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Abstract

Background

At present, treatment of hereditary haemorrhagic cerebrovascular disease remains in the symptomatic stage. It is more important to provide strategies for developing rational treatment methods, expanding our understanding with regard to the pathophysiology in the context of familial diseases.

Summary

In this article, the combined data from the literature on diseases, including familial cerebral cavernous haemangiomas, hereditary cerebral haemorrhage with amyloidosis, familial intracranial aneurysms, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, were reviewed to manage the haemorrhagic diseases discussed through genetic counselling and early prevention and treatment of these patients and their families, the genetics, pathogenesis, clinical manifestations and treatment.

Key Messages

It is important to understand and treat hereditary haemorrhagic cerebrovascular disease through genetic treatment options.

Keywords

Familial cerebral cavernous haemangioma hereditary cerebral haemorrhage with amyloidosis familial intracranial aneurysms cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy genetics

Introduction

Familial Cerebral Cavernous Haemangioma (FCCM)

Genetics

The incidence of cavernous cerebral haemangiomas (CCM) is about 0.1%–0.5% in the general population. FCCM is inherited as an autosomal dominant disease with incomplete penetrance. The prevalence rate of CCM is about 10%–50% of all cerebral vascular lesions, and great heterogeneity is seen in different populations.¹ As more than half of the mutation carriers are asymptomatic, the proportion of FCCM among CCM might be underestimated. There are three protein-coding genes (CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10) that can cause FCCM, and the detection rates of these mutations are 60%, 20% and 15%, respectively.² During disease development, the estimated clinical penetrance rates of KRIT1, CCM2 and PDCD10 are more than 50% possible.³ Therefore, we speculate that other genes might be involved in the development of this disease.

Pathogenesis

With regard to the pathogenesis of FCCM, it might involve the two-hit mechanism, that is, a complete loss of two alleles in the CCM-specific gene takes place in the affected cells during the CCM occurrence. The loss of one allele (the first strike) might lead to germline mutation, while the loss of the second allele (the second strike) results in somatic mutation.⁴ Therefore, FCCM might be recessive at the cellular level. The ‘CCM complex’ hypothesis⁵ holds that three genes that are part of signalling pathways regulate proliferation, network formation and endothelial cell growth. The three genes form the CCM complex and interact with each other, and so the inhibition of some important structures leads to FCCM. In studying the CCM complex, the acquisition of Rho kinase (ROCK) signal transduction is considered an important aspect of its pathogenesis.⁶ Some studies have shown that the ERK–MAPK pathway might participate in CCM’s pathogenesis through the PDCD10/MST4 complex.⁷ Also, Nardella, et al.⁸ have believed that autophagy is a potential key link in CCM’s pathogenesis.

Clinical Manifestations

Like sporadic CCM, the classic manifestations of FCCM include seizures (40%–70%), focal neurological deficits (FND) without intracerebral haemorrhage (25%–50%), non-specific headache (10%–30%) and intracerebral haemorrhage (ICH; 25%–32%).^{9, 10} However, due to advancements in imaging technology, a considerable number of asymptomatic cases have been reported. Most of the lesions exist in the central nervous system, but a few others can also be seen in the retina, skin and other organs. Carriers of the KRIT1 mutation have mild bleeding but more frequent seizures and extraneural manifestations, such as cutaneous vascular malformations.¹¹ The skin vascular malformation accounted for 89.2% of all KRIT1 mutation carriers, while CCM2 and CCM3 accounted for 2.7% and 8.1%, respectively.¹² In contrast, CCM2 mutation individuals have less brain damage, but the development of this is slower.¹³ However, PDCD10 gene mutation carriers are associated with a more severe aggressive phenotype, and these usually cause anomalies in childhood and are characterised by recurrent cerebral haemorrhage. It is also closely related to other diseases, such as skin vascular malformation, cavernous spinal tumours, scoliosis and some benign central nervous system tumours.¹⁴

