Genetic Insights Into Cerebrovascular Disorders: a Comprehensive Review

Genetic Insights into Cerebrovascular Disorders: a Comprehensive Review

1,2 3 4 5 Fawaz Al-Mufti, MD *, Ahmed Alkanaq, MD , Krishna Amuluru, MD , Rolla Nuoman, MD , 6 7 7 Ahmed Abdulrazzaq, DDS , Tamarah Sami, DDS , Halla Nuoaman, MD , Caroline Hayes- 5 2 8 Rosen, MD , Charles J. Prestigiacomo, MD , and Chirag D. Gandhi, MD 1 Rutgers University - Robert Wood Johnson Medical School, Department of Neurology, Division of Neuroendovascular Surgery and Neurocritical Care, New Brunswick, New Jersey, USA 2 Rutgers University - New Jersey Medical School, Department of Neurosurgery, Newark, New Jersey, USA 3 Rutgers University - Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA Journal of Vascular and Interventional Neurology, Vol. 5 Vol. and Interventional Neurology, Journal of Vascular 4 University of Pittsburgh Medical Center- Hamot, Department of Neurointerventional Radiology, Erie, Pennsylvania, USA 5 Rutgers University - New Jersey Medical School, Department of Neurology, Division of Child Neurology, Newark, New Jersey, USA 6 Rutgers University - School of Dental Medicine, Newark, New Jersey, USA 7 Rutgers University - Robert Wood Johnson Medical School, Department of Neurology, New Brunswick, New Jersey, USA 8 Westchester Medical Center, New York Medical College, Department of Neurosurgery, Valhalla, New York, USA

Keywords Cerebrovascular malformations; hereditary diseases

Introduction Genetic vascular disorders are usually present at birth; The prevalence of intracranial vascular malformation structurally, they tend to grow proportionately with the has been shown to be increasing over time. This is child, and do not regress spontaneously. The malforma- believed to be due to the advancement in radiological tions vary greatly in number, size, and location, and can procedures. Many studies examining neurological syn- also occur in the context of syndromes. Cerebrovascular dromes have aimed at early identification of intracranial malformations are defined as localized structural defects malformations, to prevent possible complications. With of the vasculature, named after the type of vessel affec- the advancement of medical genetics, represented by the ted [1]. Although the majority of vascular malformations recent breakthrough of whole exome sequencing, the are sporadic, a small proportion may be inherited. proportion of neurological disorders that can be attributed to identifiable genetic mutations is increasing. Due to the relative rarity of cerebrovascular malformations and the broad spectrum of possible complications, Vascular malformations are believed to result from a much of the evidence for genetic etiology comes from somatic mutation creating a mosaic clinical phenotype, single studies conducted in small and homogenous pop- in which two genetically distinct populations of cells ulations. exist within the same individual [2]. In this review, we reviewed published English language medical literature, With the advances of molecular technologies and medi- describing genes related to the development of intracra- cal research, genetic testing for a more proactive and nial vascular disorders, with their perspective malforma- precise clinical management is becoming a cornerstone tions. Since these genes play vital roles in the embryonic in the diagnostic workup for patients, especially for neu- process of vasculogenesis, as well as the post-embryonic rological diseases. processes of angiogenesis and arteriogenesis, it is very

Vol. 9, No. 5, pp. 21–32. Published October, 2017. All Rights Reserved by JVIN. Unauthorized reproduction of this article is prohibited *Corresponding Author: Fawaz Al-Mufti, MD. Financial Disclosures: None. This work has not been previously presented or published. 22

difficult to assign genes to a specific anatomical or his- tological category. Therefore, we classified the genetic information in relation to the underlying histopathological manifestations.

To simplify the classification process, and to make it more attributable to clinical practice, we categorized the intracranial malformations based on their pathology, which can be histologically differentiated from one another based on the underlying molecular genetics.

Methods The objective of this review was to provide a primarily Journal of Vascular and Interventional Neurology, Vol. 5 Vol. and Interventional Neurology, Journal of Vascular descriptive overview on the genetic basis of neurovascular disorders.

An electronic Medline (PubMed) search was performed using the following terms in varied combinations: “cerebrovascular malformations,” “inherited mutations,” and Figure 1. “pathogenic variants,” followed by genetic variants search of National Center for Biotechnology Informa- tion genetics databases without language restrictions.

