Genetics of Stroke

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Genetics of Stroke Mateusz G Adamski and Alison E Baird SUNY Downstate Medical Center, Department of Neurology, Brooklyn, NY, USA

This article is a revision of the previous edition article by Martin Dichgans and James F Meschia, volume 3, pp 2856–2879, © 2007, Elsevier Ltd.

123.1 INTRODUCTION Strokes result from a focal reduction of blood flow to the brain. Around 83% of strokes are due to arterial vascular occlusion (termed ischemic stroke) and around 17% are due to vascular rupture (termed hemorrhagic stroke). Arterial vascular rupture may occur into the brain parenchyma resulting in intracerebral hemorrhage (ICH) or into the subarachnoid space what results in subarachnoid hemorrhage (SAH). In about 1% of cases, strokes occur in the venous system (termed cerebral venous thrombosis). Strokes are a leading cause of morbidity and mortality in the US. There is a substantial additional burden of asymptomatic cerebrovascular disease. Evidence for a genetic basis for stroke comes from twin and family studies. Furthermore, a number of monogenic disorders cause stroke, as either a primary manifestation or a secondary manifestation. The contribution of these factors has been increasingly recognized over the past 10–20 years with the description of monogenic disorders such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Advances in genomics methods, including genomewide association studies, are permitting possible new genetic risk markers to be explored. In this chapter, we will review the genetics of stroke and cerebrovascular disease. The burden and prevalence of stroke, along with stroke classification systems, will first be described. Then, evidence from twin and family studies will be presented followed by monogenic disorders associated with stroke.

123.1.1 Prevalence and Incidence Stroke represents a serious burden to the worldwide population in terms of prevalence, incidence, long-term disability, and mortality, generating substantial costs across the globe. Stroke statistics differ by gender, age groups, and among the four main racial groups: Whites, Asians, Blacks and Hispanics. According to an estimate,

7,000,000 Americans of ≥20 years of age have had a stroke, setting the stroke prevalence at the level of 3.0%. Another projection is that by 2030, another 4 million will suffer from stroke, increasing the prevalence by 24.9% (1). Every year, 795,000 people experience a new (77%) or recurrent stroke (23%). Gender and racial differences are seen in both stroke prevalence and incidence, with higher overall incidence in women and the highest incidence and prevalence in non-Hispanic blacks (1). The distribution of stroke subtypes has not changed since 2011, with 87% of ischemic strokes, 10% of hemorrhagic strokes, and 3% of SAH strokes (2). Over the past 20–30 years, stroke incidence has declined significantly in whites, both in men and women (3). Differences in stroke prevalence and incidence between blacks and whites highlight the importance of race.

123.1.2 Mortality Stroke is now the 4th leading cause of death behind the causes of the diseases of the heart, cancer, and chronic lower respiratory diseases. In the US, a person suffers a stroke every 4 minutes and stroke causes 1 of 18 deaths (1). The 30-day mortality is 12.6% for all strokes, 8.1% for ischemic strokes, and 44.6% for hemorrhagic strokes (4).

123.1.3 Common Stroke Risk Factors Common stroke risk factors include the following: high blood pressure, atrial fibrillation (AF), smoking, diabetes mellitus (DM), transient ischemic attack (TIA), dyslipidemia, renal disease and sleep apnea, and physical inactivity. TIA substantially increases the short- and long-term stroke rates (1). High blood pressure nearly doubles the lifetime risk of stroke (5). Impaired glucose tolerance and DM respectively doubles and triples the risk of stroke (6). AF independently increases the risk of stroke by five fold throughout all ages (7). Smoking is the most important modifiable stroke risk factor that increases 2 to 4 times the risk of stroke among current smokers (8).

© 2013, Elsevier Ltd. All rights reserved.

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CHAPTER 123  Genetics of Stroke

123.1.4 Poststroke Long-term Disability Stroke is a leading cause of serious, long-term disability in the US (1). Neurological deficits, hemiparesis and cognitive deficits at six months poststroke, are present in almost half of the patients. Hemianopia, aphasia, and sensory deficits are present respectively at 19.6, 18.9 and 15.4% of patients. In addition, women were found to be at greater risk for disability and institutionalization (9). Stroke imposes a substantial economic burden both for society and individual. In the US, the mean stroke expense was $ 7657 per person in 2007, and the mean estimated stroke care lifetime cost is estimated at $ 140 048 (1).

123.2 STROKE PHENOTYPES An understanding of stroke classification is essential in reviewing stroke genetics. This is because the different monogenic disorders are specifically associated with certain stroke types and subtypes. According to the World Health Organization, stroke was defined in the 1970s as “neurological deficit of cerebrovascular cause that persists beyond 24 hours or is interrupted by death within 24 hours” (10). Stroke is a heterogeneous disease represented by five main types: ischemic stroke, hemorrhagic stroke, subarachnoid stroke, cerebral venous thrombosis and spinal cord stroke. Furthermore, ischemic stroke is subdivided into four etiological categories: atherothrombotic, small-vessel disease, cardioembolic, and other causes Table 123-1.

123.2.1 Ischemic Stroke—Subtypes, Pathomechanism Ischemic stroke occurs when a blood vessel that supplies the brain is occluded by a clot. There are two kinds of clots: thrombus and embolus. Thrombus forms in an artery that is already narrow and causes thrombotic stroke. Embolus is a clot that forms in another place

TA B L E 1 2 3 - 1    Annual Ischemic Stroke Incidence Rates per 100, 000 among Whites, Blacks, and Hispanics (11) Ischemic Stroke Subtype

Whites %

Hispanics %

Blacks %

Large-vessel disease (LVD) Intracranial LVD Extracranial LVD Small-vessel disease Cardioembolic Cryptogenic Other Total

9.09 3.41 5.68 14.77 23.86 51.14 1.14

14.77 8.72 6.04 20.81 20.13 44.30 0.67

16.75 7.85 8.90 20.94 17.28 42.93 1.05

in the blood vessels of the brain, or some other part of the body, and travels up to the brain to block a smaller artery causing an embolic stroke. Ischemic stroke may be divided in to three categories, based on the clot source. It may arise from the atherosclerotic large cerebral arteries (e.g. carotid, middle cerebral, or basilar arteries) or atherosclerotic small cerebral arteries (e.g. lenticulostriate, basilar penetrating, and medullary arteries); finally, ischemic stroke may also be cardioembolic in origin. 123.2.1.1 Large-Vessel Disease.  Large-vessel disease (LVD) or artery-to-artery embolism accounts for 15 to 20% of all ischemic strokes (12). In the case of LVD, emboli may originate from the aorta, extracranial carotid, or vertebral arteries, or intracranial arteries. The embolic material is composed of clot, platelet aggregates, or plaque debris that usually breaks off from atherosclerotic plaques (13). 123.2.1.2 Cardioembolic Stroke.  Cardioembolism accounts for 20 to 30% of all ischemic strokes (12). Embolus originating from the heart causes severe strokes, but it is also prone to early recurrence. Due to their large size, cardiac emboli flow to the intracranial vessels in most cases and cause massive, superficial, single large striatocapsular or multiple infarcts in the middle cerebral artery. 123.2.1.3 Small-Vessel Disease.  Small-vessel disease (SVD) accounts for another approximately 20 to 30% of all ischemic strokes (12). It is strongly associated with hypertension and is characterized pathologically by lipohyalinosis, microatheroma, fibrinoid necrosis, and Charcot–Bouchard aneurysms. 123.2.1.4 Other Causes.  This category includes rare causes of stroke. Patients assigned to this group should have clinical and imaging signs of a stroke. Common causes of stroke (SVD, LVD, and Cardioembolism) should be excluded (14). 123.2.1.5 Intermediate Phenotypes.  Patients are assigned to this group if the cause of stroke cannot be determined. This applies to patients with two or more potential causes of stroke, for example SVD and LVD or LVD and Cardioembolism.

