CADASIL: a short review of the literature and a description of the first family from Greece

 

 

Michail Vikelisa

Michail Xifarasb

Dimos-Dimitrios Mitsikostasa

 

a Department of Neurology, Athens Naval Hospital, Athens, Greece

b Department of Neurology, General Hospital of Nikea, Nikea, Greece

 

Reprint requests to: Dr Michail Vikelis

17 Androutsou str., Voula 16673, Greece

E-mail: m_vikelis@yahoo.co.uk

 

 

Accepted for publication: March 24, 2006

 

 

 

Summary

 

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited disease clinically characterized by migraine, subcortical ischemic events, dementia and mood disorders. We present a short review of the literature on the clinical presentation of patients with CADASIL and provide recommendations for the detection and diagnosis of similar cases. We also describe the clinical, radiological and genetic findings of two Greek patients with CADASIL, members of the same family.

 

KEY WORDS: autosomal dominant arteriopathy, CADASIL, Notch3 gene, subcortical dementia.

 

 

Introduction

 

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare autosomal dominant genetic disorder clinically characterized by a variety of symptoms including migraine, recurrent ischemic strokes, mood disorders, progressive cognitive impairment resulting in dementia, and premature death. CADASIL usually manifests itself in early or middle adulthood with the onset of migraine or an ischemic event (1-4). Worldwide, about 400 families with CADASIL have been identified.

 

 

Migraine

 

The migraine in CADASIL is accompanied by aura in most cases. Reviewing the cases of 105 patients, Desmond et al. (2) found that migraine was the presenting symptom in 42 patients (40%), occurring at a mean age of 28.3 years. Thirty (28.6%) had experienced migraine with aura, six (5.7%) migraine without aura, and six (5.7%) unspecified migraine. The specific aura subtype of the patients with aura was not reported. In another series of 83 patients (3) migraine was the initial symptom in 26 (31.3%), while late-onset migraine was reported by five patients (6%). Twenty-nine (34.5%) reported aura: the aura was always visual in six patients (7.2%), sensory and visual in 12 (14.4%), only sensory in five (6%), and sensory, visual, and dysphasic in two (2.4%). In two patients (2.4%), migraine attacks were accompanied by brief confusional episodes lasting minutes to hours. In accordance with the findings of Desmond et al. (2), few patients experienced late-onset migraine, suggesting that migraine is unlikely to occur if it is not the presenting symptom. In a more recent study, Vahedi and colleagues (5) studied aura characteristics in 41 CADASIL patients who experienced exclusively migraine with aura and noticed an unusually high frequency of attacks of migraine with atypical aura.

In conclusion, migraine, usually with aura, is a very common feature in CADASIL patients and can be the presenting symptom in about one third of them. Rare forms of migraine, such as retinal migraine, have also been described as the presenting symptom in CADASIL (6).

 

 

Stroke

 

Ischemic events, transient or permanent, are the presenting symptom in the majority of patients and the most common disease characteristic overall (2-4). They typically appear between 30 and 50 years of age. Most of the ischemic events are classic lacunar infarcts that, contrary to typical stroke, arise in the absence of hypertension or any other recognized vascular risk factors. Most patients experience multiple recurrent subcortical ischemic events, leading to a stepwise decline and a dementia syndrome with frontal lobe features. In several series of CADASIL patients, ischemic deficits were present in up to 90% of symptomatic patients, most of whom experienced recurrent ischemia. It is likely that practically all the deceased CADASIL patients in these studies suffered strokes (2-4).

 

 

Dementia

 

Another common feature in CADASIL patients is the development of cognitive deficits (2-4). The dementia in individuals with CADASIL progresses slowly and typically develops after a history of recurrent stroke. However, progressive dementia in the absence of previous strokes can also be a common presenting symptom of CADASIL (2-4). A recent study of 42 CADASIL patients (7) demonstrated that cognitive decline in CADASIL is dominated by early impairment of executive functions, while skills in other cognitive domains deteriorate with age and are found to be widely impaired in patients with dementia.

 

 

Other manifestations

 

Mood and psychiatric disturbances, including severe depression, have been observed in patients with CADASIL and can be the presenting symptoms in many of them (2,3). Seizures were reported by six patients in the review by Desmond et al. (2). Although wide variability in the time from symptom onset to death has been noted, CADASIL is believed typically to result in reduced survival.