We screened for clinical, human studies in adult patients published in the following designs: prospective random- ized, or observational, or case–control designs, retrospective analyses, and case series.

Due to increasing number of publications describing genetic basis of neurovascular disorders, it has become pertinent to perform a review of genes linked to neurovascular disorder and to delineate the implications that these genes can have on the clinical presentation and subsequently management, when it comes to genetic testing and identification of genetic variants carriers.

Intracranial Aneurysms Aneurysmal subarachnoid hemorrhage (aSAH) contin- ues to be associated with high morbidity and mortality despite advances in management [3]. The natural history of aSAH suggests an overall mortality of approximately 50%, with 10% of patients dying prior to reaching the hospital, 25% dying within 24 h of SAH onset, 45% dying within 30 days, and approximately two-thirds of patients developing a cognitive impairment in one Figure 2. domain [4–6]. United States), most commonly in people between ages The worldwide prevalence of intracranial aneurysms is of 30 and 60 years [7,8]. estimated to be between 5% and 10%, and the incidence of ruptured aneurysms is about 10 in every 100,000 per- Therefore, it becomes very important to rely on sensitive sons per year (about 30,000 individuals per year in the screening methods, where information from clinical and

Al-Mufti et al. 23 Journal of Vascular and Interventional Neurology, Vol. 5 Vol. and Interventional Neurology, Journal of Vascular

Figure 3.

Figure 4. family histories can be used to pursue specific clinical genetic testing towards an early discovery of aneurysms and prevention of intracranial hemorrhage. COL4A1-related disorders are also associated with cerebral aneurysms, as part of the hereditary angiopathy with On the molecular level, several genes have been identi- nephropathy, aneurysms, and muscle cramps (HANAC) fied which are responsible for the underlying connective syndrome [11]. It is recommended that affected individ- tissue, and vascular dysplasia which predispose the his- uals undergo molecular testing of the COL4A1 gene to topathological development of aneurysms [9]. identify the responsible mutation. Parents, siblings, and the offspring of affected individuals can be tested for the The following genes have been described in the litera- same mutation. However, not all individuals have ture as being linked to intracranial aneurysms, some of parents who are carriers for the mutation, since some of which are responsible for other syndromic clinical pre- these mutations are de novo mutations [12,13]. sentations. Ulimately this will help in the early clinical A positive genetic test of this gene can help in the man- diagnoses and prevention of aneurysmal complications. agement and prevention of related disorders, which have overlapping clinical manifestations, and can be easily COL4a1-Related Disorders attributed to different possible pathologies. COL4A1 is a gene that codes for the collagen alpha‑1 (IV) chain, which is expressed in the basement mem- Autosomal Dominant Polycystic Kidney branes of cerebral vasculature. Pathological variants of Disease (ADPKD) this gene can lead to diminished tensile strength of ves- It is estimated that 6.9% of patients with ADPKD have sels and increased fragility, manifesting as a spectrum of intracranial aneurysms [14]. This syndrome is associated disorders that involve the brain and intracranial circula- with the lae onset cysts, in both kidneys, in addition to tion [10]. These disorders include porencephaly, which other organs like the liver. Individuals with positive fam- may present with a myriad of neurological manifesta- ily history of intracranial hemorrhages or aneurysms, tions at different ages, including mental disability, seiz- usually have higher probability of developing intracra- ures, and migraine. nial aneurysms. 24