Treatment

There are currently multiple treatment methods available. The purpose of treatment is to stabilise blood vessels, reduce the risk of bleeding and prevent re-bleeding, shrink lesions or achieve a complete cure, prevent a recurrence, remove iron deposits caused by bleeding, prevent systemic effects of familial CCM and prevent inheritance. Other factors that affect treatment include the time when the patient starts treatment, the duration of the disease and whether the treatment risk is reasonable.¹⁵ Some studies have shown that sorafenib can improve the microvascular overgrowth induced by CCM1 and reduce the microvessel density to normal wild-type endothelial cells, which has potential therapeutic value.¹⁶ Also, fasudil (ROCK inhibitor) and statins might have clinical application value.¹⁷ In general, surgery for asymptomatic lesions is not recommended, especially in the functional areas, such as deep brain tissues or brain stem.^{10, 14} In the case of uncontrollable headaches with new or deteriorated FND, surgery or stereotactic radiotherapy should be performed with strict indications.¹⁸ For patients with epilepsy caused by CCM, conservative drug treatment is carried out initially. The smaller the lesion, the shorter the onset time, and the better the surgical effect, such as simple lesion resection, the success rate of these patients with longer history remained lower.¹⁹

Hereditary Cerebral Haemorrhage with Amyloidosis (HCHWA)

Genetics

Cerebral amyloid angiopathy (CAA) is an age-dependent disease. CAA-related cerebral haemorrhage accounted for at least 20% of spontaneous ICH.²⁰ HCHWA is a rare and autosomal dominant inherited disease. The common mutation types reported in the literature included Holland type, Italian type, Flanders type, Iowa type, Arctic type, Finland type and Iceland type. The pathogenic gene of the first five types is the amyloid precursor protein (mutation sites included E693Q, e693k, A692G, D694N and E693G), and the Finnish type is caused by G654A or G654T point mutation of the gliadin gene, while the Icelandic type is caused by cystatin C (CST3).

Pathogenesis

At present, the core pathogenesis of CAA mainly focuses on the structural changes of amyloid subunits. The conformational transition in naturally soluble amyloid molecules increased the contents of the β-sheet structure, which is considered to lead to the formation of more insoluble oligomer structures. These structures do not decompose physiologically and accumulate in the form of intracellular and extracellular amorphous aggregates and fibre depositions. Moreover, these can trigger the second cascade of events, including the release of inflammatory components, the complement system’s activation, oxidative stress, the change of blood–brain barrier permeability and ion channels’ formation cytotoxicity.²¹ Greenberg, et al.²² have proposed that the β-amyloid protein itself does not directly lead to vascular leakage, and the complex hemodynamic associated with CAA might play a role in the vascular network, causing cerebral haemorrhage. Also, ApoE genotypes have different effects on CAA progression. ApoE ԑ2 leads to vascular degeneration and bleeding, while ApoE ԑ4 stimulates the deposition of beta protein.²² In the correlation analysis of app-e693q mice, Moursel, et al. have proposed an overlap of extracellular matrix (ECM) receptor interaction pathways, indicating that ECM modification also participates in an early imbalance mechanism of amyloidosis-Dutch type.^{23, 24}

Clinical Manifestations

CAA is characterised by recurrent or multiple ICH, dementia and transient neurological dysfunction. Hereditary CAA is usually early onset and is associated with more severe clinical symptoms.^{25, 26} The most common haemorrhage site is in the cerebral lobe, especially the Dutch and Icelandic types.²⁷ Among all the genetic types, the Dutch type is the most common and is characterised by dementia, recurrent lobar haemorrhage and leukoencephalopathy and usually causes ICH for the first time at the age of 50.²⁸ However, Iowa ICH appears at the age of 40 years.²⁹ Other clinical manifestations include progressive dementia, cortical calcification, leukoencephalopathy, carotid artery dysplasia and thickening of skin capillaries’ basement membrane. Occipital cortical calcification has been considered a highly specific imaging feature of the Iowa-type mutation once,³⁰ and it generally occurs in the late stage of the disease. However, Sellal, et al.³¹ have confirmed that the Italian type had cortical calcification similar to that of Iowa. Dementia is a typical feature of the Arctic type (E693G), while the Flemish and Italian types are mainly characterised by dementia and cerebral haemorrhage.³² Icelandic type is often associated with fatal early ICH, and early survivors are more prone to dementia.²¹ Also, amyloid deposition can be found in the peripheral tissues, including lymphoid organs, skin, salivary glands and testis.³³ Unlike the above, the Finnish type is mainly characterised by cranial and sensory neuropathy, corneal lens dystrophy and skin relaxation.³⁴

