Cerebral Autosomal Dominant Arteriopathy - Case Study Example

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy) Lecturer & : Date: OUTLINE 1. Mode Of Inheritance Autosomal dominant 2. Symptoms Thinking problems Loss of memory stroke 3. Frequency Of Occurrence German French Arab countries 4. Discovery Of Gene History of disease Assessment of two families 5. Gene Name/Protein Name Notch homolog (NOTCH3) 6. Normal Gene Function 7. Molecular Explanations For Phenotype 8. Types Of Mutation Small in-frame deletions Missense mutations 9. Genetic Testing Predictive Diagnostic 10. Therapy And Treatment No treatment, Not preventable Therapy of stroke patients 11. Future Directions CADASIL that are not related to NOTCH3 Development of treatment methods Development of prevention methods Mode of inheritance CADASIL is known to be an inherited form of the cerebrovascular disease and it is as a result of the thickening of blood vessels’ walls where, the flow of blood to the brain is blocked. In this case, the small blood vessels in brain’s white matter are largely affected (Joutel et al., 1996). The inheritance process of CADASIL condition is considered to be in an autosomal dominant pattern, and this implies that a copy of the altered NOTCH3 has the capacity of causing the disease (Joutel et al., 1996). In this case, an infected individual inherits the disorder from an infected parent. In rare occurrences, a new mutation of NOTCH3 gene in persons with no history of the disorder may bring about the disease (Pescini et al., 2008). CADASIL is an autosomal dominant disorder implying that a single abnormal gene of NOTCH3 overrides the other uncorrupted part thereby developing the ailment (Joutel et al., 1996). This means that the child of an infected parent has a 50 percent chance of getting the disease. In rare cases, a new mutation in the gene may occur and lead to the disorder though both parents of a patient will be healthy. Persons that have defective genes are referred to as "mutation carriers." Nearly all mutation carriers at some stage in their lives develop CADASIL symptoms (Pescini et al., 2008). Symptoms In early stages, most patients develop problems related to thinking and memory (Mourad et al., 2006; Liem et al., 2008). Initially, these are mild symptoms but at a later stage, this may worsen. Stroke is known to be the most common symptom of CADASIL where, it can be classified based on the neurological signs like sensation loss, speech problems or difficulty in walking among other signs (Gouw et al., 2008). Stroke that results from CADASIL is seen to occur at the age of 30-50 years (Liem et al., 2008). However, putting into consideration all the other signs, there is a significant variation where, a patient may be free from a long time symptoms. Migraines and headaches are other symptoms of CADASIL and about a third of the CADASIL patients suffer from these symptoms. Often the headaches are predominant at a group age of 20-30 years. In most cases, an ‘aura accompanies migraines in CADASIL patients and aura refers to neurological signs that take place before or during that moment when someone is experiencing a headache (Blitstein and Tung, 2007). Mood change is considered to be another symptom of CADASIL where, a CADASIL patient suffers either from anxiety or depression. In personal cases, a patient may experience delusions, hallucinations, and anxieties (Mourad et al., 2006). However, this is treatable with the help of a specialist. A substantial number of CADASIL patient experience epileptic seizures. Some patients have undergone a series of confusion and problems in consciousness and this may be associated with fever or seizures. Proper medication can remedy the situation (Blitstein and Tung, 2007). Frequency of Occurrence CADASIL is prevalent in a number of countries globally. This disorder may be the most shared hereditary condition in terms of neurology. The occurrence of NOTCH 3 mutation has been proven to be prevalent in at least four per every 10,000 adults (Joutel et al., 1996). In the past decade, it is observed that at least 80 NOTCH mutations have affected at least 400 families who have the disorder (Liem et al., 2008). Most of these mutations have occurred in the codons that include 3, 4, 5, 6 and 11(Mourad et al., 2006). French, German and English families are linked to exon 3 while 11 maybe second most predominant in Dutch families (Liem et al., 2008). There are rare cases of CADSIL observed in the Arab countries (Tournier, Joutel and Melki, 1993). Discovery of Genes As mentioned earlier, CADASIL is a disease that is inheritable. The initial positive discovery of CADASIL gene dates back in 1996 (Dichgans et al., 2001). However, thorough analysis of CADASIL gene was undertaken in 1993 to designate and