CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is an inherited cerebrovascular disease characterized by recurrent strokes, cognitive decline, and dementia.
CADASIL (also known as familial vascular leukoencephalopathy, lacunar dementia, and multi-infarct dementia) is an inherited condition that varies widely in its symptoms, age of onset, and disease progression. The effects of CADASIL are primarily confined to the arteries in the brain. Due to a genetic defect, the smooth muscle cells that surround these arteries are gradually destroyed. Characteristic abnormalities in the brain can be seen on neuroimaging, such as magnetic resonance imaging (MRI).
The main clinical signs and symptoms of CADASIL are early ischemic (stroke-like) episodes, cognitive and behavioral disturbances, migraine headaches, and dementia. Psychiatric and mood disturbances may also be associated. These signs and symptoms usually appear between 30 and 40 years of age. Cognitive decline and migraine headaches are often the first manifestations. These are usually followed by transient ischemic attacks (TIAs) and stroke around the average age of 45. The majority of patients show severe cognitive defects and dementia by age 65.
Due to the autosomal dominant inheritance pattern, most individuals with CADASIL have a family history of the disease. However, even between family members, the severity and age of onset of clinical manifestations can vary widely.
CADASIL is caused by mutations in the NOTCH3 gene, which resides on chromosome 19. The penetrance of the disease is approximately 100%. This means that anyone with a mutation in the NOTCH3 gene will show signs of the disorder, even though age of onset and severity of symptoms may vary. When the NOTCH3 gene does not function correctly, protein builds up in the smooth muscle cells that surround the arteries in the body. This leads to degeneration of these smooth muscle cells and a resulting loss of function of the arteries, specifically in the brain and, sometimes, in the heart.
CADASIL is inherited in an autosomal dominant fashion. Thus, the majority of affected individuals have a parent that is affected as well. However, this is not always the case as there may be a new (de novo) mutation in the affected individual that was not present in either parent. Additionally, there may appear to be a lack of family history due to the affected parent dying at a young age or the failure to recognize symptoms of the disorder in a parent.
Most often, one parent of the affected individual will have signs of CADASIL and/or a NOTCH3 mutation. In this case, siblings of the affected individual have a 50% chance of inheriting the same mutation and being affected as well. However, if a mutation is identified in the affected individual and both parents test negative for this mutation, it is likely that the NOTCH3 mutation is de novo and, therefore, recurrence risk to siblings is very low. For patients with a NOTCH3 mutation, each child is at a 50% risk to inherit the same mutation and, therefore, have a diagnosis of CADASIL.
The exact prevalence of CADASIL is currently unknown. Approximately 500 affected families have been identified throughout the world. The majority of cases have been observed in European Caucasians and the number of reported cases in the United States and Canada has been lower than expected thus far. However, no formal conclusions can be drawn from this information since it is very likely that there are many affected families that have yet to be identified.
Signs and symptoms
In the vast majority of cases, patients affected with CADASIL will present with ischemic episodes, cognitive defects, migraine, or psychiatric disturbances. The onset and severity of these symptoms is highly variable, even within families.
In more than 80% of CADASIL cases, ischemic episodes are a recurrent problem. These include transient ischemic attacks (TIAs) and stroke. TIAs and stroke may have age of onset as early as the 20s or as late as the 60s. The average age of onset is 46 years. TIAs usually occur prior to a stroke, however, it is possible for a stroke to be the first sign of the CADASIL. Recurrent ischemic episodes can lead to severe disability, gait disturbance, and urinary incontinence.
In CADASIL, cognitive function worsens slowly over time due to the disturbances in blood flow to the brain that are caused by the disorder. There is variability in the onset and severity of cognitive impairment. It may onset as early as age 35 and is apparent in more than half of affected individuals by age 45. Approximately twothirds of patients over age 65 demonstrate dementia and severe loss of cognitive function. The dementia is characterized by slowing of motor function, loss of memory, and decreased initiative. Dementia in CADASIL may actually result from recurrent TIAs or strokes that were undiagnosed.
Migraine headaches are seen in approximately 30–40% of patients with CADASIL and occur at the average age of 25. These headaches most often occur with aura, which is a fleeting visual disturbance that takes place prior to the onset of the headache. Migraines are the first sign of the disorder in about half of the cases and may be the most noticeable clinical manifestation. In some patients, migraines improve after the first stroke. Severe migraine headaches may be difficult to distinguish from TIAs.
Psychiatric disturbances, such as severe depression, panic disorder, or hallucinations, occur in approximately one-third of patients. It is unknown whether these disturbances are associated with CADASIL or whether they are a reaction to the disease.
In a few cases, acute encephalopathy has been described and manifests itself with headache, fever, confusion, seizures, and coma, which can be fatal. Epilepsy, although rare, has been observed in affected individuals and usually presents during middle age. Additionally, more recently, evidence supports an increased risk for cardiac problems, such as heart attacks, due to abnormalities in the smooth muscle cells surrounding the arteries in the heart. Other symptoms may include speech defects, insensitivity to pain, loss of vision, and deafness.
Clinical manifestations of CADASIL are always associated with symmetrical lesions in the white matter of the brain that can be seen on MRI. These lesions progress with time and their patterns evolve with age. Hyperintensities in the white matter can be seen on MRI in affected individuals as early as 21 years of age, long before clinical signs and symptoms occur. Additional MRI abnormalities may be associated with CADASIL as well, such as cerebral micro-bleeds and subcortical lacunar lesions (SLL), the latter of which may be a specific marker for the disease.
The overall course of CADASIL is variable. Some patients will be severely affected by the age of 50, whereas others will be asymptomatic until their 70s. Early onset of symptoms does not necessarily mean that the disorder will progress rapidly.
CADASIL can be diagnosed via a skin or muscle biopsy. Electron microscope (EM) evaluation of the biopsy specimen will show characteristic abnormalities in smooth muscle cells. These abnormalities are very suggestive of CADASIL, however, the absence of them does not rule out the disorder.
Molecular genetic testing via sequencing of the NOTCH3 gene is also very helpful in the diagnosis of CADASIL. Approximately 95% of affected individuals will have an identifiable mutation in this gene. This testing is offered clinically and can be used to confirm a diagnosis in someone with clinical manifestations or as a predictive test in pre-symptomatic individuals. However, molecular genetic testing is only informative if a mutation can be found in a family. Once a NOTCH3 mutation has been found in an affected individual, family members can be tested for that particular mutation to determine whether or not they have a diagnosis of CADASIL.
Due to the severity of the disease and the lack of effective interventions, special considerations should be given to pre-symptomatic testing for CADASIL. Adequate counseling must be provided, including discussion of motivation for testing, impact of test results, and implications for family members and reproductive decisions. Due to the adult onset of symptoms, it is not recommended that children under the age of 18 are offered testing for CADASIL.
Prenatal diagnosis is possible via molecular genetic testing of the NOTCH3 gene in cells obtained from the fetus, however, this is not a common request due to the adult-onset nature of the disorder.
Treatment and management
Unfortunately, there are no interventions that can effectively prevent CADASIL or its clinical manifestations. Certain signs and symptoms can be treated as they appear (i.e., treating migraine headaches with a drug called acetazolamide). Supportive care can be offered to affected individuals and their families, such as counseling and emotional support.
The prognosis of CADASIL is variable. In a large study, the length of time between onset of symptoms and death ranged from 3–43 years, with a mean of 23 years. The mean age of death in CADASIL patients is about 60 years.
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Mary E. Freivogel, MS, CGC