CADASIL

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CADASIL
Other namesCADASIL syndrome
CADASIL.jpg
Brain MRI from patients with CADASIL showing multiple lesions.
Specialty Neurology, cardiology, medical genetics   OOjs UI icon edit-ltr-progressive.svg
Symptoms Migraine headaches

CADASIL or CADASIL syndrome, involving cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, 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. [1] The disease belongs to a family of disorders called the leukodystrophies. The most common clinical manifestations are migraine 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. [2] [3]

Contents

The condition was identified and named by French researchers Marie-Germaine Bousser and Elisabeth Tournier-Lasserve in the 1990s. [4] [5] Together with two other researchers, Hugues Chabriat and Anne Joutel, they received the 2019 Brain Prize for their research into the condition. [6]

Signs and symptoms

CADASIL may start with attacks of migraine with aura 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 and urinary incontinence.[ citation needed ]

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. [7]

Pathophysiology

The underlying pathology of CADASIL is progressive hypertrophy of the smooth muscle cells in blood vessels. Autosomal dominant mutations in the Notch 3 gene (on the long 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, [8] seen as granular osmiophilic deposits on electron microscopy. [9] Leukoencephalopathy follows. Depending on the nature and position of each mutation, a consensus significant loss of beta sheet structure of the Notch3 protein has been predicted using in silico analysis. [10]

Diagnosis

A micrograph showing punctate immunostaining (brown) with a Notch 3 antibody, as is characteristic in CADASIL. CADASIL - very high mag.jpg
A micrograph showing punctate immunostaining (brown) with a Notch 3 antibody, as is characteristic in CADASIL.

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, peri-ventricular white matter, and the pons, and are similar to those seen in Binswanger disease. [2] [11] These white matter lesions are also seen in asymptomatic individuals with the mutated gene. [12] While MRI is not used to diagnose CADASIL, it can show the progression of white matter changes even decades before onset of symptoms.[ citation needed ]

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. [13] [14]

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. [15] Antiplatelet agents such as aspirin, dipyridamole, or clopidogrel might help prevent strokes; however, anticoagulation may be inadvisable given the propensity for microhemorrhages. [16] Control of high blood pressure is particularly important in CADASIL patients. [15] Short-term use of atorvastatin, a statin-type cholesterol-lowering medication, has not been shown to be beneficial in CADASIL patients' cerebral hemodynamic parameters, [17] although treatment of comorbidities such as high cholesterol is recommended. [18] Stopping oral contraceptive pills may be recommended. [19] Some authors advise against the use of triptan medications for migraine treatment, given their vasoconstrictive effects, [20] although this sentiment is not universal. [18] 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. [21]

In one small study, around 1/3 of patients with CADASIL were found to have cerebral microhemorrhages (tiny areas of old blood) on MRI. [16]

L-arginine, a naturally occurring amino acid, has been proposed as a potential therapy for CADASIL, [22] but as of 2017 there are no clinical studies supporting its use. [19] Donepezil, normally used for Alzheimer's Disease, was shown not to improve executive functioning in CADASIL patients. [23]

Society and culture

John Ruskin has been suggested to have had CADASIL. [24] 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'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's awarding Whistler one farthing damages. [24]

Recent research into the illness of philosopher Friedrich Nietzsche has suggested that his mental illness and death may have been caused by CADASIL rather than tertiary syphilis. [25] Likewise, the early death of the composer Felix Mendelssohn, at age 37, from a stroke has been potentially linked to CADASIL. His sister, Fanny Mendelssohn, was similarly affected. [26] And James Dewar, best known as vocalist for Robin Trower, died age 59 from complications of CADASIL. [27]

In the movie The Sea Inside, one of the characters is stated to have CADASIL. [28]

In the Netflix 2023 limited series The Fall of the House of Usher, the main character Roderick Usher suffers from this disorder, and much of the series storyline surrounds his criminal and illicit attempts to find a cure. The limited series is based on the life's work of Edgar Allan Poe.

