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At least 199 records · Page 11Linked to original sources
PubMed2005

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) presenting with sudden sensorineural hearing loss.

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is an autosomal dominant angiopathy characterized by recurrent cerebrovascular events, migraine and dementia. We describe a case of sensorineural hearing loss as the presenting feature of this condition. We have found no previous reports in the world literature of CADASIL presenting with a sudden sensorineural hearing loss. The significance of questioning a patient with regard to family history is exemplified in this case.

Adult↗
PubMed2006

CADASIL with a novel mutation in exon 7 of NOTCH3 (C388Y).

We report a 38-year-old Japanese woman who had cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with a novel mutation (TGT to TAT) at nucleotide position 1241 (C388Y) in exon 7 of the Notch3 gene (NOTCH3). Immunostaining of a skin biopsy with a Notch3 monoclonal antibody is a beneficial method for the screening of CADASIL, particularly in the case of rare mutations outside the mutation hotspots in NOTCH3 as shown in this patient.

Adult↗
PubMedDate not supplied

[The CADASIL syndrome: a model of subcortical-cortical disconnection].

INTRODUCTION: CADASIL syndrome (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarts and Leukoencephalopathy) includes some neurological signs and symptoms (gait disturbances, epileptic seizures, pseudobulbar palsy, migraines, etc.), as well as neuropsychological dysfunctions (cognitive and executive impairment, emotional disorders and, frequently, dementia). This syndrome is a good model of white matter damage and potential disconnection syndromes. CLINICAL CASE: In this article, the neuropsychological profile of a 47 year-old woman diagnosed of CADASIL is investigated and thoroughly discussed. Results show the presence of a moderate cognitive and executive impairment, specially of memory, psychomotor abilities, executive functions and verbal fluency, but not dementia, overall suggesting the presence of a temporal-frontal-subcortical disfunction. CONCLUSION: This clinical pattern is an illuminating example of the neuropsychological consequences of the partial disconnection of prefrontal cortex from the thalamus and basal ganglia.

Brain↗
PubMedDate not supplied

Early diagnosis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): the role of MRI.

The aim of our work was to evaluate the early presence of white matter changes on magnetic resonance imaging (MRI) in young asymptomatic children of patients with full-blown cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in whom DNA analysis revealed a Notch3 Cys146Tyr missense mutation on chromosome 19. Brain MRI was performed in all subjects using axial and coronal spin-echo proton density and T2-weighted images, axial fluid-attenuated inversion recovery (FLAIR) and sagittal and axial T1-weighted images. In asymptomatic subjects with Notch3 gene mutation, MRI showed small T2 hyperintense foci in periventricular and subcortical white matter. Routine use of MRI in the initial phases of a CADASIL diagnostic work up and the subsequent recognition of early abnormal findings in asymptomatic subjects may lead to prompt diagnosis of the disease in these patients. Moreover, these findings suggest that genetic screening is warranted in the presence of a suspect clinical history with specific MRI abnormalities.

Adult↗
PubMed2005

[Japanese CADASIL case with limited dementia who had the Notch 3 R141C mutation].

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary disease characterized by recurrent transient ischemic attacks (TIA) and strokes, and vascular dementia caused by point mutations of the Notch 3 gene. Here, we report a Japanese CADASIL case who displayed limited dementia and had the Notch 3 R141C mutation. The relationship between pathogenesis and the mutation site in Notch 3 is discussed based on the case presented here.

CADASIL↗
PubMedDate not supplied

Co-existing spinal canal tumours and CADASIL - a diagnostic challenge.

We would like to present a case of a 51-year-old patient with two rare co-existing diseases. The patient was suffering from two tumours in the lumbar region of the spinal canal, which caused development of hydrocephalus. Diffuse white matter hyperintensities (WMH) were observed in our patient's brain imaging. She was also suffering from headaches and she had two mild strokes. We performed some further diagnostic procedures and found out that the patient was suffering from CADASIL. CADASIL was confirmed by both ultrastructural analysis and genetic testing.

