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PubMed2005

The spectrum of mutations for CADASIL diagnosis.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is an inherited cerebrovascular disease due to mutations of the Notch3 gene at the chromosome locus 19p13. The clinical spectrum includes recurrent ischaemic episodes, cognitive deficits, migraine and psychiatric disorders. The histopathological hallmark of CADASIL is accumulation of electron dense granules (GOM) in the media of arterioles. MRI reveals extensive cerebral white matter lesions and subcortical infarcts. CADASIL was initially thought to be a rare disorder, but increasing numbers of families have been identified; therefore, it is likely that CADASIL is still largely underdiagnosed. Here we report an update on mutations of the Notch3 gene and some information on the pathogenesis of the disease.

Brain↗
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↗
PubMed2003

Yield of screening for CADASIL mutations in lacunar stroke and leukoaraiosis.

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic disorder typified by early onset lacunar strokes, subcortical dementia, psychiatric disturbances, and migraine. Mutations in the Notch3 gene are responsible. Atypical phenotypes have been recognized, and the disease is probably underdiagnosed in the wider stroke population. Therefore, we determined the yield of screening for Notch3 mutations in lacunar stroke with or without leukoaraiosis. METHODS: Two hundred eighteen consecutive patients were studied. All had brain and carotid imaging. Polymerase chain reaction-single-stranded conformational polymorphism analysis was used to screen exons 3, 4, 5, and 6 of the Notch3 gene for mutations and polymorphisms. RESULTS: A single mutation in exon 4 (C697T) was identified in a young patient, giving an overall carrier frequency of 0.05% (95% CI, 0.0 to 2.0). For patients with onset of lacunar stroke at < or =65 years and leukoaraiosis, the yield was 2.0% (95% CI, 0.4 to 10.9). CONCLUSIONS: Notch3 mutations are rare in patients with typical strokes due to cerebral small-vessel disease. In the absence of classic features suggestive of CADASIL, screening for Notch3 mutations has a low yield.

Adult↗
PubMed2006

A novel hereditary small vessel disease of the brain.

OBJECTIVE: Only few hereditary ischemic small vessel diseases of the brain (SVDB) have been reported so far. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most frequent of them. Herein, we report a family affected by a SVDB distinct from CADASIL. METHODS: After the occurrence of a small deep infarct associated with white matter lesions both in a 46-year-old man and in his 52-year-old sister, clinical and neuroimaging investigations were conducted in 13 of their relatives originating from Portugal. Other investigations included (1) skin biopsy immunostaining with a Notch3 monoclonal antibody, (2) sequencing of the 23 exons encoding the epidermal growth factor-like domains of the NOTCH3 gene, and (3) a NOTCH3 locus haplotype analysis. RESULTS: Diffuse white matter hyperintensities were observed on T2-weighted magnetic resonance imaging (MRI) in six individuals. In contrast with MRI results in the father and paternal uncle of the proband who were hypertensive, white matter lesions were extensive in the mother who had no vascular risk factor. MRI data in four asymptomatic family members together with the results in the two initial cases were suggestive of an underlying hereditary small vessel disease of the brain. Skin biopsy and NOTCH3 gene mutation screening were negative. Haplotype analysis excluded the NOTCH3 locus. INTERPRETATION: These data strongly suggest that this family is affected by a novel hereditary small vessel disease of the brain and that the mutated gene is distinct from NOTCH3.

Brain Ischemia↗
PubMed2007

Notch2 negatively regulates myofibroblastic differentiation of myoblasts.

Myofibroblasts are one of the key cellular components involved in fibrosis of skeletal muscle as well as in other tissues. Transforming growth factor-beta1 (TGF-beta1) stimulates differentiation of mesenchymal cells into myofibroblasts, but little is known about the regulatory mechanisms of myofibroblastic differentiation. Since Notch2 was shown to be downregulated in TGF-beta1-induced non-muscle fibrogenic tissue, we investigated whether Notch2 also has a distinctive role in myofibroblastic differentiation of myogenic cells induced by TGF-beta1. TGF-beta1 treatment of C2C12 myoblasts led to expression of myofibroblastic marker alpha-smooth muscle actin (alpha-SMA) and collagen I with concomitant downregulation of Notch2 expression. Overexpression of active Notch2 inhibited TGF-beta1-induced expression of alpha-SMA and collagen I. Interestingly, transient knockdown of Notch2 by siRNA in C2C12 myoblasts and primary cultured muscle-derived progenitor cells resulted in differentiation into myofibroblastic cells expressing alpha-SMA and collagen I without TGF-beta1 treatment. Furthermore, we found Notch3 was counter-regulated by Notch2 in C2C12 cells. These findings suggest that Notch2 is inhibiting differentiation of myoblasts into myofibroblasts with downregulation of Notch3 expression.

Actins↗
PubMed2006

Investigating the association between Notch3 polymorphism and migraine.