Treatment

At present, the preventive treatment for CAA is limited. The diagnosis and treatment measures help reduce the risk of accidental and recurrent cerebral haemorrhage and avoid various risk factors. A potential drug candidate for inhibiting the formation or deposition of beta-amyloid protein has been reported in transgenic mouse models.³⁵ Studies have confirmed that³⁶ the serum amyloid P component is directly associated with the occurrence of neurotoxicity of brain neurons and can promote amyloid deposition. R-1-[6-[R-2-Carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl] pyrrolidine-2-carboxylic acid can reduce this damage and stabilise the function of the amyloid deposits from the liver and some other tissues and has great significance.

To Dutch-type CAA, CRISPR–Cas9 editing was used for genetic correction of the mutation in a human-induced pluripotent stem cell (hiPSC) line established previously. The isogenic hiPSCs generated showed typical pluripotent stem cell morphology, expressed all markers of an undifferentiated state, displayed a normal karyotype and had the capacity to differentiate into the three germ layers.³⁷

It was reported that antihypertensive therapy might protect from different types of ICH by reducing the risk of CAA-related ICH. Studies have shown that antihypertensive therapy reduces ICH by 77% over a 3.9-year follow-up.³⁸

Zhang et al.³⁹ have reported that hypertension is a useful predictive factor for CAA-related ICH at 3 months. However, there was a considerable decline in the 3-month mortality risk of patients with CAA hypertension. This was contradictory to the belief that hypertension is a risk factor for all subtypes of ICH.

Though the relationship between atrial fibrillation (AF) and anticoagulant therapy in patients with CAA is still not confirmed, it is believed to be due to CAA patients’ inherent characteristics such as recurrent ICH and high baseline risk. Therefore, it was suggested to avoid these drugs in such patient populations.⁴⁰

Furthermore, a prospective observational cohort study reported that there was >3 times higher hazard of haemorrhage for the cortical microbleed (CMB) group than the non-CMB group, with a dose-dependent relationship between the risk of haemorrhage and CMB burden.⁴¹ Cannistraro et al.⁴² suggested that anticoagulants should be avoided in patients with AF and CAA. However, patients with ≥2 CMB may require in-depth risk-benefit analysis using a multidisciplinary approach.

Familial Intracranial Aneurysms (FIA)

Genetics

Intracranial aneurysm (IA) is caused by the outward protrusion of the weakened area in the cerebral artery wall. The prevalence rate of IA in the general population ranges from 2% to 5%.^{43, 44} The mortality and disability rates remain very high after rupturing and bleeding IAs. FIA accounted for about 10% of all IAs.⁴⁵ In addition to hypertension, arteriosclerosis, diabetes and vascular anatomical differences, genetic factors also play an important role in the cause of FIA.⁴⁶ Hitchcock et al.⁴⁷ found several IA-related genetic loci, such as 1p34.3–p36.13, 4q32.2–32.3 and 5p15.2–14.3, but most of these loci are found only in the same race. Therefore, a large number of clinical data are required to verify the abovementioned genetic loci.

