Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare inherited disorder that causes progressive damage to the brain’s small blood vessels. This condition is considered the most common form of hereditary stroke disorder in adults, affecting blood flow primarily within the deep white matter. The arteriopathy causes the walls of these small vessels to thicken and become damaged, restricting necessary blood flow to brain tissue. This progressive vascular damage leads to neurological and cognitive symptoms, typically beginning in mid-adulthood.
The Genetic Basis
CADASIL is caused by a mutation in the NOTCH3 gene, which is located on chromosome 19. This gene provides instructions for making the Notch3 receptor protein, found predominantly on the surface of vascular smooth muscle cells (VSMCs) that surround small arteries. The mutations are usually missense changes that alter the number of cysteine residues within the protein’s extracellular domain.
This genetic alteration prevents the normal folding and function of the Notch3 protein. The misfolded protein then accumulates in the blood vessel walls, leading to the formation of characteristic deposits known as Granular Osmiophilic Material (GOM). This buildup of GOM progressively damages and causes the loss of the VSMCs, which are responsible for regulating blood flow in the cerebral vessels.
The disorder follows an autosomal dominant inheritance pattern. This means a person only needs to inherit one copy of the mutated NOTCH3 gene from either parent to develop the condition. Consequently, an affected individual has a 50% chance of passing the mutated gene on to any of their children.
Clinical Symptoms and Progression
The clinical manifestations of CADASIL generally involve four main categories of symptoms. Migraines with aura are often the earliest symptom, beginning in adolescence or early adulthood and frequently preceding other neurological events by many years. The aura is typically a sensory disturbance, such as visual changes or tingling sensations, that occurs before the headache.
The most frequent presentation is recurrent transient ischemic attacks (TIAs) or strokes. These ischemic episodes usually begin between the ages of 40 and 50, with the average age of a first stroke event being around 46. These strokes are often lacunar, affecting the small, deep arteries of the brain, and they frequently occur without traditional vascular risk factors like high blood pressure or high cholesterol.
Cognitive impairment represents a steadily progressive feature of the disease. This decline begins with subtle difficulties in executive functions, such as problems with attention, processing speed, and decision-making. Over time, this cognitive decline can progress to subcortical vascular dementia, significantly impacting the individual’s ability to function independently.
Psychiatric disturbances are also commonly associated with CADASIL. These manifestations often include mood disorders, such as depression, and a persistent lack of motivation, known as apathy. The overall progression of the disease is generally slow, moving from early migraines to stroke events, and eventually leading to physical disability and severe cognitive decline.
Diagnostic Procedures
The process of diagnosing CADASIL typically involves a combination of clinical assessment, brain imaging, and definitive genetic testing. Magnetic Resonance Imaging (MRI) of the brain is a foundational diagnostic tool, revealing characteristic changes in the white matter known as leukoencephalopathy. These changes appear as bright spots on imaging sequences.
A finding particularly suggestive of CADASIL is the presence of white matter lesions in the anterior temporal poles, which is relatively rare in other small vessel diseases. The MRI also commonly shows evidence of subcortical infarcts, which are small areas of dead tissue resulting from the restricted blood flow. The volume of these lesions generally correlates with the severity of the patient’s disability.
Sequencing the NOTCH3 gene is considered the gold standard for confirming a CADASIL diagnosis. This blood test identifies the specific mutations that alter the cysteine residues in the Notch3 protein. In cases where genetic testing is inconclusive or unavailable, a skin biopsy may be performed. An electron microscope examination of the skin sample can reveal the pathognomonic Granular Osmiophilic Material (GOM) deposits in the walls of the dermal arteries.
Current Management Strategies
There is currently no specific treatment or cure that can stop the progressive damage caused by the underlying genetic mutation in CADASIL. Therefore, current management focuses on supportive care and reducing the risk of further vascular events. A primary goal is the management of symptoms such as migraines and mood disorders.
Migraines are treated symptomatically, though some vasoconstrictive medications used for migraine should be approached with caution. Psychiatric symptoms like depression and apathy are managed using standard antidepressant and mood-stabilizing therapies.
Controlling general vascular risk factors is a fundamental strategy for potentially slowing the disease’s progression. Patients are strongly advised to control hypertension, manage diabetes, and strictly avoid smoking, as these factors can exacerbate vascular damage.
For stroke prevention, antiplatelet agents such as aspirin are often considered, particularly after a patient has experienced an ischemic event. However, standard anticoagulants used for other stroke types are generally avoided due to a potential increased risk of cerebral hemorrhage.