learn a hereditary disease affecting small cerebral arteries that was becoming a problem to middle-aged grownups and led to disability and dementia (Joutel et al., 1996). Conceivably, the disorder was initially described in 1955 by Dr. Van Bogaert as "Binswangers ailment with a swift development in two sisters." At this time, CADASIL was not recognized as a disease (Joutel et al., 1996). However, there exists earlier information regarding the disease since van Bogaert relate to a similar report by Mutrux (Blitstein and Tung, 2007). Various van Bogaert reports got published in Europe that touched on chronic familial vascular encephalopathy and leukoencephalopathy, subcortical dementia, a familial ailment comprising of ischemic stroke, and recurrent dementia as well as slowly progressive familial dementia with recurrent strokes (Blitstein and Tung, 2007; Joutel et al., 1996). The investigation of the two families known to be of French origin in Tournier-Lesserve and Cols region resulted to the discovery of the gene responsible for CADASIL (Blitstein and Tung, 2007). Tournier-Lesserve studied a huge number of French pedigrees where her grouping had earlier defined the disorder with linkage analysis and was able to map the locus of the disorder to chromosome 19. The documentation of the gene deficit behind the disorder made it possible to determine the molecular background and also contribute to the clinical definitions and features of CADASIL (Blitstein and Tung 2007). Protein Name/ Gene Name Notch homolog (NOTCH3) is the gene responsible for CADASIL (Joutel et al., 1996). The trans-membrane receptor gets encoded and predominantly conveyed over full-length arterial smooth-muscle cells (Bohlega et al., 2007). As a result, the pathogenic mutations alter the composition of cysteine deposits in the extracellular field of NOTCH 3 which gathers in the small arteries of the infected patient (Bohlega et al., 2007). NOTCH 3 is the gene that produces NOTCH 3 protein (Joutel et al., 1996). This protein regulates the vital muscles that include those located in the walls of small blood vessels in the brain. The mutation of chromosomes is considered to be a major problem linked to NOTCH 3 protein in relation to CADASIL and this leads to the corrosion of muscle walls in the arteries (Joutel et al., 1996). Some studies including imaging have been undertaken in cell cultures as well as in genetically modified mice and this can be related to CADASIL patient experiencing molecular and vascular mechanisms that are critical in this disorder (Joutel et al., 1996). NOTCH 3 protein expressed by NOTCH 3 gene regulates the maintenance of healthy muscles in the blood vessels. The gene is located at 19p13.2-p13.1 between the base pairs 15,159,632 and 15,200,980 (Joutel et al., 1996). The genes alignment is in genomic arrangement to a DNA contig and not less than 29 exons in NOTCH3 gene. Some research has indicated that the gene contains 33 exons (Blitstein and Tung, 2007). Normal Gene Function The NOTCH 3 directs signals to LCK receptor and TLE1 receptor in its trail (Pescini et al., 2008). The NOTCH 3 receptor is critical to the normal maintenance of the brain. CADASIL is known to be associated with chromosomal mutation of NOTCH 3 protein that leads to corrosion of the vessels walls (Pescini et al., 2008). The irregular NOTCH 3 protein gathers itself in the blood vessels of the brain and other parts of the human body. This mainly affects the inner part of the brain leading to white lesions. The pathway brought about by Notch signaling has a critical role on the growth of tissues in vertebrate as well as other cellular functions associated with the body system. NOTCH 3 proteins are known to be expressed in vascular smooth muscle cells, particularly in the small arteries (Pescini et al., 2008). Vascular smooth muscles cells refer to smooth muscles located in blood vessels where, these Smooth muscles are known to be categorized as involuntary muscles. NOTCH 3 proteins plays a fundamental role in the regulation of the stability of the vascular smooth muscle cells and when mutation takes place, there can be dementia and stroke syndrome. In this case, the central nervous system controls the Notch signaling (Pantoni et al., 2010). When a mouse gets genetically contrived in the absence of NOTCH 3, there is a noticeable structural fault of small arteries as a result of impaired development and separation of arteries cells (Pescini et al., 2008). In addition, NOTCH 3-negative mice show poor blood regulation that flows into the brain (Bohlega et al., 2007). Moreover, NOTCH3 gene encourages the replication of microscopic effects on cells muscles and the arteries of the brain. Additionally, NOTCH3 enhances the duplication of DNA. The building up of NOTCH3 is