GENETICS

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebrovascular disease leading to accumulating neurologic deficits and dementia. CADASIL has been linked to nucleotide substitutions and deletions in the Notch3 gene. All the mutations described until now lead to unpaired cysteine residue in the epidermal growth factor-like repeats. The authors report a family with CADASIL carrying a deletion in the Notch3 gene that did not involve a cysteine residue.
Comment: At least 400 families from countries around the world have been described with CADASIL. The four classic features are migraine with aura, stroke, dementia, and psychiatric disturbances. Migraine with aura, especially familial hemiplegic migraine and migraine with prolonged aura, is linked genetically to CADASIL on chromosome 19, occurs in up to 30% of patients, and when present is usually the earliest symptom. Definitive diagnosis is by skin biopsy, with characteristic depositions surrounding degenerating smooth muscle cells in the media. —Stewart J. Tepper, MD     

Acute Confusional Migraine May Be a Presenting Feature of CADASIL

Objective.— Characterize the phenomenon of acute confusional migraine (ACM) among Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) patients and emphasize the possibility of CADASIL in adults with ACM.
Background.— ACM, well described in children, has rarely been reported in adults. Although 30-60% of CADASIL patients have migraine, acute confusional state during migraine has not been described. We describe 7 patients with ACM that complicated up to 50% of the migraine episodes.
Design/Methods.— Detailed neurologic evaluation was performed in 20 CADASIL patients; International Classification of Headache Disorders 2nd edition criteria were used to diagnose migraine.
Results.— The mean age was 51 years. Fourteen patients reported headache and 11 met the criteria for migraine (mean age of onset 25). Seven patients experienced concomitant confusion, within 3 years of migraine onset. Confusion occurred either abruptly or insidiously, at the onset of aura or headache, lasting for 2-48 hours, and ending abruptly. These episodes were stereotypic, characterized by disorientation with agitation, and retrograde amnesia for the episodes. Patients reported disorientation to time and place, inability to recognize friends and relatives, difficulty with finding directions home, fear of getting lost, inability to analyze traffic lights or tell time. Patients reliably predicted the episodes and felt the need to seek a safe place for protection. Severity of the episodes progressed, but a striking improvement occurred after the first stroke.
Conclusion.— ACM may be a presenting feature and important clue, enabling CADASIL to be recognized up to a decade or earlier than at present. Therefore, a brain MRI and/or testing for Notch3 mutations should be considered in adult patients with ACM.     

CADASIL and migraine: A narrative review

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the NOTCH3 gene and is clinically characterized by recurrent stroke, cognitive decline, psychiatric disturbances and migraine. The prevalence of migraine in CADASIL is slightly higher than in the general population, and the proportion of migraine with aura is much higher. The pathophysiological mechanism that leads to increased aura prevalence in CADASIL is unknown. Possible mechanisms of the excess of migraine with aura are an increased susceptibility to cortical spreading depression (CSD) or a different expression of CSD. It is also possible that the brainstem migraine area is involved in CADASIL. Last, it is possible that the NOTCH3 mutation acts as a migraine aura susceptibility gene by itself. In this narrative review we summarize the literature about migraine in CADASIL, with a special focus on what CADASIL might teach us about the pathophysiology of migraine.     

Endothelial nitric oxide synthase (Glu298Asp) polymorphism is an independent risk factor for migraine with aura

OBJECTIVE: The aim of the present study was to evaluate whether the functional endothelial nitric oxide synthase (eNOS) Glu298Asp polymorphism, which has been demonstrated to decrease the endothelial NOS activity, might be a risk factor for migraine. BACKGROUND: It has widely demonstrated that nitric oxide (NO) is involved in migraine pathogenesis. Several genetic risk factors have been associated with migraine, but no study has unraveled a possible relationship between migraine and eNOS Glu298Asp. Methods.-One hundred fifty-six migraine patients and 125 healthy nonheadache volunteers entered the study. Demographic and clinical characteristics were carefully recorded, and a neurological workup was performed. RESULTS: eNOS AspAsp homozygous patients had a 3-fold time risk for migraine with aura (MA) when compared to migraine without aura (MO) patients (OR-3.02, 95% CI-1.21 to 7.51), and more than 2-fold time increased risk when compared to control subjects (OR-2.21, 95% CI-1.00 to 5.04). In migraine patients, no difference in age at onset, mean attack's intensity, family history for any of the studied comorbidities, or the presence of comorbidities was found in eNOS AspAsp homozygous compared to eNOS GluGlu or eNOS GluAs carriers. CONCLUSIONS: Homozygous Asp298, a common variant of the eNOS gene, is an independent risk factor for MA in this study population.     

