CADASIL
Encyclopedia
CADASIL is the most common form of hereditary stroke
disorder, and is thought to be caused by mutations of the Notch 3
gene on chromosome 19. The disease belongs to a family of disorders called the Leukodystrophies. The most common clinical manifestations are migraine headaches and transient ischemic attack
s or strokes, which usually occur between 40 and 50 years of age, although MRI
is able to detect signs of the disease years prior to clinical manifestation of disease.
gene (on the short arm of chromosome 19) cause an abnormal accumulation of Notch 3 at the cytoplasmic membrane of vascular smooth-muscle cells both in cerebral and extracerebral vessels, seen as granular osmiophilic deposits on electron microscopy.
Interestingly, the Notch 3 gene is in the same locus
as the gene for familial hemiplegic migraine
.
and urinary incontinence
.
and hyperintensities on T2-weighted images
, usually multiple confluent white matter lesions of various sizes, are characteristic. These lesions are concentrated around the basal ganglia
, periventricular
white matter
, and the pons
, and are similar to those seen in Binswanger disease. These white matter lesions are also seen in asymptomatic individuals with the mutated gene. While MRI is not used to diagnose CADASIL, it can show the progression of white matter changes even decades before onset of symptoms.
The definitive test is sequencing the whole Notch 3
gene, which can be done from a sample of blood. However, as this is quite expensive and CADASIL is a systemic arteriopathy, evidence of the mutation can be found in small and medium-sized arteries. Therefore, skin biopsies are often used for the diagnosis.
s or stroke(s). The mean age of onset of ischemic episodes is approximately 46 years (range 30–70). A classic lacunar syndrome occurs in at least two-thirds of affected patients while hemispheric strokes are much less common. Notably, ischemic strokes typically occur in the absence of traditional cardiovascular risk factors. Recurrent silent strokes, with or without clinical strokes, often lead to cognitive decline and overt subcortical dementia.
, Aggrenox, or clopidogrel
might slow down the disease and help prevent strokes. Given the propensity for cardiovascular and cerebrovascular complications, minimizing vascular risk factors and implementing therapy for primary or secondary prevention of stroke and myocardial infarction seems prudent. Stopping oral contraceptive pills is justified particularly in cases with migraine with aura. Aggressive treatment of hypercholesterolemia and hypertension is reasonable although the utility of statins and antihypertensive agents in the absence cardiovascular risk factors is unknown. Homocysteine levels are elevated in CADASIL and treatment with folic acid is reasonable. Anti-platelet therapy appears justifiable whereas anticoagulation may be inadvisable given the propensity for microhemorrhages. Administering tPA following onset of stroke is not advised for CADASIL patients, due to increased risk of microhemorrhages. Warfarin (Coumadin) should be avoided.
Some CADASIL patients have used L-Arginine, a naturally occurring amino acid, to ease symptoms such as headache. Aricept
, normally used for Alzheimer's Disease, has been shown to improve executive functioning in CADASIL patients.
has been suggested to have suffered from CADASIL The visual disturbances this caused was reported by Ruskin in his diaries, and it has also been suggested that it might have been a factor in causing him to describe James Whistler
's Nocturne in Black and Gold – The Falling Rocket
as "ask[ing] two hundred guineas for throwing a pot of paint in the public's face". This resulted in the famous libel trial that resulted in a jury
awarding Whistler one farthing damages.
The character Julia, in the 2004 Spanish film The Sea Inside, has the condition.
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
disorder, and is thought to be caused by mutations of the Notch 3
Notch 3
Neurogenic locus notch homolog protein 3 is a protein that in humans is encoded by the NOTCH3 gene.-External links:...
gene on chromosome 19. The disease belongs to a family of disorders called the Leukodystrophies. The most common clinical manifestations are migraine headaches and transient ischemic attack
Transient ischemic attack
A transient ischemic attack is a transient episode of neurologic dysfunction caused by ischemia – either focal brain, spinal cord or retinal – without acute infarction...
s or strokes, which usually occur between 40 and 50 years of age, although MRI
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
is able to detect signs of the disease years prior to clinical manifestation of disease.
Pathophysiology
The underlying pathology of CADASIL is progressive degeneration of the smooth muscle cells in blood vessels. Mutations in the Notch 3Notch 3
Neurogenic locus notch homolog protein 3 is a protein that in humans is encoded by the NOTCH3 gene.-External links:...
gene (on the short arm of chromosome 19) cause an abnormal accumulation of Notch 3 at the cytoplasmic membrane of vascular smooth-muscle cells both in cerebral and extracerebral vessels, seen as granular osmiophilic deposits on electron microscopy.
Interestingly, the Notch 3 gene is in the same locus
Locus (genetics)
In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
as the gene for familial hemiplegic migraine
Familial hemiplegic migraine
Familial hemiplegic migraine is an autosomal dominant classical migraine subtype that typically includes hemiparesis during the aura phase. It can be accompanied by other symptoms, such as ataxia, coma and epileptic seizures...
.
Clinical features
CADASIL may start with attacks of migraine with aura or subcortical transient ischemic attacks or strokes, or mood disorders between 35 to 55 years of age. The disease progresses to subcortical dementia associated with pseudobulbar palsyPseudobulbar palsy
Pseudobulbar palsy results from an upper motor neuron lesion to the corticobulbar pathways in the pyramidal tract. Patients have difficulty chewing, swallowing and demonstrate slurred speech...
and urinary incontinence
Urinary incontinence
Urinary incontinence is any involuntary leakage of urine. It is a common and distressing problem, which may have a profound impact on quality of life. Urinary incontinence almost always results from an underlying treatable medical condition but is under-reported to medical practitioners...
