CADASIL

This is part of Rare diseases.

Diagnosis: CADASIL

Synonyms: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

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Date of publication: 2010-12-27
Version: 2.0

ICD 10 code

I67.8

The disease

CADASIL is the acronym for Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (referring to changes in the white matter of the brain). It is a hereditary disease, predominantly affecting small and medium-sized arteries mainly in the brain. Thickening of arterial walls leads to oxygen deficiency and subsequent tissue death (infarction). Brain infarct (stroke) results in paresis (partial loss of movement), speech problems and cognitive impairment.

The disease was first described by Belgian neurologist Ludo van Bogaert in 1955. In 1987, Finnish researchers Vesa Sonninen and Marja-Liisa Savontaus were the first to report a Nordic case. The condition was then known as hereditary multi-infarct dementia. The current term CADASIL has been in use since 1993.

Occurrence

Exact rates of prevalence have not been established, but in Sweden the disease has been identified in at least 20 families. Globally, at least 500 families have members with the disease. In Finland and Scotland, the incidence rate has been estimated at between 20 and 40 individuals per million population.

Cause

The disease is caused by a mutation (a defect) in the NOTCH3 gene located on chromosome 19. To date over 170 different mutations causing the disorder have been identified. NOTCH3 plays an important role during foetal development as it regulates the formation of different types of tissues. The gene is expressed in the smooth muscle cells of blood vessels, but the function of the gene later in life is still unknown.

CADASIL symptoms result from changes to the walls of the arteries. Vascular smooth muscle cells gradually degenerate and are replaced by connective tissue. As a consequence the walls of arteries thicken and become more rigid, and the space inside the arteries (the lumen) becomes smaller. Normally, the cerebral white matter of the brain is supplied with blood by both long and short arteries, which penetrate deep into the brain. In CADASIL, small branches of these arteries are often damaged, resulting in decreased blood flow and subsequent oxygen deficiency (hypoxia). This lack of oxygen causes small infarcts (lacunar infarcts) in the white matter and in deeper grey matter (the basal ganglia). Less damage is often caused to the cortical grey matter as the capillary network supplies this area with blood.

The cause of degeneration of the vascular smooth muscle cells of the blood vessels is still unknown. According to one theory, small granular particles (granular osmophilic material, GOM) which accumulate in the vascular smooth muscle cells in the walls of blood vessels obstruct the signalling between cells. As a consequence, the production of various proteins is impaired.

The disease begins early in childhood, and by the age of ten changes in the walls of blood vessels can be identified. However, symptoms usually do not present until around the ages of 40 to 50.

Heredity

The inheritance pattern of CADASIL is autosomal dominant. This means that one of the parents has the disease, and so has one normal gene and one mutated gene. Sons and daughters of this parent have a 50 per cent risk of inheriting the disease. Children who do not inherit the mutated gene do not have the disorder and do not pass it down.

Figure: Autosomal dominant inheritance 

CADASIL can also be caused by a new mutation. This means that the genetic mutation occurs in an individual for the first time and is not inherited from either parent. Consequently, parents with a child with a new mutation generally do not have an increased risk of having another child with the disorder. However, the new genetic mutation will be hereditary and an adult with this mutation risks passing on the mutated gene to his/her children. To date (summer 2010) two families with new mutations have been identified.

Symptoms

Most CADASIL patients (85 per cent) are affected by TIAs (transient ischemic attacks) or minor strokes between the ages of 30 and 55.

A TIA is a short period of oxygen deficiency (hypoxia) in the brain causing stroke-like symptoms. The attacks are caused by blood clots that dissolve before hypoxia can cause permanent brain damage. Symptoms disappear within twenty-four hours.

The most common symptom of minor stroke is dysarthia (difficulty in articulating words), unilateral mild paresis and lack of sensation in an arm or leg. The dysfunction usually improves within a few days. People who have suffered a minor stroke may then experience speech difficulties, particularly when they are tired. Temporary episodes of memory loss or other cognitive problems sometimes occur.

The term “stroke” includes both brain haemorrhage and brain infarction. If a cerebral artery is blocked by a blood clot, a large number of nerve cells may be deprived of their supplies of oxygen-rich blood. After only a few minutes, these cells are irreversibly damaged, a condition known as brain infarction.

