C A D A S I L

MRI Exam if cerebral stroke is suspected

Please Avoid -

Thrombolyisis & anticoagulant treatments, Arteriography, Vasoconstricting medicines (issued from rye ergot or from Tripoptan) and products aimed at unblocking blood vessels as they increase the risk of a hemorrhage.

Clinical - Onset: Adult-hood, Recurrent Sub-cortical Ischemic Events, Strokes, Migraine like headaches, Cognitive Dysfunction: Dementia; Psychiatric disorders & Neuropathy.

CADASIL is a rare genetic condition that results from a mutation on the Notch 3 gene in chromosome 19.

SHOULD A CADASIL PATIENT TAKE ASPIRIN? Yes, There is no scientific evidence that aspirin plays a preventive role in CADASIL, however, based on what is currently known in stroke patients, we usually recommend this treatment if there is non contra-indication and the occurrence of a first ischemic event. The tough decision is deciding what to do when patients have TIA’s and strokes despite treatment with aspirin. Because of the risk of hemorrhage and lack of evidence, blood thinners such as warfarin and clot busters like TPA are not recommended.

HOW MUCH ASPIRIN SHOULD BE TAKEN? The dose of aspirin most currently evaluated in therapeutic trials is between 75 mg to 325mg. Asymptomatic CADASIL patient should have a low dosage of aspirin and a patient with a history of TIA’s or stroke could be given a higher dose of aspirin per day. It is recommended to take coated aspirin.

CADASIL is passed as a dominant mutation and offspring have a 50% chance of developing the disease. All mutation carriers develop some form of the illness (complete penetrance) though the timing and severity and symptoms may vary in family members with the same mutation. Women with CADASIL live longer than men on average. So there are other genetic and environmental factors, yet to be identified, that modulate gene expression. A de novo mutations (A de novo mutation is a new mutation) can rarely occur in exceptional isolated cases without a prior family mutation.

THE ROLE OF NOTCH3 IN STROKE

Investigators: N. Carolyn Schanen, MD, PhD
Background: CADASIL is an inherited vascular dementia characterized by migraine with aura, severe mood disturbances, recurrent ischemic strokes, and dementia. In 1996, CADASIL was shown to be caused by mutations in the NOTCH3 gene. NOTCH3, located on chromosome 19, is part of a gene family that encodes a large transmembrane receptor that is crucial for cell fate determination during embryonic development. Notch3 receptors consist of an extracellular domain involved in ligand binding and an intracellular domain involved in signal transduction, with all known CADASIL mutations residing in the extracellular domain of the Notch3 receptor.

Utilizing five independent mutations analogous to those found in CADASIL patients, we studied the effects of these mutations on protein processing and cell surface expression. Both the unprocessed full-length form and the processed heterodimeric form were observed on the cell surface, suggesting that the Notch3 CADASIL mutations do not affect protein expression, processing, or cell surface localization. Given that the mutations all occur within the extracellular, ligand-binding domain of Notch3, we also evaluated whether ligand binding to a soluble form of the Delta1 ligand would be compromised with our CADASIL mutants. Delta1-Notch3 binding was detected for all five Notch3 CADASIL mutant proteins. Thus, these mutations do not inhibit receptor-ligand interactions. For more information, go to www.americanheart.org, N. Carolyn Schanen, MD, PhD, Head, Human Genetics Research Lab, Adjunct Assistant Professor in Human Genetics, UCLA School of Medicine

CADASIL Tissue Bank - Why is brain donation important? A brain autopsy is the only way to confirm the cause of dementia. Researchers rely on information from autopsies of donated brains to learn how CADASIL and other dementias affect the brain. By understanding these diseases better, researchers hope to develop better treatments and cures for them.

Blood Test results from Testing Labs -

Date of report 08-06

DNA variant 1: Transition G > A

Nucleotide Position: 776

Codon Position: 233

Amino acid change: Cysteine > Tyrosine

Variant Type: Predicted disease associated mutation.

Date of report 08-06

DNA variant 2: Transition G > A

Nucleotide position: 1803

Codon position: 575

Amino acid position: None

Variant type: Unknown polymorphism.

Date of report 3-16-2006
DNA variant 1: Transition G > A
Nucleotide position: 743
Codon position: 222
Amino acide change: Cysteine > Tyrosine
Variant type: Disease-associated mutation

Date of report 11-8-05
DNA variant 1: Transition C > T
Nucleotide position: 499
Codon position: 141
Amino acide change: Arginine > Cysteine
Variant type: Disease-associated mutation
(R141C)

Date of this report 10-8-01
C to T base change at position 622 in exaon 4 of the Notch 3 gene resulting in the subsitution of a cysteine (TGC) for an arginine (CGS) at positon 182. (R182C)

Date of report 7-6-01
Heterozygous for a C or T base change at nucleotide 505 of the Notch 3 gene that changes a condon for arginine (CGS) to one for cysteinine (TGC) at amino acide position 169. (R169C)