.
Diagnosis
MRIs show hypointensities on T1-weighted imagesMagnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
and hyperintensities on T2-weighted images
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
, usually multiple confluent white matter lesions of various sizes, are characteristic. These lesions are concentrated around the basal ganglia
Basal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...
, periventricular
Periventricular
Periventricular means around the ventricle and may refer to:*Periventricular leukomalacia, a disease characterized by the death of the white matter near the cerebral ventricles*Periventricular nucleus, a composite structure of the hypothalamus...
white matter
White matter
White matter is one of the two components of the central nervous system and consists mostly of myelinated axons. White matter tissue of the freshly cut brain appears pinkish white to the naked eye because myelin is composed largely of lipid tissue veined with capillaries. Its white color is due to...
, and the pons
Pons
The pons is a structure located on the brain stem, named after the Latin word for "bridge" or the 16th-century Italian anatomist and surgeon Costanzo Varolio . It is superior to the medulla oblongata, inferior to the midbrain, and ventral to the cerebellum. In humans and other bipeds this means it...
, and are similar to those seen in Binswanger disease. These white matter lesions are also seen in asymptomatic individuals with the mutated gene. While MRI is not used to diagnose CADASIL, it can show the progression of white matter changes even decades before onset of symptoms.
The definitive test is sequencing the whole Notch 3
Notch 3
Neurogenic locus notch homolog protein 3 is a protein that in humans is encoded by the NOTCH3 gene.-External links:...
gene, which can be done from a sample of blood. However, as this is quite expensive and CADASIL is a systemic arteriopathy, evidence of the mutation can be found in small and medium-sized arteries. Therefore, skin biopsies are often used for the diagnosis.
Clinical course
Ischemic strokes are the most frequent presentation of CADASIL, with approximately 85% of symptomatic individuals developing transient ischemic attackTransient ischemic attack
A transient ischemic attack is a transient episode of neurologic dysfunction caused by ischemia – either focal brain, spinal cord or retinal – without acute infarction...
s or stroke(s). The mean age of onset of ischemic episodes is approximately 46 years (range 30–70). A classic lacunar syndrome occurs in at least two-thirds of affected patients while hemispheric strokes are much less common. Notably, ischemic strokes typically occur in the absence of traditional cardiovascular risk factors. Recurrent silent strokes, with or without clinical strokes, often lead to cognitive decline and overt subcortical dementia.
Treatment
No specific treatment is available. However, anti-platelet agents such as aspirinAspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
, Aggrenox, or clopidogrel
Clopidogrel
Clopidogrel is an oral, thienopyridine class antiplatelet agent used to inhibit blood clots in coronary artery disease, peripheral vascular disease, and cerebrovascular disease. It is marketed by Bristol-Myers Squibb and Sanofi-Aventis under the trade name Plavix. The drug works by irreversibly...
might slow down the disease and help prevent strokes. Given the propensity for cardiovascular and cerebrovascular complications, minimizing vascular risk factors and implementing therapy for primary or secondary prevention of stroke and myocardial infarction seems prudent. Stopping oral contraceptive pills is justified particularly in cases with migraine with aura. Aggressive treatment of hypercholesterolemia and hypertension is reasonable although the utility of statins and antihypertensive agents in the absence cardiovascular risk factors is unknown. Homocysteine levels are elevated in CADASIL and treatment with folic acid is reasonable. Anti-platelet therapy appears justifiable whereas anticoagulation may be inadvisable given the propensity for microhemorrhages. Administering tPA following onset of stroke is not advised for CADASIL patients, due to increased risk of microhemorrhages. Warfarin (Coumadin) should be avoided.
Some CADASIL patients have used L-Arginine, a naturally occurring amino acid, to ease symptoms such as headache. Aricept
Donepezil
Donepezil, marketed under the trade name Aricept by its developer Eisai and partner Pfizer, is a centrally acting reversible acetylcholinesterase inhibitor. Its main therapeutic use is in the palliative treatment of mild to moderate Alzheimer's disease. Common side effects include...
, normally used for Alzheimer's Disease, has been shown to improve executive functioning in CADASIL patients.
In popular culture
John RuskinJohn Ruskin
John Ruskin was the leading English art critic of the Victorian era, also an art patron, draughtsman, watercolourist, a prominent social thinker and philanthropist. He wrote on subjects ranging from geology to architecture, myth to ornithology, literature to education, and botany to political...
has been suggested to have suffered from CADASIL The visual disturbances this caused was reported by Ruskin in his diaries, and it has also been suggested that it might have been a factor in causing him to describe James Whistler
James Whistler
James Whistler is the name of:* James Abbott McNeill Whistler , American-born, British-based artist, known for the painting colloquially known as Whistler's Mother...
's Nocturne in Black and Gold – The Falling Rocket
Nocturne in Black and Gold – The Falling Rocket
Nocturne in Black and Gold – The Falling Rocket is an 1870s painting by James Abbott McNeill Whistler. It depicts a fireworks show in the night sky over Battersea Bridge in an industrial London city park....
as "ask[ing] two hundred guineas for throwing a pot of paint in the public's face". This resulted in the famous libel trial that resulted in a jury
awarding Whistler one farthing damages.
The character Julia, in the 2004 Spanish film The Sea Inside, has the condition.