CADASIL is slowly progressive and around half the individuals with the disease are affected by several TIAs or strokes. A patient may have several TIA episodes during a lifetime, but only two or three of them will lead to a stroke. There are significant differences between individuals. Motor and cognitive functions are affected relatively little at the onset of the disease, and people with CADASIL can lead relatively normal lives for a long time despite having suffered several strokes. Around the age of 50, concentration problems may arise and thought processes become slower. The ability to take initiatives, make plans and solve problems slowly deteriorates although memory impairment usually does not occur until a late stage of the disease. Motor function is also affected, but to a lesser degree.

Cognitive function deteriorates slowly. By the age of 60, some CADASIL patients will have developed a degree of cognitive impairment which interferes with their work and social lives. The disease affects mainly the white matter and sub-cortical grey matter of the brain, causing cognitive impairment which corresponds to damage to the frontal subcortex. In this condition the ability to recall facts and concepts is more severely affected than episodic memory (memory of events). Cognitive symptoms and degree of disability vary a great deal, even among people in the same family. The reason why some individuals develop a more severe form of the disease is still unknown. Individuals with CADASIL often live for 30 to 40 years after the onset of the first symptoms.

Before their first stroke, one third of CADASIL patients have experienced attacks of migraines with aura, where the headache is preceded by certain signs and symptoms. The aura is sometimes severe, involving symptoms such as arm and/or leg weakness, slurred speech and aphasia. Depression, sleeping problems, loss of appetite, fatigue and other signs of depression occur in approximately 20 per cent of cases. Psychiatric disorders, such as a psychosis, may occur. Around 10 per cent of individuals with the condition have epileptic seizures.

Diagnosis

The following can result in CADASIL being suspected:

  • stroke or TIA between the ages of 30 and 60
  • family history of recurrent strokes or TIAs in middle age
  • abnormalities in the white matter of the brain (in the frontal part of the temporal lobe) and lacunar infarcts (see under “Causes”) visible in a magnetic resonance scan or a CT (computed tomography) scan. Characteristic changes to the white matter of the brain are detectable before an affected person is in his or her twenties.

The diagnosis is confirmed by a skin biopsy (sample of skin tissue) examined under an electron microscope. In CADASIL, the biopsy will reveal abnormal deposits of granular osmiophilic material on smooth muscle cells of the arterial walls. The diagnosis can also be confirmed using a skin biopsy with the help of antibodies, but the sensitivity of the method is not known.

It is possible to detect mutations in NOTCH3 by a DNA analysis of a blood sample.

DNA-based diagnosis of CADASIL is possible. When the diagnosis is made the family should be offered genetic counselling. Pre-natal DNA diagnosis is possible if the mutation is known. Children under the age of 18 are tested only if they have symptoms indicative of the disease.

It is essential to exclude other diagnoses as several other conditions manifest with similar symptoms to CADASIL and test results may be inconclusive. Multiple sclerosis, MELAS syndrome, Binswanger disease, familial hemiplegic migraine, hereditary spastic paraparesis or CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy) are the most common differential diagnoses. Separate information on MELAS syndrome and hereditary spastic paraparesis is available in the rare disease database of the Swedish Board of Health and Welfare.

Treatment/interventions

There is currently no cure for the disease, and medical treatment is directed at minimising risk factors, alleviating symptoms and compensating as far as possible for functional disabilities. People with CADASIL require contact with a neurological clinic or department of medicine.

All cardiovascular risk factors should be taken into account during examination and treatment of the patient. These include high blood pressure, elevated levels of blood fats and overweight. Preventive measures are important and both smoking and excessive alcohol consumption should be avoided as they increase the risk of strokes and can precipitate the onset of CADASIL. Exercise is also important.

Blood pressure should be monitored regularly. Blood glucose and blood fat levels, and levels of vitamin B12, folic acid and homocysteine should also be measured and remedial action taken if necessary.

In order to reduce the risk of arterial blood clots both anticoagulants (which prevent clotting) and antithrombotic drugs are prescribed. Usually, low doses of acetylsalicylic acid (aspirin) or a combination of aspirin and dipyridamole are given. Sometimes clopidogrel is also used. To prevent blood coagulating warfarin can be given, although it may cause microbleeding. Thrombolytic medication should be used only in cases of infarction in the major arteries of the brain. Even then it should be used with great caution because of the risk that it might cause a haemorrhage. Because of risk of thrombosis, the use of the contraceptive pill and hormone replacement therapy during menopause should be avoided.

It is important to avoid triggering attacks of migraine. During an attack acetylsalicylic acid (aspirin), paracetamol, ibuprofen and other COX inhibitors may be taken. Standard migraine medications (selective 5-HT1 receptor antagonists) should not be used as they cause blood vessels to contract. If migraine attacks become frequent (three or more a month), preventive medication may be prescribed.