Pathogenesis

With gene detection technology progression, pathogenic screening genes related to FIA have been widely used clinically. Yan et al.⁴⁸ found ADAMTS15 p.E133Q mutation in 12 IA families. Overexpression of this mutation has accelerated the migration of endothelial cells, further leading to IA occurrence. Farlow et al.⁴⁹ have shown the TMEM132B gene’s overexpression in IA tissues. Whether the protein function loss or function gain caused by the mutation requires further confirmation. The majority of collagen (type I, type III, type IV, type V and type VI) have a significant role in arterial formation⁵⁰ and contribute to maintaining arterial integrity while being the major component of connective tissue. However, the relationship between the single-nucleotide polymorphisms of the collagen gene and IA pathogenesis is not clearly understood.⁵¹ A meta-analysis in the Chinese Han population indicated that this polymorphism could be a genetic risk factor for IA incidence in the Chinese Han population.⁵² In the French Canadian family, RNF213 mutation showed an association with FIA occurrence, and its variation can increase the ATPase activity, which might increase the risk of IA by increasing the angiogenesis activity.⁵³ Previous studies have suggested that the RNF213 gene showed a close relation to moyamoya disease.⁵⁴ Other studies⁵⁵ have demonstrated that THSD1 gene mutation can cause vascular endothelial cell–ECM binding disorder, resulting in IA formation. French IA family has commonly reported a rare mutation of p.Lys460Ter of the ANGPTl6 gene. At this time, the arterial wall can be easily damaged, increasing IA’s susceptibility.⁵⁶ A recent study showed that SOX17 deficiency could induce IA in mice with hypertension, suggesting that SOX17 deficiency acts as a potential genetic factor for the cause of IA.⁵⁷ Also, the p.H45Y mutation of the LOXL2 gene was found in the Chinese population.⁵⁸ Therefore, we believe that the pathogenic genes of FIA have great racial heterogeneity.

Clinical Manifestations

Multiple factors, including polycystic disease, family history, age and sex, are reported to be the contributory factors that affect the prevalence of unruptured intracranial aneurysms (UIAs). While the overall prevalence of UIAs was considerably higher in patients >30 years of age, the prevalence was higher in women, especially women >50 years of age. Furthermore, patients with autosomal dominant polycystic kidney disease (ADPKD), a family history of IA or subarachnoid haemorrhage (SAH) had higher prevalence.⁴⁴

The clinical manifestations of IA depend on whether the aneurysm is ruptured or not and the degree of vasospasm after rupture. UIAs usually show no symptoms or only slight dizziness and headache. The severity of ruptured IAs is related to bleeding and sometimes accompanied by disturbances in consciousness or even lead to death. The decreased cerebral blood flow during cerebral vasospasm might cause deterioration of ischaemic nerve function. Spontaneous SAH is the most common disease caused by IA rupture, which has a rapid onset and high mortality rate. The formation of large IAs or haematoma and acute hydrocephalus leads to increased intracranial pressure.⁵⁹

IA commonly occurs in the middle cerebral artery and easily ruptures in younger patients.⁶⁰ The proportion of UIAs in the posterior communicating artery remained higher when compared to IAs.⁶¹ The size of IA also remains the main factor affecting its rupture. It is found that the average annual rupture rate of IAs with a diameter of 5–15 mm is 12 times that of IAs with a diameter of less than 5.0 mm.⁶² Therefore, primary prevention of aneurysmal formation and rupture is very important.

The effect of ADPKD, an established risk factor for IAs, on acute course and long-term outcome of aneurysmal subarachnoid haemorrhage (aSAH) is still not undoubtedly established.

In 2020, the first study to compare the phenotype and prognosis of aSAH in patients with ADPKD and those without ADPKD was conducted by Nurmonen et al.⁶³ Prior to that, in 2017, Nurmonen et al.⁶⁴ reported that patients with ADPKD experience aSAH much earlier than the general population (around 10 years), with relatively small aneurysms at rupture. However, there was no difference in aSAH outcome between patients with ADPKD aSAH versus controls. Long-term angiographic follow-up is almost necessary since, in patients with ADPKD, the risk of recurrent aSAH from a de novo aneurysm increases.