largely initiated by CADASIL mutations (Bohlega et al., 2007; Joutel et al., 1996). Molecular Explanations for Phenotype Studies have indicated that when the mutations occur alongside with De novo mutations; their frequency undergoes C to T transitions and this affects the CpG dinucleotide implying that their occurrence in multiplicity indicates the hyper mutability of this disease (Joutel et al., 1996; Bohlega et al., 2007). These mutations and deletions result to rise or fall in cysteine residue level (Bohlega et al., 2007. There is a key role played by Odd number in cysteine residue composition in EGF-like replica domains of NOTCH3 of diseases pathogenesis (Bohlega et al., 2007). CADASIL defines homozygous pathogenic variant where, in a single family, the onset of Age, disorder severity and disorder progression varies significantly. The phenotype of persons homozygous for NOTCH3 pathogenic variants comes under CADASILs spectrum (Bohlega et al., 2007). Accumulation of the NOTCH3 protein is as a result of mutation of the NOTCH3 gene (Tournier et al., 1993). In addition, when the regulation of smooth muscle cell is altered, there can be problems related to the normal functioning of the body. Accumulation of NOTCH 3 proteins results in the formation of multimers (Tournier et al., 1993). Multimer refers to a protein composed which has at least two polypeptide chains (Joutel et al., 1996). A large number of these can lead to a fatal interference in smooth cells. The most noticeable problem linked with the presence of multimers is that they can aid the degeneration of smooth muscle cells (Joutel et al., 1996). The interaction of protein in NOTCH3 and other proteins in smooth muscles that are CADASIL infected helps to determine corrosion of smooth muscle cells. It is worth noting that substantial inhibition observed in the mutated NOTCH 3 protein clearance is connected to smooth muscles where, NOTCH3 protein accumulates (Joutel et al., 1996). In addition, over-expressed NOTCH3 have been proved to suppress NOTCH regulation in smooth muscles leading to deterioration of the muscles involved (Joutel et al., 1996). The downstream effect of the accumulation of NOTCH3 includes the change of arteries in the brain causing significant migraines in the patient carrying the mutated NOTCH3 gene. Also, the flow of blood may be blocked in some parts of the brain resulting in cognitive deficits and stroke signs (Pescini et al., 2008). In some cases, psychiatric problems have been cited and associated with the building up of NOTCH3 protein in smooth muscle cells (Pescini et al., 2008). The engorgement of arteries and the limitation in the flow of blood can each contribute to the symptom. Independently deterioration of smooth cells and limited flow of blood may fuel the progressive memory damage and dementia in CADSIL patients. Episodes of epileptic seizures are prevalent among many CADSIL patients. On the other hand, stroke is one of the most common CADASIL symptoms which are as a result of the smooth cell deterioration and the defects related to the brain’s arteries (Tournier et al., 1993). Phenotype-Gene Correlation Location Phenotype Phenotype MIM number Phenotype mapping key Locus/ Gene Locus/ Gene MIM number 19p13.12 CADASIL 125310 3 NOTCH3 600276 Types of Mutations CADASIL is known to have two types of mutations that include the small in-frame deletions and mis-sense mutations. These mutations repeatedly take place multiple times and they lead to an odd number of the cysteine residue in a given EGFR (Pescini et al., 2008). Additionally, studies have reported the occurrences of De novo mutations, but their exact frequency is unknown. These mutations undergo C to T transitions that affect CpG dinucleotide. Hence, their manifestations in multiplicity indicate hyper mutability of this order. Mutations and the deletions result in a gain or loss in cysteine residue, hence, justifying the critical role of an odd figure of a cysteine residue in EFG_like replica domains of NOTCH3 in the disorders pathogenesis (Blitstein and Tung, 2007). For research concerning the effects of these changes, three dimensional homology models have produced EGF domains in reference to NMR records from human fibrillin. These modules count domain mis-folding in relation to a small group of mutations (Blitstein and Tung, 2007). Genetic Testing Genetic testing has two forms: predictive and diagnostic (Markus et al., 2002). In both instances, the testing of a gene known as NOTCH3 is carried out where, the mutations in NOTCH3 genes linked to the advancement of CADASIL(Markus et al., 2002). Therefore, if an abnormality gets detected in the process of genetic testing, we can say one is suffering from CADASIL (Markus et al., 2002). This gene consists of numerous building