Blood becomes more viscous (thicker) if there is insufficient fluid in the body. It is therefore important that the individual’s fluid intake is sufficient to avoid low blood pressure (hypotonia) and dehydration. This is especially important before an operation or when the patient is suffering from gastroenteritis. Contrast X-rays of the carotid or cerebral arteries should not be carried out on people with CADASIL as this can precipitate a stroke.

Women with CADASIL should be carefully monitored during pregnancy and the first six to eight weeks after delivery as they run a higher than normal risk of developing neurological symptoms or toxaemia with cramps (pre-eclampsia).

Physiotherapists can give advice about training and activities which will help people with CADASIL recover and retain optimal levels of functioning after a stroke. The level of functional disability determines the need for aids, equipment and new routines to make daily life easier. An occupational therapist at the local hospital, or a district occupational therapist, can suggest help in these areas. In cases of speech difficulties and aphasia, a speech therapist can provide advice and training.

Living with a progressive disease is a profound challenge for the affected person and his or her family. In this situation it is essential that they receive social and psychological support. Information about local resources is also necessary.

As the disease progresses the need for daily help and support increases. Home care, personal assistance and different forms of respite care to relieve family caregivers are forms of support making it possible for the person affected to stay in familiar surroundings. Day care centres offer stimulation and provide respite for family caregivers. As the disease progresses it may be necessary to move to an assisted living facility. Plans for support and assistance should be drawn up jointly by the person with the disease, the family, a liaison officer for the disabled at the local government offices and an LSS official (LSS is the Swedish Act on Services and Support for people with disabilities).

Practical advice

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National and regional resources in Sweden

The Memory Centre, Department of Geriatrics, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 800 00.

The Neurology Clinic, Sahlgrenska University Hospital/Sahlgrenska, SE-413 45 Gothenburg, Sweden. Tel: +46 31 342 00 00.

The Memory Centre, Department of Neuropsychiatry, Skåne University Hospital, Malmö, SE-205 02 Malmö, Sweden. Tel: +46 40 33 10 00.

The Department of Medicine, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 00 00.

The Neurocentre, Norrland University Hospital, SE-901 85 Umeå, Sweden. Tel: +46 90 785ÿ 00ÿ 00.

Resource personnel

Professor Oluf Andersen, Department of Neurology, Sahlgrenska University Hospital/Sahlgrenska, SE-413 45 Gothenburg, Sweden. Tel: +46 31 342 10 00.

Associate Professor Peter Andersen, Neurocentre, Norrland University Hospital, SE-901 85 Umeå, Sweden. Tel: +46 90 785 00 00.

Anne Börjesson Hanson, Specialist physician, Department of Neuropsychiatry, Sahlgrenska University Hospital/Sahlgrenska, SE-413 45 Gothenburg, Sweden. Tel: +46 31 342 10 00.

Associate Professor Elisabeth Englund, The Pathology/Cytology Clinic, Skåne University Hospital, SE-221 85 Lund, Sweden. Tel: +46 46 17 10 00.

Katarina Jood, Specialist physician, Department of Neuropsychiatry, Sahlgrenska University Hospital/Sahlgrenska, SE-413 45 Gothenburg, Sweden. Tel: +46 31 342 10 00.

Katarina Nägga, Senior physician, Neuropsychiatric Clinic, Skåne University Hospital, SE-205 02 Malmö, Sweden. Tel: +46 40 33 10 00.

Anna Stenborg, Specialist Physician, Department of Medicine, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 616 30 00.

Associate Professor Andreas Terént, Department of Medicine, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 616 30 00.

Professor Matti Viitanen, Geriatric Clinic, Karolinska University Hospital, Huddinge, SE-141ÿ 86 Stockholm, Sweden. Tel: +46 8 585 800 00.

Courses, exchanges of experience, recreation

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Organizations for the disabled/patient associations

NHR, The Swedish Association of Persons with Neurological Disabilities, St Eriksgatan 44, Box 490 84, SE-100 28 Stockholm, Sweden. Tel: +46 8 677 70 10, fax: +46 8 24 13 15, email: nhr@nhr.se, www.nhr.se.

The Swedish Stroke Association, Måsholmstorget 3, SE-127 48 Skärholmen, Sweden. Tel: +46 8 721 88 20, fax: +46 8 721 88 29, email: info@strokeforbundet.se, www.strokeforbundet.org.

