CADASIL

This is part of Rare diseases.

Diagnosis: CADASIL

Synonyms: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Innehåll


Date of publication: 2014-10-29
Version: 3.0

ICD-10

I67.8

The disease

The word CADASIL is an acronym formed from the initial letters of C for Cerebral, A for autosomal, D for dominant, A for arteriopathy, S for subcortical (under the cerebral cortex), I for infarction, and L for leukoencephalopathy (changes in the white matter of the brain). It is a hereditary disease affecting small and medium-sized arteries, mainly in the brain. The arterial walls become more narrow and rigid, which leads to oxygen deficiency and subsequent cerebral infarction. The consequences of brain infarct (stroke) include hemiparesis, speech problems, cognitive impairment and psychiatric symptoms.

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, and at least 500 families have the condition globally. In Finland and Scotland the estimated incidence of CADASIL is two to four individuals per 100,000 population.

Cause

The disease is caused by a mutation in the NOTCH3 gene, on chromosome 19 (19p13.1-13.2). This gene encodes a single pass transmembrane, heterodimer receptor protein, NOTCH3(N3), which is important for the development and normal intra-cellular signalling function of the muscle cells of the blood vessel walls. The gene is active in the smooth muscle cells of blood vessels, but the function of the gene later in life is still unknown.

In CADASIL, symptoms are caused by changes in the arterial walls. Muscle cells are broken down and replaced by connective tissue. The arterial walls become thicker and 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. This lack of oxygen causes necrosis (tissue death) in the form of small infarcts in the white matter and in deeper grey matter (the basal ganglia) of the brain. These are called lacunar infarcts.

The reason why the muscle cells in the arterial walls break down is not yet known. One theory is that the small granular particles (granular osmiophilic material) which accumulate in the smooth vascular muscle cells in the walls of the blood vessels prevent the cells signalling to each other, so impairing the production of different proteins. Cell cultures show that muscle cells from a person with CADASIL divide more slowly than normal.

The disease presents at an early age. Changes in the walls of the blood vessels are found from around the age of ten, although symptoms usually appear for the first time when the individual has passed fifty.

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 disease and do not pass it down.

Figure: Autosomal dominant inheritance

The syndrome may 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 (2014) few new mutations have been identified.

Symptoms

The majority (60 per cent) of people with CADASIL experience either a transient ischaemic attack (TIA) or a mild stroke at between the ages of 40 and 60.

A TIA is a short period of oxygen deficiency, causing symptoms similar to a stroke. Symptoms disappear within 24 hours. The most common symptom of minor stroke is mild paralysis 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 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. In CADASIL, it is usually a cerebral 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, the brain cells are irreversibly damaged (brain infarction). Small brain haemorrhages, which do not result in clinical symptoms, occur in between 30 and 70 per cent of those with CADASIL, often in the part of the brain called the thalamus.

Before the first stroke, almost half of those affected have experienced a migraine with aura (an attack preceded by a sensory disturbance). The aura is sometimes very severe and causes symptoms in the form of numbness or impaired strength in an arm or leg, unclear speech or other language problems. In those people who also have migraine with aura it is difficult to differentiate between a TIA/mild stroke, and an attack of migraine. In some people the disease progresses slowly, involving gradual loss of functions but without clear TIAs or a stroke. It becomes more difficult for, to example, plan and carry out an activity (loss of executive function). Jobs at work can take longer, and the individual with CADASIL may become tired more quickly and not manage to work a whole day.

The progression of the disease is slow, and approximately half of those with the disease have a new TIA or a new cerebral infarction. On average, a person with the disease experiences several short periods of transient neurological symptoms but only two or three of them cause strokes. The number can vary greatly between individuals. As motor and cognitive functions are only mildly affected at the onset of the disease, individuals often manage to cope with everyday life despite recurrent cerebral infarctions. Movement is usually not severely affected and only a few individuals experience extensive paralysis, for example paralysis on one side of the body (hemiparesis).

Cognitive function deteriorates slowly. By late middle age many people have developed difficulties in concentrating and a degree of cognitive impairment. There is a gradual deterioration in the ability to plan, take the initiative and solve problems. Some people with the disease develop such severe cognitive disabilities that they interfere with work and social life. The disease affects mainly the white matter and the basal ganglia, the grey matter deep in the brain, causing cognitive impairment which corresponds to damage to the frontal subcortex. In this condition the memory of events (episodic memory) is not as severely affected as in Alzheimer’s disease. 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.

Memory loss, sadness, sleeping problems, loss of appetite, fatigue and other symptoms of depression occur in approximately 20 per cent of all 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 but without high blood pressure
  • family history of recurrent strokes or several TIAs in middle age
  • hyperdensities in the white matter of the brain (in the anterior part of the temporal lobe) and lacunar infarcts (see under “Causes”) visible in a magnetic resonance scan or a CT (computed tomography) scan. In some people, characteristic changes to the white matter of the brain occur in the twenties. Everyone with CADASIL has changes to the white matter of the brain by around the age of 40.

The diagnosis is confirmed by a skin biopsy, including arteries. When this is examined under an electron microscope the biopsy will reveal abnormal deposits of granular osmiophilic material (GOM) outside the muscle cells of the arteries. The presence of GOM is confined to cases of CADASIL and can also be confirmed by the immunohistochemical (IHC) demonstration of N3ECD in a skin biopsy.