Two genes, PKD1 and PKD2, were found to be respon- been linked to the different types of this syndrome. In sible for the autosomal dominant inheritance of this dis- type IV, or vascular EDS, a mutation in COL3A1 causes ease. Due to the 50% chance of inheriting the gene from molecular pathology of procollagen III synthesis, a an affected parent, and the late onset of cystic forma- major component of the connective tissue of blood ves- tions, the genetic diagnosis of this disease in family sels, viscera, and uterine wall [16]. Therefore, life- members at risk can help in preventing the catastrophic threatening complications can result from the fragility of consequences of possible intracranial aneurysms, espe- these tissues, including the possibility of fusiform aneur- cially when there is only one family member diagnosed ysm development in intracranial arterial circulation. clinically with ADPKD. EDS type IV is inherited in an autosomal dominant fash- More than 85% of the cases are caused by the PKD1 ion, with 50% of the cases being inherited from a parent gene. Familial mutation should be identified in affected [21]. However, Jorgensen A et al. [22] studied the differ- individuals before testing other family members. Each ent mutations of COL3A1 gene, and found that biallelic sibling has a 50% chance of inheriting the same muta- mutations (two different mutations on the two alleles) Journal of Vascular and Interventional Neurology, Vol. 5 Vol. and Interventional Neurology, Journal of Vascular tion; however, around 40% of mutations are de novo in are more severe than the null mutations. Therefore, with which case the risk for recurrence to siblings is very low more than 600 mutations being reported to the EDS var- [15,16]. iants’ database [13], it becomes essential to perform molecular testing on affected individuals, before pursu- It is worth mentioning that the PKD1 gene is adjacent to ing the genetic testing on other family members. There the tuberous sclerosis syndrome gene TS2; therefore, a is a great variability in the age of presentation of compli- contiguous deletion syndrome has been described cations, according to the different types of variants in [13,17,18]. the gene alleles, for an early diagnosis and timely prevention. Autosomal Dominant Hyper-IgE Syndrome Although this syndrome was first described as an Cerebral Vasospasm immune deficiency disorder, characterized by cutaneous and repeated infections, it has been recently discovered Following SAH, the most important prognostic determi- that other skeletal and vascular malformations are asso- nants for outcome are neurological grade on initial ciated with this syndrome. examination, volume of subarachnoid blood on initial computerized tomography (CT), age, preexisting hyper- In addition to the association with Chiari 1 malforma- tension, re-bleeding, and cerebral infarction from cere- tion, a major cause of mortality and morbidity associated bral vasospasm [23–26]. Typically cerebral vasospasm with this syndrome [19]. after aSAH begins three days after ictus and peaks after 7–8 days. Radiographic vasospasm is seen in 30%–70% This is an autosomal dominant disorder with complete of angiograms performed at day 7 after aSAH. Twenty penetrance and minimal intrafamilial variation due to to thirty percent of patients develop clinical or sympto- STAT3 mutations [13]. matic vasospasm which heralds a poorer prognosis [27– 29]. Understanding the genetic basis of cerebral vaso- The majority of cases are due to de novo mutations; spasm can potentially assist in the early identification however, some cases are inherited. According to a study and management of patients at risk. by Holland SM et al. [20], 18 mutations were identified in familial and sporadic cases, five of which represented The pathophysiology of this disorder is still not well mutational hotspots. Therefore, after a molecular testing understood; however, based on several recent molecular of an affected individual has identified, the responsible studies, it was found that several genes play a role in the mutation, siblings and offspring can be genetically tes- multiple physiological processes that constitute delayed ted for the same mutation, especially when the immuno- cerebral ischemia [30]. logical testing is inconclusive. These genes include variants that determine the severity Ehlers-Danlos Syndrome (EDS) Type IV of the cerebral vasospasm response as well as genes that (Vascular Type) determine the molecular basis of initiation and propaga- EDS is a group of several types of connective tissue dis- tion of the vasospasm response in the vascular smooth orders. Classically, EDS presents as joint hypermobility muscle cells (Table 2). Cerebral vasospasm varies in with hyperextensible skin; however, several genes have severity, and multiple trials have been implemented to Al-Mufti et al. 25