blocks and mutation of any of these blocks results to CADASIL. A routine genetic testing of the whole gene is seen to be a very tedious procedure and in this case, clinicians focus only on the part of the gene that exhibits abnormality (Blitstein and Tung 2007). Diagnostic genetic testing is applicable in a situation where there is a resilient medical suspicion that a person is CADASIL infected (Markus et al., 2002). This is also in a situation where one shows sign of CADASIL or an MRI scan performed in the brain or skin biopsy results indicates a diagnosis of CADASIL, and the confirmation of the same can be undertaken by genetic test. In case of mutation within the NOTCH3 gene, this provides a 100 percent certainty of the diagnosis. Patients exhibiting signs such as migraine have higher chances of having mutation of NOTCH3 gene and it is at least 90 percent. A blood sample or in some cases a spit is taken in the generic testing of CADASIL (Markus et al., 2002). A period of 6-8 weeks is ample for clinicians to conclude the test (Tournier et al., 1993).There is the necessity of a predictive genetic testing for persons that have no symptoms of CADASIL, but they have an affected immediate family member mainly the (parent, a child or sibling). A person suffering from CADASIL has about 50% possibilities of having similar gene mutation. If a person inherits a gene mutation, they will certainly at some point in their lifetime experience signs of the disorder. Nevertheless, it is impossible to tell whether a person will be affected or the age in which they may be affected (Tournier et al., 1993). Genetic testing is closely linked to the analysis of CADASIL condition. The screening of 23 exons that encodes the 34 EGFR can lead to an accurate specificity when a mutation culminating into an uneven number of the cysteine residue in an EGFR exists and these results to 100 percent sensitivity. A biopsy of the skin that has ultra-structural examination needs to be limited to a pair of uncommon settings. One should involve the screening of 23 exons, and the other should have MRI features that signify the disease and the acknowledgment of series variant of the unknown implication not in line with cysteine residue. Genetic testing is done to identify a patient who has a typical clinical syndrome and typical neuro-imaging features. In some health institution, genetic testing comes with special requests. This is as a result of white matter that shows commonness in migraine accompanied by an aura. In this case, a period of 30 years can pass in CADASIL since the beginning of migraine with aura up to the experiencing of the first stroke. It is critical for the patient and the medical practitioner to discuss the diagnosis and forthcoming management of the ailment (Bohlega, 2007) Therapy and Treatment The treatment as well as the prevention of this disorder is known never to exist. However, symptoms that develop as a result of the ailment can be treated with an aim of enhancing patients life (Forteza et al., 2001). Migraines attacks are manageable by use of common painkillers, but unfortunately, they are not sufficient (Forteza et al., 2001). Vasoconstrictor drugs used to treat migraines are not recommended for CADASIL patients since they incur vessel contraction and escalate the risk of blood reduction flowing to the brain. Initially, aspirin was prescribed to prevent stroke after its first occurrence (Forteza et al., 2001). The drug enhances the fluidity of the blood and reduces platelets formation, which is one of the root causes of stroke in the society. Additionally, CADASIL patient do not demonstrate the importance of aspirin as well as the Psychiatric ailments that results in symptoms such as depression that is treatable with anti-depressant drugs. However, these medications are sometimes not effective (Forteza et al., 2001; Tournier et al., 1993). Currently, the treatment of CADASIL is experimental and it is mainly because of different therapeutic studies that considered few patients. As a result, the management of severe conditions of migraine, stroke, psychiatric disorder and epilepsy derails advancements in other groups of patients. Its recommended that old-fashioned ways of dealing with surgical and medical glitches may suit CADASIL patients. Additionally, efforts to pull through patients with dementia form a basis of the opinion that the normal procedure of motor cortical reformation takes place in CADASIL as axonal damage escalates gets predisposed in the absence of confirmation (Tournier et al., 1993). Ignorance is prevalent in numerous areas where, the appliance of thrombolytic and ischemic brain in CADASIL patient is still in practice. Hypothetically, this characterizes a huge risk of bleeding mostly in patients with multiple