By using DNA testing it is possible to detect mutations in the NOTCH3 gene. At the time of diagnosis it is important that the family is offered genetic counselling. Carrier and prenatal diagnosis, as well as pre-implantation genetic diagnosis (PGD) in association with IVF (in vitro fertilization), are available to families where the mutation is known. Children under 18 are tested only if it is suspected that they have the disease.

Other diseases can give similar symptoms and test results so it is important to eliminate them before confirming CADASIL (differential diagnosis). These include multiple sclerosis, MELAS syndrome, Binswanger disease, familial hemiplegic migraine, hereditary spastic paraparesis or CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy). 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 no cure for the syndrome, and treatment focuses on treating risk factors, alleviating symptoms and compensating for loss of function. People with CADASIL require contact with a neurology clinic or a hospital 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, for example abstaining from smoking or being restrictive in alcohol intake. Both smoking and high 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. Levels of blood glucose, haemoglobin (Hb), blood fats, levels of vitamin B12 and folic acid should also be measured and remedial action taken if they are deficient.

Usually, people who have had TIA or a stroke receive low doses of acetylsalicylic acid (aspirin) or a combination of aspirin and dipyridamole. Sometimes clopidogrel is also given. However, treatment with both acetylsalicylic acid and clopidogrel should not continue in the long term. To prevent blood coagulating warfarin may be given, although it may cause microbleeding and is therefore not routinely recommended. Thrombolytic medication should be used only in cases of infarction in the major arteries of the brain and with the greatest caution because of the risk of haemorrhage associated with confluent changes in the white matter. Because of risk of blood clots (thrombosis), the use of contraceptive pills containing oestrogen and hormone replacement therapy during menopause should be avoided.

It is important to avoid stimuli which might trigger 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 called triptans) 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 in the form of betablockers or amitriptyline.

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 in association with surgical procedures, during physical training 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.

If they become pregnant, women with the condition run an increased risk of toxaemia with cramps (pre-eclampsia) and the first six to eight weeks after delivery they run a higher than normal risk of developing neurological symptoms or migraines, which may be severe. For these reasons, women with CADASIL should be carefully monitored during their pregnancies.

Rehabilitation is needed to help people with CADASIL recover and retain optimal levels of functioning after a stroke. This includes practising motor skills as well as speech and cognitive functions, while taking into account physical and mental restrictions. The need for aids, adaptations and new working methods varies according to the individual’s degree of disability and are necessary 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. It is also important that they are provided with information about available support from Sweden’s public services.

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 suitable support should be drawn up jointly by the person with the disease, the family, a liaison officer for the disabled or a 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

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

Neurology Clinic, Sahlgrenska University Hospital/Sahlgrenska, SE-413 45 Gothenburg, Sweden. Tel: +46 31 342 10 00.

Memory Clinic, Neuropsychiatric Department, Skåne University Hospital, SE-205 02 Malmö, Sweden. Tel: +46 40 33 10 00.

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

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

Resource personnel

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

Chief Physician Anne Börjesson Hanson, Neuropsychiatry, Sahlgrenska University Hospital/Mölndal, SE-431 41 Gothenburg, Sweden. Tel: +46 31 343 10 00.

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

Associate Professor Katarina Jood, Neurochemistry Laboratory, Sahlgrenska University Hospital/Sahlgrenska, SE-413 45 Gothenburg, Sweden. Tel: +46 31 342 10 00.

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

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

Professor Matti Viitanen, Department of Geriatrics, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Tel: +46 8 585 800 00.

Courses, exchanges of experience, recreation

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Organizations for the disabled/patient associations etc.

There are currently no special associations for people with CADASIL, but the following organizations are involved with neurological disorders, stroke and dementia.

Neuro Sweden, Box 49084, St Eriksgatan 44, SE-100 28 Stockholm, Sweden. Tel: +46 8 677 70 10, email: info@neuroforbundet.se, www.neuroforbundet.se.

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

Dementia Association, Lundagatan 42 A, SE-117 27 Stockholm, Sweden. Tel: +46 8 658 99 20, email: rdr@demensforbundet.se, www.demensforbundet.se.

Courses, exchanges of experience for personnel

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Research and development

Clinical research is ongoing at Swedish centres (see under “National and regional resources in Sweden”) in collaboration with the Finnish CADASIL group. For information contact Matti Viitanen, Department of Geriatrics, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden. Email: matti.viitanen@ki.se

Information material

Short summaries of all the database texts are available as leaflets, in Swedish only. These leaflets may be ordered or printed out. (See under “Mer hos oss” in the right hand column.)

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.

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, 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.

Liem MK, Oberstein SA, van der Grond J, Ferrari MD, Haan J. CADASIL and migraine: A narrative review. Cephalalgia 2010; 30: 1284-1289.

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.

Rinnoci V, Nannucci S, Valenti R, Donnini I, Bianchi S, Pescini Fet al. Cerebral hemorrhages in CADASIL: report of four cases and a brief review. J Neurol Sci 2013; 330: 45-51.

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.

Thal DR, Grinberg LT, Attems J. Vascular dementia: different forms of vessel disorders contribute to the development of dementia in the elderly brain. Exp Gerontol 2012; 47: 816-824.

Tikka S, Baumann M, Siitonen M, Pasanen P, Pöyhönen M, Myllykangas L, Viitanen M et al. CADASIL and CARASIL. Brain Pathol 2014; 24: 525-544.

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 (select “GeneReviews”, then “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, Sweden.

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: 2014-10-29
Version: 3.0
Publication date of the Swedish version: 2014-06-23

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 422, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

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