MTHFR T677 homozygosis influences the presence of aura in migraineurs

It has been suggested that folate metabolism could be involved in migraine pathogenesis. We analysed the 5',10'-methylenetetrahydrofolate reductase (MTHFR) genotypic distribution in a large migraine sample. We genotyped 230 migraine patients (152 migraine without aura (MO) and 78 migraine with aura (MA)) and 204 nonheadache controls. The incidence of TT homozygosis for migraine in general (12%), MO (9%) and MA (18%) did not significantly differ from that found in healthy controls (13%). Differences were significant when the frequency of TT homozygosis between MA and MO (P = 0.03, OR = 2.34, 95% CI = 1.04-5.26) was compared. There was a tendency for a higher frequency of the MTHFR T allele in the MA group (42%) as compared to MO (29%) and controls (36%). These differences were significant only in the case of MA vs. MO (P = 0.006, OR = 1.75, 95% CI = 1.15-2.65). These results could indicate that the MTHFR C677T polymorphism, causing mild hyperhomocystinaemia, might be a genetic risk factor for experiencing aura among migraineurs. Overall, however, there was no association between migraine and the C677T MTHFR polymorphism.     

Search for correlations between genotypes and electrophysiological patterns in migraine: the MTHFR C677T polymorphism and visual evoked potentials

Interictally, migraineurs have on average a reduction in habituation of pattern-reversal visual evoked potentials (PR-VEP) and in mitochondrial energy reserve. 5,10-Methylenetetrahydrofolate reductase (MTHFR) is involved in folate metabolism and its C677T polymorphism may be more prevalent in migraine. The aim of this study was to search in migraineurs for a correlation between the MTHFR C677T polymorphism and the PR-VEP profile. PR-VEP were recorded in 52 genotyped migraine patients: 40 female, 24 without (MoA), 28 with aura (MA). Among them 21 had a normal genotype (CC), 18 were heterozygous (CT) and 13 homozygous (TT) for the MTHFR C677T polymorphism. Mean PR-VEP N1-P1 amplitude was significantly lower in CT compared with CC, and tended to be lower in TT with increasing age. The habituation deficit was significantly greater in CC compared with TT subjects. The correlation between the cortical preactivation level, as reflected by the VEP amplitude in the first block of averages, and habituation was stronger in CC than in CT or TT. The MTHFR C677T polymorphism could thus have an ambiguous role in migraine. On one hand, the better VEP habituation which is associated with its homozygosity, and possibly mediated by homocysteine derivatives increasing serotoninergic transmission, may protect the brain against overstimulation. On the other hand, MTHFR C677T homozygosity is linked to a reduction of grand average VEP amplitude with illness duration, which has been attributed to brain damage.     

Acetazolamide for the prophylaxis of migraine in CADASIL: a preliminary experience

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited microangiopathy caused by NOTCH3 mutations. It is characterized by migraine, with or without aura, ischemic events, psychiatric and cognitive disturbances. There is no approved treatment for migraine prophylaxis in CADASIL, but acetazolamide has been anecdotally reported to be effective. We retrospectively reviewed our database of patients with a genetic diagnosis of CADASIL to identify how many of them were treated with acetazolamide for the prophylaxis of migraine. The efficacy and the tolerability of this treatment were checked looking at the clinic reports. Acetazolamide was prescribed in seven patients; the mean duration of treatment was 6 months, and the daily dose ranged from 125 to 500 mg. Three patients had a total and sustained remission, while in two patients a reduction in attacks and an improvement of the headache intensity were recorded. In one of these, acetazolamide was deliberately taken only during the migraine attack and the beneficial effect started 1 h after administration. In two patients, the drug did not produce any beneficial effect. Mild side effects were recorded in two patients. Our preliminary experience expands previous reports and confirms the possible efficacy of acetazolamide in CADASIL migraine. Based on these data, a randomized controlled trial seems worthy to be carried out to test the efficacy and safety of this drug.     