123.2.2 Hemorrhagic Stroke—Subtypes and Pathomechanisms Hemorrhagic stroke results from a weakened vessel that ruptures and bleeds into the surrounding brain. The blood accumulates and compresses the surrounding brain tissue. There are two distinct mechanisms for two main types of hemorrhagic strokes: bleeding directly into the brain parenchyma (ICH), or bleeding into the cerebrospinal fluid containing sulci, fissures, and cisterns (SAH). Other disorders involving bleeding inside the skull include epidural and subdural hematomas, which are usually caused by a head injury and are not considered strokes.

CHAPTER 123  Genetics of Stroke 123.2.2.1 Intracerebral Hemorrhage.  Primary spontaneous ICH occurs as a result of the spontaneous rupture of small blood vessels damaged by hypertension or amyloid angiopathy. This has an incidence of 7–17 per 100, 000 and accounts for 78–85% of all cases (15). Secondary spontaneous ICH occurs in the presence of a preexisting lesion such as avascular or parenchymal abnormality, the most common cause being arteriovenous malformations. Other causes include arteriovenous malformations, cavernous hemangiomas, intracranial aneurysms, venous sinus thrombosis, hemorrhagic transformation of ischemic stroke, coagulopathy, intracranial tumors, or vasculitis. 123.2.2.2 Subarachnoid Hemorrhage.  Rupture of a cerebral aneurysm is the most common cause and accounts for about 85% of SAH. Cerebral aneurysms are present in about 2% of asymptomatic adults. Intracranial aneurysms are found in 2–5% of all autopsies; however, the incidence of rupture is only 2–20/100,000 individuals/year (16). Nonaneurysmal perimesencephalic SAH accounts for 21–68% of angiography negative SAH (17). The presentation of this subgroup is typically indistinguishable from other types of SAH, but their prognosis is excellent.

123.2.3 Cerebral Venous Thrombosis Cerebral venous thrombosis (CVT)—i.e. thrombosis of the intracranial veins and sinuses—is a rare type of cerebrovascular disease that affects about five people per million and accounts for 0.5% of all strokes (18). The risk factors for venous thrombosis in general are linked classically to the Virchow triad of stasis of the blood, changes in the vessel wall, and changes in the composition of the blood. Risk factors are usually divided into acquired risks and genetic risks (19).

123.2.4 Spinal Cord Stroke Spinal cord infarction is uncommon and accounts for 1.2% of all strokes (20). It is a rare but often devastating disorder caused by a wide array of pathologic states. The onset of spinal cord infarction is typically abrupt, and the vascular territory involved largely defines neurologic presentation.

123.2.5 Stroke Classification It is not always possible to identify a specific cause of stroke; in fact, most registers failed to do so in 25–39% of stroke patients (21). Number of classifications on stroke subtype have been published. Their purpose was to uniformly classify patients for clinical trials, genetic, or epidemiological studies and to help classify patients for therapeutic decision making in daily practice. Stroke Data Bank Subtype Classification (22) recognized five major groups: brain hemorrhages; brain

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infarctions; cardioembolic stroke; lacunar stroke; and stroke from rare causes or undetermined etiology. The Oxfordshire Community Stroke Project (OCSP) was proposed to characterize this population-based epidemiological study. This classification was based on clinical findings only. OCSP classification recognized four types of stroke: lacunar infarct (LACI); total anterior circulation infarct (TACI); partial anterior circulation infarct (PACI); and posterior circulation infarcts (POCI). The Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification is the most commonly used by clinical researchers (14). This classification is used to categorize ischemic stroke etiology into five groups: largeartery atherosclerosis; cardioembolism; small-vessel occlusion (lacunae); stroke of other determined cause; and stroke of undetermined cause.

123.3 HERITABILITY: TWIN AND FAMILY STUDIES In twin studies, the concordance rates for stroke are 17.7% in monozygotic twins and 3.6% in dizygotic twins (23,24). The heritability of stroke has varied in family studies, but allowing for some methodological weaknesses, it appears that a family history of stroke increases a subject’s stroke risk by 2- to 3-fold (25,26). In the Framingham study, using the information obtained across three generations, including the original and offspring cohorts, a parental history of stroke was associated with an approximately 2-fold increase in stroke risk: a paternal history of stroke was associated with a relative risk of 2.4 and a maternal history with a risk of 1.4 (25). In later studies, looking at the heritability of stroke subtypes, the large-artery atherosclerosis and small-vessel subtypes were found to be more commonly inherited than the cardioembolic subtype (27). Few studies have separated ischemic stroke risk from that of ICH, probably because of the smaller frequency of the ICH stroke type and the difficulty in retrospectively obtaining this information. It appears that ICH in a first-degree relative increases a subject’s odds by as much as 2- to 6-fold (28). SAH has a distinct clinical profile, and a family history of SAH has been associated with an increased risk for SAH of about 4-fold (29); because of this association, screening of first-degree relatives of patients with SAH is currently recommended (30). Evidence of a geneenvironment interaction with smoking, another risk factor for SAH, also may exist for aneurysmal SAH (31).

123.4 SINGLE-GENE DISORDERS CAUSING STROKE Single-gene disorders is a group of diseases caused by mutation in a single gene. In contrast, polygenic disorders are due to interaction of multiply gene mutations with lifestyle and environmental factors.

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CHAPTER 123  Genetics of Stroke

123.4.1 Ischemic Stroke Ischemic stroke was divided into etiological categories according to TOAST criteria (14).

123.4.2 Small-Vessel Disease  

123.4.3 CADASIL – Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (NOTCH3 gene) Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)—Online Mendelian Inheritance in Man (OMIM) #125310 (http:/www.ncbi. nlm.nih.gov/omim/125310. Accessed June 20, 2011)—is an autosomal dominant disorder. It affects small arterial vessels due to mutation in the NOTCH3 gene mapped on 19p13.2-p13.1. From 1955, symptoms were recognized as Binswanger disease without hypertension (32), until 1991 when the relevant gene was mapped on chromosome 19 (33). Product of the NOTCH3 gene large type-1 transmembrane receptor (NOTCH3—N3) is mainly expressed in vascular smooth muscle cells and pericytes. Mature N3 consists of two independent domains: intracellular N3-ICD present in nucleus and responsible for gene expression regulation and extracellular N3-ECD. In CADASIL, mutations are present in N3-ECD within one of the 34 epidermal growth factor (EGF)-like repeat domains, each including six cysteine residues. All mutations, missense, deletion, and splice site, lead to an odd number of cysteine residues. Odd number of cysteines due to CADASIL mutations has been linked to multimerization of N3-ECD (34). Deposits of multimerized N3-ECD are components of the granular osmiophilic material pathognomonic for CADASIL on electron microscopy. 123.4.3.1 Clinical Presentation.  CADASIL starts at the mean age of 45 years and leads to death in 10 to 25 years (35). The disease is characterized by five main symptoms: migraine with aura, subcortical ischemic events, mood disturbances, apathy, and cognitive impairment. Migraine with aura occurs in approximately 20–40% of CADASIL patients—five times more than in general population. Frequency of migraine without aura is the same as in general population (32). Migraine is also a first presenting symptom in 34–36% of patients—usually before the age of 40 years (35). Symptoms, frequency, and severity of migraines vary across patients. Most attacks involve visual and sensory aura lasting 20–30 minutes, followed by prolonged headache. Atypical attacks with basilar, hemiplegic, or prolonged aura may be difficult to differentiate from ischemic episodes. Frequency of migraines may increase until first stroke, thereafter it cease or decrease. Subcortical ischemic events represented by TIA and ischemic strokes affect up to 84% of patients with

