1/10. Vasculopathic changes of cadasil can be focal in skin biopsies.Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (cadasil) is a newly described cause of vascular dementia. Pathologic examination shows multiple small infarcts in the deep cerebral white matter together with a nonatherosclerotic, nonamyloid angiopathy involving the media of small cerebral arteries. Ultrastructurally, characteristic granular material is present in the basal lamina of vascular smooth muscle cells in cerebral and extracerebral blood vessels. The ultrastructural changes have also been demonstrated in skin biopsies of affected patients; consequently, some investigators have recently recommended skin biopsies for the diagnosis of cadasil. This study describes a 54-year-old male with a family history for strokes who had clinical and radiological features suggestive of cadasil. A skin biopsy was performed to confirm the diagnosis. Initially, the characteristic vasculopathic changes of cadasil were not identified within small blood vessel walls. However, multiple deeper sections in other areas showed electron-dense material associated with vascular smooth muscle cells, characteristic of cadasil. Subsequent genetic testing demonstrated a single nucleotide substitution at position 659 on chromosome 19p13.1 causing an amino-acid change (Cys --> Phe), a finding indicative of cadasil. The involvement of blood vessels within the dermis makes skin biopsy a useful adjunct in the diagnosis of cadasil. However, as illustrated by this case, the findings may be focal, requiring a thorough evaluation of the entire biopsy specimen.- - - - - - - - - - ranking = 1keywords = family (Clic here for more details about this article) |
2/10. Majewski osteodysplastic primordial dwarfism type II (MOPD II): natural history and clinical findings.A description of the clinical features of Majewski osteodysplastic primordial dwarfism type II (MOPD II) is presented based on 58 affected individuals (27 from the literature and 31 previously unreported cases). The remarkable features of MOPD II are: severe intrauterine growth retardation (IUGR), severe postnatal growth retardation; relatively proportionate head size at birth which progresses to true and disproportionate microcephaly; progressive disproportion of the short stature secondary to shortening of the distal and middle segments of the limbs; a progressive bony dysplasia with metaphyseal changes in the limbs; epiphyseal delay; progressive loose-jointedness with occasional dislocation or subluxation of the knees, radial heads, and hips; unusual facial features including a prominent nose, eyes which appear prominent in infancy and early childhood, ears which are proportionate, mildly dysplastic and usually missing the lobule; a high squeaky voice; abnormally, small, and often dysplastic or missing dentition; a pleasant, outgoing, sociable personality; and autosomal recessive inheritance. Far-sightedness, scoliosis, unusual pigmentation, and truncal obesity often develop with time. Some individuals seem to have increased susceptibility to infections. A number of affected individuals have developed dilation of the CNS arteries variously described as aneurysms and Moya Moya disease. These vascular changes can be life threatening, even in early years because of rupture, CNS hemorrhage, and strokes. There is variability between affected individuals even within the same family.- - - - - - - - - - ranking = 1keywords = family (Clic here for more details about this article) |
3/10. Retinal manifestations in fibromuscular dysplasia.fibromuscular dysplasia of the arteries (FMD) is a segmental angiopathy which may produce obstruction of the carotid, cerebral, renal, mesenteric, coronary or iliac arteries. Except for lesions related to arterial hypertension, retinal manifestations have not yet been reported. This paper describes the case of a 10-year-old boy with progressive deafness, a history of an unexplained stroke and progressive occlusions of the retinal arterioles in the fundus periphery. This resulted in retinal neovascularization and recurrent retinal and vitreous hemorrhages. Despite repeated photo- and cryocoagulation the eyes progressed to a tractional retinal detachment which was successfully treated by vitrectomy and scleral buckling. The diagnosis of FMD was made on the basis of a histopathological examination of a temporal artery biopsy. The child also presented an asymptomatic but severe aneurysmal dilatation of the aorta and CT scan and MRI showed dilated cerebral arteries. The father of our patient had died at the age of 27 years either from myocardial infarction or rupture of a dissecting aortic aneurysm. He was highly myopic and had lost one eye from retinal detachment. The younger brother of our patient also presents aneurysmal dilatation of the aorta and tortuous cerebral vessels. Ocular examination is still normal. The findings in this family are compatible with an autosomal dominant inheritance with variable expression.- - - - - - - - - - ranking = 1keywords = family (Clic here for more details about this article) |