See also

Related Research Articles

Vascular dementia (VaD) is dementia caused by problems in the blood supply to the brain, resulting from a cerebrovascular disease. Restricted blood supply (ischemia) leads to cell and tissue death in the affected region, known as an infarct. The three types of vascular dementia are subcortical vascular dementia, multi-infarct dementia, and stroke related dementia. Subcortical vascular dementia is brought about by damage to the small blood vessels in the brain. Multi-infarct dementia is brought about by a series of mini-strokes where many regions have been affected. The third type is stroke related where more serious damage may result. Such damage leads to varying levels of cognitive decline. When caused by mini-strokes, the decline in cognition is gradual. When due to a stroke, the cognitive decline can be traced back to the event.

<span class="mw-page-title-main">Binswanger's disease</span> Medical condition

Binswanger's disease, also known as subcortical leukoencephalopathy and subcortical arteriosclerotic encephalopathy, is a form of small-vessel vascular dementia caused by damage to the white brain matter. White matter atrophy can be caused by many circumstances including chronic hypertension as well as old age. This disease is characterized by loss of memory and intellectual function and by changes in mood. These changes encompass what are known as executive functions of the brain. It usually presents between 54 and 66 years of age, and the first symptoms are usually mental deterioration or stroke.

<span class="mw-page-title-main">Cerebrovascular disease</span> Condition that affects the arteries that supply the brain

Cerebrovascular disease includes a variety of medical conditions that affect the blood vessels of the brain and the cerebral circulation. Arteries supplying oxygen and nutrients to the brain are often damaged or deformed in these disorders. The most common presentation of cerebrovascular disease is an ischemic stroke or mini-stroke and sometimes a hemorrhagic stroke. Hypertension is the most important contributing risk factor for stroke and cerebrovascular diseases as it can change the structure of blood vessels and result in atherosclerosis. Atherosclerosis narrows blood vessels in the brain, resulting in decreased cerebral perfusion. Other risk factors that contribute to stroke include smoking and diabetes. Narrowed cerebral arteries can lead to ischemic stroke, but continually elevated blood pressure can also cause tearing of vessels, leading to a hemorrhagic stroke.

<span class="mw-page-title-main">Stroke</span> Death of a region of brain cells due to poor blood flow

Stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functioning properly.

<span class="mw-page-title-main">Perivascular space</span>

A perivascular space, also known as a Virchow–Robin space, is a fluid-filled space surrounding certain blood vessels in several organs, including the brain, potentially having an immunological function, but more broadly a dispersive role for neural and blood-derived messengers. The brain pia mater is reflected from the surface of the brain onto the surface of blood vessels in the subarachnoid space. In the brain, perivascular cuffs are regions of leukocyte aggregation in the perivascular spaces, usually found in patients with viral encephalitis.

<span class="mw-page-title-main">Intraparenchymal hemorrhage</span> Medical condition

Intraparenchymal hemorrhage (IPH) is one form of intracerebral bleeding in which there is bleeding within brain parenchyma. The other form is intraventricular hemorrhage (IVH).

<span class="mw-page-title-main">Periventricular leukomalacia</span> Degeneration of white matter near the lateral ventricles of the brain

Periventricular leukomalacia (PVL) is a form of white-matter brain injury, characterized by the necrosis of white matter near the lateral ventricles. It can affect newborns and fetuses; premature infants are at the greatest risk of neonatal encephalopathy which may lead to this condition. Affected individuals generally exhibit motor control problems or other developmental delays, and they often develop cerebral palsy or epilepsy later in life. The white matter in preterm born children is particularly vulnerable during the third trimester of pregnancy when white matter developing takes place and the myelination process starts around 30 weeks of gestational age.

<span class="mw-page-title-main">Watershed stroke</span> Medical condition

A watershed stroke is defined as a brain ischemia that is localized to the vulnerable border zones between the tissues supplied by the anterior, posterior and middle cerebral arteries. The actual blood stream blockage/restriction site can be located far away from the infarcts. Watershed locations are those border-zone regions in the brain supplied by the major cerebral arteries where blood supply is decreased. Watershed strokes are a concern because they comprise approximately 10% of all ischemic stroke cases. The watershed zones themselves are particularly susceptible to infarction from global ischemia as the distal nature of the vasculature predisposes these areas to be most sensitive to profound hypoperfusion.