CADASIL. In 70% of patients, these are the first CADASIL symptoms (35), occurring at the mean age of 49 years (32). Ischemic events are almost always subcortical and lacunar, affecting white matter and basal ganglia. Patients experience recurrent strokes, leading to progressive disability and pseudobulbar palsy. Mood disturbances and apathy are the most common psychiatric manifestations of CADASIL. Mood disorders are present in 20% of patients with moderate depression, being the most common symptom. Other manifestations include aggression, agitation, delusional states, dysthymia, emotional lability, mania, paranoia, and schizophrenia-like symptoms (36). Apathy is present in 40% of patients with CADASIL and is associated positively with the load of white matter MRI lesions and with a decrease in quality of life (37). Cognitive impairment is the second most frequent symptom in patients with CADASIL, rarely present at the onset of the disease. Frequency varies from 30 to 90% depending on patient’s age (36). Cognitive deficit is slowly progressing, worsening after recurrent strokes. Other clinical manifestations include primary and secondary to stroke seizures 5–10% of patients, ocular symptoms, and ICHs (32) Figure 123-1. 123.4.3.2 Diagnosis.  Genetic testing for the presence of EGF domain mutation in NOTCH3 gene is the only method to diagnose CADASIL. Due to the expensive and time-consuming procedure, patients should be preselected for genetic analysis based on diagnostic screening criteria and clinical presentation. MRI neuroimaging is the primary test that may be supported with the results from skin biopsy. 123.4.3.3 Neuroimaging.  In most cases, MRI changes precede other common symptoms by 10–15 years appearing at the age of 30–35 years (32). Angiography is usually normal and is contraindicated due to increased risk of complications. MRI changes are present in T2and T1-weighted images and fluid attenuated inversion recovery (FLAIR). Typically, symmetrical and diffuse MRI changes are present in periventricular areas and centrum semiovale. LACIs occur mostly in external capsule and anterior part of temporal lobes—location characteristic for CADASIL (32). Less frequently, changes may be present in the basal ganglia and thalamus, sporadically in the brainstem and corpus callosum (39). Focal microbleeds are commonly found in CADASIL patients (40). 123.4.3.4 Skin biopsy.  Skin biopsies, based on two methods, were shown to be helpful in selecting patients for genetic testing. Samples stained with monoclonal antibodies specific for NOTCH3 showed high sensitivity (93%) and high specificity (100%) (41), whereas ultrastructural testing for extracellular deposits of granular osmiophilic material (GOM) in the tunica media was less sensitive (57%) and equally specific (100%) (42). 123.4.3.5 Treatment.  So far, there is neither a specific nor a proven treatment for CADASIL. Separate treatment of CADASIL symptoms has also not been validated.

CHAPTER 123  Genetics of Stroke

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FIGURE 123-1  Pathophysiology of CADASIL (38), by permission of Elsevier Inc. Cerebral autosomal dominant arteriopathy with subcortical

infarcts and leukoencephalopathy (CADASIL), autosomal dominant disorder due to mutation in the Notch 3 gene. This gene is located on chromosome 19, on the p (short) arm, at 19p13.2 to p13.1. Notch 3 gene contains 33 exons; the majority of single-point or missense mutations occur on exons 2 to 6. There is an accumulation of osmophilic granules in smooth muscle of blood vessels throughout the vasculature, particularly in the brain, the retina, and the skin.

123.4.4 CARASIL – Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (HTRA1) Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL)—OMIM #600142 (http://omim.org/entry/600142; Accessed June 20, 2011)—is an autosomal recessive disorder. It was named after Bowler and Hachinski in 1994 (43). Disease was diagnosed approximately in 50 Asian cases; except for two Chinese patients, all come from Japan (44). So far, there was only one Caucasian case of CARASIL carrying HTRA1 gene nonsense mutation (44). Disease affects small arterial vessels due to mutations in the HTRA1 gene mapped on chromosome 10q25.3-q26.2 (45). HTRA1 gene codes for HtrA serine peptidase/protease 1 (HTRA1) that represses signaling by transforming growth factor (TGF)-b family members (46). Genome-wide linkage analysis in six consanguineous Japanese families with CARASIL identified 45 mutations in HTRA1 gene. In the case of a mutation, protein fails to repress TGF-b, and the amount of TGF-b is increased in the media of cerebral small arteries (45). As a result, intense arteriosclerosis is present mainly in the small penetrating arteries of the basal ganglia and cerebral white matter. Different than CADASIL, there are no GOM deposits of amyloid in the tunica media (46). 123.4.4.1 Clinical Presentation.  Cerebral onset of CARASIL is between 20 and 45 years of age, with the

mean age of 32 (46). Duration of life ranges from 10 to 20 years; however, patients become bed-ridden within 10 years of onset (45). The disease is characterized by four main symptoms: ischemic stroke or stepwise deterioration; cognitive deficits; orthopedic complications; and alopecia (premature baldness). 123.4.4.2 Ischemic Stroke or Stepwise Deterioration.  Characteristic lacunar strokes localized in basal ganglia and brainstem are present in 50% of the patients. Remaining patients develop stepwise deterioration, pseudobulbar palsy, pyramidal and extrapyramidal signs and gait disturbances (46). 123.4.4.3 Cognitive Deficits.  Cognitive deficits occur in almost all CARASIL patients developing dementia by the age of 30–40 years. Symptoms that may occur include: forgetfulness, dyscalculia, time disorientation, personality changes, emotional incontinence, severe memory dysfunction, and finally abulia and akinetic mutism (46). Focal signs like aphasia or apraxia and abnormal behavior were not seen (46). 123.4.4.4 Orthopedic Complications.  80% of CARASIL cases develop acute middle to lower back pain. Spondylosis deformans or disk degeneration occurs, based on magnetic resonance imaging (MRI) and X-ray imaging, in cervical and/or thoracolumbar spine (46). Other orthopedic complications include osseous structures like kyphosis, ossification of intraspinal canal ligaments, deformity of the elbows, and arthropathy of the knee joints (47).

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CHAPTER 123  Genetics of Stroke

123.4.4.5 Alopecia.  Hair loss present in 90% of the patients starts as early as adolescence and is limited to the head (46). Alopecia is less prominent but also present in affected women (47). 123.4.4.6 Diagnosis.  Patients presenting with CARASIL’s­ characteristic symptoms, lacunar strokes and white matter changes and cognitive deficits, alopecia and spondylosis, should be tested for HTRA1 gene mutations to confirm the diagnosis. Differential diagnosis should include Binswanger disease, angiitis of the central nervous system (CNS), CADASIL, chronic progressive multiple sclerosis, and leukodystrophies with dermatologic or skeletal disorders (46). 123.4.4.7 Treatment.  At present, there is neither specific treatment of CARASIL itself nor its symptoms.