OBJECTIVE: The aim of the present study was to evaluate whether the functional Notch3 polymorphism T6746C, which is not causative for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), might be a risk factor for migraine. BACKGROUND: It has been recently demonstrated that migraine is characterized by subclinical brain infarctions and white matter lesions. Several genetic risk factors have been associated with migraine, but no study has unraveled a possible relationship between migraine and Notch3, which is involved in vascular damage. Mutations in Notch3 gene have been demonstrated to be pathogenetic for CADASIL, a small vessel disease of the brain characterized by migraine. METHODS: A total of 156 migraine patients and 128 nonheadache healthy volunteers entered the study. Demographic and clinical characteristics were carefully recorded, and a neurological work-up was performed. Moreover, each subject underwent a blood sampling for Notch3 genotype determination. RESULTS: Notch3 genotypes as well as allele frequencies did not differ in migraine patients compared to controls, even adjusting for the presence of possible confounds. No difference has been found either in migraine patients with aura or in those without aura. CONCLUSIONS: These findings support the view that functional polymorphism T6746C in Notch3 gene is not involved in increasing the risk of migraine or migraine subtypes.

Adult↗
PubMed2006

A new de novo Notch3 mutation causing CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is one of the most common hereditary forms of stroke, and migraine with aura, mood disorders, or dementia, are also frequently found in these patients. Missense mutations in the Notch3 gene that create or destroy cysteine residues, have been found in most cases with a family history of the disease, although a few sporadic cases harbouring Notch3 mutations have also been described. Here, we describe a 44-year-old patient with clinical features of CADASIL who was a carrier of a new Notch3 mutation: cys128-->gly. Both parents were alive and healthy, and negative for the mutation. This case illustrates the interest of analysing the Notch3 gene in cases with clinical features of CADASIL, even in the absence of a family history of the disease.

Adult↗
PubMed2004

A novel NOTCH3 frameshift deletion and mitochondrial abnormalities in a patient with CADASIL.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which leads to strokes and dementia, is caused by single missense mutations or, in a few cases, small deletions in the NOTCH3 gene. These mutations result in a gain or a loss of 1 (or, rarely, 3) cysteine residue in 1 of 34 epidermal growth factor-like repeats in the extracellular amino-terminal region of NOTCH3. OBJECTIVE: To describe a patient with a novel NOTCH3 mutation in whom clinical and laboratory findings of mitochondrial abnormalities were associated with a diagnosis of CADASIL. Patient A patient with a history of migraines, repeated transient ischemic attacks, and generalized fatigue underwent muscle biopsy, brain magnetic resonance spectroscopic imaging, and screening of mitochondrial DNA and NOTCH3. RESULTS: Molecular genetic analysis showed a NOTCH3 mutation (the first documented frameshift deletion in a patient with CADASIL) in exon 4. Although the screening of mitochondrial DNA did not show mitochondrial mutations, findings from muscle biopsy and brain magnetic resonance spectroscopic imaging showed signs of mitochondrial impairment (ultrastructural mitochondrial abnormalities and increased parenchymal brain lactate, respectively). CONCLUSIONS: A patient with CADASIL and a 5-base pair deletion leading to a frameshift mutation showed clinical and laboratory evidence of mitochondrial dysfunction. This adds to the previously reported hypothesis of a pathogenetic role of NOTCH3 or, less specifically, a microvascular pathologic effect on mitochondrial energy metabolism.

Base Sequence↗
PubMed2006

Heritability of MRI lesion volume in CADASIL: evidence for genetic modifiers.

BACKGROUND AND PURPOSE: The phenotypic expressivity shows striking variability among individuals with CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), a small vessel disease caused by mutations in NOTCH3. However, little is known about the factors that underlie this variability. We sought to quantify the contribution of modifying genetic effects to individual differences in the volume of cerebral ischemic lesions. METHODS: One hundred and fifty-one affected individuals (mean age+/-SD=45.7+/-10.4) from 95 unrelated families with CADASIL underwent MRI. The volume of lesions visible on T2-weighted images and the intracranial volume (ICV) were quantified and vascular risk factors were assessed. Because of a skewed distribution, lesion volume measures were square-root transformed. Variance component methods were used to estimate the heritability of lesion volumes (ie, the proportion of variation caused by additive genetic factors) after adjusting for covariates. RESULTS: In multivariate analyses, higher age, a larger ICV, and a higher diastolic blood pressure were independently associated with a larger volume of T2-visible lesions (all P<0.05). After adjustment for age the point estimate for the heritability of the square-root-transformed measure of T2 lesion volume was 0.634 (SE=+/-0.286). Adjustment for age, sex, ICV, and diastolic blood pressure increased the estimated heritability to 0.738 (SE+/-0.255). CONCLUSIONS: Heritability estimates in CADASIL suggest a strong modifying influence of genetic factors distinct from the causative NOTCH3 mutation on the amount of ischemic brain lesions. These findings justify a systematic search for genetic variants that modify disease progression.

Adult↗
PubMed2003

[CADASIL: a case with clinical, radiological, histological and genetic diagnoses].