Table 2. Genes Responsible for Intracranial Capillary and AVMs GENE ASSOCIATED SYN- INHERI- MAIN CLINICAL FEATURES NOTES DROMES TANCE ENG [69–75] HHT. AD Epistaxis, cutaneous telangiectasia, and Most common HHT gene in North AVMs. America. Juvenile Polyposis Syndrome AD Hamartomatous polyps of the GI tract. SMAD4 gene also causes this syndrome. ACVRL1 [69– HHT AD Second most common gene for 73,76,77] HHT in north America. Heritable Pulmonary Arterial AD Pulmonary vascular stenosis, with secon- Other genes that can cause this con- Hypertension dary right ventricular hypertrophy. dition are KCNK3, CAV1, SMAD9, and BMPR1B. SMAD4 [69–73] HHT AD Juvenile Polyposis syndrome AD See above See test GDF2 [36,69] HHT AD No known association with other phenotypes. RASA1 [11,12– Parkes Weber Syndrome AD Capillary malformations and fistulas. Or 14] AVMs. CM-AVM AD It is characterized by the atypical capillary malformations together with AVMs. Journal of Vascular and Interventional Neurology, Vol. 5 Vol. and Interventional Neurology, Journal of Vascular STAMBP [41,69] MIC-CAP) syndrome AR Congenital microcephaly and capillary Both parents are obligate carriers malformations of the skin. for pathologic mutations, except in cases of uniparental disomy. PIK3CA [69,78– Segmental overgrowth syn- Somatic muta- - MCAP of the brain.- Cutaneous capillary It is also associated with the clinical 80] dromes tion, with pos- malformations. picture of CLOVES. sible gonadal mosaicim

create gene therapies through modifying the CV (ALK1) responsible for type 2 HHT; (3) SMAD4, which response [31]. was found to be associated with the HHT variably associated with juvenile polyposis; and (4) GDF2 causing Intracranial Capillary and HHT type 5 (HHT5) [36].

Arteriovenous Malformation The proportions of cases caused by each gene are differ- Syndromes ent (Table 1). With ENG and ACVRL1 being responsible for >80% of the cases. Therefore, a family history Arteriovenous malformation (AVM) of the brain is a that includes the ethnicity of the affected individual very serious type of vascular malformation and may lead plays an important role in determining the order of to seizures and intracranial hemorrhages. It is believed molecular testing for each gene [13]. HHT is inherited in that a multifactorial etiology is responsible for the devel- an autosomal dominant fashion. The majority of cases opment of AVM, where the genetic factors predispose to are inherited [37]. Therefore, the risk for siblings and the development of vascular pathologies [32–34]. offspring to inherit the mutation is 50%. The specific pathologic variant needs to be identified in the affected Due to the common pathways of embryonic vasculogen- individual, before testing other family members. sis and arteriogensis, it is not uncommon to find a histopathological overlap between the different vascular mal- RASA1-Related Syndromes formations. The following genes have been found to be responsible for the development of AVMs. Mutations of this gene can lead to a dominantly inherited capillary malformation-AVM syndrome (CM-AVM). Hereditary Hemorrhagic Telangiectasia This syndrome is characterized by multiple round, pink- This disorder is classically presented by the characteris- ish capillary patches on the skin, usually on face and tic epistaxis during childhood; however, the develop- limbs. In about 30% of the cases, AVMs were found in ment of clinical signs and symptoms can continue to soft tissue, bone, and the brain [38]. adolescence before a clinical diagnosis becomes possible; therefore, an early genetic diagnosis can prevent It is estimated that 1 in 100,000 Northern Europeans is a severe possible complications related to the AVMs in the carrier for RASA1 gene mutation reported that RASA1 brain, liver, and lungs, which can lead to calamitous gene mutations can lead to wide phenotypic variability, consequences [35]. represented by different syndromes with different histopathological manifestations [39,40]. In Parkes Weber Four genes have been identified to be responsible for syndrome, individuals who had multiple capillary mal- HHT: (1) ENG, which is associated with hereditary formations, in addition to the AVMs and skeletal over- hemorrhagic telangiectasia type 1 (HHT1); (2) ACVRL1 growth, also harbored RASA1 mutations. 26

