Stroke in young people
Christos Tziotzios, Jesse Dawson, Matthew Walters, Kennedy R Lees in Stroke in Practice, 2017
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.
Migraine: diagnosis and treatment
Stephen D. Silberstein, Richard B. Upton, Peter J. Goadsby in Headache in Clinical Practice, 2018
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited arterial disease of the brain that has been mapped to chromosome 19 in two unrelated French families (Table 6.9).36 Hutchinson et al37 found four members of an Irish family with CADASIL who had a history and preceding diagnosis of FHM. The complete CADASIL syndrome consists of recurrent episodes of focal brain deficits (recurrent strokes) that start in mid-adult life and often lead to dementia, residual motor disability, and pseudobulbar palsy. Even before clinical symptoms or signs have developed, MRIs of at-risk individuals are often abnormal, with extensive areas of increased T2 signals in the white matter. FHM is distinguished from CADASIL by its earlier onset, benign prognosis, and normal MRI findings. It is defined as migraine with aura with some hemiparesis, with at least one first-degree relative having identical attacks. Cases with associated cerebellar degeneration may be localized to chromosome 19. This suggests that a unique process, not typical of migraine, occurs in these families (Figures 6.13 and 6.14).
Vascular Dementia
Marc E. Agronin in Alzheimer's Disease and Other Dementias, 2014
There are two subtypes of subcortical VaD that are important to consider. Binswanger's disease, also known as subcortical arteriosclerotic encephalopathy or ischemic periventricular leucoencephalopathy, is a slowly progressive dementia associated with chronic hypertension and manifested by prominent executive impairment. It is characterized by damage to small, penetrating blood vessels in subcortical regions that results in episodic hypoperfusion and white matter degeneration (Libon, Price, Davis Garrett, & Giovannetti, 2004). Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy or CADASIL is an autosomal dominant disorder mapped to mutations in the Notch 3 gene on chromosome 19, which produces a slowly progressive dementia in adults, usually striking in the mid-40s (Chabriat et al., 2009). It involves a microangiopathic process that affects arterioles and capillaries, resulting in small ischemic infarcts throughout subcortical structures. CADASIL may progress over 20 years and involve transient ischemic attacks and strokes, focal neurologic symptoms, headaches, mood disorders, and seizures, in addition to dementia. The dementia associated with CADASIL is characterized by prominent slowing in mental processing speed and deficits in executive function and attention. In later stages, it closely resembles Binswanger's Disease.
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
Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary stroke disorder and the most common cerebral small vessel disease which is caused by mutations in the NOTCH3 gene. The mutated NOTCH3 receptor protein is expressed predominantly in vascular smooth muscle cells and is resistant to degradation. The subsequent buildup of the abnormal protein leads to apoptosis of these cells. The loss of vascular smooth muscle cells in the brain resulted in artery stenosis and manifests as various neurological symptoms [37,38].
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].
Related Knowledge Centers
- Chromosome 19
- Mutation
- Pseudobulbar Palsy
- Stroke
- Transient Ischemic Attack
- Leukodystrophy
- Migraine
- Magnetic Resonance Imaging
- Aura
- Subcortical Dementia