1/32. White matter dementia in cadasil.Cerebral white matter disorders may be associated with profound neurobehavioral dysfunction. We report a 62-year-old man who had a slowly progressive 25-year history of personality change, psychosis, mood disorder, and dementia. neurologic examination disclosed abulia, impaired memory retrieval, and preserved language, with only minimal motor impairment. Neuropsychological testing found a sustained attention deficit, cognitive slowing, impaired learning with intact recognition, and perseveration. magnetic resonance imaging of the brain revealed extensive leukoencephalopathy. Right frontal brain biopsy showed ill-defined white matter pallor with hyaline narrowing of white matter arterioles. Granular osmiophilic material adjacent to vascular smooth muscle cells on electron microscopy of a skin biopsy, and an arginine for cysteine replacement at position 169 in the 4 EGF motif of the notch 3 region on chromosome 19q12 established the diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (cadasil). This case illustrates that cadasil can manifest as an isolated neurobehavioral disorder over an extended time period. The dementia associated with cadasil closely resembles that which may occur with other white matter disorders, and represents an example of white matter dementia.- - - - - - - - - - ranking = 1keywords = leukoencephalopathy (Clic here for more details about this article) |
2/32. migraine with aura and white matter abnormalities: Notch3 mutation.The authors report on an Italian family with eight affected members who show autosomal dominant migraine with prolonged visual, sensory, motor, and aphasic aura. These symptoms are associated with white matter abnormalities on brain MRI. All living affected members carry a Notch3 mutation (Arg153Cys) previously reported in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (cadasil). White matter abnormalities occur in a variable percentage of the general migraine population; cadasil should be suspected in migraineurs with prolonged atypical aura and white matter abnormalities.- - - - - - - - - - ranking = 0.5keywords = leukoencephalopathy (Clic here for more details about this article) |
3/32. Visual electrophysiological responses in subjects with cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (cadasil).OBJECTIVES: To evaluate visual electrophysiological responses in subjects with cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (cadasil). methods: Three subjects (one male and two females, mean age 55.3 /-2.9 years) belonging to an Italian family already diagnosed with cadasil through clinicopathological and genetic studies and 14 control subjects (6 males and 8 females, mean age 52.7 /-3.6 years) were enrolled in the study. Flash electroretinogram (ERG), oscillatory potentials (OPs) and simultaneous recordings of pattern electroretinogram (PERG) and visual evoked potentials (VEPs) were assessed in all 3 subjects with cadasil and age-matched controls. RESULTS: Subjects with cadasil showed: reduced ERG, OP and PERG (N35-P50, P50-N95) amplitudes with respect to our normal limits; delayed PERG (N35, P50) and VEP (P100) implicit times when compared with our normal limits; and VEP (N75-P100) amplitudes and retinocortical times within our normal limits. CONCLUSIONS: Subjects with cadasil present a dysfunction in the outer, middle and innermost retinal layers when the index of neural conduction in the postretinal visual pathways is normal. The delay in visual cortical responses observed in subjects with cadasil may be ascribable to retinal impairment with a possible functional sparing of the postretinal visual structures.- - - - - - - - - - ranking = 2.5keywords = leukoencephalopathy (Clic here for more details about this article) |
4/32. Arg133Cys mutation of Notch3 in two unrelated Japanese families with cadasil.OBJECTIVE: More than 80 unrelated, but all Caucasian, patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (cadasil), originating from various communities around the world, have been molecularly identified. To clarify the occurrence of cadasil in Orientals, we investigated Japanese families presenting as cadasil. methods: We performed the PCR-SSCP and sequence analyses using genomic dna, isolated from venous blood of participants under informed consent. patients: We identified two unrelated Japanese families with cadasil, including 5 affected members through 2 generations. RESULTS: Each of the affected individuals developed recurrent strokes without risk factors resulting in progressive dementia, pseudobulbar palsy, and gait disturbances which started after the fifth decade of life. Although affected individuals had no vascular risk factors, they showed various degrees of narrowing of retinal arteries. Their MRI/CTs showed characteristics of the disease; bilateral small infarcts in the thalamus, basal ganglia, brain stem, and deep white matter in addition to the findings of leukoaraiosis. On SPECT imaging, there was severe hypoperfusion in the cortex as well as in the white matter. Ultrastructural studies revealed an abnormal deposition of granular osmiophilic materials (GOM) within the basal lamina of pericytes in muscular capillaries. On PCR-SSCP and sequence analyses, a heterozygous Arg133Cys mutation was present, in the affected individuals, in the exon 4 of Notch3 gene which is the hot spot region for cadasil mutations in Caucasian families. None of the non-affected members nor the 50 Japanese normal controls revealed this mutation. CONCLUSION: Thus, our results confirm that cadasil is a geographically widespread disorder caused by a Notch3 mutation.- - - - - - - - - - ranking = 0.5keywords = leukoencephalopathy (Clic here for more details about this article) |
5/32. cadasil (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy): diagnostic skin biopsy changes determined by electron microscopy.Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (cadasil) is a familial vascular disorder associated with migraines, recurrent ischemic strokes, and early-onset multiinfarct dementia. The diagnosis of cadasil is made ultrastructurally by finding characteristic granular, electron-dense, osmiophilic material attached to vascular smooth muscle cells. These changes have been found in brain, skeletal muscle, nerve, and skin. We describe a woman with cadasil diagnosed on the basis of brain and skin electronmicroscopic findings. Dermatologists and dermatopathologists need to be aware of this disorder because characteristic electronmicroscopic changes on a skin biopsy specimen are diagnostic.- - - - - - - - - - ranking = 2.5keywords = leukoencephalopathy (Clic here for more details about this article) |