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare inherited cerebrovascular disease. The onset of clinical symptoms occurs with migraine with aura, transient ischemic attacks, recurrent subcortical ischemic infarcts, neuropsychiatric changes reaching subcortical dementia. Brain magnetic resonance images show multiple deep cerebral infarcts in white matter and basal ganglia and diffuse leukoencephalopathy. Neuropathologic hallmark consists of deposition of small electron dense granular patches related to the basement membrane of vascular smooth muscle cells with degeneration of smooth muscle cells and media and luminal obliteration. Recently, the genetic characteristics of this disorder have been reported. Missense mutations in notch3 gene localized in chromosome 19 are involved in its pathogenesis. Only three families from Spain have been reported. Here we describe a patient with typical clinical symptoms, neuroimaging and pathology of CADASIL. C406T (Arg110Cys) mutation in notch3 gene was found. We comment on the clinical symptoms of different members of the patient's family.

Dementia, Multi-Infarct↗
PubMed2001

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.

Base Sequence↗
PubMed2004

Distribution pattern of Notch3 mutations suggests a gain-of-function mechanism for CADASIL.

Mutations in Notch3 cause the syndrome CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). The mechanism by which these mutations result in a CADASIL phenotype has been widely speculated upon. A first step toward understanding a disease mechanism is to learn whether the mutations result in the loss of Notch3 function, in particular, its role in signaling or in the gain of a novel function. Notch3 genomic sequences were analyzed for sites of conservation across species. We present here a bioinformatic analysis of the Notch paralogs and orthologs that suggest that CADASIL mutations result in a gain of function. This finding diminishes the likelihood that a Notch3 signaling deficit is responsible for the phenotype and increases the likelihood that CADASIL joins the growing list of neurological diseases with protein deposits due to misfolding and aggregation.

Animals↗
PubMed2000

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.

Arginine↗
PubMed2002

Notch3 gene polymorphism and ischaemic cerebrovascular disease.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a type of hereditary stroke and dementia. More than 90% of patients with CADASIL have mutations in the Notch3 gene. All mutations either create or destroy a cysteine residue in the epidermal growth factor-like repeats. In addition, five polymorphisms, which lead to amino acid substitutions, have been identified within the Notch3 coding sequence. However, whether these polymorphisms affect Notch signalling or are involved in cerebrovascular diseases is unknown. In the present study, we investigated a possible association between a T6746C polymorphism in the Notch3 coding region and the occurrence of symptomatic ischaemic cerebrovascular disease (CVD) was investigated. Two hundred and thirty five patients with CVD, as confirmed by brain CT or MRI, and 315 age and sex matched control subjects were analyzed for genotype frequencies of the T6746C polymorphism in Notch3. The genotype distributions were: patients with CVD, C/C 14.0%, C/T 45.5%, and T/T 40.4%; controls, C/C, 14.3%; C/T, 47.9%; T/T, 37.8%. The Japanese population has a higher C allele frequency of the T6746C polymorphism than European populations. There was no significant difference between the T6746C polymorphism in patients with CVD and controls (chi(2)=0.414, p=0.813). This was confirmed by the results of multiple logistic regression analysis including established risk factors (chi(2) =4.65, p=0.311). In conclusion, the results indicate that T6746C polymorphism in the intracellular domain of the Notch3 gene is not associated with an increased risk for CVD.

Aged↗
PubMed2006

Mitochondrial DNA sequence variation and mutation rate in patients with CADASIL.

Mutations in the NOTCH3 gene cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is clinically characterised by recurrent ischemic strokes, migraine with aura, psychiatric symptoms, cognitive decline and dementia. We have previously described a patient with CADASIL caused by a R133C mutation in the NOTCH3 gene and with a concomitant myopathy caused by a 5650G>A mutation in the MTTA gene in mitochondrial DNA (mtDNA). We assume that the co-occurrence of the two mutations is not coincidental and that mutations in the NOTCH3 gene may predispose the mtDNA to mutations. We therefore examined the nucleotide variation in the mtDNA coding region sequences in 20 CADASIL pedigrees with 77 affected patients by conformation-sensitive gel electrophoresis and sequencing. The sequence variation in mtDNA was then compared with that among 192 healthy Finns. A total of 180 mtDNA coding region sequence differences were found relative to the revised Cambridge reference sequence, including five novel synonymous substitutions, two novel nonsynonymous substitutions and one novel tRNA substitution. We found that maternal relatives in two pedigrees differed from each other in their mtDNA. Furthermore, the average number of pairwise differences in sequences from the 41 unrelated maternal lineages with CADASIL was higher than that expected among haplogroup-matched controls. The numbers of polymorphic sites and polymorphisms that were present in only one sequence were also higher among the CADASIL sequences than among the control sequences. Our results show that mtDNA sequence variation is increased within CADASIL pedigrees. These findings suggest a relationship between NOTCH3 and mtDNA.

Adult↗