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CADASIL: Variable Genetics Predict Unique Presentations
Abstract & Commentary
By Alan Z. Segal, MD, Associate Professor of Clinical Neurology, Weill Cornell Medical College. Dr. Segal reports no financial relationships relevant to this field of study.
Synopsis: The clinical features of CADASIL vary depending on the specific mutation that is present in the NOTCH3 gene.
Source: Lee YC, Liu CS, Chang MH, et al. Population-specific spectrum of NOTCH3 mutations, MRI features and founder effect of CADASIL in Chinese. J Neurol 2009, published online DOI 10.1007/s00415-009-0091-3
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is recognized as a heritable cause of stroke, related to mutations in the NOTCH3 genome. NOTCH3 codes for a large transmembrane protein receptor, with an extracellular domain consisting of multiple tandem repeats of an epidermal growth factor (EGF)-like molecule. The NOTCH3 gene consists of 33 exons and the majority of CADASIL mutations occur in exons 2-6. The NOTCH3 protein is rich in cysteine-cysteine disulfide bonds. CADASIL mutations typically consist of a substitution (often arginine) for one of these cysteine residues. The normal function of NOTCH3 is well recognized, as it plays an integral role in cell signaling pathways during development. It is not clear, however, how mutated forms of NOTCH3 might cause the arteriopathy in CADASIL.
Clinically, CADASIL may present with white matter infarcts, but may also present with migraine, dementia, and other neuropsychiatric symptoms. CADASIL may be diagnosed pathologically with the finding on electron microscopy of granular osmophilic material (GOM), adjacent to the basement membrane of the smooth muscle cells within arterioles. Although CADASIL is strictly a CNS disorder, GOM can be found widely throughout the body, and is most practically diagnosed on a skin biopsy. Neuroimaging in CADASIL shows confluent areas of high signal on MRI (leukoaraiosis) and also more discrete areas of lacunar infarction. Recently, it has been suggested that involvement of the anterior temporal lobe and external capsule was useful in differentiating between CADASIL and the more common hypertensive cerebral small vessel disease.
No clear gold standard for the diagnosis of CADASIL exists since some patients lack a family history (due to mild, unrecognized disease in family members or de novo mutations), while others may have a clinically classical syndrome, but lack genetic findings. Sensitivity of skin biopsy is less than 50% in some series. MRI findings cannot be considered pathognomonic. Furthermore, while CADASIL was initially identified and thought to be clustered in European populations, recent large series have been published from Korea and, in the current report, in a Chinese population in Taiwan.
Lee et al report on 39 patients with clinically suspected CADASIL, 21 having NOTCH3 mutations. Almost half of the mutations were found to be R544C, an arginine substitution for cysteine on exon #11. Interestingly, 85% of the mutations in the recently reported Korean population were also in exon 11 (the vast majority but not all of these were R544C).1 In contrast to these findings among Asians, a large British series found 94% of the mutations in exons 26, in keeping with prior French and other European populations.2 Only 10% of patients in the Korean population and 28% of the current Taiwanese series had mutations in this more centromeric section of the chromosome.
No patient with the R544C mutation in either the Taiwanese or Korean study was from a common pedigree, suggesting a "founder effect" from a common remote ancestor. Such population genetics would be expected in island populations and for a disorder such as CADASIL that occurs later in life and does not affect fertility.
In the current study, six intracerebral hemorrhages (ICHs) were found in five patients (24%), all of whom had a history of hypertension, three having prior treatment with aspirin. All of these patients had R544C mutations. MRI showed white matter hyperintensities in the anterior temporal lobe in 43%, in contrast to the recent British study, which showed sensitivity of 89% and specificity of 86% for this finding. MRI localization appears to correlate with genetics, since all of the patients in the current study with mutations in exons 26 had anterior temporal lobe findings, while only one of the patients with R544C in exon 11 had involvement of this area. In addition, the Korean cohort again seems to match the Taiwanese much more closely showing on 20% anterior temporal lobe involvement. Similarly, the Korean population had a 25% hemorrhage rate (all having the R544C mutation). None of the patients in the British series were reported to have hemorrhage.
One weakness of Lee's study is that skin biopsies were either negative or not done, limiting pre-genomic diagnostic accuracy to clinical and radiologic grounds. Nevertheless, these data provide an elegant example of how the clinical spectrum of a disease can be closely correlated with its population genetics. While the precise mechanism through which a NOTCH3, exon 11, R544C mutation might produce CADASIL is unknown, its unique clinical phenotype is easily recognizable. Asian patients lack the classical anterior temporal leukoaraiosis seen in Western cohorts, but more often present with hypertension and ICH. Whether hypertension and CADASIL interact in an additive fashion to produce ICH is unknown. From a therapeutic perspective, aspirin therapy might be prescribed for patients presenting primarily with ischemic disease, but might be withheld from Asians at risk for bleeding.
Lee's study is a fascinating example of how a syndrome with varied clinical features might be a direct manifestation of heterogeneity in its underlying genetics. The next step is to investigate how these various genotypes can functionally produce such marked differences in brain pathology.
1. Choi JC, Kang SY, Kang JH, et al. Intracerebral hemorrhage in CADASIL. Neurology 2006; 67: 2042.
2. Markus HS, Martin RJ, Simpson MA, et al. Diagnostic strategies in CADASIL. Neurology 2002; 59: 1134.