Table 1. Genes Influencing Cerebral Vasospasm GENE MOLECULAR ACTION ROLE VARIANTS DESCRIBED NOTES COMT Breaking down of catecholamine Underexpression following COMT-A allele, Homozygous This gene is absent in 22q deletion [30,81–85] SAH leads to poor out- state more likely to develop CV. syndrome, leading to high risk for come. hepatoblastoma. eNOS Production of the vasodilator, Overexpression is protec- eNOS SNPs were described, Aneurysm and other vascular mal- [30,86,87] nitric oxide. tive against CV. being responsible for CV. formations have been linked to variants of eNOS gene. Hp [30,88,90] Production of haptoglobin which Some forms of Hp are Hp 2–2 allele has more CV ten- Haptoglobins are secreted by the binds to free hemoglobin for proinflammatory, predis- dency than Hp 1–1 allele. liver. uptake by macrophages. posing to CV. SERPINE1 Production of Plasminogen Acti- High levels lead to 4G/5G SNP on the promotor 4G variant leads to higher levels of [30,91,92] vator Inhibitor-1 (PAI-1). increased CV area. PAI-1 and higher chance for CV. APOE [30,93– Production of apolipoprotein E, Poor lipid transport in CNS Three common alleles for three ApoE4 allele associated with wors- 95] involved in lipid metabolism and can aggravate CV by inter- forms of ApoE, ApoE2, ened neurological consequences transport. fering with cell membrane ApoE3, and ApoE4 following CV. repair. Studies have shown that this allele is associated with higher risk for Alzheimer’s disease. RYR [30,96– Ryanodine receptors of the vascu- Low activity receptors lead RYR1, RYR2, and RYR3 are Underexpression of RYR2, and het- Journal of Vascular and Interventional Neurology, Vol. 5 Vol. and Interventional Neurology, Journal of Vascular 98] lar smooth muscle cells. to reduced vasorelaxation the three isoforms of these erozygosity of RYR1 c6178G>T receptors polymorphism are associated with increased CV. CBS An enzyme that acts on homocys- During the enzyme action, 699CT, 699TT, and 1080TT 1080TT variant leads to reduced [30,99,100] teine and serine to make cysta- H2S is released, which is a variants. activity and CV followed by cere- thionine. vasodilator. Decreased bral ischemia secondary to vaso- activity of CBS leads to spasm. reduced vasodilation and CV.

RASA1-associated syndromes have an autosomal domi- chance of being a carrier. Only few cases of this disease nant mode of inheritance [13]. Molecular testing of the have been molecularly identified; therefore, the preva- affected individual is required before testing other fam- lence of this disease is unknown. ily members. Around 30% of cases are due to de novo mutations [39]; therefore, depending on the results of PIK3CA-Related Syndromes parents, the risk for siblings can be 50% when the muta- Mutations of this gene are usually post-zygotic, leading tion was found in one of the parents, and very minimal to somatic mosaicism that might involve overgrowth of recurrence when it was found to be a de novo mutation. the affected tissues. The variability associated with this gene mutation can Clinically, it is manifested as megalencephaly-capillary extend to the molecular and developmental embryology. malformation (MCAP), which is primarily manifesting Cases of mosaic individuals were found to have a nega- as neurological disorders associated with severe mental tive result on molecular testing, but passed down the disabilities and cutaneous capillary malformations, that mutations to their children, due to the germline mosai- can be associated with focal or generalized overgrowth. cism phenomenon (where the gonads carry the mutation in some or all of the germ cells, while the tested periph- PIK3CA mutations can also manifest as congenital eral tissues are spared from the mutated cell population). lipomatous asymmetric overgrowth of the trunk, lym- phatic, capillary, venous, and combined-type vascular STAMBP-Associated Syndrome malformations, epidermal nevi, and skeletal and spinal Pathogenic variants of this gene are known to be respon- anomalies (CLOVES) syndrome. sible for microcephaly-capillary malformation (MIC- CAP) syndrome, which is characterized by microce- Since information regarding the hereditability of this phaly, cutaneous capillary malformations, developmen- syndrome is lacking, it is theoretically possible for the tal delay, phalangeal malformations, and sever seizure affected individual to have gonadal mosaicism. If the disorder [13]. molecular testing identified the responsible variant, a preimplantation genetic testing becomes a possibility for MIC-CAP syndrome follows an autosomal recessive offspring embryonic selection. mode of inheritance, with most cases due to inheritance of two different pathogenic variants from parents (com- In addition, prenatal genetic testing is also available for pound heterozygous) [41]. Therefore, parents of the this gene, which might be indicated in cases where fetal affected individual are obligate carriers, while each sib- sonographic examinations reveal overgrowth or other ling has a 25% chance of being homozygous and a 50% signs of MCAP or CLOVES syndromes. Al-Mufti et al. 27