123.4.5 RVCL – Retinal Vasculopathy with Cerebral Leukodystrophy (TREX1) Retinal vasculopathy witch cerebral leukodystrophy— RVCL - OMIM #192315 (http://omim.org/entry/192315; Accessed June 20, 2011)—is an autosomal dominant disease caused by mutations in TREX1 gene on chromosome 3p21. Since 2007, RVCL encompasses three diseases—cerebroretinal vasculopathy (CRV), hereditary vascular retinopathy (HVR), and hereditary endotheliopathy with retinopathy and stroke (HERNS). Although clinical symptoms differ in the pathomechanisms of those three diseases, genetic mutations are the same (48). The TREX1 gene codes for 3′ > 5′ DNA exonuclease. Mutations are present in C-terminus of TREX1 gene and cause frame shift. Gene product retains exonuclease activity but loses normal perinuclear localization (48). 123.4.5.1 Clinical Presentation.  RVCL ranges from 30 to 50 years of age, and death occurs within 5–10 years from the symptoms onset (49). Features commonly noted in patients with RVCL include neurological and ophthalmological manifestations. Other organs may also be involved and appear as renal impairment, proteinuria, hematuria, micronodular cirrhosis, gastrointestinal bleeding, anemia, and Reynaud’s phenomenon. 123.4.5.1.1 Neurological Manifestations.  A neurological manifestation encompasses clinical, radiological, and pathological changes. Strokes are usually localized in deep white matter and often resemble tumors due to irregular shape, mass effect, and edema. Other manifestations include seizures, migraine-like headaches, motor/sensory/cereberral deficits, and psychiatric disturbances (50). Localized necrotic changes in the walls of the vessels may resemble obliterative vasculopathy. 123.4.5.1.2 Ophthalmological Manifestations.  Progressive visual loss is the main feature of RVCL. Predominantly changes occur around macula. Loss of vision is secondary to retinopathy, microaneurysms with telangiectasia, and capillary dropout.

123.4.5.2 Diagnosis.  Genetic screening for TREX1 mutation will be positive and negative for mutations in NOTCH3 and HTRA1 genes. 123.4.5.3 Treatment.  There is no specific treatment for RVCL.

123.4.6 Large-artery disease 123.4.6.1 EDS IV – Ehlers–Danlos Syndrome Type IV (COL3A1).  Ehlers–Danlos Syndrome type IV (EDS IV)—OMIM#130050 (http://omim.org/entry/130050; Accessed June 20, 2011)—is an autosomal dominant disease. EDS IV is the vascular type, one of the six types of Ehlers–Danlos Syndrome (51). Disease is caused by mutation in type III collagen (COL3A1) gene on chromosome 2q31 (52). Mutations in COL3A1 are responsible for the structural defects in the protein pro α 1(III) chain of collagen type III. Presence of at least two major symptoms is indicative of the diagnosis; however, laboratory tests are needed. Four major diagnostic criteria include 1) thin and translucent skin, 2) fragility or rupture of arteries, uterine or intestines, 3) extensive bruising, and 4) characteristic facial appearance (51). 123.4.6.1.1 Clinical Presentation.  Major clinical manifestations are seen in most patients by the age of 40 years, and median life span reaches 48 years (52). Vascular type is characterized by the highest mortality among other EDS types, high pregnant-related complications, fragile vessel prone to rupture joint hypermobility dermatological manifestations, and gastrointestinal complications. Dermatological manifestations are usually the earliest in EDS IV. Vascular complications are leading causes of death with cerebrovascular events represented by stroke in young age, carotid–cavernous fistula, dissection of extracranial and intracranial segments of the vertebral and carotid arteries and aneurysms (53). In EDS IV, due to high complication rate, arteriography is not recommended (53). 123.4.6.1.2 Diagnosis.  In addition to the presence of at least two major diagnostic criteria, abnormal structure of COL3A1 protein or identification of COL3A1 gene mutations is required to confirm the diagnosis (52). 123.4.6.1.3 Treatment.  In EDS IV, there is no specific treatment, and medical interventions are limited to symptomatic treatment.

123.4.7 PXE – Pseudoxanthoma Elasticum (ABCC6) Pseudoxanthoma elasticum (PXE)—OMIM #264800 (http://omim.org/entry/264800; Accessed June 20, 2011)— is an autosomal recessive disease affecting connective tissue. Disease is an effect of the mutation in ABCC6 gene on chromosome 16p13.11. Polymorphisms in xylosyltransferase genes XYLT1 and XYLT2 may modify severity of PXE. The prevalence is estimated to be about one in

CHAPTER 123  Genetics of Stroke 25,000 to 100,000, with high variability both in the age of onset and in the severity of organ involvement. The disease primarily affects the skin, retina, and cardiovascular system. PXE is characterized pathologically by high elastic fiber mineralization (elastorrhexia), resulting in increased rate of elastin synthesis and degradation (54). 123.4.7.1 Clinical Presentation.  The skin is the first affected organ. Yellow papules of 1 to 5 mm are the primary skin lesions. They are typically located on the neck and in flexural surfaces. Mucosal, genital, and navel area lesions are found less frequently. The eye contains thin layer of elastic tissue called Bruch’s membrane, located between the retinal pigment epithelium and the choriocapillaris. Elastic fiber alterations result in angioid streaks, characteristic for PXE. Other ocular manifestations—less specific for PXE— include appearance of ‘peau d’orange, drusen, and cometlike streaks. Cardiovascular system complications occur due to the changes in elastic fiber-rich arterial wall. Slowly progressing segmental arterial narrowing affects small- and medium-size arteries. Cardiovascular manifestations of PXE may be further divided in to the occlusive arterial disease and mucosal bleeding. Most commonly observed are coronary artery disease, arterial hypertension, restrictive cardiomyopathy, sudden cardiac failure, and gastrointestinal hemorrhages (55). Neurological complications in PXE are mainly expressed by increased incidence of ischemic strokes due to smallvessel disease (56). ICH has also been reported in few PXE patients (57). However, IA has not been found in any of 100 PXE patients studied by Berg and colleagues (56). 123.4.7.2 Diagnosis and Treatment.  Presence of angioid streaks in eye examination and dermal elastorrhexia (with or without clinically visible skin changes) represent the minimum criteria to diagnose PXE. Occurrence of ABCC6 gene mutation in one of the 31 exons confirms the diagnosis (55). There is no specific treatment; however, antiplatelet drugs, high blood pressure, and contact sports should be avoided. Symptomatic treatments include retinal laser treatment and photodynamic therapy and valvular surgery in selected cases (57).

