CADASIL is a progressive genetic disease that affects the blood flow in small blood vessels and in particular the cerebral vessels within the brain. It is an extremely rare disease, however, the most common single gene (monogenic) small vessel disease (SVD). It is a and CADASIL is an acronym for its lengthy description (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy). These words describe the where, how and what about the disease and their meaning will follow. If you are looking for a more detailed scientific explanation please use this link;

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy     (CADASIL).

This rather baffling acronym with its meaning needs a lot of explaining so hopefully this breakdown will help you understand how it was named and what it means.

CADASIL

Stands for:

Definition:

Which practically means:

C

Cerebral

Relating to the cerebrum of the brain (area of the brain located in the front part of the skull)

CADASIL leads to a number of complications affecting the brain’s function, including migraines, seizures, mental health changes, cognitive impairment, strokes.

A

Autosomal

Refers to belonging to, or being located on, or transmitted by, an autosome (a type of chromosome that carries genetic information)

CADASIL is an inherited condition The disease primarily affects small blood vessels in the white matter of the brain. It is caused by a mutation in the Notch3 gene, which alters the muscular walls in small arteries.

It is an autosomal dominant inheritance disorder, meaning that one parent carries and passes on the defective gene. Most individuals with CADASIL have a family history of the disorder.

D

Dominant

Refers to being a controlled feature (a controlling gene or trait)

A

Arteriopathy

Describes any disease affecting the arteries or arterioles (blood vessels that carry oxygenated blood away from the heart through to the rest of the body)

CADASIL is a form of cerebrovascular disease that occurs when the thickening of blood vessel walls blocks the flow of blood to the brain.

S

Sub-cortical

Sections of the brain that are located below the cerebral cortex

CADASIL causes strokes, which are types of ‘infarcts”. These cerebral infarcts (ischaemic strokes affecting the brain) are observed in 70% to 80% of people with CADASIL.

I

Infarcts

Refers to a clinical event that stops the supply of oxygen via the blood circulation and cause areas of the brain to become dead (damaged) tissue.

L

Leukoencephalopathy

“Leuko” refers to the brain’s white matter.

This is the part of the brain that contains myelinated nerve fibres, and is described as ‘white’ due to the color of myelin (the insulation that covers nerve fibres).

“Encephalopathy” refers to disease in which the functioning of the brain is affected by some agent or condition. Leukoencephalopathy refers to a disease of the brain’s white matter

CADASIL is a type of leukoencephalopathy. At this stage, there is limited understanding about it’s pathophysiology.

Hence the acronym CADASIL.

What are the symptoms of CADASIL? How does it progress?

It should be noted that there is no strict pattern to the following symptoms however they are based on the history of those who have had CADASIL. Early symptoms, often in your twenties or thirties are migraines and a change in your moods as well as how you control those moods and their changes. Strokes caused by lack of blood flow known as ischaemic events can occur from your 30s and onwards. These symptoms gradually worsen with migraines with auras and mood disorders becoming more possible. Mini-strokes also are known as Transient Ischaemic Attacks (TIAs) can occur as well as those caused by blood clots or bleeding and sometimes these events can be recurrent. Multiple strokes can lead to partial or complete paralysis. Up to two thirds of those with CADASIL endure recurrent strokes or dementia.

Cognitive abilities can decline such as memory loss, a lower attention span, difficulty in multitasking, temper control, mood swings and changes in personality such as apathy. These can lead to depression and serious emotional disturbances potentially affecting the person, their family, and their caregivers. The late 50s to 60s can see the onset of dementia and other cognitive problems.

Vision and speech can be affected but seizures are not common however tremors and jerks do occur. It is well to remember that there is no set or fixed pattern for these symptoms occurring in those diagnosed with CADASIL and some remain well into their 70’s.

What causes CADASIL?

CADASIL is caused by the mutation of a single gene named NOTCH3 which is situated on Chromosome 19. A mutation is a permanent change in a piece of our genetic makeup (DNA) that prevents it from doing its original function. This gene is responsible for the proper functioning of the vascular smooth muscle cells (VSMCs) which provide the structural integrity and regulate the desired diameter of the blood vessel. In CADASIL the mutation means that progressive and inadequate blood flow causes the degeneration of the VSMC in the arteries.

VSMC make up the majority of the blood vessel wall and regulate the local blood pressure and volume of blood vessels (by contraction and relaxation) travelling through the blood vessels. In CADASIL, both the structural integrity of the blood vessels and their capacity to dilate and contract is affected. Degeneration of VSMCs in CADASIL leads to progressive wall thickening and fibrosis. This causes narrowing of the vessels internal diameter in small and medium-sized arteries that penetrate deep into the brain.

In other words, due to CADASIL, the muscle cells in your blood vessels (arteries, veins and capillaries) that regulate how much blood, and thus oxygen, your organs get is damaged by the mutation and your organs are not able to work optimally.

How does it progress?

The symptoms of CADASIL gradually increase in intensity as the degeneration of the arteries continues. It is not rapidly progressive and the average life expectancy can reach into the 70’s but this can be variable.

Management of CADASIL

Unfortunately, there is no proven treatment or cure for CADASIL. Treatment is mainly aimed at relieving and managing the symptoms, maintaining quality of life and being stroke-free. Migraines should be treated with standard migraine painkillers such as Migraleve with the vital exception of those drugs known as Triptans who work by restricting blood flow which is more likely to cause strokes. Some of those drugs are Imitrex, Imigran, Sumatriptan and Rizatriptan. Other drugs are known as Antiplatelets work by preventing blood cells called platelets from clumping together and forming clots. Two of these that have shown some benefit are Aspirin and Clopidogrel.

There are some medications that are in use to prevent migraines however always consult your clinician about their use. Some of those are Valproic Acid, Topiramate, Gabapentin, Propranolol and tricyclic antidepressants. Acetazolamide, which dilates blood vessels has also been used.

Never use thrombolytic agents (clot-dissolving medication) as it increases bleeding in the brain for those with CADASIL.

Standard anti-depressant drugs can be used to treat depression and in fact, we recommend this in conjunction with cognitive behaviour therapy.

A randomised trial with Aricept (Donepezil), a drug used for Alzheimer’s did not prove effective however some people may benefit due to improved concentration and attention.

More study needs to be undertaken as to the proven benefits and safety of these drugs and other options.

Never take any drug without first consulting your clinician.

Your personal health plays a significant role in how you can treat CADASIL. Smoking is a proven risk factor for strokes so please give it up. Birth control pills are also known risk factors. Maintain a healthy lifestyle as possible with regular exercise and be in charge of those factors such as high blood pressure, diabetes and high cholesterol that increase your risk of stroke. Wherever possible take advantage of supportive therapies such as physical, speech or any that are available through your allied and community health systems.

Complications

Diabetes, Hypertension and excessive build-up of cholesterol in the blood (Hypercholesterolaemia) need to be carefully monitored as they are all risk factors in CADASIL.

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