scholarly journals Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) presenting with stroke in a young man

2019 ◽  
Vol 12 (7) ◽  
pp. e229609
Author(s):  
Louise Dunphy ◽  
Amir Rani ◽  
Yaw Duodu ◽  
Yousef Behnam
Keyword(s):  
White Matter ◽  
Autosomal Dominant ◽  
Age Of Onset ◽  
Cerebral Atrophy ◽  
Microvascular Disease ◽  
Lower Limbs ◽  
Receptor Protein ◽  
External Capsule ◽  
Ct Head ◽  
Epidermal Growth

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is caused by mutations in the NOTCH3 gene which maps to the short arm of chromosome 19 and encodes the NOTCH3 receptor protein, predominantly expressed in adults by vascular smooth muscle cells and pericytes. The receptor has a large extracellular domain with 34 epidermal growth factor-like repeats encoded by exons 2–24, the site at which CADASIL mutations are most commonly found. Migraine with aura is often the earliest feature of the disease, with an increased susceptibility to cortical spreading depression suggested as a possible aetiological mechanism. Stroke, acute encephalopathy and cognitive impairment can also occur. Hypertension and smoking are associated with early age of onset of stroke. It diffusely affects white matter, with distinct findings on T2- weighted MRI, involving the external capsule, anterior poles of the temporal lobe and superior frontal gyri, displaying a characteristic pattern of leucoencephalopathy. Affected individuals have a reduced life expectancy. An effective treatment for CADASIL is not available. The authors describe a 35-year-old manwith an unremarkable medical history, presenting to the emergency department with slurred speech and increased confusion 3 days following a fall. He was a smoker and consumed 16 units of alcohol weekly. He was hypertensive and tachycardic. Physical examination confirmed increased tone in his lower limbs and dysarthria. His CT head showed severe cerebral atrophy, multiple small old infarcts and moderate background microvascular disease. Further investigation with an MRI head confirmed multiple white matter abnormalities with microhaemorrhages. The possibility of a hereditary vasculopathy was rendered as the appearances were thought consistent with a diagnosis of CADASIL. Genetic testing identified the NOTCH3 gene thus confirming the diagnosis. This paper provides an overview of the aetiology, clinical presentation, pathogenesis, investigations and management of CADASIL.

scholarly journals A Japanese hereditary spastic paraplegia family with a rare nonsynonymous variant in the SPAST gene

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Takuya Morikawa ◽  
Shiroh Miura ◽  
Takahisa Tateishi ◽  
Kazuhito Noda ◽  
Hiroki Shibata
Keyword(s):  
Molecular Diagnosis ◽  
Hereditary Spastic Paraplegia ◽  
Autosomal Dominant ◽  
Family Members ◽  
Pathogenic Variant ◽  
Lower Limbs ◽  
Spastic Paraplegia ◽  
Nonsynonymous Variant ◽  
Japanese Family ◽  
Functional Variants

AbstractSpastic paraplegia (SPG) type 4 is an autosomal dominant SPG caused by functional variants in the SPAST gene. We examined a Japanese family with three autosomal dominant SPG patients. These patients presented with typical symptoms of SPG, such as spasticity of the lower limbs. We identified a rare nonsynonymous variant, NM_014946.4:c.1252G>A [p.Glu418Lys], in all three family members. This variant has previously been reported in a Russian SPG family as a “likely pathogenic” variant.5 Ascertainment of additional patients carrying this variant in an unrelated Japanese SPG family further supports its pathogenicity. Molecular diagnosis of SPG4 in this family with hereditary spastic paraplegia is confirmed.

scholarly journals Blood Pressure Control in Aging Predicts Cerebral Atrophy Related to Small-Vessel White Matter Lesions

2017 ◽  
Vol 9 ◽  
Author(s):  
Kyle C. Kern ◽  
Clinton B. Wright ◽  
Kaitlin L. Bergfield ◽  
Megan C. Fitzhugh ◽  
Kewei Chen ◽  
...  
Keyword(s):  
Blood Pressure ◽  
White Matter ◽  
Blood Pressure Control ◽  
Cerebral Atrophy ◽  
White Matter Lesions ◽  
Pressure Control ◽  
Small Vessel

CADASIL Syndrome: A Genetic Form of Vascular Dementia

1998 ◽  
Vol 11 (2) ◽  
pp. 71-77 ◽  
Author(s):  
Stephen Salloway ◽  
Joseph Hong
Keyword(s):  
Vascular Dementia ◽  
Autosomal Dominant ◽  
Microvascular Disease ◽  
The Elderly ◽  
Dominant Form ◽  
Genetic Features ◽  
Autosomal Dominant Form ◽  
Family Gene ◽  
Cerebral Arteriopathy ◽  
Genetic Form