123.4.8 Small-Vessel Disease and Large-Artery Disease 123.4.8.1 FD – Fabry Disease (GLA).  Fabry Disease (FB)—OMIM# 301500 (http://omim.org/entry/301500; Accessed June 20, 2011)—is an X-linked congenital dysfunction of glycosphingolipid (GSL) catabolism subsequent to deficient or absent activity of the lysosomal enzyme alpha-galactosidase A (α-gal A) coded by gene GLA located on chromosome Xq22.1. α-gal A activity in FD patients is usually lower than 1%, whereas the symptoms of enzyme deficiency are present below the level of 5–10% (58). Defects in α-gal A impair its ability to

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degrade membrane GSL, especially globotriaosylceramide (Gb3), which accumulates in various tissues throughout the body (59). Gb3 is found in all parts of blood vessel wall, in Schwann cells, dorsal root ganglia and in CNS neurons, leading to organ dysfunction (60). Polymorpisms in genes, coding for interleukin-6, endothelial nitric oxide synthase, factor V and protein Z, affect the phenotypic expression of single-gene disorder in FD probably due to protein interactions (60). The incidence of FB is estimated at one in 55000 male births (58); however, results from a newborn screening study by Spada at al. estimate higher rate of FD incidence falling between one in 3,100 and one in 4,600 individuals (61). Some patients with residual α-gal A activity develop a variant of the disease in which they develop only cardiac disease, specifically left ventricular hypertrophy, with or without renal failure, in the sixth decade of life (62). Although FB is an X-linked disease, it also affects females. Some woman may develop significant lifethreatening conditions, requiring medical treatment and intervention (63). 123.4.8.2 Clinical Presentation.  Major clinical manifestations develop from childhood until third decade in most cases. Median life span is decreased by 15–20 years (58). Clinical onset is characterized by painful burning sensations in the hands and feet (acroparesthesias), typical skin lesions (angiokeratomas), hypohidrosis, and corneal opacities. Further stages of the disease lead to the renal failure and vascular disease of the heart and the brain, with premature death in the fourth and fifth decades of life. Late-onset variants start from the sixth decade, and patients develop renal and/or cardiac disease without other neurologic symptoms. Based on results from Fabry Outcome Survey (64), neurologic symptoms were the most frequent, affecting 75% of males and 61% of females. Renal failure was present in 19% of males and 3% of females. Cardiac manifestations were recorded in 60% of males and in 50% of females. Cerebrovascular events occurred in 25% of males and 21% of females, and stroke was present in 5% of females and in 9% of males. 123.4.8.2.1 Pain and Skin Lesions.  Neuropathic burning pain (acroparesthesia) usually involves hands and feet. It may be transient or may persist for several hours. The acroparesthesia is typically resistant to treatment with conventional analgesics and may require narcotic analgesics, phenytoin, amitriptyline, or gabapentin or combinations of these drugs (65). The pain is supposed to be caused by lysosomal accumulation of GSL in peripheral nerves, dorsal root ganglia, and the spinal cord and atrophy of the small, unmyelinated nerves involved in pain and temperature sensation (58). FD is characteristic of angiokeratomas—vascular lesions characterized by thin-walled vessels beneath a hyperkeratotic epidermis. Skin lesions are usually located in periumblical, scrotum, and penis areas (58) Figure 123-2.

CHAPTER 123  Genetics of Stroke

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(a)

(b)

FIGURE 123-2  Umblical (a) and thigh (b) angiokeratomas— vascular leasions characteristic for Fabry Disease. Image courtesy of M. Podolec-Rubis, MD and K. Podolec, MD (Department of Dermatology UJ Medical College).

123.4.8.2.2 Impaired Renal Function and Cardiac Changes.  Renal failure occurs in midadulthood; the first indication is often isosthenuria, followed by proteinuria and gradual decline in glomerular filtration rate over time, leading to end-stage renal failure (66). Cardiac complications of FD may include cardiac arrhythmias and conduction defects developed in the first two decades of life—progressive left ventricular hypertrophy, aggravated by arterial hypertension, which is followed by progressive impairment of diastolic filling that leads to decreased cardiac output and early death (58). 123.4.8.2.3 Neurological Changes.  Population studies estimate that FD is responsible for 1.2% of cryptogenic strokes in patients younger than 55 years, and women are more likely to be affected than men (27% vs 12%) (67). Stroke may result from either cardiac or vascular factors and may cause both large- and small-vessel diseases. The large vessels dilate, resulting in dolichoectatic changes characteristic for FD. Subsequent flow stagnation increases the risk of artery-toartery embolism and vessel thrombosis. These changes are found more frequently in the posterior circulation

(60). Stenosis in small arterial vessels is caused by gradual accumulation of GSL in endothelial and vascular smooth muscle cells (67). 123.4.8.3 Diagnosis.  FD may be diagnosed based on the direct measurement of α-gal activity in leukocytes or plasma in all except heterozygotic patients. In those subjects, gene sequencing and genetic linkage studies may be necessary (60). 123.4.8.4 Treatment.  Treatment with α–gal enzyme replacement therapy (ERT), approved by the US Food and Drug Administration in 2003, results in the reduction in the amount of vascular endothelial GSL deposits. ERT decreased the progression and severity of the changes observed in kidney, heart, skin, and liver. Unfortunately, ERT treatment did not change the incidence of stroke and other vasculopathic manifestations of the disease (67). Therefore, the use of antiplatelet and antihypertensive treatment is necessary to prevent secondary and primary strokes (60). 123.4.8.5 Homocystinuria (CBS).  Homocystinuria indicates an increased urinary excretion of the oxidized form of homocysteine, homocystine. Classic homocystinuria­—OMIM#236200 (http://omim.org/ entry/236200; Accessed June 20, 2011)—is an autosomal recessive metabolic disorder caused by mutation in the gene encoding cystathionine beta-synthase (CBS) located on chromosome 21q22.3. The CBS gene has been both cloned and sequenced, revealing more than 140 mutations (68). Homocystinuria is characterized by elevated levels of plasma. Usually, plasma homocysteine concentrations rises above 100 mmol/l, which is around 10-fold higher than normal (69). Homocysteine level elevation with a normal methionine level may be caused by metabolic errors that affect the conversion of homocysteine to methionine, such as methylene tetrahydrofolate reductase deficiency and disorders of cobalamin (vitamin B12) metabolism. The mechanism by which elevated homocysteine concentrations result in clinical manifestations remains unclear, although it has been shown to directly damage endothelium and promote smooth muscle cell proliferation (69). The incidence of homocystinuria differs across countries and is estimated from 1:58,000 to 1:1,000,000, with overall rate of 1:344,000 (68). Clinically, two equally prevalent phenotypes have been described: a milder pyridoxal phosphate (vitamin B6), responsive form, and a more severe pyridoxal phosphate, nonresponsive form. 123.4.8.6 Clinical Presentation.  The most common type homocystinuria type I is characterized by intellectual disability, lens dislocation, skeletal abnormalities, and thrombotic vascular disease due to a deficiency of the enzyme cystathionine synthase. Homocystinuria may also be due to defects in methyl cobalamin formation, which are specific for homocystinuria type II characterized by the triad of megaloblastic anemia, homocystinuria, and hypomethioninemia. Homocystinuria type III is a result of the deficiency of the enzyme methyltetrahydrofolate

CHAPTER 123  Genetics of Stroke reductase. Type III is characterized by homocystinuria and homocystinemia with low- or normal-blood methionine levels (70). Homocysteinuria can cause stroke through atherosclerosis, thromboembolism, small-vessel disease, and arterial dissection. Cerebrovascular events represent around 30% of thromboembolic complications (71). 123.4.8.7 Diagnosis and Treatment.  The diagnosis of homocystinuria is based on clinical symptoms and laboratory studies. Plasma tests usually reveal hyperhomocysteinemia, hypermethioninemia, and hypocysteinemia, and the urinary excretion of methionine, homocysteine, and its oxidized form (homocystine) is elevated. Cultured fibroblasts, amniotic fluid, and chorionic villi cells are used to evaluate the activity of cystathionine synthase activity (72). Treatment in hypocysteinemia is aimed at lowering the plasma level of homocysteine—possibly to the normal values. Patients must adhere to a methionine-restricted diet. Roughly 50% of them respond to pyridoxine (vitamin B6). In addition, folate, betaine, and vitamin B12 are used to promote metabolism of homocysteine to methionine (72). Dietary supplementation with folic acid lowers plasma homocysteine concentrations by about 25%. Additional B-vitamin lowers homocysteine by about 10 to 15% (73).

