CADASIL or CADASIL syndrome, involving cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, is the most common form of hereditary
stroke
A stroke is a disease, medical condition in which poor cerebral circulation, blood flow to the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemorr ...
disorder, and is thought to be caused by
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
s of the ''
Notch 3'' gene on
chromosome 19
Chromosome 19 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 19 spans more than 58.6 million base pairs, the building material of DNA. It is considered the most gene-rich chromos ...
. The disease belongs to a family of disorders called the
leukodystrophies. The most common clinical manifestations are
migraine
Migraine (, ) is a common neurological disorder characterized by recurrent headaches. Typically, the associated headache affects one side of the head, is pulsating in nature, may be moderate to severe in intensity, and could last from a few hou ...
headaches and
transient ischemic attacks 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.
The condition was identified and named by French researchers
Marie-Germaine Bousser
Marie-Germaine Bousser (born 11 August 1943) is a French neuroscientist. She won the Brain Prize in 2019 for her work on CADASIL.
Biography
Bousser graduated from Paris-Sorbonne University in neuro-psychiatry in 1972 with her thesis devoted to ...
and
Elisabeth Tournier-Lasserve
Élisabeth Tournier-Lasserve (born 1954) is a French neurologist, medical geneticist, university professor and hospital practitioner in genetics. Together with three colleagues, she was the co-recipient of the Brain Prize in 2019, the world's la ...
in the 1990s. Together with two other researchers,
Hugues Chabriat Hugues may refer to
People:
* Hugues de Payens (c. 1070–1136), French soldier
* Hugues I de Lusignan (1194/95 –1218), French-descended ruler a.k.a. Hugh I of Cyprus
* Hugues IV de Berzé (1150s–1220), French soldier
* Hugues II de Lusignan ...
and
Anne Joutel
Anne Joutel (born 1965) is a French neurologist and neuroscientist who is Research Director at the Institute of Psychiatry and Neurosciences of Paris. In 2019, together with three colleagues, she was awarded the Brain Prize, the largest prize awa ...
, they received the 2019
Brain Prize
The Brain Prize, formerly known as The Grete Lundbeck European Brain Research Prize, is an international scientific award honouring "one or more scientists who have distinguished themselves by an outstanding contribution to neuroscience and who are ...
for their research into the condition.
Signs and symptoms
CADASIL may start with attacks of
migraine
Migraine (, ) is a common neurological disorder characterized by recurrent headaches. Typically, the associated headache affects one side of the head, is pulsating in nature, may be moderate to severe in intensity, and could last from a few hou ...
with
aura
Aura most commonly refers to:
* Aura (paranormal), a field of luminous multicolored radiation around a person or object
* Aura (symptom), a symptom experienced before a migraine or seizure
Aura may also refer to:
Places Extraterrestrial
* 1488 ...
or subcortical transient ischemic attacks or strokes, or mood disorders between 35 and 55 years of age. The disease progresses to
subcortical dementia associated with
pseudobulbar palsy
Pseudobulbar palsy is a medical condition characterized by the inability to control facial movements (such as chewing and speaking) and caused by a variety of neurological disorders. Patients experience difficulty chewing and swallowing, have in ...
and
urinary incontinence.
Ischemic strokes are the most frequent presentation of CADASIL, with approximately 85% of symptomatic individuals developing
transient ischemic attacks 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. It is worthy of note that 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. A case of CADASIL presenting as schizophreniform organic psychosis has been reported.
Pathophysiology
The underlying pathology of CADASIL is progressive hypertrophy of the
smooth muscle cells in
blood vessel
The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide awa ...
s.
Autosomal dominant
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
mutations in the ''
Notch 3'' gene (on the long arm of chromosome 19) cause an abnormal accumulation of Notch 3 at the
cytoplasmic
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
membrane of vascular smooth muscle cells both in
cerebral and extracerebral vessels, seen as granular
osmiophilic deposits on
electron microscopy
An electron microscope is a microscope that uses a beam of accelerated electrons as a source of illumination. As the wavelength of an electron can be up to 100,000 times shorter than that of visible light photons, electron microscopes have a hi ...
.
Leukoencephalopathy Leukoencephalopathy (leukodystrophy-like diseases) is a term that describes all of the brain white matter diseases, whether their molecular cause is known or unknown. It can refer specifically to any of these diseases:
*Progressive multifocal leuko ...
follows. Depending on the nature and position of each mutation, a consensus significant loss of betasheet structure of the Notch3 protein has been predicted using
in silico
In biology and other experimental sciences, an ''in silico'' experiment is one performed on computer or via computer simulation. The phrase is pseudo-Latin for 'in silicon' (correct la, in silicio), referring to silicon in computer chips. It ...
analysis.
Diagnosis
MRIs show hypointensities on
T1-weighted images 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
The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an ext ...
, peri-
ventricular white matter
White matter refers to areas of the central nervous system (CNS) that are mainly made up of myelinated axons, also called tracts. Long thought to be passive tissue, white matter affects learning and brain functions, modulating the distribu ...
, and the
pons
The pons (from Latin , "bridge") is part of the brainstem that in humans and other bipeds lies inferior to the midbrain, superior to the medulla oblongata and anterior to the cerebellum.