<span class="mw-page-title-main">MELAS syndrome</span> Medical condition

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is one of the family of mitochondrial diseases, which also include MIDD, MERRF syndrome, and Leber's hereditary optic neuropathy. It was first characterized under this name in 1984. A feature of these diseases is that they are caused by defects in the mitochondrial genome which is inherited purely from the female parent. The most common MELAS mutation is mitochondrial mutation, mtDNA, referred to as m.3243A>G.

Familial hemiplegic migraine (FHM) is an autosomal dominant type of hemiplegic migraine that typically includes weakness of half the body which can last for hours, days, or weeks. It can be accompanied by other symptoms, such as ataxia, coma, and paralysis. Migraine attacks may be provoked by minor head trauma. Some cases of minor head trauma in patients with hemiplegic migraine can develop into delayed cerebral edema, a life-threatening medical emergency. Clinical overlap occurs in some FHM patients with episodic ataxia type 2 and spinocerebellar ataxia type 6, benign familial infantile epilepsy, and alternating hemiplegia of childhood.

<span class="mw-page-title-main">Sneddon's syndrome</span> Medical condition

Sneddon's syndrome is a form of arteriopathy characterized by several symptoms, including:

<span class="mw-page-title-main">NOTCH3</span> Protein-coding gene in the species Homo sapiens

Neurogenic locus notch homolog protein 3(Notch 3) is a protein that in humans is encoded by the NOTCH3 gene.

<span class="mw-page-title-main">Leukoencephalopathy with vanishing white matter</span> Neurological disease

Leukoencephalopathy with vanishing white matter is an autosomal recessive neurological disease. The cause of the disease are mutations in any of the 5 genes encoding subunits of the translation initiation factor eIF2B: EIF2B1, EIF2B2, EIF2B3, EIF2B4, or EIF2B5. The disease belongs to a family of conditions called the Leukodystrophies.

Megalencephalic leukoencephalopathy with subcortical cysts is a form of hereditary CNS demyelinating disease. It belongs to a group of disorders called leukodystrophies. It is characterized by early-onset enlargement of the head (macrocephaly) as well as delayed-onset neurological deterioration to include spasticity, epilepsy, and lack of muscular coordination. MLC does not appear to be a disease that is fatal at birth or early in life despite its symptoms, although the number of patients throughout history known to have the disease is fairly limited.

A silent stroke is a stroke that does not have any outward symptoms associated with stroke, and the patient is typically unaware they have suffered a stroke. Despite not causing identifiable symptoms, a silent stroke still causes damage to the brain and places the patient at increased risk for both transient ischemic attack and major stroke in the future. In a broad study in 1998, more than 11 million people were estimated to have experienced a stroke in the United States. Approximately 770,000 of these strokes were symptomatic and 11 million were first-ever silent MRI infarcts or hemorrhages. Silent strokes typically cause lesions which are detected via the use of neuroimaging such as MRI. The risk of silent stroke increases with age but may also affect younger adults. Women appear to be at increased risk for silent stroke, with hypertension and current cigarette smoking being amongst the predisposing factors.

Migraines are often hereditary. It is estimated that 60% of migraine cases are caused by genetics. The role of natural selection in the development of migraines is not known. Fitness-impairing disorders, including migraines, tend to disappear as a result of natural selection, and their frequency decreases to near the rate of spontaneous mutation. However, it is estimated that migraines affect 15-20% of the population and is increasing. This could suggest that a central nervous system (CNS) susceptible to severe, intermittent headache has been linked to an important survival or reproductive advantage. Five possible evolutionary explanations exist: i) migraine as a defence mechanism, ii) migraine as a result of conflicts with other organisms, iii) migraine as a result of novel environmental factors, iv) migraine as a compromise between genetic harms and benefits, and v) headache as a design constraint. These considerations allow the treatment and prevention of migraine to be approached from an evolutionary medicine perspective.