Intracranial Cavernous Angiomatous Apolipoprotein E Apolipoprotein E (APOE) is involved in lipid transport Malformation and metabolism, and cell membrane maintenance and Histopathologically, Familial Cerebral Cavernous Mal- repair. Mutation in the gene encoding APOE, especially formations (FCCM) are spongy vascular lesions, often the APOE*ɛ2 allele, has been associated with the devel- complicated by calcification and thrombosis [42]. They opment of lobar and deep ICH [52,53]. can usually be diagnosed with MRI examinations of the brain and the spinal cord. Otten P et al. [43] estimated The gene encoding APOE has been linked to increased an approximately 90% of patients with CCM remain risk of developing ICH. Another variant of APOE has asymptomatic throughout their whole life. Therefore, a been linked to the pathogenesis of cerebral amyloid genetic diagnosis of this disorder can help reducing mor- angiopathy. bidity and mortality rates in individuals at high risk of inheriting mutations of this disease [44], especially in Polyamine-Modulated Factor 1 / Solute Carrier Family 25-Member 44 Journal of Vascular and Interventional Neurology, Vol. 5 Vol. and Interventional Neurology, Journal of Vascular cases where brain MRI imaging for individuals experi- encing new neurologic symptoms is indicated, although The 1q22 gene has been identified as a susceptibility it can be difficult sometimes to detect new asympto- locus for nonlobar ICH, where the polyamine-modulated matic hemorrhages. factor 1 (PMF1) and the solute carrier family 25-member 44 (SLC25A44) genes are found [54]. The PMF1 Three genes (KRIT1, CCM2, and PDCD10) have been protein is required for chromosomal alignment and seg- identified of having loss of function mutations in fami- regation during mitosis, and SLC25A44 codes for a lies with FCCM; they are inherited in an autosomal mitochondrial carrier protein [55]. Mutations involving dominant mode [45] suggested that a fourth gene is these genes have been implicated in cerebral small ves- responsible for FCCM in some families at a region of sel disease contribute to the pathophysiology of ICH. 3q. Methylenetetrahydrofolate Reductase As for other autosomal dominant disorders, family history and clinical investigation can play a critical role in The methylenetetrahydrofolate reductase (MTHFR) determining family members to be tested for mutations gene is located on chromosome 1 (1p36.3), and two of these genes. Somatic mosaicism and de novo muta- common alleles, the C677T (thermolabile) allele and the tions were described for these genes [45–48]; therefore, A1298C allele, have been identified [56]. The MTHFR a negative family history does not exclude the genetic gene is responsible for converting homocysteine to etiology of this malformation. methionine, thereby reducing the level of plasma homocysteine [57–59]. Polymorphisms in the MTHFR gene and resultant elevation in plasma total homocysteine Spontaneous Intracerebral have been found to be elevated with cerebral hemor- Hemorrhage rhage with both homozygous and heterozygous MTHFR gene mutations [57,59–61]. Homozygous MTHFR gene Spontaneous, nontraumatic intracerebral hemorrhage mutation is associated with reduced plasma folate levels, (ICH) is a leading cause of morbidity and mortality but not with increased plasma HCY levels. throughout the world [49]. Multiple factors have been implicated in the etiology of ICH, and these include It is postulated that MTHFR predisposes to the develop- hypertension, alcohol use, current cigarette smoking, ment of ICH by accelerating atherosclerosis and promot- race, gender, and use of oral anticoagulants and/or anti- ing plaque rupture via excessive inflammation and platelet agents. The heritability of ICH risk has been chronic endothelial wall stress [59,62]. Hyperhomocys- estimated at 44% and the familial aggregation of ICH teinaemia is a known risk factor for coronary artery dis- has been observed, and a few genes have been found to ease, peripheral vascular disease, cerebral ischemia, be associated with ICH at the population level [50,51]. venous thrombosis, and atherosclerosis [60–62]. Folate Unfortunately, large scale studies are lacking and much supplementation to reduce plasma homocysteine levels of the evidence for genetic risk factors for ICH comes might be useful in patients with the MTHFR polymor- from single studies conducted in relatively small and phism [51]. homogenous populations. Some of the genetic variants associated with ICH backed by the strongest level of Multiple trials have implicated other genes, related to available evidence include the following. lipid metabolism, inflammation, hemostasis, and the 28

symptoms like vomiting, exercise intolerance, and weakness.