The Dementia Association, Lundagatan 42A, SE-117 41 Stockholm, Sweden. Tel +46 8 658 99 20, fax: +46 8 658 60 68, email: rdr@demensforbundet.se, www.demensforbundet.se.

Courses, exchanges of experience for personnel

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Research and development (R&D)

Clinical research is ongoing at Swedish medical centres (see under “National and Regional Resources in Sweden”), in collaboration with the Finnish CADASIL group. For information, please contact Matti Viitanen, Geriatric Clinic, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden, email: matti.viitanen@ki.se.

Information material

An information leaflet on CADASIL that summarises the information in this database text is available free of charge from the customer service department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2010-4-17). Address: SE-120 88 Stockholm, Sweden. Tel: +46 75 247 38 80, fax: +46 35 19 75 29, email: publikationsservice@socialstyrelsen.se. Postage will be charged for bulk orders.

Literature

Arboleda-Velasquez JF, Rampal R, Fung E, Darland DC, Liu M, Martinez MC et al. CADASIL mutations impair Notch3 glycosylation by Fringe. Hum Mol Genet 2005; 14: 1631-1639.

van Bogaert L. Encephalopatie sous-corticale progressive (Binswanger) a evolution rapide chez deux soeurs. Med Hellen 1955; 24: 961-972.

Dichgans M, Mayer M, Uttner DP, Brüning R, Müller-Höcker J, Rungger G et al. The phenotypic spectrum of CADASIL: Clinical findings in 102 cases. Ann Neurol 1998; 44: 731-739.

Dichgans M. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: phenotypic and mutational spectrum. J Neurol Sci 2002; 203-204: 77-80.

Dotti MT, Federico A, Mazzei R, Bianchi S, Scali O, Conforti FL et al. The spectrum of Notch3 mutations in 28 Italian CADASIL families. J Neurol Neurosurg Psychiatry 2005; 76: 736-738.

Federico A, Bianchi S, Dotti MT. The spectrum of mutations for CADASIL diagnosis. Neurol Sci 2005; 26: 117-124. Review.

Haritunians T, Chow T, De Lange RP, Nichols JT, Ghavimi D, Dorrani N et al. Functional analysis of a recurrent missense mutation in Notch3 in CADASIL. J Neurol Neurosurg Psychiatry 2005; 76: 1242-1248.

Kalimo H, Ruchoux M-M, Viitanen M, Kalaria RN. CADASIL: a common form of hereditary arteriopathy causing brain infarcts and dementia. Brain Pathol 2002; 12: 371-384.

Kalimo H, Miao Q, Tikka S, Mykkänen K, Junna M, Roine S et al. CADASIL: the most common hereditary subcortical vascular dementia. Future Neurol 2008; 3: 683-704.

Lesnik Oberstein SA, Haan J. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Panminerva Med 2004; 46: 265-276. Review.

Leyhe T, Wiendl H, Buchkremer G, Wormstall H. CADASIL: underdiagnosed in psychiatric patients? Acta Psychiatr Scand 2005; 111: 392-397.

Nakamura T, Watanabe H, Hirayama M, Inukai A, Kabasawa H, Matsubara M et al. CADASIL with NOTCH3 S180C presenting anticipation of onset age and hallucinations. J Neurol Sci 2005; 238: 87-91.

Peters N, Opherk C, Bergmann T, Castro M, Herzog J, Dichgans M. Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies. Arch Neuro 2005; 62: 1091-1094.

Razvi SS, Davidson R, Bone I, Muir KW. The prevalence of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) in the west of Scotland. J Neurol Neurosurg Psychiatry 2005; 76: 739-741.

Roine S, Poyhonen M, Timonen S, Tuisku S, Marttila R, Sulkava R, Kalimo H, Viitanen M. Neurologic symptoms are common during gestation and puerperium in CADASIL. Neurology 2005; 64: 1441-1443.

Tikka S, Mykkänen K, Ruchoux MM, Bergholm R, Junna M, Pöyhönen M et al. Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients. Brain 2009; 132: 933-939.

Uchino M, Hirano T, Uyama E, Hashimoto Y. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and CADASIL-like disorders in Japan. Ann N Y Acad Sci 2002; 977: 273-278.

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: cadasil

GeneReviews (University of Washington)
www.genetests.org (klicka på GeneReviews, sedan Titles)
Search: cadasil

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Professor Matti Viitanen, Karolinska University Hospital, Huddinge, Stockholm.

The relevant organisations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Date of publication: 2010-12-27
Version: 2.0
Publication date of the Swedish version: 2010-06-15

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

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