123.4.9 Cardioembolic Stroke 123.4.9.1 MS – Marfan Syndrome (FBN1).  Marfan Syndrome (MS)—OMIM#154700 (http://omim.org/ entry/154700; Accessed June 20, 2011)—first described by Antoine-Bernard Marfan in 1986 is an autosomal dominant disorder of connective tissue caused by heterozygous mutation in fibrilin-1 gene (FBN1) located on chromosome 15q21.1. Main manifestations of MS involve cardiovascular system, eyes, skeleton, pulmonary system, skin, and dural sac. Family history is not conclusive in 27% of cases due to sporadic de novo FBN1 gene mutations (74). Both hereditary and new mutations in FBN1 gene lead to abnormal protein folding and enhanced proteolytic degradation. Mutant protein boosts matrix metalloproteinase (MMP) 2 and 9 activity and interferes with TGF β (TGFβ) pathway. Recent evidences show that both abnormal TGFβ pathway and mutations in TGFBR1 and TGFBR2 genes may lead to Marfan-like phenotypes including Marfan syndrome II and Loeys– Dietz aortic aneurysm syndrome. 123.4.9.2 Clinical Presentation. 123.4.9.2.1 General Complications.  Clinical characteristics of MS include tall stature, arm span higher than patient’s height, reduced upper-to-lower body segment ratio, pectus carinatum or excavatum, ectopia lentis, scoliosis, mitral valve prolapse, aortic root dilatation, and aortic dissection (74). 123.4.9.2.2 Neurological Complications.  In the largest retrospective study of MS patients by Wityk et al.

9

(75), neurovascular complications were found in 3.5% of patients. TIA was the most common complication, and cardiac source of embolism was found in 77% of all ischemic events. Neither cerebral artery dissection nor intracranial aneurysms (IA) were found in any of the studied patients. Another two studies by Conway and colleagues—firstly, found no statistical difference in the prevalence of IA between MS patients and general population (76); secondly, found no MS patients among 710 neurosurgical patients treated for IA (77). 123.4.9.3 Diagnosis.  One of 500 so far discovered mutations in FBN1 gene spanning 235 kb may occur in any of 65 exons, making the genetic testing costly and time consuming (78). Therefore, according to revised Ghent criteria, diagnosis is established primarily on clinical characteristics and family history (79). Personal or familial history of thoracic aortic aneurysm in tall, thin patients optionally with scoliosis, arachondactyly should always be suspected of MS.

123.4.10 Familial Cardiomyopathies and Familial Arrhythmias Cardioembolic stroke and TIA are common complications of all types of cardiomyopathy, with AF being the main cause. Cardiomyopathies are classified according to their morphological characteristics as hypertrophic (HCM), dilated (DCM), arrhythmogenic right ventricular (ARVC), and restrictive cardiomyopathy (RCM). A genetic cause has been shown in significant number of patients: HCM (50%), DCM (35%), and ARVC (30%) (80). Cardiac dysrhythmias may be divided to supraventricular and ventricular. Dysrhythmias has been linked to number of genes and chromosomal loci. AF has been extensively studied and was mapped to four genes and nine chromosomal loci (81). In a largest study on 900 patients with hypertrophic cardiomyopathy by Maron at al. (82), 57 (6%) experienced thromboembolic event. Six of them were due to hemorrhagic stroke or brain tumor; Ischemic stroke occurred in 44 patients; 70% out of the remaining 51 with nonhemorrhagic thromboembolic event. Cardioembolic etiology of ischemic stroke was definite in eight cases and probable in 31, all of them had AF.

123.4.11 Other causes 123.4.11.1 MELAS – Mitochondrial Encephalo­ myopathy, Lactic Acidosis, and Stroke (A3243G).  MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes syndrome)— OMIM# 540000 (http://omim.org/entry/540000; Accessed June 20, 2011)—can be caused by mutation in several mitochondrial genes, including MTTL1, MTTQ, MTTH, MTTK, MTTC, MTTS1, MTND1, MTND5, MTND6, and MTTS2. Mitochondrial (mt) DNA is inherited exclusively from the mother (maternally

10

CHAPTER 123  Genetics of Stroke

inheritance). The most common mtDNA mutation—Ato-G transition at nucleotide 3243—is present in 80% of MELAS patients (67). A3243G mutation is in the tRNA—leucine (UUR) gene, associated with respiratory chain complex I deficiency (67). The prevalence of the A3243G mutation varies across different population—it is estimated to be 7.59 per 100 000 persons in North East England, 16.3 per 100 000 in Northern Finland, and 236 per 100 000 in Australia (83). Although the etiology of MELAS is not completely understood, there is likely a role for mitochondrial angiopathy, vascular dysfunction, and hyperemia, as well as mitochondrial-mediated cytopathic mechanisms, resulting in energy failure. Neuronal hyperexcitability may also play a role (84). 123.4.11.1.1 Clinical Presentation.  Normal early development, followed by stroke-like episodes (before the age of 40 years), mitochondrial encephalomyopathy, and lactic acidosis, is typical for MELAS. Other clinical manifestations of MELAS may include exercise intolerance, short stature, central and peripheral nervous system involvement, hearing loss, and eye, heart, and gastrointestinal complications with accompanying DM (67). CNS manifestations include stroke-like episodes, seizures, encephalopathy or dementia, headache, and elevated level of proteins in cerebrospinal fluid. Peripheral nervous system manifestations are represented by myopathy and peripheral neuropathy. The etiology of stroke-like lesions is not yet understood. The lesions have predilection to the posterior areas of the brain and may not follow arterial territory distribution (67). 123.4.11.1.2 Diagnosis and Treatment.  Due to unequal load of mutated mtDNA, its content varies across different tissues, and genetic tests are not always conclusive. Sue at al. compared the detection rates for A3243G point mutation in muscle, blood, and hair follicles and found that in 50% mutation was absent in blood (85). Therefore, clinical symptoms, a key factor in the MELAS diagnosis, supported by laboratory tests, confirmed by biopsy and genetic studies are all essential in the diagnostic workup. Patients usually have increased lactate and pyruvate levels in serum and cerebrospinal fluid, and elevated lactate to pyruvate ratio. Muscle biopsy reveals typical ragged-red fibers (86). Recently Janssen et  al. presented a new method to diagnose MELAS—the mitochondrial energy-generating system (MEGS). MEGS as an indicator for the overall mitochondrial function related to energy production showed a great capacity for detection of subtle mitochondrial dysfunction (83). This method may be very useful in diagnosing patients with rare or new mitochondrial DNA mutations, and with low mutation loads. Several treatment approaches have been tested to treat MELAS patients so far. Coenzyme Q10 and its synthetic analog Idebenone have been used to improve electron transfer in the mitochondrial respiratory chain. Their role in MELAS remains to be proven (67). Clinical

trial with another agent, dichloroacetate, was terminated earlier owing to frequent peripheral nerve toxicity (87). Finally, treatment with L-arginine (L-arg) shortly after the onset of stroke-like episodes improved patient’s outcome and normalized the concentration of lactate and pyruvate (88).