Mental disorders due to cerebral microvascular disease have been known for over 100 years. Recently, an autosomal dominant form of cerebral arteriopathy (CADASIL) has been described in association with a Notch3 family gene on the short arm of chromosome 19. CADASIL causes subcortical lacunar infarction and dementia in over 80% of cases and depression in a large proportion of patients. Clinically, CADASIL may appear to be very similar to hypertensive microvascular disease (Binswanger's disease), a condition that is seen in the elderly. This article reviews the clinical, pathologic, and genetic features of CADASIL. CADASIL is of interest to neurologists and psychiatrists because it is the first syndrome of vascular dementia and depression with an identified gene. How the gene causes the widespread arteriopathy is not yet known. Insights gained from the study of CADASIL should help us better understand its etiology, as well as the options for treatment of the more common forms of microvascular disease seen in the elderly.

scholarly journals HNF1α mutations are present in half of clinically defined MODY patients in South-Brazilian individuals

2008 ◽  
Vol 52 (8) ◽  
pp. 1326-1331 ◽  
Author(s):  
Jorge de Faria Maraschin ◽  
Caroline Kannengiesser ◽  
Nádia Murussi ◽  
Nicole Campagnolo ◽  
Luís Henrique Canani ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Age Of Onset ◽  
Pancreatic Beta Cell ◽  
Early Age ◽  
Hepatocyte Nuclear Factor ◽  
Cell Dysfunction ◽  
Monogenic Form ◽  
Hepatocyte Nuclear Factor 1Α ◽  
Relative Prevalence ◽  
Clinical Diagnostic Criteria

Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes mellitus characterized by autosomal dominant inheritance, early age of onset, and pancreatic beta cell dysfunction. Heterozygous mutations in at least seven genes can cause MODY. In the present study we investigated the relative prevalence of GCK (glucokinase) and HNF1α (hepatocyte nuclear factor 1α) mutations, the more frequent causes of MODY, in 13 South-Brazilian families with multiple cases of diabetes consistent with MODY. Heterozygous variants in GCK and HNF1α genes were observed respectively in one (7.7%), and six (46.2%) families. The six HNF1α variants are likely to cause diabetes in the families where they were observed. However, we could not ascertain whether the GCK Gly117Ser variant found in one family is a causal mutation. In conclusion, we have confirmed in a South-Brazilian population that HNF1α mutations are a common cause of monogenic diabetes in adults selected with strict clinical diagnostic criteria.

scholarly journals Cyst fluid from human autosomal dominant polycystic kidneys promotes cyst formation and expansion by renal epithelial cells in vitro.

1992 ◽  
Vol 3 (4) ◽  
pp. 984-994
Author(s):  
M Ye ◽  
M Grant ◽  
M Sharma ◽  
L Elzinga ◽  
S Swan ◽  
...  
Keyword(s):  
Growth Factor ◽  
Autosomal Dominant ◽  
Renal Cysts ◽  
Secretory Activity ◽  
Collagen Matrix ◽  
Fluid Secretion ◽  
Cyst Formation ◽  
Cyst Fluid ◽  
Epidermal Growth

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive renal enlargement, culminating in renal insufficiency in over one half of affected individuals. The highly variable onset and clinical course of ADPKD may be due to factors extrinsic to the genetically defined renal cysts. In this study, cyst fluid samples from 12 nonazotemic and 18 azotemic ADPKD subjects were examined for in vitro biologic activity that promotes cellular proliferation and the secretion of fluid by renal epithelial monolayers, two pathogenetic mechanisms that have critical roles in the formation and the rate of expansion of renal cysts. Cyst fluid added to culture medium (final concentrations, 1 to 20%) caused Madin-Darby canine kidney cells and human kidney cortex (HKC) cells derived from primary cultures to form cysts in Type I collagen matrix. Cyst fluid stimulated the net transepithelial secretion of fluid by polarized monolayers composed of these same cells. Absolute levels of fluid secretory activity determined by MDCK bioassay were correlated directly with the rate of fluid secretion by HKC cell monolayers and with the extent of cyst formation by MDCK and HKC cells embedded in collagen matrix. The secretory activity of urine was negligible; secretory activity was detectable in the serum of normal and ADPKD subjects, but the levels were much lower than in cyst fluid. cAMP agonists prostaglandins E1 and E2, arginine vasopressin, and 8-Br-cAMP stimulated fluid secretion by MDCK and HKC monolayers, but these substances did not cause HKC cells to form cysts in collagen matrix, whereas cyst fluid did. Among other naturally occurring growth factors and autacoids, only epidermal growth factor and transforming growth factor alpha stimulated cyst formation by HKC cells; however, the capacity of cyst fluid to stimulate fluid secretion was not affected by treatment with antiserum to epidermal growth factor. It was concluded that potent, and possibly unique, substances in the cyst fluids of individuals with ADPKD support and augment biologic processes in renal epithelial cells that may be important in the promotion of progressive cyst expansion.

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