<span class="mw-page-title-main">Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy</span> Medical condition

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is disease of the arteries in the brain, which causes tissue loss in the subcortical region of the brain and the destruction of myelin in the CNS. CARASIL is characterized by symptoms such as gait disturbances, hair loss, low back pain, dementia, and stroke. CARASIL is a rare disease, having only been diagnosed in about 50 patients, of which ten have been genetically confirmed. Most cases have been reported in Japan, but Chinese and caucasian individuals have also been diagnosed with the disease. CARASIL is inherited in an autosomal recessive pattern. There is currently no cure for CARASIL. Other names for CARASIL include familial young-adult-onset arteriosclerotic leukoencephalopathy with alopecia and lumbago without arterial hypertension, Nemoto disease and Maeda syndrome.

Élisabeth Tournier-Lasserve 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 largest brain research prize.

Anne Joutel 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 awarded for brain research.

References

  1. ↑ Joutel A, Corpechot C, Ducros A, et al. (October 1996). "Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia". Nature. 383 (6602): 707–10. Bibcode:1996Natur.383..707J. doi:10.1038/383707a0. PMID   8878478. S2CID   4351873.
  2. 1 2 Chabriat H, Vahedi K, Iba-Zizen MT, et al. (October 1995). "Clinical spectrum of CADASIL: a study of 7 families. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy". Lancet. 346 (8980): 934–9. doi:10.1016/s0140-6736(95)91557-5. PMID   7564728. S2CID   44289660.
  3. ↑ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology . Saunders Elsevier. p.  545. ISBN   978-0-7216-2921-6.
  4. ↑ "CADASIL History". www.cadasilfoundation.org. Archived from the original on 2021-05-15. Retrieved 2018-03-03.
  5. ↑ Chabriat, H.; Joutel, A.; Vahedi, K.; Iba-Zizen, M. T.; Tournier-Lasserve, E.; Bousser, M. G. (1996). "[CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)] - Abstract". Journal des Maladies Vasculaires. 21 (5): 277–82. PMID   9026542.
  6. ↑ Office, FENS. "The Brain Prize 2019: French neuroscientists honoured for outstanding research into small vessel strokes in the brain". FENS.org. Archived from the original on 2021-05-15. Retrieved 2021-03-04.
  7. ↑ Ho, Cyrus S.H.; Mondry, Adrian (2015). "CADASIL presenting as schizophreniform organic psychosis". General Hospital Psychiatry. 37 (3): 273.e11–273.e13. doi:10.1016/j.genhosppsych.2015.02.006. PMID   25824603.
  8. ↑ Joutel A, Andreux F, Gaulis S, et al. (March 2000). "The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients". J. Clin. Invest. 105 (5): 597–605. doi:10.1172/JCI8047. PMC   289174 . PMID   10712431.
  9. ↑ Ruchoux MM, Guerouaou D, Vandenhaute B, Pruvo JP, Vermersch P, Leys D (1995). "Systemic vascular smooth muscle cell impairment in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy". Acta Neuropathol. 89 (6): 500–12. doi:10.1007/BF00571504. PMID   7676806. S2CID   24884723.
  10. ↑ Vlachakis D, Champeris Tsaniras S, Ioannidou K, Papageorgiou L, Baumann M, Kossida S (October 2014). "A series of Notch3 mutations in CADASIL; insights from 3D molecular modelling and evolutionary analyses". Journal of Molecular Biochemistry. 3 (3): 97–105.
