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Stroke and Transient Ischemic Attacks of the Brain and Eye
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
CADASIL causes a type of stroke and dementia whose key features include migraine, recurrent subcortical ischemic events, and vascular dementia with associated diffuse white matter abnormalities on neuroimaging (Figures 12.99, 12.100).
Migraine: diagnosis and treatment
Published in Stephen D. Silberstein, Richard B. Upton, Peter J. Goadsby, Headache in Clinical Practice, 2018
Stephen D. Silberstein, Richard B. Upton, Peter J. Goadsby
In 1996, Joutel et al identified Notch3 as the defective gene in CADASIL.40 Members of the Notch gene family encode evolutionarily conserved transmembrane receptors that are involved in cell fate specification during embryonic development. The Notch3 gene includes 33 exons encoding a protein of 2321 amino acids. Its extracellular domain contains 34 epidermal growth factor-like repeats that are involved in ligand-binding, whereas the intracellular domain carries the intrinsic signal-transducing activity. CADASIL gene identification has provided the information needed to set up a direct genotypic diagnostic test.39
Stroke in young people
Published in Christos Tziotzios, Jesse Dawson, Matthew Walters, Kennedy R Lees, Stroke in Practice, 2017
Christos Tziotzios, Jesse Dawson, Matthew Walters, Kennedy R Lees
CADASIL is a systemic disease of the vasculature whose clinical effects are confined to the brain.3 Its name encapsulates the key clinical and radiological features of the condition. It is associated with mutations in the notch 3 gene that codes for a transmembrane protein involved in intercellular signalling. The phenotype is variable; however, in typical cases, affected patients remain symptom-free until the third decade of life, when they develop migrainous symptoms, usually with aura. Subcortical stroke occurs in the fourth and fifth decades, with subsequent dementia and occasionally an associated depressive illness and/or seizure disorder. The distinctive clinical picture should raise suspicion of CADASIL, and a careful family history is an essential component of the evaluation. Relatives of an affected patient may have been misdiagnosed with other causes of progressive neurological symptoms, such as multiple sclerosis or Alzheimer’s disease, and this should be borne in mind. CADASIL is associated with distinctive magnetic resonance appearances, characteristically widespread white matter disease with particular involvement of the temporal poles. Genetic testing is now available, and many of the mutations in the notch 3 gene have been identified. Given the progressive nature of the condition and the absence of specific therapeutic options, appropriate counselling should always be undertaken before the genetic tests are performed.
Clinical neuroimaging in intracerebral haemorrhage related to cerebral small vessel disease: contemporary practice and emerging concepts
Published in Expert Review of Neurotherapeutics, 2022
Martina Goeldlin, Catriona Stewart, Piotr Radojewski, Roland Wiest, David Seiffge, David J Werring
Monogenic cerebral small vessel diseases – including Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), COL4A1 or COL4A2 mutations – can also cause ICH. CADASIL is caused by various mutations in the NOTCH3 gene, a transmembrane receptor which is solely expressed in smooth muscle cells [46]. Although the mutation is known, pathophysiological mechanisms leading to lacunar ischemia, dementia, migraine, neuropsychiatric disturbances, and seizures are not fully understood yet [46,47]. Intracerebral hemorrhage occurs in about 25% of CADASIL patients [48] and is seemingly associated with specific mutations (in particular R544C) and presence of deep cerebral microbleeds [49]. Clinical and neuroimaging characteristics associated with a high probability of NOTCH3-positive CADASIL include familial history of stroke, temporal pole hyperintensities, external capsule lacunes, and severe white matter hyperintensities [50]. Given that only a minority of patients with suspected CADASIL test positive for NOTCH3 mutations [50], neuroimaging may be a useful screening method to identify patients with a high yield of genetic testing.
Genetic diseases mimicking multiple sclerosis
Published in Postgraduate Medicine, 2021
Chueh Lin Hsu, Piotr Iwanowski, Chueh Hsuan Hsu, Wojciech Kozubski
The majority of affected individuals became symptomatic in their adulthood. Migraine with aura (MA), transient ischemic attacks, and cognitive deficits are the main clinical presentations of CADASIL and affect approximately 50, 85, 60% of patients, respectively [39-42]. MA is often the symptom of onset and may be present years prior to strokes. Female patients were found to be affected more frequently than males under 50 years of age [43]. More than one- half of the patients reported having at least one episode of the so-called atypical aura, with the involvements of behavior (confusion, hallucinations) and motor systems (hemiplegic, basilar aura) rather than the typical visual and sensory disturbances [39,44]. Strokes in CADASIL present mainly as lacunar syndrome, ranging from the pure motor/ sensory deficits, ataxic hemiparesis to clumsy hand syndrome, and sensorimotor weakness [45]. In contrast to MA, ischemic strokes in CADASIL patients have been estimated to affect more males than females under the same age range (<50 years) [43]. Cognitive deficits such as the decline in executive functions are the direct result of repetitive lacunar strokes and progress as patients age [46,47]. Mood disturbances including major depressive syndrome, manic and bipolar disorders have been documented [48,49]. The presence of dementia, urinary incontinence, gait disturbances, and the lesions pattern on neuroimaging can lead to confusion with MS [50-58].
Pharmacogenomics of drugs used to treat brain disorders
Published in Expert Review of Precision Medicine and Drug Development, 2020
Two susceptibility loci have been identified, one for lobar ICH on chromosomal region 12q21.1 (rs11179580) and another one for nonlobar ICH on chromosomal region 1q22 (rs2984613)[164]. Twelve variants of the CETP gene associate with increased risk for ICH. The strongest association was found with the CETP rs173539 locus [165]. Patients carrying the G-6 allele in the promoter of the angiotensinogen gene or carriers of the G-217/G-6 haplotype are more likely to develop stroke than noncarriers and tend to respond better to angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers [166]. Two other susceptibility loci (a genomic region on 22q13 encompassing PARVB-rs9614326, and an intergenic region with numerous copy number variants on 17p12, rs11655160) may contribute to ICH [167]. A locus on chromosome 16q24.2 is associated with small vessel stroke. The SNP rs12445022, linked to mRNA expression of ZCCHC14 in arterial tissues and whole blood DNA methylation (cg16596957), is associated with cerebral white matter hyperintensities, but not intracerebral hemorrhage [168]. Common variants in familial cerebral small vessel disease genes (COL4A1, COL4A2, NOTCH3, HTRA1, TREX1, and CECR1) confer risk of stroke. COL4A2 is associated with both lacunar IS (rs9515201) and deep ICH (rs4771674); and HTRA1 (rs79043147) is associated with lacunar IS [169]. CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is caused by mutations in the NOTCH3 gene (p.R61W; p.R75P; p.D80G; p.R213K) [170]. Inflammation is a pathogenic factor connected to atherothrombotic and cardioembolic stroke. rs1205 in CRP and rs1800779 and rs2257073 in NOS3 are associated with cardioembolic stroke [171]. The rs9349379[G] allele in PHACTR1 is associated with lower risk of migraine and increased risk of myocardial infarction and cervical artery dissection, a major cause of ischemic stroke in young adults [172]. CAT rs1001179 carriers have a higher susceptibility to cerebral palsy after perinatal hypoxic-ischemic encephalopathy [173].