Cadasil

leukoencephalopathy, NOTCH3 gene, HTAR1 gene, dementia, cerebral ischemia, stroke, TIA, migraine, microangiopathy, cMRI, genetic test, orphan disease

CADASIL is a rare (approx. 5-9/100,000) autosomal dominant inherited microangiopathy caused by a defective NOTCH3 gene, which leads to vascular protein deposits and severe disorders of the cerebral microcirculation and causes cerebral ischemia (stroke/TIA, often subcortical, lacunar), migraine with aura, etc. in early adulthood.It causes neurological and neuropsychiatric deficits and leads to leukoencephalopathy and dementia in advanced stages.

CARASIL is an autosomal recessive form of microangiopathy caused by a defective HTAR1 gene, which is associated with similar symptoms to CADASIL, but occurs less frequently overall and often also has motor function disorders. Leukoencephalopathy and dementia also occur late in the course of the disease.

Both diseases are rare diseases (so-called orphan diseases), cannot currently be cured causally and have a shortened life expectancy. Treatment is symptomatic and is also intended to minimize cerebrovascular damage mechanisms and delay the progression of the disease by reducing cardiovascular risk.

CADASIL is caused by a genetic mutation in the NOTCH 3 gene on chromosome 19 and is inherited in an autosomal dominant manner. The NOTCH3 gene encodes the transmembrane receptor NOTCH3, which is expressed in the vascular wall, especially in vascular smooth muscle cells. The mutation leads to structural changes in the epidermal growth factor receptor(EGFR) protein (contains 5 or 7 cysteine residues instead of the normal 6) and this results in deposits of the defective protein aggregates in the vascular walls.

The changes are found throughout the body, but lead to severe symptomatic circulatory disorders and reduced blood flow in the microcirculation, particularly in the brain.

The result is repeated ischemia (mostly microinfarcts) that lead to strokes or TIAs at a young age (30 or even earlier-50 years). This is the most common typical symptomatology in 60-85% of patients (Chabriat H et al 2009), therefore always CADASIL as DD for stroke/TIA in young people!

In addition, there is often a history of migraine at an early stage, particularly often with aura (approx. 20-40% of patients).) and atypical forms of migraine (basilar migraine, hemiplegic migraine), as well as affective disorders, often episodic (depression, manic-depressive illness, apathy), sometimes also (reversible) disorders of consciousness, and other neurological deficits such as ataxia, gait disorders, motor disorders, pseudobulbar palsy (here also consider CARASIL as a possible DD).

The symptoms of the initial manifestation can be very heterogeneous and initially only migraine or only psychiatric abnormalities can occur, for example, and cerebral ischemia can only be added later in the course of the disease (important family history and possibly imaging) (Dichgans M et al 1997, Wurthmann S et al 2025).

Due to the reduced blood flow and repeated ischemia, nerve cells die, synaptic connections (white matter) are reduced and neurogenesis occurs. The irreversible loss of nerve tissue leads to impaired brain function in affected areas, cognitive impairment and ultimately to the development of subcortical dementia (≥40% of patients (Chabriat H et al 2009)).

In addition, as the disease progresses, cardiac changes with arrhythmias, decrease in heart rate variability, increased risk of MI and sudden cardiac death.

A very rare autosomal recessive form is associated with a mutation of the HTRA1 gene and is known as CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy). Symptoms: Spastic gait disturbance. Dementia, apathy, irritability, stroke-like events. Spondylosis deformans. Alopecia.

Early diagnosis is important!

Medical history including family history (very important!)

General clinical examination

Thorough neurological examination incl.

neuropsychological testing (cognitive impairments can be detected early on in the course of the disease using good neuropsychological testing procedures)

If necessary, psychiatric examination for clarification and DD of psychiatric symptoms (often depression or manic-depressive symptoms, apathy).

Further diagnostics according to symptoms and to clarify underlying diseases and risk assessment, e.g. laboratory, ECG, vascular diagnostics, further cardiological diagnostics if necessary, etc.