CADASIL↗
PubMed1998

The phenotypic spectrum of CADASIL: clinical findings in 102 cases.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an increasingly recognized autosomal dominant disorder that leads to cerebrovascular manifestations in early adulthood. This study delineates the phenotypic spectrum and the natural history of the disease in 102 affected individuals from 29 families with biopsy-proven CADASIL. Recurrent ischemic episodes (transient ischemic attack [TIA] or stroke) were the most frequent presentation found in 71% of the cases (mean age at onset, 46.1 years; range, 30-66 years; SD, 9.0 years). Forty-eight percent of the cases had developed cognitive deficits. Dementia (28%) was frequently accompanied by gait disturbance (90%), urinary incontinence (86%), and pseudobulbar palsy (52%). Thirty-nine patients (38%) had a history of migraine (mean age at onset, 26.0 years; SD, 8.2 years), which was classified as migraine with aura in 87% of the cases. Psychiatric disturbances were present in 30% of the cases, with adjustment disorder (24%) being the most frequent diagnosis. Ten patients (10%) had a history of epileptic seizures. To delineate the functional consequences of ischemic deficits, we studied the extent of disability in different age groups. The full spectrum of disability was seen in all groups older than age 45. Fifty-five percent of the patients older than age 60 were unable to walk without assistance. However, 14% in this age group exhibited no disability at all. Kaplan-Meier analysis disclosed median survival times of 64 years (males) and 69 years (females). An investigation of the 18 multiplex families revealed marked intrafamilial variations.

Adult↗
PubMed1996

A human homolog of bacterial acetolactate synthase genes maps within the CADASIL critical region.

CADASIL, a recently identified autosomal dominant condition characterized by the recurrence of subcortical infarcts leading to dementia, was previously mapped to chromosome 19p13.1 within a 2-cM interval, D19S226-D19S199. No recombination event was observed with D19S841, a highly polymorphic microsatellite marker isolated from a cosmid mapped to this region. We recently identified within this cosmid a conserved sequence that we used to screen a fetal brain cDNA library and isolated an ubiquitous and abundantly transcribed gene. We did not detect any mutation of this gene in CADASIL patients, suggesting that it is not implicated in this disorder. Interestingly, this gene encodes a putative protein homologous to several thiamine pyrophosphate-binding proteins previously identified in bacteria, yeast, and plants. The proteins with the highest degree of similarity were the acetolactate synthase enzymes which, in prokaryotes, are involved in the branched chain amino acid biosynthetic pathway, raising fascinating questions on the yet unknown function of this gene in mammals.

Acetolactate Synthase↗
PubMed2002

CADASIL and genetics of cerebral ischaemia.

Recent advances suggest the existence of several autosomal dominantly inherited forms of cerebrovascular disorders. Mutations in diverse genes may induce direct pathological changes in intracranial vessels to cause cerebral ischaemic or haemorrhagic strokes leading to cognitive impairment and dementia. Similar pathology may also be caused by systemic vascular disease resulting from mutations and polymorphisms in genes that regulate cardiovascular physiology, blood coagulation and metabolic functions. The most common form of familial stroke appears to be CADASIL or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. CADASIL is an arterial disease that has been linked to nucleotide substitutions and deletions in the Notch 3 gene. The pathogenesis of the disorder or how the mutations lead to cerebral infarcts and dementia is not known. However, elucidation of the microvascular pathology associated with such genetic disorders not associated with physiological risk factors for cardiovascular disease or stroke can bear much light on primary vascular mechanisms that lead to ischaemic blood flow and neuronal vulnerability.

Animals↗
PubMed1995

Identification of the characteristic vascular changes in a sural nerve biopsy of a case with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy' (CADASIL) has recently been identified as a hereditary disorder with characteristic fine structural changes of small intracerebral arteries and arterioles. Electron microscopically there are characteristic perivascular deposits of granular electron-dense material resembling immunoglobulin deposits. The present case from a family with four affected members in three successive generations shows that similar vascular changes as described in the central nervous system are present in blood vessels of the sural nerve, although less pronounced and, therefore, affording electron microscopy for their unequivocal detection. Nevertheless it has been shown for the first time that the diagnosis of CADASIL can be verified by a sural nerve biopsy. Occasional focal accumulation of pinocytotic vesicles opposite the granular deposits suggests exocytosis as one of the possible pathomechanisms for their production.

