Indirect anamnesis indicated the recurrent loss of consciousness for patient III.4. On examination, the patient had impaired sensation to pinprick and light touch on the right side of face and torso, and in her right limbs. Patient III.3 had an 18-year history of fluctuating right-sided numbness and a minor ischemic event with motor difficulties in her right hand for fine motor tasks. Sibling II.4 consecutively developed depression, headache, gait ataxia, episodes of aphasia, and a slowly progressive memory decline with accompanying personality change. Sibling II.3 denied any neurological symptoms in a structured interview and did not show any deficit in the neurological examination. Clinically, he remained with aphasia and a moderate tetraparesis. He developed mild cognitive impairment in multiple domains. Sibling II.2 suffered a first ischemic stroke at 53 years and then presented >10× with small subcortical infarcts or transient focal neurological episodes. Neuropsychological evaluation demonstrated impaired memory and executive functions.įamily history revealed neurological symptoms in 2 siblings and a niece ( Figure 1 Table 2). Clinical examination showed gait apraxia and a mild right-sided hemiparesis. Recurrent episodes of hemiparesis and tetraparesis had so far been interpreted as a psychosomatic disorder. Past medical history comprised memory deficits over the preceding months, episodes of presyncope and hemicrania for several years, and a major depressive disorder for >30 years. In vitro single-particle analysis of D80G and several other cysteine-sparing mutations demonstrated a multimerization behavior comparable with cysteine-affecting CADASIL mutations, thus providing biochemical support for their pathogenicity.Ī 79-year-old woman (index patient Figure 1, II.1) was referred to our specialized neurovascular outpatient clinic because of recurrent falls and progressive gait impairment. We here describe several members of a family with a CADASIL-archetypical clinical and imaging phenotype carrying a novel cysteine-sparing NOTCH3 mutation (D80G). Of note, to date, no data are available from biochemical analysis or animal models. 12 Incomplete diagnostic workup of reported cases or discrepancies in the clinical phenotype so far precluded a final appraisal on the pathogenicity of these variants. 10, 11 There is an ongoing debate whether these sequence variants also cause CADASIL, are associated with another form of cerebral SVD, or are not pathogenic and therefore represent rare single-nucleotide polymorphisms occurring in the general population. Importantly, there are several reports on NOTCH3 mutations that do not alter the number of cysteine residues. 9 This technique allows studying the propensity to form multimers on a molecular level in a highly controlled setting. 8 We were recently able to reproduce the spontaneous multimerization of mutant NOTCH3 in vitro using recombinant NOTCH3 proteins and a single-particle detection assay. It has therefore been proposed that mutant proteins may promote aggregate formation via their unpaired sulfhydryl groups. The vast majority of CADASIL-related NOTCH3 mutations result in the gain or loss of a cysteine residue, 7 leading to an odd number of cysteines. GOM is pathognomonic for CADASIL, and therefore, it has a diagnostic value when observed in ultrastructural analyses of skin biopsies. 3 – 5 NOTCH3 deposits are believed to promote the formation of granular osmiophilic material (GOM) on the surface of vascular smooth muscle cells and pericytes. 2 Accumulation and deposition of the NOTCH3 extracellular domain within vessel walls have been recognized as key pathological features in CADASIL and occur both in patients and in a transgenic mouse model of the disease. 1 This hereditary cerebral small vessel disease (SVD) is caused by mutations in the NOTCH3 gene that encodes for a large type I transmembrane receptor mainly expressed in vascular smooth muscle cells and pericytes. Customer Service and Ordering InformationĬerebral autosomal–dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic disease leading to stroke and vascular dementia.Stroke: Vascular and Interventional Neurology.Journal of the American Heart Association (JAHA).Circ: Cardiovascular Quality & Outcomes.Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB).
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