646 research outputs found
A developmental and genetic classification for malformations of cortical development: update 2012.
Malformations of cerebral cortical development include a wide range of developmental disorders that are common causes of neurodevelopmental delay and epilepsy. In addition, study of these disorders contributes greatly to the understanding of normal brain development and its perturbations. The rapid recent evolution of molecular biology, genetics and imaging has resulted in an explosive increase in our knowledge of cerebral cortex development and in the number and types of malformations of cortical development that have been reported. These advances continue to modify our perception of these malformations. This review addresses recent changes in our perception of these disorders and proposes a modified classification based upon updates in our knowledge of cerebral cortical development
Ultra-high-field MR imaging in polymicrogyria and epilepsy
BACKGROUND AND PURPOSE:
Polymicrogyria is a malformation of cortical development that is often identified in children with epilepsy or delayed development. We investigated in vivo the potential of 7T imaging in characterizing polymicrogyria to determine whether additional features could be identified.
MATERIALS AND METHODS:
Ten adult patients with polymicrogyria previously diagnosed by using 3T MR imaging underwent additional imaging at 7T. We assessed polymicrogyria according to topographic pattern, extent, symmetry, and morphology. Additional imaging sequences at 7T included 3D T2* susceptibility-weighted angiography and 2D tissue border enhancement FSE inversion recovery. Minimum intensity projections were used to assess the potential of the susceptibility-weighted angiography sequence for depiction of cerebral veins.
RESULTS:
At 7T, we observed perisylvian polymicrogyria that was bilateral in 6 patients, unilateral in 3, and diffuse in 1. Four of the 6 bilateral abnormalities had been considered unilateral at 3T. While 3T imaging revealed 2 morphologic categories (coarse, delicate), 7T susceptibility-weighted angiography images disclosed a uniform ribbonlike pattern. Susceptibility-weighted angiography revealed numerous dilated superficial veins in all polymicrogyric areas. Tissue border enhancement imaging depicted a hypointense line corresponding to the gray-white interface, providing a high definition of the borders and, thereby, improving detection of the polymicrogyric cortex.
CONCLUSIONS:
7T imaging reveals more anatomic details of polymicrogyria compared with 3T conventional sequences, with potential implications for diagnosis, genetic studies, and surgical treatment of associated epilepsy. Abnormalities of cortical veins may suggest a role for vascular dysgenesis in pathogenesis
Mutations in the Na+/K+-ATPase Ī±3 Gene ATP1A3 Are Associated with Rapid-Onset Dystonia Parkinsonism
AbstractRapid-onset dystonia-parkinsonism (RDP, DYT12) is a distinctive autosomal-dominant movement disorder with variable expressivity and reduced penetrance characterized by abrupt onset of dystonia, usually accompanied by signs of parkinsonism. The sudden onset of symptoms over hours to a few weeks, often associated with physical or emotional stress, suggests a trigger initiating a nervous system insult resulting in permanent neurologic disability. We report the finding of six missense mutations in the gene for the Na+/K+-ATPase Ī±3 subunit (ATP1A3) in seven unrelated families with RDP. Functional studies and structural analysis of the protein suggest that these mutations impair enzyme activity or stability. This finding implicates the Na+/K+ pump, a crucial protein responsible for the electrochemical gradient across the cell membrane, in dystonia and parkinsonism
Cellular and clinical impact of Haploinsufficiency for genes involved in ATR signaling
Ataxia telangiectasia and Rad3-related (ATR) protein, a kinase that regulates a DNA damage-response pathway, is mutated in ATR-Seckel syndrome (ATR-SS), a disorder characterized by severe microcephaly and growth delay. Impaired ATR signaling is also observed in cell lines from additional disorders characterized by microcephaly and growth delay, including non-ATR-SS, Nijmegen breakage syndrome, and MCPH1 (microcephaly, primary autosomal recessive, 1)-dependent primary microcephaly. Here, we examined ATR-pathway function in cell lines from three haploinsufficient contiguous gene-deletion disorders--a subset of blepharophimosis-ptosis-epicanthus inversus syndrome, Miller-Dieker lissencephaly syndrome, and Williams-Beuren syndrome--in which the deleted region encompasses ATR, RPA1, and RFC2, respectively. These three genes function in ATR signaling. Cell lines from these disorders displayed an impaired ATR-dependent DNA damage response. Thus, we describe ATR signaling as a pathway unusually sensitive to haploinsufficiency and identify three further human disorders displaying a defective ATR-dependent DNA damage response. The striking correlation of ATR-pathway dysfunction with the presence of microcephaly and growth delay strongly suggests a causal relationship
Bilateral renal artery stenosis and epidermal nevus syndrome in a child
Epidermal nevus syndrome is a rare congenital sporadic neuro-ectodermic disorder, characterized by the presence of epidermal nevi in association with various developmental abnormalities of the skin, eyes, nervous, skeletal, cardiovascular and urogenital systems. We describe a 5-year-old boy with conjunctival lipodermoid, cervical and facial sebaceous nevi who presented at 3Ā years of age with hypertension due to bilateral renal artery stenosis together with multiple vascular anomalies (aorta, celiac trunk, superior mesenteric artery) as shown by magnetic resonance angiography. Systemic arterial hypertension was difficult to control despite combined anti-hypertensive drugs and the surgical repair of the aortic coarctation
Recommended from our members
Somatic PDGFRB activating variants in fusiform cerebral aneurysms
The role of somatic genetic variants in the pathogenesis of intracranial-aneurysm formation is unknown. We identified a 23-year-old man with progressive, right-sided intracranial aneurysms, ipsilateral to an impressive cutaneous phenotype. The index individual underwentĀ a series of genetic evaluations for known connective-tissue disorders, but the evaluations were unrevealing. Paired-sample exome sequencing between blood and fibroblasts derived from the diseased areas detected a single novel variant predicted to cause a p.Tyr562Cys (g.149505130T>C [GRCh37/hg19]; c.1685A>G) change within the platelet-derived growth factor receptor Ī² gene (PDGFRB), a juxtamembrane-coding region. Variant-allele fractions ranged from 18.75% to 53.33% within histologically abnormal tissue,Ā suggesting post-zygotic or somatic mosaicism. In an independent cohort of aneurysm specimens, we detected somatic-activating PDGFRB variants in the juxtamembrane domain or the kinase activation loop in 4/6 fusiform aneurysms (and 0/38 saccular aneurysms; Fisher's exact test, p < 0.001). PDGFRB-variant, but not wild-type, patient cells were found to have overactive auto-phosphorylation withĀ downstream activation of ERK, SRC, and AKT. The expression of discovered variants demonstrated non-ligand-dependent auto-phosphorylation,Ā responsive to the kinase inhibitor sunitinib. Somatic gain-of-function variants in PDGFRB are a novel mechanism in the pathophysiology of fusiform cerebral aneurysms and suggest a potential role for targeted therapy with kinase inhibitors
- ā¦