Biopsy↗
PubMed2003

CADASIL: new cases and new questions.

We described the first two unrelated Polish families with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). In the morphological examination with light microscopy, two kinds of changes were observed: (1). panarteritis nodosa-like changes with eosinophilic fibrinoid necrosis of the vessel wall and perivascular inflammatory infiltrates and (2). basophilic granular material in the tunica media characteristic of CADASIL. At electron microscopy, we found deposits of granular osmophilic material (GOM) within the wall of arteries, veins and capillary vessels. Our findings imply two questions requiring further investigation: Why in the genetically determined vascular disorder are the features of systemic inflammatory vascular disease present? Why in capillary walls deprived of smooth muscle cells are deposits of GOM present?

Adult↗
PubMed2004

Subcortical angiopathic encephalopathy in a German kindred suggests an autosomal dominant disorder distinct from CADASIL.

A cerebral arteriopathy with subcortical infarcts and leukoencephalopathy is described with a pedigree suggestive for an autosomal dominant condition. In contrast to the vasculopathy designated with the acronym CADASIL, no deposits of granular osmiophilic material were detected in the vasculature and no point mutations in the NOTCH 3 gene were found. The disease occurred in a family living near Hamburg, Germany, and affected 11 women and 11 men over the last six generations. Onset of the disease was between the age of 12 and 50. Clinical symptoms included gait disturbances, dysarthria, sensomotoric deficits and a progressive dementia. Migraine-like complaints and epileptic seizures were observed in one case each. Cranial computer tomography and magnetic resonance imaging scans showed large confluent areas with decreased density in the white matter and small necroses in the brain stem, the basal ganglia and the white matter. A correlation with factors predisposing for vascular diseases could not be demonstrated. In five cases an autopsy was performed which disclosed an angiopathy affecting predominantly the penetrating arteries with consecutive lacunar infarcts, diffuse demyelination and rarefication of the subcortical white matter and degeneration of the pyramidal tracts. Histologically, the vessels showed concentric and excentric intimal proliferation, an elastosis and hyalinosis, splitting of the lamina elastica interna and a degeneration of the tunica muscularis. Electron microscopy revealed fragmentation and thickening of the basal lamina but electron-dense granules characteristic for CADASIL were not detected.

Adult↗
PubMed2001

Reversible coma with raised intracranial pressure: an unusual clinical manifestation of CADASIL.

A 50-year-old woman presented with recurrent episodes of headache, nausea and disturbed consciousness that were fully reversible within a few days. Clinical and radiological findings suggested raised intracranial pressure, which on one occasion was confirmed by intracranial pressure monitoring. Magnetic resonance imaging performed in the asymptomatic interval disclosed a diffuse leukoencephalopathy. Brain biopsy surprisingly revealed the typical vascular changes of CADASIL and subtle endothelial alterations. The white matter showed edematous changes and reactive gliosis. Mutational analysis of the Notch3 gene revealed a previously unreported mutation. We suggest that a transient disturbance of the blood-brain barrier related to the underlying vascular pathology may have caused this unusual presentation of CADASIL.

Coma↗
PubMed2004

An Italian case of CADASIL with mutation CGC-TCG in codon 1006, exon 19 Notch3 gene.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is commonly overlooked or misdiagnosed owing to its recent identification. It is characterized clinically by recurrent cerebral infarcts, usually appearing between the ages of 30 and 50 years, subcortical dementia, and pseudobulbar palsy. It begins with migraine with aura in approximately one-third of patients. The pathological hallmark of angiopathy is the presence of characteristic granular osmiophilic material (GOM) within the basal lamina of smooth muscle cells. The defective gene in CADASIL is Notch3, which encodes a large transmembrane receptor, and 70% of missense mutations are in exons 3 and 4. Each gene defect leads to either a gain or loss of a cysteine residue in the extracellular N-terminal domain of the molecule. We report the case of a 53-year-old woman admitted to the hospital for transient ischemic attack and stroke-like episodes recurrent since age 43 years. The patient had pseudobulbar palsy, pyramidal signs, and cognitive impairment but not frank dementia. Cerebral MRI showed periventricular diffuse and confluent ischemic lesions. Ultrastructural study revealed an abnormal deposition of granular osmiophilic material (GOM) within the basal lamina in skin capillaries. Direct sequence analysis of the Notch3 gene was performed. Since no mutation was detected in exons 3 and 4, the remaining exons were sequenced and a missense mutation, CGC-TGC in codon 1006 of exon 19 was found. The mutation led to a gain of a cysteine residue. This is the first missense mutation in codon 1006 of exon 19 of the Notch3 gene to be described in Italy and the second reported in the literature.