Seizures in this disorder are associated with stroke-like episodes and even cortical blindness. Due to the special and uncommon combination of symptoms associated with the presentation of this syndrome, a clinical diagnosis can be very difficult. Moreover, the maternal inheritance pattern of the syndrome makes the prediction of affected family members very difficult, due, in part, to the variability associated with mitochondrial inheritance.

Despite the presence of biochemical testing that might identify metabolic disorders associated with the disease,

Journal of Vascular and Interventional Neurology, Vol. 5 Vol. and Interventional Neurology, Journal of Vascular a mitochondrial DNA mutation analysis might become necessary to reach a definite diagnosis in a family, and to test other family members for proper management of the clinical manifestations. Since this disorder is due to mitochondrial genome mutations, it follows the maternal mode of inheritance. Variability in the severity and clinical manifestations of this disease in the offspring are expected, due to the different proportions of the mutated mitochondrial population in different body tissues.

Figure 5. Cerebral Autosomal Dominant Arteriopathy

with Subcortical Infarcts and Leukoencephalopathy CNS microenvironment, in the pathobiology of ICH This disease is characterized by early adulthood multiple [51]. However, despite accumulating evidence, it is dif- strokes that lead to progressive cognitive deficit and ficult at this point to speculate how and to what extent eventually dementia. Early symptoms of this disease, this information can be used to prevent and treat ICH. before strokes ensue, are migraine headache and unspe- No clear causality, hence, further investigations are cific neuropsychiatric symptoms [13]. Given the dra- required to delineate the roles of these mutations in ICH matic clinical consequences of this disease, genetic test- pathogenesis, with the goal of identifying new targets ing becomes critical to the early diagnosis of individuals for treatment and prevention of ICH. at risk.

Ischemic and Metabolic Syndromes NOTCH3 gene was identified as being related to the dis- of the Brain order. Due to the variable expression of the pathogenic variants of this gene, parental molecular testing is neces- These syndromes are usually manifested as ischemic sary for individuals undergoing genetic testing, in order strokes in young adults. Since they can be caused by to identify the the responsible pathogenic variants [63]. specific monogenic disorders, or as part of metabolic It follows the autosomal dominant mode of inheritance, diseases, genetic testing for individuals at risk can pro- with siblings having a 50% chance of inheriting an iden- vide early identification and management options for tified mutation. affected family members. Cerebral Autosomal Recessive Arteriopathy Mitochondrial Encephalomyopathy, Lactic with Subcortical Infarcts and Acidosis, and Stroke-Like Episodes; Myopathy, Leukoencephalopathy, Maeda Syndrome Mitochondrial-Encephalopathy-Lactic Acidosis- (CARASIL) Stroke Unlike cerebral autosomal dominant arteriopathy with As the name of this syndrome implies, it is one of the subcortical infarcts and leukoencephalopathy, the com- most common mitochondrial encephalomyopathies. It mon presenting symptom of this disorder is spastic gait usually presents with severe seizures, with metabolic disturbance during adulthood. Stroke-like episodes usu-

Al-Mufti et al. 29

ally follow with slower progression of the disease over tion in beta-chain is usually due to one amino acid sub- 20 years. stitution at position 6 of the polypeptide (valine to gluta- mate). HTRA1 gene was identified as the gene associated with CARASIL, and it is inherited in an autosomal recessive Early diagnosis and treatment of individuals with SCD mode. Therefore, there is a 25% chance for siblings to is essential for early prevention and proper treatment of inherit the two mutations from both parents to be affec- strokes. Different treatment modalities for SCD are ted. available.

Fabry Disease Retinal Vasculopathy with Cerebral Leukodystrophy Fabry Disease is an X-linked recessive metabolic disease that results from α-galactosidase (α-Gal A) enzyme Several leukodystrophy syndromes have been described, deficiency and resultant lysosomal accumulation of glo- most of them are due to the autosomal recessive inheri- botriaosylceramide (GL-3) in cells throughout the body. tance of different genes. However, cerebroretinal vascul- Journal of Vascular and Interventional Neurology, Vol. 5 Vol. and Interventional Neurology, Journal of Vascular opathy syndrome is characterized by vascular patholo- Affected males usually present with cardiomyopathy, gies that lead to blindness, memory loss, neuropathies, end stage renal failure, and stroke. and ischemic strokes.

