Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy, or CADASIL, is the most common form of hereditary cerebral small vessel disease. This genetic disorder affects the small arteries, primarily those deep within the brain, leading to a progressive reduction in blood flow. This inherited condition is a significant cause of stroke and dementia in adults, often manifesting in mid-adulthood.
Genetic Origin and Vascular Damage
The root cause of CADASIL is a mutation in the NOTCH3 gene, which is located on chromosome 19. This gene provides the blueprint for a large transmembrane receptor protein, the NOTCH3 receptor, found predominantly on the surface of vascular smooth muscle cells (VSMCs) that surround small arteries. The vast majority of disease-causing mutations are missense changes that alter the number of cysteine residues in the extracellular domain of the NOTCH3 protein. This alteration disrupts the proper folding of the protein, which then leads to its misfolding and accumulation.
The misfolded protein fragments build up on the surface of the VSMCs, forming characteristic deposits known as granular osmiophilic material (GOM). The accumulation of this material within the vessel wall causes the small arteries to thicken and narrow, a process called arteriopathy. This thickening stiffens the blood vessels and impedes their ability to regulate blood flow effectively. The resulting restricted blood flow, or ischemia, damages the surrounding brain tissue, particularly the deep white matter, which is highly sensitive to reduced oxygen and nutrient supply.
This chronic damage to the white matter, known as leukoencephalopathy, and the occurrence of small, localized strokes (infarcts) are the physical manifestations of the disease process. While the protein accumulation can occur in blood vessels throughout the body, the effects are most pronounced and symptomatic in the brain.
Common Clinical Manifestations
The first signs of CADASIL typically emerge in young to middle adulthood, usually between the ages of 30 and 50. One of the most frequent early symptoms is recurrent migraine headaches, often presenting with a preceding sensory disturbance known as an aura.
Ischemic episodes, which include transient ischemic attacks (TIAs) and full strokes, are a major feature of the disease, with the first stroke typically occurring between 45 and 59 years of age. These strokes are often subcortical, meaning they affect the areas of the brain beneath the outer cortex. Recurrent strokes lead to a stepwise decline in neurological function and are a primary cause of disability.
Cognitive impairment frequently accompanies the progression of the disease, often beginning with difficulties in executive function, attention, and processing speed. This decline can eventually progress to subcortical vascular dementia, which affects the majority of individuals by age 65. Mood disturbances, such as depression and apathy, are also common clinical manifestations that can appear early in the disease course.
Diagnostic Confirmation Methods
A diagnosis of CADASIL is initially suspected based on a combination of a characteristic set of symptoms, such as recurrent subcortical strokes and migraines with aura, along with a family history of similar neurological issues. Neuroimaging plays a central role in the diagnostic process, with Magnetic Resonance Imaging (MRI) being the preferred method. MRI scans reveal distinctive patterns of damage, including subcortical infarcts and diffuse white matter hyperintensities.
A highly suggestive finding on MRI is the involvement of specific brain regions, such as the anterior temporal poles and the external capsules. These radiologic features, while not exclusive to CADASIL, are strongly indicative of the disorder when seen alongside the clinical presentation. However, the definitive confirmation of a CADASIL diagnosis relies on genetic testing.
Genetic testing is performed on a blood sample to identify the characteristic pathogenic mutation in the NOTCH3 gene. If genetic testing results are inconclusive or unavailable, a skin biopsy may be used as a supplementary diagnostic method. This involves examining blood vessels under an electron microscope to look for the pathognomonic granular osmiophilic material deposits.
Treatment and Management Strategies
Currently, there is no specific treatment available that can halt or reverse the underlying blood vessel damage. Management, therefore, focuses on supportive care, symptom relief, and preventing the recurrence of stroke.
Controlling high blood pressure is particularly important, as hypertension and smoking have been shown to accelerate the disease’s progression and lead to an earlier onset of stroke. Physicians often prescribe antiplatelet agents, such as low-dose aspirin, to reduce the risk of future ischemic strokes. However, powerful blood thinners (anticoagulants) are often avoided due to the potential for increased risk of bleeding in the brain.
Migraine and Mood Management
For the management of migraines, standard prophylactic medications are used, with acetazolamide and valproic acid sometimes specifically employed for CADASIL-related headaches. Standard antidepressant drugs and cognitive behavioral therapy are used to address mood disturbances like depression and apathy.
Rehabilitation
Physical, occupational, and speech therapy are utilized as part of a comprehensive rehabilitation strategy to help manage the progressive physical and cognitive challenges.
Inheritance Patterns and Risk
CADASIL is inherited in an autosomal dominant pattern, which means a person only needs to inherit one copy of the mutated NOTCH3 gene from one parent to develop the disorder. This inheritance pattern results in a 50% chance for an affected individual to pass the pathogenic gene copy to any of their children.
Although most cases are inherited, the mutation can occasionally occur spontaneously, meaning there is no prior family history of the disease. Genetic counseling is strongly recommended for individuals diagnosed with CADASIL and their family members, providing a thorough discussion of the risks and implications associated with genetic testing and family planning.