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Genomics of vascular dementia and stroke

Presented by
Prof. Elisabeth Tournier-Lasserve, Saint Louis Hospital, France
ECNP 2020
Cerebrovascular diseases are very heterogeneous from both a clinical and an aetiopathogenetic point of view. These diseases can lead to epilepsy, vascular dementia, cerebral infarcts, or haemorrhages. Some of these diseases affect large cerebral vessels while others affect small cerebral vessels, which may result in cerebral small vessel disease (cSVD) [1].

cSVD is a term used by neurologists to designate several small arteries diseases (40-200 mm), such as superficial perforating arteries and deep basal ganglia perforating arterioles. These diseases are responsible for 20-30% of stroke cases in adult patients (both ischaemic and haemorrhagic), according to Prof. Elisabeth Tournier-Lasserve (Saint Louis Hospital, France). Furthermore, cSVD is the main cause of vascular dementia, which is the second most common cause of dementia.

Small vessels are not visible on MRI or CT scans. Only the consequences of small vessel disease can be perceived: hypersignals of the white matter, infarcts, and deep haematomas. The most common cSVD is sporadic cSVD, and major risk factors are age and hypertension. Over the past 20 years, several other rare inherited monogenetic conditions have also been identified that are considered risk factors. Interestingly, similar neuropathological features are found between sporadic cSVD and several types of monogenic cSVD. Therefore, identification of correlated gene mutations in those conditions is important to understand mechanisms of monogenetic, but also sporadic, cSVD.

The first indication for a genetic component of cSVD was cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), identified in the late ‘70s and early ‘80s. This was a novel hereditary condition found within one family. A single patient was affected by cerebral infarcts but had no risk factors. Two of his offspring were affected as well; they also had a cerebral infarct at the young age of 30, and again, no vascular risk factors were identified. A total of 57 family members took part in a study and it emerged that 19 of them were affected by the same disease. Analysis of the brain of 1 of the patients showed that the disease was caused by microangiopathy, which was responsible for thickening of the media of brain arterioles. Moreover, a biomarker was identified. In the basal lamina of vascular smooth muscle cells in brain and skin vessels, granular osmiophilic material (GOM) was found [2].

Between 1990 and 2000, there was a huge increase in genetic tools which were important to map the affected gene. It was possible to show linkage to chromosome 19, which was a very strong and useful marker [3]. Using this biomarker, researchers could recruit almost 50 affected families throughout Europe. The mutated gene was identified as a member of the NOTCH3 receptor family; it was a large extracellular domain including 24 EGF-like motifs, each containing 6 cysteines [4]. So far, >100 families have been described in France and the disease has been described all over the world; there are >150 distinct mutations leading to an odd number of cysteine residues in EGF motifs.

Also, it emerged that 10% of the cases of hereditary cSVD referred for molecular screening are patients with CADASIL; 1 in 1000 individuals in the large gnomAD databases carry a CADASIL mutation [5]. Before the discovery of CADASIL, many patients were misdiagnosed and treated with immunosuppressants and other inadequate drugs. Thus, gene identification allowed the characterisation of all clinical and MRI features of CADASIL in a large set of mutated patients and their families.

The mechanism of the disease is complex. The starting point is the aggregation of Notch3ECD in the brain vessels [6]. This promotes abnormal recruitment of functionally important extracellular matrix (ECM) proteins that may ultimately cause multifactorial toxicity. Furthermore, dysregulation of TIMP3 activity could contribute to mutant-NOTCH3ECD toxicity by impairing ECM homeostasis in small vessels. Additional genes have been identified that are mutated in other monogenic cSVD. This type of cSVD is caused by multiple genes and there is a large diversity in the encoded mutated proteins.

Researchers have also shown that mutations upregulating COL4A1 lead to pontine autosomal dominant microangiopathy & leukoencephalopathy (PADMAL), a severe early-onset ischaemic cSVD [7]. PADMAL was described in Germany in a large family in 1993. It causes severe cSVD that starts early (around 30 years) and has a high frequency of infarcts in the pons. PADMAL is a cSVD caused by an upregulation of a major component of the cerebral vascular matrisome, and the question is whether any other matrisome genes are involved in cSVD. “It turns out that mutations are found in less than 20% of the patients, so other genes must play a role,” speculated Prof. Tournier-Lasserve (see Table).

Table: Gene mutations involved in cSVD account for less than 20% [1]


“The missing genes may be identified with new strategies such as next-generation sequencing, but the real challenge is to sort out the causative ones from the hundreds of rare non-pathogenetic exonic variants that each individual possesses. What we currently do, is to search exome-wide for genes enriched in rare ‘qualifying variants’ in ‘extreme’ cSVD unrelated probands as compared to large control cohorts, using various gene-based collapsing burden tests [1].”


  1. Tournier-Lasserve E. Genomics of vascular dementia and stroke. PL.03.01. ECNP Congress 2020.
  2. Tournier-Lasserve E, et al. 1991 Oct;22(10):1297-1302.
  3. Tournier-Lasserve E, et al. Nat Genet. 1993 Mar;3(3):256-9.
  4. Joutel A, et al. 1996 Oct 24;383(6602):707-10.
  5. Joutel A, et al. 1997 Nov 22;350(9090):1511-5.
  6. Monet-Leprêtre M, et al. 2013 Jun; 136(6): 1830–1845.
  7. Verdura E, et al. Ann Neurol. 2016 Nov;80(5):741-753.

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