 

 

MRI findings

 

Brain magnetic resonance imaging (MRI) plays a central role in the diagnosis and evaluation of CADASIL. Its findings include diffuse hyperintensities on T2-weighted imaging (T2-WI) that are found consistently in the white matter and are particularly frequent in the periventricular areas, although they also occur in the basal ganglia and pons, and hypointensities on T1-WI that may also be found in the white matter, the basal ganglia and pons (2,3). However, T2 hyperintensities occur in the absence of T1 hypointensities in up to one third of affected individuals. Even young, asymptomatic children with CADASIL can have small T2 hyperintensities in periventricular and subcortical white matter, as shown in a study by Fattapposta and colleagues (8). Unfortunately, the MRI features are non-specific, as they are also observed in other conditions such as angiitis or metachromatic leukodystrophy. More recent studies have shown that the distribution of MRI abnormalities in patients with CADASIL differs from that seen in patients with leukoaraiosis secondary to hypertension (9,10). Involvement of the external capsule and the anterior temporal lobe were found to show high sensitivity and specificity in differentiating MRI CADASIL findings from MRI findings of the leukoencephalopathy usually associated with hypertension. Nevertheless, these characteristic findings can be absent in some cases, as was shown in a more recent study of 112 CADASIL patients, which also demonstrated that MRI lesion load increased progressively with age and correlated with some clinical features including stroke and dementia (11). In this study, the severity of high-signal-intensity lesion load (measured using the modified Scheltens scale) was found to be maximal in the frontal, parietal, and anterior temporal cortex, and the external capsule; intermediate in the pons; and relatively low in the corpus callosum, caudate, globus pallidus, cerebellum, midbrain, and medulla.

In conclusion, MRI studies in CADASIL suggest that patients with a suspicious clinical history and specific abnormal MRI findings in the absence of vascular risk factors should be considered for genetic testing to rule out CADASIL syndrome (8-11).

 

 

Pathology

 

The pathological hallmark of CADASIL is a small vessel non-amyloid non-atherosclerotic arteriopathy with media thickened by osmiophilic, granular, electron-dense material (GOM) of unknown origin (12,13). The observation that this could also be detected on skin biopsy led to the suggestion that this may be a useful diagnostic technique (14), but although initial studies suggested that skin biopsies were abnormal in almost all symptomatic cases of CADASIL (14,15), other studies have questioned this (16). A possible explanation is that the deposition of GOM in the skin arterioles varies between families and between mutations.

 

 

Genetics

 

CADASIL is an inherited disease with mutations in the transmembrane receptor of the Notch3 gene on chromosome 19q12 (17). The product of the Notch3 gene is a 2321 amino acid type I transmembrane protein and a component of an intercellular signaling pathway essential for controlling cell fate during development (18). The extracellular portion of this protein contains 34 tandem repeats of an epidermal growth factor (EGF) motif, each of which contains six cysteine residues binding within the domain as three cysteine-cysteine disulphide bonds. The mutations that have been demonstrated in CADASIL occur in these EGF repeats, which are encoded for by the first 23 exons. Most described mutations are found in exons 3 and 4 and almost 90% can be detected within a few exons (exons 2-6) (19,20).

The mutational spectrum in CADASIL has recently been shown to comprise missense mutations (approximately 95%), splice site mutations, and small deletions (17-21). Certain mutations were particularly common, and most of these (80%) were C to T transitions affecting CpG dinucleotides, and this is consistent with their multiple occurrences resulting from hypermutability of this sequence (22).

In a recent large prospectively recruited cohort of CADASIL subjects, no Notch3 genotype-phenotype correlations were determined, implying that modulating factors, such as smoking or high homocysteine levels influence phenotype (23).

 

 

Differential diagnosis

 

The differential diagnosis of CADASIL includes diseases that have clinical characteristics and MRI findings resembling those of CADASIL, such as Binswanger’s disease, multiple sclerosis, and primary CNS angiitis (24-26). However, these diseases are sporadic and findings such as hypertension in Binswanger’s disease and involvement of the spinal cord or optic nerves, or oligoclonal bands in the spinal fluid in multiple sclerosis will be lacking in patients with CADASIL (2-4).

Other, more uncommon, disorders to be considered in the differential diagnosis include hyperhomocystinemia, hereditary dyslipoproteinemias, hereditary thrombotic disorders, Fabry disease and adrenoleukodystrophies (27). These disorders can be differentially diagnosed from CADASIL on the basis of clinical signs, mode of inheritance and the results of laboratory tests.

 

 

Diagnosis

 

CADASIL should be considered a possibility in any patient with migraine (with or without aura), stroke or a mood disorder whose imaging demonstrates multiple abnormalities (especially if the external capsule and anterior temporal lobe areas are particularly affected), which arise in the absence of hypertension or other recognized vascular risk factors. A family history of similar disease and premature death is supportive, if present. It must also be remembered that, as noted by Razvi et al. (28), restriction of family history to premature stroke alone is probably inadequate to identify affected CADASIL pedigrees. A false-negative family history was commonly documented in their series of individuals presenting with features of CADASIL.

For individuals with a typical clinical phenotype and radiological findings, genetic testing and skin biopsy should be considered to establish the diagnosis. Skin biopsy is diagnostic if GOM is present. Nevertheless, it can sometimes be negative. Genetic screening should initially include exons 2 to 6. If found to be negative, screening of the remaining exons should be considered, although diagnosis by mutation detection can be a major undertaking in many patients (27).