Brain↗
PubMed1995

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.

Adult↗
PubMed2001

A CADASIL case with normal skin biopsy and without mutations in exons 3 and 4 of the Notch3 gene.

The diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is usually confirmed by genetic testing or skin biopsy. We here report the case of a 69-year-old woman with recurrent transient ischemic attacks (TIAs) and strokes, seizures, and dementia without any mutations in exons 3 and 4 of the Notch3 gene and with a normal skin biopsy, but who showed characteristic CADASIL abnormalities on brain pathological examination. Our findings suggest that negative results in these two tests do not exclude the disease and a leptomeningeal biopsy or a second skin biopsy should be considered in such cases.

Aged↗
PubMed2003

Cerebral arterial pathology of CADASIL and CARASIL (Maeda syndrome).

Two familial cerebro-vascular diseases characterized by different cerebral arterial pathologies and presenting in non-hypertensive young and middle-aged adults are described. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by the deposition of smudged periodic acid-Schiff (PAS)-positive granules known as granular osmiophilic materials (GOM) in the media of small arteries and arterioles. The medial smooth muscle cells are completely lost, and intense adventitial fibrosis is present. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), or Maeda syndrome, is characterized by intense arteriolosclerosis without GOM deposition. Fibrous intimal proliferation, hyaline degeneration of the media, thickening and splitting of the internal elastic lamina, and concentric narrowing of the lumen are characteristic features. In PAS preparation, small arteries are occasionally stained homogeneously due to exudative changes, but never exhibit granular appearance in CARASIL (Maeda syndrome). Each of the small arterial changes is intense in the cerebral medullary and leptomeningeal arteries, leading to multifocal, confluent, or diffuse ischemic changes in the cerebrum. The authors suggest that CARASIL be referred to as 'Maeda syndrome' or 'CARASIL (Maeda syndrome)' to avoid confusion with CADASIL.

Adult↗
PubMed1998

CADASIL: a review with proposed diagnostic criteria.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) can be considered as a new disease predominantly affecting the small vessels of the brain with an autosomal dominant transmission linked to chromosome 19. This review includes an historical perspective showing how the disease was identified from the spectrum of vascular leukoencephalopathies. More than two hundred patients have now been described, belonging to at least 30 unrelated pedigrees in Europe, America and Asia. The clinical features include four major neurological presentations associated in variable degrees during the course of the disease: migraine with or without aura, strokes or stroke-like episodes, major psychiatric symptoms and dementia. The patients are free of the classical vascular risk factors. The disease has a progressive or stepwise course with age at onset in the forties and a mean duration of 13.6 +/- 10.7 years. Death occurs in the fifties in a characteristic condition associating a pseudo-bulbar syndrome and subcortical dementia. Cerebral magnetic resonance imaging (MRI) is highly contributive to the diagnosis, showing a diffuse leukoencephalopathy with subcortical infarcts in the basal ganglia and white matter. Pathological data show macroscopic lesions similar to Binswanger's disease but different lesions of the small vessels including thickening of the media, characteristic PAS+ granular material and narrowing of the lumen. Skin biopsy may be a valuable diagnostic tool, showing ultrastructural alterations of skin vessels similar to those of brain vessels. The disease is highly homogeneous on a genetic basis and the identification of the gene Notch 3 on chromosome 19 has opened new avenues for research and genetic counselling. The pathogenesis of the disease has still to be elucidated. A definite diagnosis relies on genetical or pathological data. Diagnostic criteria are proposed to recognize the disease on clinical and imaging parameters. So far, no treatment has been reported to be successful for CADASIL. Copyright Lippincott-Raven Publishers

Journal Article↗