No association between bipolar disorder risk polymorphisms in ANK3 and CACNA1C and common migraine

(Headache 2011;51:713‐725) Background.— Migraine and bipolar disorder are characterized by a high level of co‐morbidity, and a common familial–genetic basis has recently been hypothesized for the 2 disorders. Genome‐wide association studies have reported strong evidence of association between the polymorphisms rs10994336[T] in the ANK3 gene and rs1006737[A] in the CACNA1C gene and risk of bipolar disorder. Objective.— The aim of this study was to evaluate the hypothesis of a genetic linkage between migraine and bipolar disorder by investigating the familial transmission of the 2 bipolar disorder risk polymorphisms, in a sample of family trios with probands with childhood migraine, and unrelated controls. Methods.— Our sample comprised 192 family trios, each with a proband with childhood migraine (137 migraine without aura, 44 migraine with aura) and 228 unrelated controls. The markers rs10994336 and rs1006737 were genotyped using a TaqMan single nucleotide polymorphism Genotyping Assay. The transmission disequilibrium test analysis for the family trios and the case–control analysis were performed using the program UNPHASED. Results.— The allelic and genotypic transmission disequilibrium test analysis did not show any evidence of transmission distortion of the 2 markers in both migraine overall (rs10994336: OR = 1.61, P = .11; rs1006737: OR = 1.12, P = .49) and in the migraine without aura and migraine with aura subgroups. Likewise, the case–control analysis of alleles and genotypes frequencies did not show any evidence of association. Conclusion.— In the present study, we did not find evidence for association between the bipolar disorder risk polymorphisms rs10994336 in the ANK3 gene and rs1006737 in the CACNA1C gene in migraine. However, as these are variants that have a small effect on the risk of bipolar disorder (OR < 1.5), we cannot exclude a similar small effect on migraine susceptibility with the present sample size.     

Lack of association of endothelial nitric oxide synthase polymorphisms and migraine

Objective.— The aim of this study was to evaluate if 2 functional endothelial nitric oxide synthase (eNOS) gene polymorphisms might be risk factors for migraine.
Background.— Nitric oxide synthase promotes the synthesis of nitric oxide (NO). NO is a potent vasodilator and mediates several processes involved in migraine pathophysiology. Only one study has suggested an association with migraine with aura.
Methods.— We performed a sex- and age-matched case-control study using 2 eNOS polymorphisms (rs1800779 and rs1799983), which are in linkage disequilibrium. Genotypes were obtained with allele-specific probes in a real-time polymerase chain reaction assay. Genotypic and allelic distributions were compared with χ² method. We also estimated the reconstructed haplotypes and calculated ORs for individual haplotypes.
Results.— A total of 337 migraine patients (188 with aura) and 341 healthy controls were recruited. We found no significant differences in the distribution of genotypes and alleles for either polymorphism among clinical subgroups. Neither rs1800779 nor rs1799983 polymorphisms increased the risk for suffering from migraine aura.
Conclusions.— As others have previously reported, we failed to demonstrate genetic association of the eNOS gene with migraine.     

Recognizing CADASIL: a Secondary Cause of Migraine with Aura

Purpose of Review

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is an important disease to consider in the differential diagnosis of migraine with aura. This review examines current literature regarding migraine in CADASIL, as well as diagnostic and treatment modalities.

Recent Findings

Recent studies have shown that smoking is a modifiable risk factor for progression of CADASIL (Chabriat et al. in Stroke 47:4–11, 2015). Specific imaging changes and findings on clinical exam can predict disease progression. However, migraine symptoms often precede MRI changes (Guey et al. in Cephalalgia 36:1038–47, 2015). A recent paper on migraine treatment in CADASIL reevaluates the prevailing belief that vasoconstrictive abortive medications are contraindicated in these patients (Tan and Markus in PLoS ONE 11:e0157613, 2016).