4/10. Familial hemiplegic migraine and autosomal dominant arteriopathy with leukoencephalopathy (cadasil).Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (cadasil) is a recently described familial cerebrovascular disorder shown to map to chromosome 19q12. Familial hemiplegic migraine has also been shown in some families to map close to the cadasil locus. The fully developed cadasil phenotype consists of recurrent strokes developing in the fourth decade, progressing to a pseudobulbar palsy, spastic quadriparesis, and subcortical dementia. In an Irish family 15 members were fully investigated by magnetic resonance scanning; 10 had typical magnetic resonance features of cadasil. Five members of this family had familial hemiplegic migraine and 4 of these had magnetic resonance evidence of cadasil. Two other members had migraine with and without aura as a presenting clinical symptom of cadasil. This disorder has been shown by linkage analysis to map to the cadasil locus at chromosome 19. The phenotype at presentation of cadasil in this family was variable and age related and included familial hemiplegic migraine, migraine with and without aura, transient ischemic attacks, strokes, and spinal cord infarction. This family study increases our understanding of the spectrum of clinical manifestations of this underrecognized familial cerebrovascular disorder.- - - - - - - - - - ranking = 4keywords = family (Clic here for more details about this article) |
5/10. A four-generation Dutch family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (cadasil), linked to chromosome 19p13.We describe a four-generation Dutch family suffering from cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (cadasil). Of twenty affected family members, ten are still alive. Age at onset of the strokes was between 29 and 52 years, with a mean of 41.8 years. This family has the typical clinical and radiological features of cadasil (except for the occurrence of ischemic heart disease at a relatively young age in some subjects), and is linked to chromosome 19p13. This disease has so far been described in families from finland, france, germany, italy, japan, spain and the United Kingdom, and there is a remarkable clinical and genetical homogeneity among all families reported, including this Dutch family.- - - - - - - - - - ranking = 8keywords = family (Clic here for more details about this article) |
6/10. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: study of two American families with predominant dementia.Few European families have been reported with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (cadasil). We describe four patients from two independent American families. All four cases underwent comprehensive clinical, neuropsychological and pathological examination. Pathological data were correlated with clinical features. dementia was a prominent and constant feature in all subjects. The families differed in phenotypical presentation and we analyzed possible pathological substrates that may account for the differences. autopsy showed multiple ischemic infarcts in the white matter, abnormal vasculature with thickening and degeneration of the vessel wall. The clinical course in the first family was characterized by early dementia without stroke-like episodes; however, autopsy demonstrated strokes in the basal ganglia and thalamus. The members of the second family developed dementia later and had history of several clinically evident strokes. Pathological examination showed only widespread degeneration of the white matter. Our study of two American families with cadasil suggests that involvement of the basal ganglia and thalamus is important for early development of dementia and clinically can present as a gradual dementia, resembling a neurodegenerative process. Selective damage of the white matter and central gray matter provides further insight to the pathogenesis of vascular dementia.- - - - - - - - - - ranking = 2keywords = family (Clic here for more details about this article) |
7/10. Phenotypic variability of cadasil and novel morphologic findings.Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (cadasil) is a non-arterio-atherosclerotic, non-amyloidotic arteriopathy affecting preferentially the small arteries and arterioles of the brain. The morphologic hallmark is the presence of a characteristic granular alteration of the arterial media that ultrastructurally corresponds to the accumulation of electron-dense material surrounding the smooth muscle cells. Although the presence of this granular osmiophilic material (GOM) was originally described as limited to brain vessels, identical electron microscopic findings have been demonstrated in the media of peripheral tissue arteries, allowing for a pathologic diagnosis of the disease by a simple skin, muscle or nerve biopsy. We report some atypical features identified in our cadasil patients that broaden the phenotypic expression of this disease. Firstly, we identified a cortical infarct in an otherwise typical cadasil