Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Familial cerebral cavernous malformation (CCM) is an autosomal dominant disorder producing vascular anomalies throughout the central nervous system associated with seizures and hemorrhagic stroke. Linkage analysis has shown evidence for at least three genetic loci underlying this disorder with a founder mutation in the Mexican/Hispanic community. We report the first family of Chinese ethnic origin with CCM having a novel mutation in the CCM1 gene. The mutation in exon 19 causes a premature stop codon (Q698X) predicted to produce a truncated Krev1 interaction-trapped 1 (KRIT1) protein. Members of the family with this mutation have a wide range in age of onset with seizures, ataxia, spinal cord vascular malformation, headaches and skin lesions. An additional unrelated sporadic subject with brain lesions compatible with CCM as well as vascular skin findings suggesting the blue rubber bleb nevus (BRBN) syndrome has no mutation detected in the CCM1 gene. These findings expand the phenotype of and demonstrate further evidence for the heterogeneity in the CCM syndrome.
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PMID:Cerebral cavernous malformation: novel mutation in a Chinese family and evidence for heterogeneity. 1195 62

Cerebral cavernous malformations (CCM) are irregularly shaped and enlarged capillaries in the brain that are prone to hemorrhage, resulting in headaches, seizures, strokes and even death in patients. The disease affects up to 0.5% of the population and the inherited form has been linked to mutations in one of three genetic loci, CCM1, CCM2 and CCM3. To understand the pathophysiology underlying the vascular lesions in CCM, it is critical to develop a reproducible mouse genetic model of this disease. Here, we report that limited conditional ablation of Ccm2 in young adult mice induces observable neurological dysfunction and reproducibly results in brain hemorrhages whose appearance is highly reminiscent of the lesions observed in human CCM patients. We first demonstrate that conventional or endothelial-specific deletion of Ccm2 leads to fatal cardiovascular defects during embryogenesis, including insufficient vascular lumen formation as well as defective arteriogenesis and heart malformation. These findings confirm and extend prior studies. We then demonstrate that the inducible deletion of Ccm2 in adult mice recapitulates the CCM-like brain lesions in humans; the lesions display disrupted vascular lumens, enlarged capillary cavities, loss of proper neuro-vascular associations and an inflammatory reaction. The CCM lesions also exhibit damaged neuronal architecture, the likely cause of neurologic defects, such as ataxia and seizure. These mice represent the first CCM2 animal model for CCM and should provide the means to elucidate disease mechanisms and evaluate therapeutic strategies for human CCM.
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PMID:Conditional deletion of Ccm2 causes hemorrhage in the adult brain: a mouse model of human cerebral cavernous malformations. 2159 42

Cerebral cavernous malformations (CCMs) are proliferative sinusoidal vascular lesions and are the most common vascular malformations of the brain. They can occur sporadically or secondary to an underlying genetic predisposition where multiple lesions are commonly seen. Dubowitz syndrome is a clinically-diagnosed rare genetic disorder with an unknown molecular basis. An association between these conditions has not been reported previously. A 30-year-old woman with a Dubowitz-like syndrome presented with acute left leg weakness, gait ataxia and transient loss of consciousness. Imaging revealed five CCMs with recent hemorrhage in relation to one lesion in the left middle cerebellar peduncle. A recurrent hemorrhage from the same lesion occurred ten weeks later and she underwent microsurgical excision of this malformation. Genetic analysis revealed an unbalanced chromosomal rearrangement involving partial deletion of chromosome 7q21, the locus of the CCM1/KRIT1 gene known to be associated with familial CCMs. This is the first description of CCMs in association with the Dubowitz phenotype. The genetic basis of Dubowitz syndrome may be heterogeneous but, for the first time, overlap is demonstrated between this condition and multiple CCMs, with a possible common genetic etiology. Knowledge of this association may be of help in the management of acute neurological presentations in Dubowitz-like syndromes. Keywords: Hemangioma, Cavernous, Central nervous system, Dubowitz syndrome, Genetics.
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PMID:Multiple cerebral cavernous malformations in association with a Dubowitz-like syndrome. 3259 39