123.4.12 NF 1 – Neurofibromatosis type I(NF-1) Neurofibromatosis type I (NF1)—OMIM# 162200 (http://omim.org/entry/162200; Accessed June 20, 2011)—also known as von Recklinghausen disease is an autosomal dominant disorder caused by mutation in the neurofibromin gene (NF1) on chromosome 17q11.2. New mutations are very common, since 50% of patients are the first to be affected in the family (89). The NF1 gene codes for neurofibromin, a protein that is highly expressed in the nervous system. It functions as a tumor suppressor, and therefore, its loss leads to development of benign and malignant tumors (89). NF1 is approximately one per 2500 to 3000 individuals (90). NF1 decreases mean and median ages at death from 70.1 and 74 years to 54.4 and 59 years, respectively (91). 123.4.12.1 Clinical Presentation.  Clinical features of NF1 encompasses cafe-au-lait spots, intertriginous freckling, and Lisch nodules, cutaneous, subcutaneous, and plexiform neurofibromas, macrocephaly, optic glioma, and other neoplasms (92). Based on the most common clinical features, the National Institutes of Health Consensus Development Conference formulated the diagnostic criteria for NF1 (93) (Table 123-2). Reports on the incidence of neurological complication vary among authors, from 2.5% according to Roser at al. (94) to 20% and 26%, respectively; according to Griffiths et al. (95) and Hsieh et al. (96) Epilepsy (8.7%) and cerebral infarction (7.2%) are the most common neurological complications (96).

123.4.13 Ischemic and Hemorrhagic Stroke 123.4.13.1 SCD – Sickle-Cell Disease (HBB).  Sicklecell disease (SCD) refers to all the different genotypes that cause the characteristic clinical syndrome, whereas TABLE 123-2     NF1 Diagnostic Criteria (93) At least two of the following criteria are required to diagnose NF1 Six or more cafe´-au-lait macules (>0.5 cm in children or >1.5 cm in adults) Axillary or inguinal regions freckling At least 2 neurofibromas of any type or one plexiform fibroma Optic pathway glioma Two or more Lisch nodules (iris hamartomas) Osseous dysplasia A first-degree relative with NF1 diagnosed by these criteria

CHAPTER 123  Genetics of Stroke sickle-cell anemia—OMIM# 603903 (http://omim.org/ entry/6039030; Accessed June 20, 2011)—represents the most common form of SCD, which is the result of the mutation in beta globin (HBB) gene located on chromosome 11p15.4. The most common type of sicklecell disease is the homozygosity for the βS allele (HbS), and the remaining types include hemoglobin SC disease (HbSC disease) with coinheritance of the βS and βC alleles and HbS/β-thalassemia due to coinheritance of βS with a β-thalassemia allele (97). HbS is caused by a T>A mutation in the β-globin gene in which the 17th codon is changed from thymine to adenine and the sixth amino acid in the β-globin chain becomes valine instead of glutamic acid (98). Mutant protein causes β globin chains to crystalize, resulting in a sickled appearance. Changes disrupt erythrocyte architecture and flexibility and promote cellular dehydration with physical and oxidative cellular stress (98). The disease severity is determinant by the rate and extent of HbS polymerization. Several mechanisms are involved in the pathophysiology of the SCD: vaso-occlusion with ischemia-reperfusion injury and hemolytic anemia causing hemoglobin and arginase-1 release into the circulation. Often triggered by inflammation, vaso-occlusion is caused by entrapment of erythrocytes and leucocytes in the microcirculation, causing vascular obstruction and tissue ischemia. Subsequent reperfusion of blood flow further promotes tissue injury (99). Hemolysis, also driven by HbS polymerization, causes anemia, fatigue, cholelithiasis, and, what was recently noticed, a progressive vasculopathy (97). Hemoglobin released from hemolyzed erythrocytes generates reactive oxygen species (ROS), such as the hydroxyl and superoxide radical. ROS are a potent scavenger of nitric oxide that disrupts endothelial cell function and induces the nitric oxide resistance (100), whereas free plasma arginase-1 transforms arginine—a nitric oxide substrate—into ornithine, decreasing bioavailability of nitric oxide in SCD patients (101). In the largest autopsy study, Manici et  al. (102) reviewed the cause of death in 306 SCD patients. The most common cause of death for all sickle variants and for all age groups was infection (33 to 48%) due to Streptococcus pneumoniae or Haemophilus influenza. Other causes of death included stroke (9.8%), complications of therapy (7%), splenic sequestration (6.6%), pulmonary emboli/thrombi (4.9%), renal failure (4.1%), pulmonary hypertension (2.9%), hepatic failure (0.8%), massive hemolysis/red cell aplasia (0.4%), and left ventricular failure (0.4%). In 40.8% of them, death was sudden and unexpected; in 28.4% occurred within 24 hours after presentation; and in 63.3% was associated with acute events (102). 123.4.13.1.1 Clinical Presentation.  Sickle-cell disease phenotype is very complex, ranging from early childhood mortality to virtually no-symptom condition. Clinical features are a consequence of vaso-occlusion, hemolysis anemia, or infection.

11

Complications due to vaso-occlusion are complex and include painful episodes, stroke, acute chest pain, priapism, liver disease, splenic sequestration, spontaneous abortion, leg ulcers, osteonecrosis, and proliferative retinopathies renal insufficiency. Complications of hemolysis include anemia, cholelithiasis, and acute aplastic episodes. Infections are caused by Streptococcus pneumoniae in children and Eserichia coli in adults, causing sepsis, and both Salmonella and Staphylococcus aureus causing osteomyelitis (103). Sickle-cell anemia is the most common cause of stroke in children. 11% of sickle-cell anemia patients suffer from stroke by 20 years and 24% by 45 years of age (104). Adams et al. (105) found a higher than previously expected (11 to 24% versus 6 to 8%) incidence of cerebral vascular events in the first 2 weeks of life of SCD patients. This finding reflects a large number of silent strokes. Ischemic stroke (54%) is the most common type of cerebrovascular accident, followed by hemorrhagic stroke (34%) and TIA (11%). The greatest risk of ischemic stroke is in the first two decades of life, whereas hemorrhagic stroke falls in the third decade (100). 123.4.13.1.2 Diagnosis and Treatment.  All newborns are screened for sickle-cell disease in the US. Diagnosis is based on hemoglobin high-performance liquid chromatography (HPLC), electrophoresis, or isoelectric focusing. Transcranial Doppler ultrasound is a useful tool to screen for significantly narrowed vessels in highrisk children and adults. Genetic counseling requires genetic tests for globin gene mutations (106). Prenatal and antenatal tests are also available (103). Hydroxycarbamide is a cytotoxic drug that increases the fetal hemoglobin (HbF) concentration, which inhibits HbS polymerization. Treatment decreases the frequency of painful episodes, acute chest syndrome, demand for blood transfusion, and admission of SCD patients to hospital. It may also protect against cerebrovascular events and decrease hypoxemia and proteinuria (97). Blood transfusion with ion chelators in case of chronically transfused patients with sickle-cell disease has an established role in SCD treatment. Repeated transfusions improve oxygen saturation and reduce red blood cell sickling (69). Introduced 30 years ago, bone marrow transplantation is the only potential cure for sickle-cell anemia; however, due to safety concerns, it is limited to HLA-compatible siblings (97).