Summary

CADASIL is an autosomal dominantly inherited vasculopathy causing ischemic pathology in younger individuals due to a mutation in the NOTCH3 gene. The mutation results in impaired arterial contractility due to accumulation of granular osmiophilic extracellular material (GOM) in vascular smooth muscle cells (VSMCs). Clinical manifestations include migraine with and without aura, cognitive decline, ischemic events, and mood disorders. The presenting symptom is often migraine with aura. Characteristic MRI changes are often present. Genetic screening is available to confirm NOTCH3 mutation and pathognomic changes are often seen in skin biopsy. Treatment of migraine is similar to the general population, but with some notable and specific differences. Further studies in CADASIL, other small vessel arteriopathies, and migraine may help us understand more about the pathophysiology of these conditions and help with treatment development.

     

Diagnostic criteria for CADASIL in the International Classification of Headache Disorders (ICHD-II): are they appropriate?

We reviewed the characteristics of headache in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), to verify the appropriateness of the International Classification of Headache Disorders, second edition (ICHD-II) criteria. Available data were found through Medline/PubMed using the keyword “cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)”. The search was restricted to studies published in English in the years between 1993 and 2008. We excluded studies that did not report original data on CADASIL and information regarding the presence of headache. We found 34 studies reporting data on 749 patients overall; 387 (51.7%) patients had headache. According to the authors’ definition, 356 (92%) patients were reported as having migraine and 31 (8%) as having headache. Of the 356 patients who were defined as migraineurs, 125 (35.1%) had migraine with aura, 7 (2%) migraine without aura, 156 (43.8%) unspecified migraine and 68 (19.1%) had more than one type of migraine. Among the 31 patients reported as suffering from headache, the headache was not further detailed in 18 (58.1%) patients; it was defined as chronic in 6 (19.3%), as resembling migraine with aura in 4 (12.9%), as resembling migraine without aura in 2 (6.5%) and as tension type in 1 (3.2%) patient. In patients with CADASIL, the headache was usually referred to as migraine and mostly as migraine with aura. However, this referral is formally incorrect since the diagnostic criteria for any type of migraine in the ICHD-II require that the disturbance is not attributed to another disorder. For this reason, we suggest updating the ICHD-II in relation to CADASIL. Our suggestion is to insert a new category referred to as Headache attributed to genetic disorder including Headache attributed to CADASIL.     

Influence of MTHFR genotype on contingent negative variation and MRI abnormalities in migraine

BACKGROUND: The MTHFR C677T genotype has been associated with increased risk of migraine, particularly of migraine with aura (MA) in selected clinical samples and with elevated homocysteine. The hyper-homocysteinemia may favor the vascular and neuronal mechanism underlying migraine, and the risk of stroke. OBJECTIVE: The first aim of the present study was to examine the Contingent Negative Variation (CNV) amplitude and habituation pattern in a migraine sample versus non-migraine subjects, at the light of the MTHFR genotype, according to an unrelated and clinical based case-control panel. The second aim was to compare the frequency of Magnetic Resonance Imaging (MRI) subclinical brain lesions across the different C677 genotypes in the same migraine sample, selected for the young age and the absence of any cardiovascular risk factor. METHODS: One hundred and five 18-45 year old out-patients, 90 affected by migraine without aura (MO) and 15 by MA, and 97 non-migraine healthy subjects, age and sex matched, were selected for the genetic analysis. All subjects had a common ethnic origin from Puglia. Sixty-four migraine subjects and 33 control subjects were submitted to the recording of the CNV. All migraine subjects underwent the MRI evaluation. RESULTS: The frequency of homozygosis was 14.33% in normal subjects, versus 25.7% in MA + MO group (chi2-test: 10.80 P= .001). The frequency of homozygosis in MO patients, was 25.5% (MA versus N: chi2-test: 9 P= .003), in MA group it was 26.6%. Considering the MTHFR genotype in migraine patients and controls, the C677TT subjects exhibited a reduced habituation index of the early CNV (iCNV), in respect with both C677TC and C677CC; in the migraine group, there was a significant decrease of CNV habituation in patients with homozygosis and a positive correlation between the habituation index values and the homocysteine levels. Nineteen migraine patients exhibited subclinical brain lesions (18.05%): patients with C677T homozygosis did not exhibit a higher risk for MRI abnormalities. CONCLUSIONS: This unrelated and clinical based case-control study showed that genetically induced hyper-homocysteinemia may favor the neuronal factors predisposing to migraine, while it does not influence the presence of subclinical vascular brain lesions probably linked with increased risk of stroke.     