 

 

Frequency and clinical course

 

The prevalence of CADASIL remains unclear. In a recent report, Razvi et al. (29) analyzed a Scottish population for carriership of mutations in Notch3 and found a prevalence of 1.98 individuals per 100,000. It is uncertain whether these data can be extrapolated to other populations.

Data on the clinical course of CADASIL are scarce. In a recent study, Peters and colleagues (30) prospectively followed eighty CADASIL subjects for a mean period of about two years and observed that the extent and mode of progression varied greatly among subjects and that some patients showed a marked and rapid deterioration, whereas others remained stable or even improved. Most patients with worsening disability in this cohort had experienced a new stroke, indicating that recurrent stroke is a major determinant of disability progression in CADASIL.

 

 

Treatment

 

No specific treatment is currently available for CADASIL. Antithrombotic agents such as aspirin are often used. Yet, there are no data proving the efficacy of this or any other agent in CADASIL (27,28). The current approach includes aggressive management of the major cerebrovascular risk factors of hypertension, diabetes, hyperlipidemia and smoking.

 

 

Description of cases

 

A 55-year-old right-handed woman was referred to our department for assessment of progressive cognitive decline. The patient had worked for 30 years as a nurse, but the memory and concentration problems she had been suffering for the past couple of years had worsened to the point that she had had to stop working. Her past medical history was significant for headaches since adolescence (the description of these headaches suggested migraine with aura) occurring with a frequency of about one per month. Twenty-five years earlier she had also been diagnosed with anxiety disorder, previously treated with benzodiazepines and serotonin selective reuptake inhibitors. With the exception of moderate hypercholesterolemia responsive to statins, she presented no other vascular risk factor, such as hypertension, diabetes or smoking.

Her family history was significant for headaches and premature death. Both her mother and grandmother had also suffered from headaches and a similar progressive illness, associated with memory problems, difficulty in walking and cognitive impairment, that had lasted a few years and resulted in death before the age of 60.

The patient recorded a score of 29/30 on the Mini-Mental Status Examination and a score of 85/100 on Addenbrook’s cognitive examination scale. Cranial nerves and fundi were normal. There was no motor or sensory deficit or cerebellar signs. Examination of other systems was normal. There were no abnormal reflexes. The patient’s routine blood examination (including homocysteine levels), chest x-ray, ECG and carotid Doppler studies were normal. Results of investigations for cerebral vasculitis, multiple sclerosis and metabolic causes of leukoencephalopathy were unremarkable.

Brain MRI (Fig.1, over) showed extensive patchy hyperintensities on T2-WI located in the periventricular, subcortical and deep white matter of the cerebral hemispheres. Involvement of the external capsule, in particular, was noted. Similar foci were present in the basal ganglia and brainstem without hypointensities on T1-WI.

In view of the possibility of CADASIL, genetic studies were performed on a sample of the patient’s blood, by sequencing exons 3 and 4 of the Notch3 gene. In the protein coding sequence of exon 4, a heterozygous Arg169Cys (CGC/TGC) mutation was detected. This mutation, substituting an arginine codon in the epidermal growth factor-like repeats (EGFRs) of the Notch3 receptor with a cysteine codon on one allele, has been described by Joutel et al. (1) as a disease-causing mutation in CADASIL patients.

The patient’s close family members underwent neurological evaluation. She has a 32-year-old daughter and a 30-year-old son. The latter has a five-year history of migraine with aura. Although their neurological examinations and brain MRI scans were normal, the two underwent genetic studies and the son was shown to be a carrier of the same heterozygous Arg169Cys mutation. The patient also has two sisters (aged 57 and 51) and two brothers (aged 49 and 46). Both the sisters and the eldest brother underwent a brain MRI scan and genetic testing, which gave normal findings. The youngest brother, who is reported to have a history of psychosis, refused to be evaluated.

The pedigree includes 13 individuals from five generations (Fig.2). Two individuals (our patient and her son) were found to be affected, on the basis of their clinical manifestations and the results of MRI and genetic testing. Two additional individuals (our patient’s mother and grandmother) were probably affected, too (going by the historical information obtained from relatives). It was also suspected, again on the basis of historical information obtained from relatives, that our patient’s youngest brother, who refused investigation, may also be affected.

 

 

Concluding remarks

 

Although the number of newly diagnosed CADASIL cases continues to rise as physicians become aware of the condition (more families with CADASIL are being reported, particularly during the last decade), its prevalence remains unclear. Nevertheless, these facts suggest that the disease is probably underdiagnosed. Greater sensitivity to the earliest manifestations and subsequent clinical course of CADASIL will allow the formation of patient cohorts for observational studies as well as therapeutic trials. Diagnosis of CADASIL is important not only for prognosis of symptomatic patients but also for the counseling of asymptomatic family members who may be at risk as well.

 

 

Acknowledgments

 

We are grateful to the patients for consenting to the publication of this study.

 

 

References

 

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