Imaging: primarily MRI (more sensitive than cCT), possibly cCT (often available more quickly and with restrictions for MRI)

Confirmation of diagnosis by genetic test for NOTCH3 gene and/or skin biopsy for detection of osmiophilic granules (osmiophilic granules in the basement membrane of arterioles (electron microscopy, immunohistochemistry from skin biopsy).

Prenatal diagnosis if necessary: possible if family history is known, i.e. mutation of the NOTCH3 gene is already known in one parent, as autosomal dominant inheritance and 50/50 risk in each child. Determination is based on a blood sample, but detailed genetic counseling with a specialist in human genetics, information and consent are essential!

in the case of recessive inheritance of the HTAR1 gene (CARASIL), only homozygous gene carriers are directly affected (lower probability of disease, as both parents are gene carriers and would also have to pass on the affected gene), but offspring can be heterozygous gene carriers without disease if a defective gene is passed on by one parent.

For diagnostic procedure see also current guidelines!

CADASIL: cMRI: diffuse white matter changes, leukoencephalopathy. Multifocal, patchy confluent T2 signal elevations in the subcortical medulla with temporal emphasis, in basal ganglia, capsula externa and brainstem. Lacunar defects in T1 and FLAIR. Microbleeds in T2*, small patchy diffusion defects.

CARASIL: cMRI: T2 signal enhancement in the subcortical medulla with periventricular and temporal emphasis, but also capsula externa, cerebellum and brainstem.

For examples and variability of typical signs in imaging see also Yamamoto Y et al 2023.

subcortical arteriosclerotic encephalopathy (SAE)

other leukoencephalopathies

Multiple sclerosis (MS)

Vasculitides (cerebral manifestation)

Other cerebral microangiopathies

Fabry disease

No cure possible to date, therefore symptomatic treatment and risk minimization:

Treatment of underlying diseases: e.g. cardiovascular risk factors and chronic diseases (e.g. hypertension, diabetes mellitus, lipometabolic disorders or LDL reduction), optimized drug therapy and lifestyle changes (diet, exercise, important: no smoking!), cognitive training;

Treatment of symptoms e.g. migraine (caution: no treatment with triptans!), stroke therapy, TIA and secondary prophylaxis,

SCF/G-CSF (Stem cell factor (SCF) combined with granulocyte colony-stimulating factor (G-CSF)) is currently still being researched in the experimental stage in animal models and could possibly help to prevent the progression of CADASIL in the future if the results are positive.

Bender B, Bornemann A, Reimold M et. al. (2012). Imaging Findings in Autosomal-dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) - CADASIL - the most common familial stroke syndrome. Rofo 184(8): 679-683 DOI: 10.1055/s-0032-1318829

Chabriat H, Joutel A, Dichgans M et. al.(2009). Cadasil. Lancet Neurol. 8(7):643-53. doi: 10.1016/S1474-4422(09)70127-9

Dichgans M, Mayer M, Brüning R, et.al. (1997). Hereditary microangiopathy: CADASIL. Dt Ärztebl 94: A-227–230. https://www.aerzteblatt.de/archiv/erbliche-mikroangiopathie-cadasil-aa106b0d-111f-4014-a7cc-869d5dc82425

Joutel A, Corpechot C, Ducros A et al (1996). Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 1996; 383: 707-710. https://www.nature.com/articles/383707a0

Rufa A, Guideri F, Acampa M et al (2007). Cardiac autonomic nervous system and risk of arrhythmias in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Stroke 38(2):276-80. doi/10.1161/01.STR.0000254530.38417.07

Wurthmann S, Kastrup O, Wurthmann C et. al. (2025). Refractory chronic depression in a CADASIL patient with a physically asymptomatic course: a case report. Fortschr Neurol Psychiatr 93(07/08): 306-310 DOI: 10.1055/a-2512-7605. https://www.thieme-connect.com/products/ejournals/abstract/10.1055/a-2512-7605#publication-history-container

Yamamoto Y., Liao Y. C., Lee Y. C. et. al. (2023). Update on the epidemiology, pathogenesis, and biomarkers of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. J. Clin. Neurol. 19, 12-27.

https://www.dgn.org/leitlinie/diagnostik-akuter-zerebrovaskularer-erkrankungen

AWMF Guideline Leukodystrophies and hereditary leukoencephalopathies in adulthood