The 1246G-->A polymorphism of the HCRTR2 gene is not associated with migraine

Studies in experimental animals have suggested that the hypocretin/orexin system may be involved in migraine pathophysiology. Using a case-control design study, we genotyped 246 migraine patients and 239 healthy controls for the 1246G-->A polymorphism of the hypocretin receptor 2 (HCRTR2) gene. Genotypic and allelic frequencies of the examined polymorphism were similarly distributed between cases and controls (chi2 = 2.22, P = 0.14 and chi2 = 2.45, P = 0.29, respectively). When different migraine subgroups were compared (migraine with aura vs. migraine without aura and episodic vs. chronic migraine) no significant difference was found. Comparison of the clinical features of the disease with the 1246G-->A genotypes showed no significant difference. Our data suggest that the HCRTR2 gene is not a genetic risk factor in migraine.     

Tumor necrosis factor gene polymorphism in migraine

OBJECTIVE: To better define the involvement of human leukocyte antigen region (HLA) genes in migraine via an association study of the tumor necrosis factor (TNF) genes, located in the HLA class III region, with migraine with and without aura. BACKGROUND: Migraine without aura and migraine with aura are disorders involving multiple factors-environmental and genetic. In a previous study, we hypothesized a protective role for the HLA-DR2 antigen, providing additional basis for the proposed genetic heterogeneity between migraine without aura and migraine with aura. The cytokines produced by TNF genes are polypeptide effectors of inflammatory reaction and endothelial function.METHODS: Tumor necrosis factor (TNF)-308 (TNF-308A and TNF-308G alleles) and lymphotoxin alpha (TNFB*1 and TNFB*2 alleles) polymorphisms were analyzed by the NcoI-cleaved polymerase chain reaction-amplified fragments in 47 patients with migraine without aura, 32 patients with migraine with aura, and 101 migraine-free controls.RESULTS: The frequency of TNFB*2 allele was significantly increased in our patients with migraine without aura as compared with the control group (78.72% versus 61.4%, Pc =.004), but no significant differences were found between patients with migraine with aura and controls. Additionally, there was a significant decrease of TNFB*1 homozygotes in patients with migraine without aura compared with the control group (2.13% versus 16.8%, Pc =.0201). Carriage of the TNFB*2 allele confers a high risk for the development of migraine without aura. No significant association was found at TNF-308 polymorphism. CONCLUSION: These data support the hypothesis that lymphotoxin alpha could be a susceptibility gene in migraine without aura and confirm previous data indicating that migraine with and without aura are distinct entities with different genetic backgrounds.     

Lack of interaction between a polymorphism in the dopamine D2 receptor gene and the clinical features of migraine

The purpose of this study was to evaluate whether a particular genotype of the dopamine D2 receptor (DRD2) gene would affect the clinical features of migraine. In a group of 118 migraineurs (55 migraine with aura and 63 migraine without aura patients), we tested the association of the biallelic C/T NcoI DRD2 polymorphism with several characteristics of the disease. Genotype and allele frequencies resulted similarly distributed in migraine with aura and migraine without aura patients (chi2 = 1.58, P = 0.45 and chi2 = 0.09, P = 0.77, respectively). The different DRD2 genotypes (C/C, C/T and T/T) had no significant effects on age at onset of migraine, presence of premonitory phenomena, frequency of headache attacks, associated symptoms, psychological features and quality of life of our migraine patients. The results of our study do not support a role for the DRD2 gene in modifying the clinical features of migraine.     