The pons is also called the pons Varolii ("bridge of Va ...
, 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-size arteries. Therefore, skin biopsies are often used for the diagnosis.
Treatment
No specific treatment for CADASIL is available. While most treatments for CADASIL patients' symptoms – including migraine and stroke – are similar to those without CADASIL, these treatments are almost exclusively empiric, as data regarding their benefit to CADASIL patients are limited.
Antiplatelet agents such as
aspirin
Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat inc ...
,
dipyridamole, or
clopidogrel
Clopidogrel — sold under the brand name Plavix, among others — is an antiplatelet medication used to reduce the risk of heart disease and stroke in those at high risk. It is also used together with aspirin in heart attacks and following ...
might help prevent strokes; however, anticoagulation may be inadvisable given the propensity for microhemorrhages.
Control of high blood pressure is particularly important in CADASIL patients.
Short-term use of atorvastatin, a
statin-type cholesterol-lowering medication, has not been shown to be beneficial in CADASIL patients' cerebral hemodynamic parameters,
although treatment of comorbidities such as high cholesterol is recommended.
Stopping oral contraceptive pills may be recommended.
Some authors advise against the use of
triptan medications for migraine treatment, given their vasoconstrictive effects, although this sentiment is not universal.
In this regard, the advent of the "Ditans" such as Lasmiditan, lacking vasoconstrictive effect, and the "Gepants" such as Ubrogepant and Rimegepant, are attractive alternatives, albeit not yet field-tested in this condition. As with other individuals, people with CADASIL should be encouraged to quit smoking.
In one small study, around 1/3 of patients with CADASIL were found to have cerebral microhemorrhages (tiny areas of old blood) on
MRI.
L-arginine, a naturally occurring amino acid, has been proposed as a potential therapy for CADASIL, but as of 2017 there are no clinical studies supporting its use.
Donepezil, normally used for Alzheimer's Disease, was not shown not to improve executive functioning in CADASIL patients.
Society and culture
John Ruskin
John Ruskin (8 February 1819 20 January 1900) was an English writer, philosopher, art critic and polymath of the Victorian era. He wrote on subjects as varied as geology, architecture, myth, ornithology, literature, education, botany and pol ...
has been suggested to have had CADASIL.
Ruskin reported in his diaries having visual disturbances consistent with the disease, and it has also been suggested that it might have been a factor in causing him to describe
James Whistler
James Abbott McNeill Whistler (; July 10, 1834July 17, 1903) was an American painter active during the American Gilded Age and based primarily in the United Kingdom. He eschewed sentimentality and moral allusion in painting and was a leading pr ...
's ''
Nocturne in Black and Gold – The Falling Rocket
''Nocturne in Black and Gold – The Falling Rocket'' is a c. 1875 painting by James Abbott McNeill Whistler held in the Detroit Institute of Arts. The painting exemplified the Art for art's sake movement – a concept formulated by Pierre Ju ...
'' as "ask
ngtwo 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's awarding Whistler one farthing damages.
Recent research into the illness of philosopher
Friedrich Nietzsche
Friedrich Wilhelm Nietzsche (; or ; 15 October 1844 – 25 August 1900) was a German philosopher, prose poet, cultural critic, philologist, and composer whose work has exerted a profound influence on contemporary philosophy. He began his ...
has suggested that his mental illness and death may have been caused by CADASIL rather than tertiary syphilis. Likewise, the early death of the composer
Felix Mendelssohn
Jakob Ludwig Felix Mendelssohn Bartholdy (3 February 18094 November 1847), born and widely known as Felix Mendelssohn, was a German composer, pianist, organist and conductor of the early Romantic period. Mendelssohn's compositions include sym ...
, at age 37, from a stroke has been potentially linked to CADASIL. His sister,
Fanny Mendelssohn
Fanny Mendelssohn (14 November 1805 – 14 May 1847) was a German composer and pianist of the early Romantic era who was also known as Fanny (Cäcilie) Mendelssohn Bartholdy and, after her marriage, Fanny Hensel (as well as Fanny Mendelssohn He ...
, was similarly affected. And
James Dewar
Sir James Dewar (20 September 1842 – 27 March 1923) was a British chemist and physicist. He is best known for his invention of the vacuum flask, which he used in conjunction with research into the liquefaction of gases. He also studied a ...
, best known as vocalist for
Robin Trower
Robin Leonard Trower (born 9 March 1945) is an English rock guitarist who achieved success with Procol Harum throughout 1967–1971, and then again as the bandleader of his own power trio known as the Robin Trower Band.
Biography
Robin Trowe ...
, died age 59 from complications of CADASIL.
In the movie
The Sea Inside
''The Sea Inside'' ( es, Mar adentro) is a 2004 Spanish psychological drama film co-written and directed by Alejandro Amenábar, who also co-produced, scored and edited. It is based on the real-life story of Ramón Sampedro (played by Javier Bard ...
, one of the characters is stated to have CADASIL.
See also
*
Proteopathy
* CARASIL (
cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy)
References
Further reading
* In
External links
A patient storyat ''The New York Times''
{{DEFAULTSORT:Cadasil Syndrome
Deficiencies of intracellular signaling peptides and proteins
Cerebrovascular diseases
Skin conditions resulting from errors in metabolism
Syndromes