CADASIL syndrome

Medical quality assurance by Dr. Albrecht Nonnenmacher, MD at October 20, 2016
StartDiseasesCADASIL syndrome

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic disorder that is exceptionally rare. It is characterized by cerebral infarction which is the death of brain cells due to brain ischemia- a blockage of blood flow. It is also characterized by dementia, migraines, and mood disorders. It is also known as familial vascular leukoencephalopathy and hereditary dementia, multi-infarct type.

Contents

Definition & Facts

CADASIL is caused by a single mutated dominant gene, notch 3 that codes for a protein that is present on muscle tissue surrounding arteries. This gene is located on chromosome 19, one of 23 chromosomes passed on by parents. 90 percent of people with CADASIL have mutations affecting notch 3.

CADASIL is passed down through autosomal dominant inheritance and most people with this condition have a family history of it. It is equally common among men and women, and symptoms typically manifest when people are in their 40's. It is unknown how many people this condition affects. Two Paris-based doctors discovered and named the condition in 1996.

Symptoms & Complaints

CADASIL patients experience migraines (with migraine auras such as bright lights that appear in one's visual field), transient ischemic attacks, and seizures (epilepsy). Loss of fine motor skill, urinary incontinence, fecal incontinence, and difficulty walking are also symptoms.

Cognitive impairment occurs with this condition. Inattention, difficulty concentrating, memory loss, and speech disorders occur.

Psychiatric problems such as depression and other mood disturbances are also symptoms.

Causes

Notch 3 is key to the generation and regulation of human tissues. CADASIL results from chromosome 19 errors occurring in governance and generation of smooth muscle cells of arteries. The result is that those cells as they age are replaced with the wrong kind of tissue, tissue that is connective instead of muscular.

Cell walls become thickened and rigid, reducing blood flow and causing ischemia. As oxygen supply to white matter (which consists of axons that connect gray matter to each other) and gray matter (which consists of neuronal cell bodies) is reduced, infarcts occur.

Only one copy of the defective gene can result in the condition. However, spontaneous mutations of Notch 3 have been observed, and “new” mutations may occur in which a person has no family history of the condition yet develops it.

Stroke risk for those with CADASIL may be increased by smoking, hypertension, and diabetes mellitus. CADASIL was first discovered among Europeans but can be found among all ethnicities.

Diagnosis & Tests

Prior to 2000 CADASIL patients were sometimes diagnosed with multiple sclerosis, Alzheimer’s disease, or one of a variety of neurodegenerative diseases. Referral for today’s formal testing relies on medical history, family history, and presenting complaints. Tests can include:

  • Skin biopsy. A biopsy can reveal various abnormalities of the blood vessels that concurrently exist in the brains of those with CADASIL.
  • Magnetic resonance imaging (MRI) of the brain can show hyperintensities which are spots that appear brighter on an MRI than surrounding tissue and are often indicative of lesions or reduced blood flow.
  • Genetic testing. Even though Chromosome 19 is twice the size of most chromosomes, Notch3 can be definitively “sequenced” with gene analysis. It is considered the most reliable procedure for identification of CADASIL.

Treatment & Therapy

Aspirin can be used to reduce the risk of stroke. Valproic acid and topiramate may be used to prevent migraines. Antidepressants are helpful for those struggling with depression associated with this condition.

Occupational therapy, speech therapy, psychotherapy, counseling can help patients cope with and address progressive neurologic deficiency and loss of intellectual function. As with many degenerative diseases, counseling for family and significant others will be beneficial to patients.

Prevention & Prophylaxis

CADASIL condition is a genetic disease and thus cannot be prevented. Knowing one's family history will allow proper genetic counseling so that one may assess one's risk of developing this condition.

Unfortunately, the late symptom onset of the condition precludes early counseling intervention without identifying families most at risk. With advent of CRISPR and other gene-editing possibilities, early identification may allow actual “healing” intervention in at-risk individuals before adulthood.