Leukocyte mitochondrial DNA A to G polymorphism at 11084 is not a risk factor for Japanese migraineurs

Mitochondrial dysfunction has been reported in patients with migraine. We investigated leukocyte mitochondrial DNA 11084 A to G polymorphism in 166 Japanese migraineurs and 483 Japanese controls. The migraine group consisted of 43 patients suffering from migraine with aura (MWA) and 123 from migraine without aura (MOA). The frequency of the transition was 7.2% (12/166) in the migraine group and 7.3% (35/483) in the controls. The frequency of the transition was 4.7% in MWA and 8.1% in MOA. There was no significant difference among the groups (chi-square test). The mitochondrial DNA 11084 A to G transition was more common in Japanese subjects than reported in Caucasians; however, this polymorphism is not a genetic risk factor for migraine in Japanese patients.     

CADASIL presenting as status migrainosus and persisting aura without infarction

Different types of migraine have been reported in 20–40% of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We describe a novel migrainous manifestation of CADASIL consisting in status migrainosus and persistent aura without infarction. The symptoms resolved after i.v. treatment with lorazepam and mannitol.     

Alcohol Dehydrogenase 2 Genotype and Risk for Migraine

( Headache 2010;50:85-91)
Background/Objectives.— Alcohol has been traditionally considered a possible migraine trigger factor. Alcohol-dehydrogenase (ADH) enzymes are thought to play important roles in the metabolism of ethanol. Relevant polymorphism has been found only for 2 of the ADH genes (mapped on chromosome ): ADH 1B, betapolypeptide ( ADH2 ) and ADH3 . The polymorphism rs1229984, located in the third exon of the human ADH2 gene, causes the amino acid substitution Arg48His. The aim of this study was to investigate the possible association between ADH2 polymorphism and the risk for migraine and for triggering migraine attacks.
Methods.— We studied the frequency of the ADH2 genotypes and allelic variants in 197 patients with migraine and 255 healthy controls using allele-specific PCR amplification and Msl I-RFLP's analyses.
Results.— The frequencies of ADH2 Arg/His genotype and of ADH2 His allele were significantly lower in patients with migraine when compared with those of controls, and were unrelated with the age of onset of migraine attacks, family history of migraine or presence of aura. The frequency of the allelic variant ADH2 His ( ADH2*2 ) was significantly higher in the group of patients who reported triggering of migraine by alcohol when compared with the group who reported no effect.
Conclusion.— The results of the present study suggest that ADH2 Arg/His genotype should be associated with a decreased risk for migraine, while the ADH2 His allelic variant should be related with the risk for triggering migraine attacks after alcohol consumption in our population of migraine patients.     

MIGRAINE: EPIDEMIOLOGY, GENETICS, AND COMORBIDITY

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the NOTCH3 gene. Knowledge of disease expression in young adult NOTCH3 mutation carriers (MCs) is limited.
Objective: To characterize clinical, neuropsychological, and radiological status in NOTCH3 MCs younger than 35 years.
Design: Clinical characterization and blinded survey comparing MCs with non-MCs.
Setting: Referral center.
Participants: Individuals younger than 35 years who were at a 50% risk of a NOTCH3 mutation, from our CADASIL database. Thirteen individuals, from 8 families, met the criteria.
Methods: Comprehensive clinical, genetic, neuropsychological, and radiological investigations. Magnetic resonance images were scored according to a standardized white matter hyperintensities rating scale.
Results: Six individuals, from 5 families, were MCs. Clinical symptoms consisted of migraine (with aura), stroke, and stroke-like episodes. We did not find evidence for psychiatric disturbances, functional disability, or cognitive dysfunction, compared with non-MCs. Radiologically, a characteristic magnetic resonance imaging lesion pattern emerged for all MCs. This comprised white matter hyperintensities in the anterior temporal lobes, the frontal lobes, and the periventricular frontal caps.
Conclusions: Migraine (with aura) and stroke can present in NOTCH3 MCs younger than 35 years; however, more importantly, physical function and cognition are intact. Possible subtle cognitive dysfunction needs to be assessed in a larger study. White matter hyperintensities on magnetic resonance imaging are characteristic, and are consistently visualized from the age of 21 years and onward. Awareness of the clinical and radiological features of CADASIL in those younger than 35 years should increase early diagnosis and allow for customized counseling of young adults from families with CADASIL.