What is CADASIL

What is CADASIL?

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;

https://bmcmedicine.biomedcentral.com/track/pdf/10.1186/s12916-017-0778-8


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 and how you control those moods. 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 (TIA’s) 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 2/3rds 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. 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 compose the majority of the blood vessel wall and regulate the local blood pressure and volume of blood vessels (by contraction and relaxation). 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.


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.


Are there any treatments?

Unfortunately, there is no proven treatment or cure for CADASIL. Treatment is mainly aimed at relieving and managing the symptoms. 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.

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.

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.


How do you get CADASIL?

CADASIL is an inherited condition caused by mutations in the NOTCH3 gene on Chromosome 19. It is inherited in an autosomal dominant pattern. We have 22 pairs of non-sex chromosomes called autosomes and 1 pair of sex chromosomes; the X and the Y. A woman has 2 X chromosomes whilst a man has 1 X and 1Y Chromosome. CADASIL is an autosomal dominant disorder which means the faulty copy (allele) dominates the good copy producing the disorder.

What happens in every pregnancy if one parent is affected?

  • There is a 50% chance that the child will inherit a faulty copy and a working copy and will get CADASIL.
  • There is a 50% chance that the child will inherit both working copies, will not get CADASIL and cannot pass it on.

What happens in every pregnancy if both parents are affected?

This is a very rare occurrence in an Autosomal Dominant pattern.

  • There is a 25% chance that the child will inherit both working copies, will not get CADASIL and cannot pass it on.
  • There is a 50% chance that the child will inherit a faulty copy and a working copy and will get CADASIL.
  • There is a 25% chance that the child will inherit both faulty copies and usually will be severely affected.

 

It also can be a new mutation, therefore, it will be the first time and there will be no family history.


 Who should be tested for CADASIL?

As can be seen from the above charts there is a high risk (50%) that other family members could have CADASIL and be exposed to passing it on to future family members. Before any family testing, we strongly urge you to receive genetic counselling and please understand that the function of this open and two-way process is to guide you in your decision making so that you are fully aware this disorder, how it is inherited, what your choices are for the current situation and for any future family.

Its purpose is to educate you in the all the relevant aspects of what it means to have CADASIL from how to diagnosis it, what testing methods are used and what that involves, how to manage it, what reproduction options are yours, how to prevent it and what resources and entitlements belong to you. The ultimate aim is for you to have every available piece of knowledge so that you can make educated choices. These are your choices and no one else’s so please make sure you are totally satisfied that you are in control of this very difficult situation.

Preimplantation Genetic Diagnosis (PGD).

Pre-implantation genetic diagnosis (PGD) is a technique that enables couples at risk of passing on a genetic disorder who undergo in-vitro fertilization (IVF) to have their embryos screened before a pregnancy is established so that only healthy embryos are selected to be transferred into the woman’s uterus. PGD can be used to screen for known single gene disorders.

Diagnosis:

Diagnoses of CADASIL can be made through genetic testing which is done by a blood test which is extremely accurate however it can be time-consuming. Scanning the brain using a Magnetic Resonance Image (MRI) machine shows known characteristic changes in the brain and is very helpful in diagnosis and is very safe with no radiation involved.  A skin biopsy is where a piece of skin is taken and under an electron microscope with high magnification abnormal collections of Granular Osmiophilic Material (GOM) is frequently seen as an indicator of CADASIL.