6/32. Retinal findings in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (cadasil).We describe a 45-year-old man with biopsy proven cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (cadasil). This patient demonstrated unique retinal findings, including arteriole narrowing and sheathing, irregular choroidal filling on fluorescein angiography, and patchy visual field loss. cadasil is a hereditary, nonamyloid, nonathersclerotic microangiopathy. This disorder has been mapped to chromosome 19 with mutations in the Notch 3 gene. Deposits of granular osmiophilic material in the basal lamina of the smooth muscle cells of small vessels are considered pathognomonic for cadasil and are typically seen only on electron microscopy. Although cadasil is a systemic vascular disease affecting the entire arteriole tree, we are unaware of other reports describing the retinal findings observed in our patient.- - - - - - - - - - ranking = 2.5keywords = leukoencephalopathy (Clic here for more details about this article) |
7/32. cadasil: neuropsychological findings in three generations of an affected family.Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (cadasil) is a hereditary brain disease with a variety of neurologic and psychiatric manifestations. We studied 3 members of a family who each had leukoencephalopathy on neuroimaging studies and a characteristic mutation for cadasil in the notch 3 region of chromosome 19q12. In all 3 cases, neurobehavioral impairment dominated the clinical picture, and a pattern of psychiatric dysfunction heralding cognitive decline emerged. Neuropsychological evaluation revealed diverse deficits, but a profile of frontal lobe dysfunction, declarative memory impairment suggestive of a retrieval deficit, and relatively preserved language was evident. These cases provide a cross-sectional study of the evolution of cadasil, and suggest that, as in other diseases characterized by white matter dementia, psychiatric dysfunction may occur initially, followed by pervasive cognitive dysfunction later in the course of the disease. cadasil should be considered in young adults with unexplained leukoencephalopathy on neuroimaging studies, and in those with neurobehavioral dysfunction and a suggestive family history.- - - - - - - - - - ranking = 1.5keywords = leukoencephalopathy (Clic here for more details about this article) |
8/32. A novel mitochondrial dna mutation and a mutation in the Notch3 gene in a patient with myopathy and cadasil.Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (cadasil) is characterized by cerebral symptoms, but peripheral nerve or muscle involvement has not been reported. We describe a patient who had a stereotypic clinical presentation of cadasil and, in addition, myopathy with ragged-red fibers, suggesting a mitochondrial disorder. Therefore we determined the nucleotide sequence in the entire coding region of the patient's mtDNA by conformation-sensitive gel electrophoresis and sequencing. Sequence of the exon 4 in the Notch3 gene was determined in a similar fashion. We found that the patient had myopathy with ragged-red fibers, and ultrastructural examination revealed mitochondrial aberrations. cadasil was due to an R133C mutation in Notch3; in addition, we found a novel mutation 5650G>A in the tRNAAla gene in mtDNA. The mutation was heteroplasmic, with the proportions of the mutant genome being 99% in muscle, 96% in the buccal epithelium, 95% in the skin, and 65% in the blood. The absence of the mutation in a maternal cousin four times removed indicated that it was new in the pedigree. We suggest that the mtDNA mutation is pathogenic, as it was associated with a relevant clinical phenotype, it was not found among controls, and it altered a structurally important segment in the amino acid acceptor stem in the tRNAAla. Furthermore, its absence in nine patients from five families with R133C suggests that its relationship with the Notch3 mutation is coincidental.- - - - - - - - - - ranking = 0.5keywords = leukoencephalopathy (Clic here for more details about this article) |
9/32. 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.- - - - - - - - - - ranking = 0.5keywords = leukoencephalopathy (Clic here for more details about this article) |
10/32. Very high prevalence of right-to-left shunt on transcranial Doppler in an Italian family with cerebral autosomal dominant angiopathy with subcortical infarcts and leukoencephalopathy.BACKGROUND AND PURPOSE: Cerebral autosomal dominant angiopathy with subcortical infarcts and leukoencephalopathy (cadasil) is an autosomal dominant hereditary disease whose clinical expression is a stepwise subcortical vascular dementia. Initial presentation of the disease involves transient or stabilized focal neurological deficits, migraine and mood changes. Recently, a high prevalence of right-to-left shunt (RLS) due to patent foramen ovale has been reported in subjects with migraine. The aim of our study was to determine the prevalence of RLS in cadasil with and without migraine. methods: We performed transcranial Doppler with gaseous contrast in 5 members of an Italian family with cadasil, diagnosed by means of genetic and skin biopsy criteria. We then compared the prevalence of RLS in 40 consecutive subjects with juvenile stroke, 80 asymptomatic subjects affected by migraine with aura and 50 normal controls. RESULTS: A very high prevalence of RLS was found in cadasil patients (4/5, 80%), as opposed to young subjects with ischemic stroke (15/40, 37%), asymptomatic subjects with migraine (32/80, 40%) and normal controls (8/50, 16%). All the subjects with cadasil and migraine (4/4) showed RLS. The difference between cadasil patients and controls was highly significant (p = 0.006). CONCLUSIONS: We suggest an association between cadasil and RLS, possibly due to the abnormal development of the endocardial cushion influenced by Notch 3 mutation. Our hypothesis needs to be tested in larger samples.- - - - - - - - - - ranking = 2.5keywords = leukoencephalopathy (Clic here for more details about this article) |
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