micro bleeds in their brains MRI (Markus et al., 2002). Patients who use aspirin to inhibit more lacunar infarctions are seen to be at risk (Forteza et al., 2001). Up to date, there is no confirmation of cerebral hemorrhage linkage to the usage of anti-platelet agents and research indicates no findings in relation to platelet role in those that have CADASIL (Forteza et al., 2001). Here, neurotic attacks zeros on the mid layer of the vessels (Tournier, 1993). After a stroke, kinesis therapy is critical to prevent motor disorder. For cases of speech problems, language therapy is highly recommended (Forteza et al., 2001). In case of severe aftermath like paralysis, psychomotricity, ergo therapy aid patients to manage the disability and appreciate their body shape so as to adapt to their environment (Forteza et al., 2001).To manage cognitive disorders, peer group participation may be encouraged to cheer up patients and prevent the feeling of being burdensome. Where there is loss of independence, the patient may require specialized homecare to aid them get on with their daily routines (Tournier, 1993). Future Directions CADASIL condition has provoked concerns as prototypical for the complementary and common forms of ischemic cerebral small artery contaminations as well as sub-cortical ischemic vascular dementia (Joutel et al., 1996). There is increasing evidence of the condition where, there are conditions which resemble CADASIL and are not related to NOTCH3. Considering the current advancements in understanding CADASIL, the disease is still a mystery and specifically in close pathogen etic contrivances (Auer and Peter, 2001). In future, the core element of clinical advancement that is to some level varies in different families and in some cases, in members of the same family. In the coming future, the developments and proper assessment of the processes for pharmacological engrossment and cognitive restoration need to be prioritized (Auer and Peter, 2001). Treatment processes need to enhance the discourse of the cognitive aspects of the disorder and comprise the functional effect of intermediations (Auer and Peter, 2001). The usage of CADASIL scale is the modest and precise screening device used by medics to determine patients with positive signs of CADASIL before going for genetic testing (Auer and Peter, 2001). This may be applied in health institutions in categorizing CADASIL patients where there is low proficiency of the disorder, and to show an increased standardization group of patient without NOTCH3-negative who are thought to exhibit symptoms of CADASIL (Auer and Peter, 2001). In future, the research should be precisely carried out to exactly understand the mechanisms that trigger the NOTCH3 gene anomaly and lead to the collusion of the brain arteries (Auer and Peter, 2001). Presently mice that have NOTCH3 gene anomaly have been developed. Features that touch on signs severity as well as disorder progression that vary from one individual to another are under research, and medical trials are underway to determine the efficiency of medications by various health institutions globally. Presently, there is a lot that is known concerning the unforeseen consequences of the generic disorder. Microscopes that are highly powered have shown abnormal accumulation of NOTCH3 protein on the wall of small blood vessels of patients suffering from CADASIL (Auer and Peter, 2001). Annotated Bibliography Auer, D. and Peter, M. 2001. Differential lesion patterns in CADASIL and sporadic subcortical arteriosclerotic encephalopathy: MR imaging study with statistical parametric group comparison. Radiology 320: 443-51. Visual rating indicated developed lesion tallies for CADASIL in the sequential and temporopolar white matter. The MR imaging strategy is useful in the diagnosis work-up in individuals with CADASIL Bohlega, S., Al Shubili, A., and Edris, A. 2007. CADASIL in Arabs: clinical and genetic findings. BMC Med. Genet 331: 67-70 CADASIL cases have been identified in most countries but not among Arab countries, it’s a rare occurrence. CADASIL cases are rare in Arabs, with clinical phenotype and genotype related to that in extra cultural groups. Blitstein, M. and Tung, G. 2007.MRI of cerebral microhemorrhages. AJR Am J Roentgenol 189: 720-725. There are connected risks of cerebral microhemorrhages in diverse types of stroke patients. Cerebral microhemorrhages have been progressively identified on gradient on weighted MRI arrangements present in diverse people. Tournier-Lasserve, E., Joutel, A., and Melki, J. 1993. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12. Nat Genet 123: 256–259 CADISAL has been reported to be a major cause of stroke. In the absence of hypertension, CADASIL is recurrent in subcortical strikes that begin in the mid age of a person. In fact, in some patients it leads to dementia. Joutel, A., Corpechot, C., Ducros, A., Vahedi, K., Chabriat, H., Mouton, P. 1996. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383:707–710. Investigation of Notch3 mutations in CADASIL to see how the hereditary adult-onset condition causes stroke and dementia Pescini, F., Bianchi, S., Salvadori, E., Poggesi, A., Dotti, M.T., Federico, A. 2008. Pathogenic mutation on exon 21 of the NOTCH3 gene causing CADASIL in an octogenarian paucisymptomatic patient. J Neurol Sci. 267:170–173. The evaluation of the Pathogenic mutation on exon 21 of the NOTCH3 gene causing CADASIL in an octogenarian paucisymptomatic patient Mourad, A., Levasseur, M., Bousser, M.G., Chabriat, H. 2006. CADASIL with mini­mal symptoms after 60 years. Rev Neurol 162:827–831. The study how CADASIL manifests with mini­mal symptoms after 60 years. Liem, M.K., Lesnik, S.A., Vollebregt, M.J., Middelkoop, H.A., van der Grond, J., Helderman-van, A.T. 2008. Homozygosity for a NOTCH3 mutation in a 65-year-old CADASIL patient with mild symptoms. A family report. J Neurol 255: 1978–80. Investigation of Homozygosity for a NOTCH3 mutation in a 65-year-old CADASIL patient with mild symptoms. Gouw. A., van der Flier, W.M., Pantoni, L., Inzitari, D., Erkinjuntti, T., Wahlund, L.O. 2008. On the etiology of incident brain lacunes: longitudinal observations from the LADIS study. Stroke 39:3083–3085. Longitudinal observations from the LADIS study to investigate the etiology of incident brain lacunes Dichgans, M., Herzog, J., Gasser, T. 2001. NOTCH3 mutation involving three cysteine residues in a family with typical CADASIL.Neurology; 57: 1714–17. The study of NOTCH3 mutation involving three cysteine residues in a family with typical CADASIL Pantoni, L., Pescini, F., Nannucci, S., Sarti, C., Bianchi, S., Dotti, M.T. 2010. Comparison of clinical, familial, and MRI features of CADASIL and NOTCH3-negative patients. Neurology 74:57–63. Comparison of clinical, familial, and MRI features of CADASIL and NOTCH3-negative patients Markus, H.S., Martin, R.J., Simpson, M.A., Dong, Y.B., Ali, N., Crosby, A.H., Powell, J.F. 2002. Diagnostic strategies in CADASIL. Neurology 59:1134–1138. Understanding the diagnostic strategies in CADASIL. Genetic testing has two forms: predictive and diagnostic Forteza, A.M, Brozman, B., Rabinstein, A.A., Romano, J.G., Bradley, W.G. 2001. Acetazolamide for the treatment of migraine with aura in CADASIL. Neurology 57: 2144–45. Studying the safety and efficacy of Acetazolamide for the treatment of migraine with aura in CADASIL Reference Auer, D., and Peter, M. 2001. Differential lesion patterns in CADASIL and sporadic subcortical arteriosclerotic encephalopathy: MR imaging study with statistical parametric group comparison. Radiology 320: 443-51 Blitstein, M., and Tung G. 2007.MRI of cerebral microhemorrhages. AJR Am J Roentgenol 189: 720- 725. Bohlega, S., Al Shubili, A., and Edris, A. 2007. CADASIL in Arabs: clinical and genetic findings. BMC Med. Genet 123: 67-70 Dichgans, M., Herzog, J., Gasser, T. 2001. NOTCH3 mutation involving three cysteine residues in a family with typical CADASIL.Neurology 57: 1714–17. Forteza, A.M, Brozman, B., Rabinstein, A.A., Romano, J.G., Bradley, W.G. 2001. Acetazolamide for the treatment of migraine with aura in CADASIL. Neurology 57: 2144–45. Gouw. A., van der Flier, W.M., Pantoni, L., Inzitari, D., Erkinjuntti, T., Wahlund, L.O. 2008. On the etiology of incident brain lacunes: longitudinal observations from the LADIS study. Stroke 39:3083–3085. Joutel, A., Corpechot, C., Ducros, A., Vahedi, K., Chabriat, H., Mouton, P. 1996. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383:707–710. Liem, M.K., Lesnik, S.A., Vollebregt, M.J., Middelkoop, H.A., van der Grond, J., Helderman-van, A.T. 2008. Homozygosity for a NOTCH3 mutation in a 65-year-old CADASIL patient with mild symptoms. A family report. J Neurol 255: 1978–80. Markus, H.S., Martin, R.J., Simpson, M.A., Dong, Y.B., Ali, N., Crosby, A.H., Powell, J.F. 2002. Diagnostic strategies in CADASIL. Neurology 59:1134–1138. Mourad, A., Levasseur, M., Bousser, M.G., Chabriat, H. 2006. CADASIL with mini­mal symptoms after 60 years. Rev Neurol 162:827–831. Pantoni, L., Pescini, F., Nannucci, S., Sarti, C., Bianchi, S., Dotti, M.T. 2010. Comparison of clinical, familial, and MRI features of CADASIL and NOTCH3-negative patients. Neurology 74:57–63. Pescini, F., Bianchi, S., Salvadori, E., Poggesi, A., Dotti, M.T., Federico, A. 2008. Pathogenic mutation on exon 21 of the NOTCH3 gene causing CADASIL in an octogenarian paucisymptomatic patient. J Neurol Sci. 267:170–173. Tournier-Lasserve, E., Joutel, A., and Melki, J. 1993. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12. Nat Genet 120: 256–259 Read More