patient. Secondly, we observed GOM in skin arteries of a 30-year-old man with hemiplegic migraine, the son of a woman who had died with cadasil. This confirms that it may be possible to diagnose the disease at a preclinical stage by the ultrastructural evaluation of peripheral tissue biopsy material, particularly for individuals for whom there is a supporting family history. Thirdly, ultrastructural examination of the skin, and subcutaneous and striated muscle of an unrelated and apparently sporadic patient with neuropathologic and neuroradiologic evidence of cadasil in meningeal and cerebral vessels failed to reveal diagnostic lesions in peripheral arteries. Thus, the possibility of a false-negative pathologic diagnosis in patients with a clinicoradiologic diagnosis of cadasil, if one relies solely on a peripheral tissue biopsy, does exist. Additionally, we have identified heat shock proteins (Hsp70 and alphaB crystallin) and ubiquitin in the vascular myocytes of affected arteries.- - - - - - - - - - ranking = 1keywords = family (Clic here for more details about this article) |
8/10. Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS).We describe a Chinese American family with a hereditary syndrome consisting of retinopathy, nephropathy, and stroke, affecting 11 members spanning three generations. Ophthalmologic evaluations revealed macular edema with capillary dropout and perifoveal microangiopathic telangiectases. Several members had renal abnormalities with proteinuria and hematuria. Initial manifestations were visual impairment and renal dysfunction; neurologic deficits occurred in the third or fourth decade of life. Symptoms included migraine-like headache, psychiatric disturbance, dysarthria, hemiparesis, and apraxia. neuroimaging consistently demonstrated contrast-enhancing subcortical lesions with surrounding edema. Ultrastructural studies showed distinctive multilaminated vascular basement membranes in the brain and in other tissues, including the kidney, stomach, appendix, omentum, and skin. Genetic analysis ruled out linkage to the cadasil locus on chromosome 19. Distinct from cadasil, hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS) is an autosomal dominant multi-infarct syndrome with systemic involvement.- - - - - - - - - - ranking = 1keywords = family (Clic here for more details about this article) |
9/10. Autosomal dominant cerebral arteriopathy: neuropsychiatric syndrome in a family.Though familial vascular leukoencephalopathy was described two decades ago, recent studies focus on a disorder termed Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (cadasil), a dominantly inherited disorder causing recurrent strokes and eventual dementia. The phenotypic boundaries of cadasil remain indistinct and novel clinical features continue to arise in the literature. However, the associated histopathology is fairly consistent, typically demonstrating granular thickening of cerebral arterioles. The authors evaluated a 38-year-old man who suffered from progressive change in personality and intellect. His father, paternal aunt, and older sister had succumbed to a similar disorder. The authors examined relatives from three generations, including another sister with transient focal symptoms followed by persisting psychiatric disorder, and reviewed the radiographic studies from the propositus and his siblings. All the siblings showed diffuse white matter signal change on magnetic resonance imaging. brain biopsy from the propositus revealed normal cortex and white matter but granular sclerosis of leptomeningeal arterioles. While the family's illness likely represents another instance of cadasil, their presentation is unique because neuropsychiatric disorders predominate over focal ischemic symptoms.- - - - - - - - - - ranking = 5keywords = family (Clic here for more details about this article) |
10/10. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (cadasil). Neuropathological and in vitro studies of abnormal elastogenesis.This study was performed on a family of cadasil (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy) subjects. Neuropathological alterations of small arteries consisting in thickening, reduplication and fragmentation of the internal elastic lamella, and granular periodic acid-Schiff-positive material deposited in the arterial media were demonstrated in 1 autopsy case by histochemistry and electron microscopy. This material reacted with a monoclonal antibody anti-elastin (aE), as demonstrated by immunohistochemistry and immunoelectron microscopy. Significant increases of aE-immunoreactivity and elastin mRNA expression were found in cultured skin fibroblasts from 5 family members genetically affected by cadasil, but not genetically and clinically healthy members. These results suggest that alterations of the elastic apparatus are associated with cadasil genotype and related to the clinical expression of the disease.- - - - - - - - - - ranking = 2keywords = family (Clic here for more details about this article) |
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