Treatment

The incidence and mortality rates of UIAs have been shown to increase with age, aneurysms and the proportion of posterior circulation aneurysms.⁶⁵ Whether asymptomatic patients need preventive surgery remains to be controversial. Given the poor prognosis of aSAH caused by IA rupture, besides the prevention and treatment of cerebral vasospasm and the management of intracranial pressure, endovascular intervention or craniotomy is often used.⁶⁶

It is important to repair the ruptured aneurysm as early as possible to prevent re-bleeding and cerebral ischaemia and improve the neurological status of the patient.⁶⁷ Though repair can be done by either endovascular coiling or neurosurgical clipping, endovascular coiling is preferred due to the flexibility in treatment. However, multiple clinical and radiologic factors, such as patient age, clinical condition, the size, shape and location of the ruptured aneurysm, any additional aneurysms, the certainty as to which one bled, the estimated risks of treatment by clipping or coiling, available equipment and individual skill level, determine the method of repair.⁶⁸ For example, surgical clipping is preferred for young patients due to good long-term resistance to recurrence, re-bleeding and the requirement for retreatment.⁶⁹

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)

Genetics

CADASIL is a special type of cerebrovascular disease or vascular dementia that is caused by the Notch3 gene mutation. This gene is located on 19p13.1–13.2, consists of 33 exons and encodes a relatively large single transmembrane cell surface receptor. At present, there are more than 200 kinds of CADASIL related to Notch3 gene mutations reported, and most of these are distributed in exons 2–24,⁷⁰ and there are great differences among different races. Gong et al.⁷¹ have found that the proportion of p.R544C locus in exon 11 is as high as 65.1%, and all these were obtained from Asian countries. However, exon 22 p.R1231C has been reported in a large European cohort.^{72, 73} Different from the above, Kim et al.⁷⁴ have shown that mutations in exons 3, 9, 11 and 22 were commonly seen in Korean people, and this might be due to insufficient sample size. Therefore, to avoid statistical bias, future studies on increased sample size by limiting race and clinical subtypes are expected to reveal the underlying mechanism of Notch3 gene mutation in ICH’s pathogenesis in patients with CADASIL.

Pathogenesis

The pathogenic variation of Notch3 in CADASIL resulted in 34 epidermal growth factor receptors (EGFRs). The loss or increase of a cysteine residue in the EGFR domain unpairs the cysteine residues, destroys the formation of a sulphur bond and leads to the aggregation of the mutated Notch3 extracellular domain. The toxic effect leads to the degeneration of vascular smooth muscle cells, which remains the disease’s core pathogenesis.⁷⁵ The mutation of CADASIL might be caused by the downstream regulation of the Goldilocks signalling pathway to produce high- or low-activity Notch3 protein, and overactivation and low activation of Notch signalling protein might lead to the disease phenotype.⁷⁶ However, some studies⁷⁷ have a different viewpoint from the above, that is, r169c mutation can lead to an active Notch signal, while R1031C or c455r mutation shows the opposite. However, R1031C mutation can reduce stroke sensitivity of Notch3^−/− mice less than 12 months old, which is another area that is worthy of further study. The role of astrocytes in CADASIL has also been further emphasised,⁷⁸ and its number and terminal pods are affected by Notch3 signal transduction.

Clinical Manifestations

CADASIL’s typical features include recurrent subcortical ischaemic events, progressive dementia, headache, pseudobulbar palsy, depression and urinary incontinence. Generally, they have a CADASIL family history. However, individuals with CADASIL and cerebral haemorrhage as the main manifestations are gradually increasing. Studies⁷² have shown that cerebral haemorrhage is caused by bleeding mainly in the thalamus and basal ganglia, and most of them have a history of hypertension.

Zhang et al.⁷⁹ have considered that CADASIL patients’ vascular risk factors with cerebral haemorrhage were lighter than primary ICH patients, but almost all were accompanied by cerebral small vessel disease imaging features such as white matter change, microbleeds or lacunar infarction. It is undeniable that a family history of stroke and severe white matter changes in neuroimaging are risk factors for a cerebral haemorrhage in patients with CADASIL, and the recurrence rate and mortality rate of stroke with haemorrhage as initial manifestations remained higher.⁸⁰

