Multiple Telangiectases of the Brain

MICHAEL, JOSEPH C.

doi:10.1001/archneurpsyc.1936.02260090067003

Cited by 63 publications

(2 citation statements)

References 9 publications

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“…Since its initial description, CCM has been recognized to be a heritable disorder (14)(15)(16). Genetic analysis of kindreds with familial CCM has mapped three autosomal dominant loci causing this disease.…”

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confidence: 99%

KRIT1 , a gene mutated in cerebral cavernous malformation, encodes a microtubule-associated protein

Günel

Laurans

Shin

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

111

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Mutations in Krev1 interaction trapped gene 1 (KRIT1) cause cerebral cavernous malformation, an autosomal dominant disease featuring malformation of cerebral capillaries resulting in cerebral hemorrhage, strokes, and seizures. The biological functions of KRIT1 are unknown. We have investigated KRIT1 expression in endothelial cells by using specific anti-KRIT1 antibodies. By both microscopy and coimmunoprecipitation, we show that KRIT1 colocalizes with microtubules. In interphase cells, KRIT1 is found along the length of microtubules. During metaphase, KRIT1 is located on spindle pole bodies and the mitotic spindle. During late phases of mitosis, KRIT1 localizes in a pattern indicative of association with microtubule plus ends. In anaphase, the plus ends of the interpolar microtubules show strong KRIT1 staining and, in late telophase, KRIT1 stains the midbody remnant most strongly; this is the site of cytokinesis where plus ends of microtubules from dividing cells overlap. These results establish that KRIT1 is a microtubule-associated protein; its location at plus ends in mitosis suggests a possible role in microtubule targeting. These findings, coupled with evidence of interaction of KRIT1 with Krev1 and integrin cytoplasmic domain-associated protein-1 alpha (ICAP1 ␣), suggest that KRIT1 may help determine endothelial cell shape and function in response to cell-cell and cell-matrix interactions by guiding cytoskeletal structure. We propose that the loss of this targeting function leads to abnormal endothelial tube formation, thereby explaining the mechanism of formation of cerebral cavernous malformation (CCM) lesions. C erebral cavernous malformation (CCM) is a disease affecting brain vasculature. Characteristic lesions affect capillaries and have grossly dilated vascular channels lined by only a single layer of endothelium without normal vessel wall elements such as smooth muscle or intervening neural parenchyma (1). The nature of these lesions suggests an abnormality in normal development of these capillaries; however, the mechanism of their occurrence and an explanation for their focal nature have remained elusive.The aberrant channels in CCM lesions are fragile, commonly resulting in intracranial hemorrhage. Clinical signs and symptoms are largely determined by the size and location of the hemorrhage, and range from incidental findings on MRI (Fig. 1) to rare catastrophic cerebral hemorrhage resulting in death. The disease has been recognized as a common clinical entity because of the advent of MRI (2). Both MRI and autopsy studies suggest a prevalence of cavernous malformation up to 0.5%, although only 20-30% of affected individuals develop symptomatic disease (3-8).Symptomatic patients typically present in the third through the fifth decades of life (3) with headaches, seizures, or focal neurological deficits. Treatment ranges from therapy with anti-epileptic drugs in patients with seizures, to surgical excision of accessible lesions in patients who suffer from hemorrhage or intractable seizures (9-13).Si...

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mentioning

confidence: 99%

KRIT1 , a gene mutated in cerebral cavernous malformation, encodes a microtubule-associated protein

Günel

Laurans

Shin

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

111

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“…Davison and Rosenheck (1937) report a case of mesencephalic telangiectases and discuss the rarity of neurological signs in telangiectasia of the central nervous system. Michael and Levin (1936) on the other hand, report a family with hereditary telangiectasia which caused convulsions and focal neurological signs. In their review of previous cases of telangiectasia, neurological manifestations, often transient, were said to be common.…”

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confidence: 99%

Hereditary haemorrhagic telangiectasia: neuropathological observations.

Heffner¹,

Solitare²

1969

Journal of Neurology, Neurosurgery & Psychiatry

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CLINICAL HISTORY This 65-year-old Negro man was first seen at the Yale-New Haven Hospital at the age of 54 with anaemia secondary to gastrointestinal bleeding. Diagnostic studies included an upper gastrointestinal series, barium enema, and sigmoidoscopy, but no source of bleeding was found. At the age of 63 he again entered hospital with melaena and offered the history of occasional episodes of epistaxis. Multiple telangiectases were noted on the lips, palate, tongue, conjunctive, and skin. Gastroscopy revealed numerous telangiectases on the anterior gastric wall. The diagnosis of OslerWeber-Rendu disease was made. The patient's daughter, aged 37, also had a history of anaemia and telangiectasia and a grandchild suffered from epistaxis, telangiectases, and anaemia.A year later the patient was hospitalized with persistent severe bifrontal headaches. Neurological examination disclosed hyperactive reflexes and bilateral positive Babinski signs which subsequently became normal during his hospital stay. Skull radiographs and cerebrospinal fluid examinations were normal. The clinical impression was temporal arteritis, prompting a biopsy of the right temporal artery which showed slight arteriosclerosis. The patient's symptoms spontaneously resolved and he was discharged from the hospital without a definitive diagnosis. He was seen six months later com-

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Ataxia-Telangiectasia

Korein¹

1961

Arch Neurol

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In 1941 Madame Louis-Bar1 described a 9-year-old boy with progressive cerebellar ataxia and bilateral symmetrical telangiectasia involving the sclerae, the external ears, and the exposed skin of the extremities.The disease is usually familial and includes abnormality of eye movements, dysarthria, decreased deep reflexes, tendency to frequent sinopulmonary infections and retardation of physical development. Between 1956 and 1960, a series of independent re-ports from 8 medical centers described 22 children with this syndrome.2-11 The most notable of these is the excellent paper by Boder and Sedgwick, which reports on 8 cases.3 * The present report deals with another case which we have observed. The available literature is reviewed and discussed and the possible relationship of the disease to the hereditary ataxias and the phakomatoses is considered.

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Multiple Telangiectases of the Brain

Cited by 63 publications

References 9 publications

KRIT1 , a gene mutated in cerebral cavernous malformation, encodes a microtubule-associated protein

KRIT1 , a gene mutated in cerebral cavernous malformation, encodes a microtubule-associated protein

Hereditary haemorrhagic telangiectasia: neuropathological observations.

Ataxia-Telangiectasia

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