically related or even result from different variants in the same gene. For the elucidation of the cause of OCCS, exome or genome sequencing on multiple lesional tissues is the primary goal.
Topics: Abnormalities, Multiple; Central Nervous System Cysts; Eye Abnormalities; Fingers; Humans; Phenotype; Skin Abnormalities
PubMed: 30580480
DOI: 10.1002/ajmg.c.31667 -
Singapore Medical Journal Jul 2012Aicardi syndrome is a rare neurodevelopmental disease characterised by congenital chorioretinal lacunae, corpus callosum dysgenesis, seizures, polymicrogyria, cerebral...
Aicardi syndrome is a rare neurodevelopmental disease characterised by congenital chorioretinal lacunae, corpus callosum dysgenesis, seizures, polymicrogyria, cerebral callosum, chorioretinopathy and electroencephalogram abnormality. We present a case of Aicardi syndrome with callosal hypogenesis in a 4.5-month-old baby who presented with infantile spasms. Ophthalmoscopy revealed chorioretinal lacunae. The clinical and magnetic resonance imaging features were diagnostic of Aicardi syndrome.
Topics: Agenesis of Corpus Callosum; Aicardi Syndrome; Brain; Choroid; Cornea; Female; Humans; Infant; Magnetic Resonance Imaging; Malformations of Cortical Development; Ophthalmoscopy; Radiography; Retina; Spasms, Infantile
PubMed: 22815034
DOI: No ID Found