CADASIL

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DiseasesDB = 2161
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OMIM = 125310
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MeshID = D046589

CADASIL (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. [Joutel A, Corpechot C, Ducros A, et al. Notch 3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 1996;383:707-710. PMID 8878478] 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.Chabriat H, Vahedi K, Iba-Zizen MT, et al. Clinical spectrum of CADASIL: a study of 7 families. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Lancet 1995;346:934-939 PMID 7564728]

Pathophysiology

The underlying pathology of CADASIL is progressive degeneration of the smooth muscle cells in blood vessels. Mutations in the "Notch 3" 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, [Joutel A, Andreux F and Gaulis S et al. The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients, J Clin Invest 105 (2000), 597–605. PMID 10712431 ] seen as granular osmiophilic deposits on electron microscopy. [Ruchoux MM, Guerouaou D, Vandenhaute B et al. Systemic vascular smooth muscle cell impairment in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, Acta Neuropathol (Berl) 89 (1995), 500–512. PMID 7676806 ]

Interestingly, the "Notch 3" gene is in the same locus as the gene for familial hemiplegic migraine.

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 palsy and urinary incontinence.

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, periventricular white matter, and the pons, and are similar to those seen in Binswanger disease. ] [Ropper AH, Brown RH (eds) Cerebrovascular Diseases in Adams and Victor's Principles of Neurology. 2005 McGraw-Hill, New York ISBN 007141620] These white matter lesions are also seen in asymptomatic individuals with the mutated gene. [Tournier-Lasserve E, Joutel A, Melki J, et al. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy maps on chromosome 19q12. Nat Genet 1993;3:256-259. PMID 8485581] While MRI is not used to diagnose CADASIL, it can show the progression of white matter changes even decades before onset of symptoms.

The most definitive diagnostic tool is a blood test to screen for the mutated "Notch 3"; Though costly, some insurance companies do cover the cost if deemed medically necessary. Since CADASIL is a systemic arteriopathy, evidence of blood vessel damage is seen in small- and medium-sized arteries. Therefore, skin biopsies have been used for diagnosis; [Joutel A, Favrole P, Labauge P, et al. Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis. Lancet. 2001 15;358(9298):2049-51. PMID 11755616] however, this method is less reliable than the blood screen.Athena Diagnostics is currently the only laboratory in the United States that screens for CADASIL. The actual blood draw can take place at one's local doctor's office or laboratory. For information on this test, visit www.athenadiagnostics.com.

Clinical Course

Strokes in CADASIL - Strokes or TIAs are the most common initial presentation of CADASIL. 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. 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 aspirin, Aggrenox, or Plavix 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.

External links

* [http://www.cadasilfoundation.org/ The CADASIL Foundation] A site devoted to promoting awareness, support and research for CADASIL among patients, their families and friends, and healthcare providers.
* [http://www.cadasil.org.uk/ The CADASIL support group] A site devoted to raising awareness and forming a support group for CADASIL
* [http://www.ulf.org/types/Cadasil.html United Leukodystrophy Foundation: CADASIL]
* [http://www.athenadiagnostics.com Athena Diagnostics] The only lab able to provide molecular testing for CADASIL.

References