GLA gene mutations are responsible for the develop- The genetic mutations responsible for cerebroretinal ment of this disease, which is more common among vasculopathy were identified in TREX1 gene. It is males, who usually inherit the pathogenic mutation from inherited in autosomal dominant fashion, with several their mothers. It has incomplete penetrance and variable family members affected among different generations. expression. Although enzymatic studies are useful in the identification and diagnosis of individuals at risk, Moyamoya Disease genetic testing may be the only available diagnostic test Moyamoya disease is an autosomal dominant disorder when the mutation of GLA gene leads to defects on the caused by RNF213 gene mutations [67]. It is character- cellular processing of the gene [13,64]. ized by the histopathological hyperplasia of arterial intima, and smooth muscle hypertrophy leading to the As an X-linked recessive disorder, males are much more distortion of innermost elastica, and eventually progres- likely to be affected than females. Carrier females may sive narrowing and obstruction of blood vessels. show a dramatic decrease in the enzymatic activity test, which makes them candidates for the genetic testing to Clinically, Moyamoya presents as ischemic stroke and confirm their carrier status. A carrier female has a 50% TIA. At a younger age, a child may develop a stroke that chance of passing the disease-causing mutation to each was triggered by exercise or secondary to fever-causing of her offsprings; therefore, the risk for a son of hers to illness. These cerebral ischemic episodes can evolve into be affected is 50%, and the risk for her daughter to epilepsy and other neurological manifestations. become a carrier like her mother is also 50%. It is worth mentioning that Moyamoya is more prevalent It is important to consider the fact that 5% of affected among Japanese and East Asian population. Although it males had a spontaneous mutation, rather than inheriting is inherited in an autosomal dominant mode, the reduced the mutation from their mothers [65]. penetrance of the disease can make it difficult to identify affected individuals in a family without undergoing Sickle-Cell Disease genetic testing to detect the specific familial mutation. It is estimated that one in four individuals with Sickle- cell disease (SCD) will develop stroke before they reach Clinical Genetic Testing 45 years of age [66]. The pathological basis of cerebral Genetic testing, in general, involves the analysis of ischemia secondary to SCD involves nonatherosclerotic nucleic acids (DNA or RNA) of tissue cells. Peripheral vascular disease of cerebral arteries, leading to narrow- blood is usually used for the collection of DNA from the ing and occlusion. white blood cells, when inherited genetic variants, or germ-line mutations, are being investigated. Genetically speaking, SCD is an autosomal recessive disorder that is caused by the inheritance of two mutated In this review, most of the mutations being described are beta-chain of hemoglobin from both parents. The muta- inheritable, or germ-line. However, in some conditions, 30

it becomes necessary to investigate the expression of standing of the underlying genetic and molecular etiolo- specific genes via the quantitative assays of RNA, to gies, it is still difficult to discern a relation between a confirm the genetic variant of interest. RNA quantitative single gene mutation and a resultant cerebrovascular assessment needs to be done on the tissue of interest; in pathology. This is likely due to the multifactorial etiolo- this review, the tissue of interest is the brain vasculature, gies, where genetic variants can become pathologic where multiple novel mutations were discovered via when coinciding with environmental factors. post-mortem genetic analysis of the brain vasculature. Advances in gene-editing technologies have ushered in a It is important to mention that after the confirmation of new era of personalized medicine with the potential to an association between a neurovascular disease and spe- modify these molecular genetic variants. An accurate cific genetic variants, it becomes possible for clinicians molecular diagnosis of monogenic inherited disorders to perform genetic testing on individuals suspected of can provide early preventative treatment for the neuro- carrying a specific mutation using peripheral blood sam- logical complications, in addition to a better understand- ples. In these situations, the main reason behind the ing of the underlying pathology. Solving the molecular Journal of Vascular and Interventional Neurology, Vol. 5 Vol. and Interventional Neurology, Journal of Vascular genetic testing would be to confirm a clinical diagnosis enigmas lying underneath these terminal hereditary dis- of a neurovascular disorder; or to pursue specific man- eases can also help in providing future gene-modulation agement for preventing a disorder with neurovascular therapy. sequels, based on family and clinical histories. References

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