  11. ↑ Ropper AH, Brown RH, eds. (2005). "Cerebrovascular Diseases". Adams and Victor's Principles of Neurology. New York: McGraw-Hill. ISBN   978-0-07-141620-7.
  12. ↑ Tournier-Lasserve E, Joutel A, Melki J, et al. (March 1993). "Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps to chromosome 19q12". Nat. Genet. 3 (3): 256–9. doi:10.1038/ng0393-256. PMID   8485581. S2CID   13031278.
  13. ↑ Joutel A, Favrole P, Labauge P, et al. (December 2001). "Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis". Lancet. 358 (9298): 2049–51. doi:10.1016/S0140-6736(01)07142-2. PMID   11755616. S2CID   31459077.
  14. ↑ Ueda M, Nakaguma R, Ando Y (March 2009). "[Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)]". Rinsho Byori (in Japanese). 57 (3): 242–51. PMID   19363995.
  15. 1 2 André, Charles (April 2010). "CADASIL: pathogenesis, clinical and radiological findings and treatment". Arq. Neuro-Psiquiatr. 68 (2): 287–99. doi: 10.1590/S0004-282X2010000200026 . PMID   20464302.
  16. 1 2 Lesnik Oberstein, S. A.; van den Boom, R.; van Buchem, M. A.; van Houwelingen, H. C.; Bakker, E.; Vollebregt, E.; Ferrari, M. D.; Breuning, M. H.; Haan, J. (2001-09-25). "Cerebral microbleeds in CADASIL". Neurology. 57 (6): 1066–1070. doi:10.1212/wnl.57.6.1066. ISSN   0028-3878. PMID   11571335. S2CID   22934154.
  17. ↑ Peters, N (15 September 2007). "Effects of short term atorvastatin treatment on cerebral hemodynamics in CADASIL". J Neurol Sci. 260 (1–2): 100–105. doi:10.1016/j.jns.2007.04.015. PMID   17531269. S2CID   6502194.
  18. 1 2 Rutten, Julie; Lesnik Oberstein, Saskia A.J. (1 January 1993). "Cadasil". In Pagon, Roberta A.; Adam, Margaret P.; Ardinger, Holly H.; Wallace, Stephanie E.; Amemiya, Anne; Bean, Lora J.H.; Bird, Thomas D.; Ledbetter, Nikki; Mefford, Heather C.; Smith, Richard J.H.; Stephens, Karen (eds.). GeneReviews. University of Washington, Seattle. PMID   20301673 – via PubMed.
  19. 1 2 "Questions about cadasil". www.cambridgestroke.com.
  20. ↑ Sencen, Lisa. "CADASIL".
  21. ↑ "CADASIL - About the Disease - Genetic and Rare Diseases Information Center". rarediseases.info.nih.gov. Archived from the original on 2021-10-27. Retrieved 2017-04-01.
  22. ↑ Peters, N (August 2008). "Enhanced L-arginine-induced vasoreactivity suggests endothelial dysfunction in CADASIL". Journal of Neurology. 255 (8): 1203–1208. doi:10.1007/s00415-008-0876-9. PMID   18537053. S2CID   42107389.
  23. ↑ Susman, Ed (2008-04-03). "Donepezil Fails to Improve Cognition in Patients with CADASI... : Neurology Today". Neurology Today. 8 (7): 25. doi:10.1097/01.NT.0000316148.27827.bc. S2CID   72564626.
  24. 1 2 Kempster PA, Alty JE (September 2008). "John Ruskin's relapsing encephalopathy". Brain. 131 (Pt 9): 2520–5. doi:10.1093/brain/awn019. PMID   18287121.
  25. ↑ Hemelsoet D, Hemelsoet K, Devreese D (March 2008). "The neurological illness of Friedrich Nietzsche". Acta Neurol Belg. 108 (1): 9–16. PMID   18575181.
  26. ↑ "Blogger". accounts.google.com.
  27. ↑ "Jimmy Dewar, singer/bassist for Robin Trower's Rock Sensation". Rock and Roll Paradise. 23 March 2019. Retrieved 2 July 2021.
  28. ↑ Fisher, Christopher (14 March 2011). "CADASIL, A Vascular Brain Disorder, Is Often Misdiagnosed As Multiple Sclerosis". BMED Report. Retrieved 28 July 2021.

Further reading

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