Treatment

The reports on CADASIL and cerebral haemorrhage revealed that patients with CADASIL have two-way manifestations of cerebral infarction and cerebral haemorrhage. Therefore, it is necessary to screen these diseases with susceptibility-weighted imaging before deciding to clinically apply antiplatelet drugs.⁸¹ It is still unclear whether antiplatelet drugs are effective in preventing ischaemic stroke. Antiplatelet drugs are used to treat CADASIL. In Japan, over half of patients receive antiplatelet drugs.⁸² Some studies⁸³ have believed that cilostazol is associated with a lower risk of bleeding than aspirin and has more clinical application value. A 2020 European guidelines clearly state that antiplatelet drugs are not recommended for patients with CADASIL without a history of ischaemic stroke.⁸⁴ Due to the lower risk of low-dose aspirin, it is commonly used in patients with ischaemic stroke. However, there is currently no data evaluation on the safety or efficacy of antiplatelet therapy in patients with CADASIL. It is uncertain whether anticoagulant therapy should be applied to patients with CADASIL. Anticoagulant-related cerebral haemorrhage is not common.⁸⁵ Pathologically, the characteristic of CADASIL is the destruction of vascular wall structure. In vitro experimental studies suggest that the ROCK inhibitor fasudil can alleviate CADASIL-related pathological changes.⁸⁶ Decreased baseline relaxation of vascular smooth muscle cells due to abnormalities in sGC/cGMP signalling and inadequate H₂O₂ production compound defects in vessel reactivity in animal models.⁸⁷

Besides, it is necessary to strictly control patients’ blood pressure with CADASIL and cerebral haemorrhage, and lowering blood pressure to too low might further lead to ischaemic stroke.⁸⁸ At present, it is unclear whether the cerebral haemorrhage in this disease is caused by hypertension and is a part of the disease process related to specific genotypes or due to the use of antithrombotic drugs. Currently, there are no data to support the safety or efficacy of thrombolysis or thrombectomy in patients with CADASIL with acute stroke, but there are cases of clinical treatment using thrombolytic drugs.⁸⁹

Summary

At present, genetic diseases have brought great pressure on patients’ physical and mental health conditions, family and society, but treatment remains to be in the symptomatic stage. The advancements in genetics and genomics make it possible to discover the pathogenic genes associated with cerebrovascular diseases. It is more important to understand and treat genetic disorders through genetic treatment options.

For CCM, research is currently underway on treatment methods for familial CCM to prevent inheritance to the next generation. In addition, treatment can be achieved through genetic repair of a human-induced pluripotent cell line from a patient with Dutch-type CAA. Regarding UIA, endovascular coiling can be a better alternative in terms of surgical treatment. Based on the expression of the NOTCH3 gene, analysis of human biological samples revealed abnormalities in the NOTCH3 signalling pathway, with a focus on abnormal ECM proteins. In the future, it can serve as a new method for treating CADASIL.

Footnotes

Acknowledgements

The authors acknowledge the support of the Jilin Province Bethune Natural Science Foundation Project of China for funding this project.

Authors’ Contribution

Wanting Hou and Yanbo Hou conceptualised, drafted and wrote the manuscript. Xiangshan Ren and Jingyao Liu reviewed and commented on the drafted manuscript.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest concerning the research, authorship and/or publication of this article.

Funding

The author disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This work funded by the Jilin Province Bethune Natural Science Foundation Project of China (no. 20210101465JC).

ORCID iD

Jingyao Liu

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Hereditary Haemorrhagic Cerebrovascular Disease: Implications for Clinical Management

Abstract

Background

Summary

Key Messages

Keywords

Introduction

Familial Cerebral Cavernous Haemangioma (FCCM)

Genetics

Pathogenesis

Clinical Manifestations

Treatment

Hereditary Cerebral Haemorrhage with Amyloidosis (HCHWA)

Genetics

Pathogenesis

Clinical Manifestations

Treatment

Familial Intracranial Aneurysms (FIA)

Genetics

Pathogenesis

Clinical Manifestations

Treatment

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)

Genetics

Pathogenesis

Clinical Manifestations

Treatment

Summary

Footnotes

Acknowledgements

Authors’ Contribution

Declaration of Conflicting Interests

Funding

ORCID iD

References