123.4.14 MMD – Moyamoya Disease Moyamoya disease (MMD) is an uncommon cerebrovascular disorder predominantly affecting East Asians. The disease was named after characteristic cerebral angiographic picture “moyamoya” what in Japanese means “something hazy like a puff of cigarette smoke, drifting in the air.” The pathogenesis of the disease remains to be discovered. Data from epidemiological studies indicate that infection in the head and neck might be implicated

12

CHAPTER 123  Genetics of Stroke

TA B L E 1 2 3 - 3    Genetic Types of MMD (http://omim.org/entry/252350; Accessed June 20, 2011) Phenotype

Location

Phenotype MIM Number

Gene/Locus

Gene/Locus MIM Number

Moyamoya disease 1–MYMY1 Moyamoya disease 2–MYMY2 Moyamoya disease 3–MYMY3 Moyamoya disease 4–MYMY4 Moyamoya disease 5–MYMY5

3p26-p24.2 17q25.3 8q23 Xq28 10q23.31

252350 607151 Unknown 300845 614042

Unknown RNF213 Unknown Unknown ACTA2

Unknown 613768 Unknown Unknown 102620

in the development of MMD (107). Genetic factors also play an important role in MMD. Associations with loci on chromosomes 3, 8, 10, 17, and X have been described (Table 123-3). MMD inheritance pattern is polygenic or autosomal dominant with a low penetrance (108). The incidence of MMD is highest in countries in East Asia; however, it is also present throughout the world in people of many ethnic groups. MMD onset peaks in two age groups: children who are approximately 5 years of age and adults in their mid-40s (109). There are nearly twice as many female patients as male patients (110). MMD affects—usually bilaterally—terminal portions of the internal carotid vessels as well as cerebral vessels originating from the circle of Willis. In addition to the steno-occlusion, affected arteries show fibrocellular thickening of the intima, an irregular folding of the internal elastic lamina, and reduction of the media. The perforating arteries in subcortical areas are either dilated (in children) or stenotic with thick walls (in adults). These changes predispose to microaneurysmal formation and subsequent intracerebral and intraventricular hemorrhage (111). 123.4.14.1 Clinical Presentation.  Symptoms may be divided in two main etiological categories: related to ischemia and related to hemorrhage. Ischemic symptoms are more common in children and comprise ischemic stroke and TIA. Ischemia may cause hemiparesis, dysarthria, aphasia, and cognitive impairment. Seizures, visual deficits, syncope, or personality changes are less common in ischemic etiology. Hemorrhage is common in adults (50%); however, it was also noted in children (112). It may be located in intraventricular, intraparenchymal, or subarachnoid space. Hemorrhage is either due to rupture of dilated, fragile affected vessels, or rupture of saccular aneurysms in the circle of Willis (107). Rare symptom include seizures, migraine-like headache, choreiform movements due to basal ganglia involvement and occasionally present ophthalmologic findings like “morning glory disk” (110). 123.4.14.2 Diagnosis and Treatment.  Diagnosis of patients suspected of MMD is based on imaging studies. Research committee on Spontaneous Occlusions of the Circle of Willis of the Ministry of Health and Welfare of Japan published revised diagnostic criteria (Table 123-4). Additional useful diagnostic tests include electroencephalography (EEG) and cerebral blood-flow studies.

So far, there is no treatment that reverses the primary disease process; however, symptomatic treatment focused on improvement of cerebral blood flow reduces the frequency of MMD symptoms (107). Medical ­therapy— antiplatelet and less frequently anticoagulant—is used mainly in children due to very low percentage of hemorrhagic strokes, whereas surgical treatment is used both in young and adult patients. Since the external carotid artery is spared in MMD, direct, indirect, and combined surgical bypass operations are performed to improve the cerebral blood flow (110).

123.4.15 Collagen Type IV (COL4A1 Gene and COL4A2 Gene) The collagen IV molecule is a heterotrimer composed of two alpha-1 chains and one alpha-2 chain. COL4A1 OMIM# 120130 and COL4A2 OMIM# 120090 genes are coding for alpha-1 chain and alpha-2 chain of type IV collagen respectively. They are associated together structurally and functionally with each other (http://omim. org; Accessed June 20, 2011). Both genes are located on chromosome 13q34 and are universally expressed in basement membranes during early stages of development (113). A number of mutations have been described for COL4A1 gene (114) and recently also for COL4A2 gene (115,116). In addition to porencephaly, infantile hemiplegia and hemorrhagic stroke COL4A1 gene mutations induce cerebral small-vessel disease (117). Hemorrhagic strokes are usually associated with physical activity, trauma and anticoagulant therapy, whereas SVD was expressed as leukoaraiosis (63.5%), microbleeds (52.9%), lacunar infarction (13.5%), and dilated perivascular spaces (19.2%) (118). Based on results by Janne et  al. (115), mutations in COL4A2 gene contribute to sporadic cases of ICH, due to intracellular accumulation of gene product.

123.4.16 Hemorrhagic Stroke 123.4.16.1 CCM 1 to 3-Cerebral Cavernous Malfor­mations (KRIT1, Malcavernin, PDCD10).  Cerebral cavernous malformations (CCM) are relatively common lesions occurring incidentally or in autosomal dominant fashion. The autosomal dominantly inherited type is caused by mutations in one of at least three

CHAPTER 123  Genetics of Stroke

13

TA B L E 1 2 3 - 4    Diagnostic Criteria for MMD (107,112) 1. Cerebral angiography findings: a. Stenosis or occlusion at the terminal portion of the ICA and/or at the proximal portion of the ACAs and/or the MCAs. b. Abnormal vascular networks in the vicinity of the occlusive or stenotic lesions in the arterial phase. c. “a” and “b” are present bilaterally. 2. MRI and MRA findings: a. MRA showing stenosis or occlusion at the terminal portion of the ICA and at the proximal portion of the ACAs and MCAs. b. MRA showing an abnormal vascular network in the basal ganglia. Abnormal vascular network can also be diagnosed when more than 2 apparent flow voids are observed in one side of the basal ganglia on MRI. c. (1) and (2) are observed bilaterally. 3. Elimination of the following conditions: arteriosclerosis, autoimmune disease, meningitis, brain neoplasm, Down syndrome, Recklinghausen disease, head trauma, irradiation to the head and other conditions (sickle-cell disease, tuberous sclerosis). 4. Pathological findings: a. Intimal thickening with resulting stenosis or occlusion of the lumen usually observed on both sides, both in and around the terminal portion of the ICA. Lipid deposits are infrequently noted in the proliferating intima. b. Stenosis of various degrees or occlusion associated with fibrocellular thickening of the intima, a waving of the internal elastic lamina, and an attenuation of the media is characteristic for ACAs, MCAs, and posterior communicating arteries, constituting the circle of Willis. c. Perforators and anastomotic branches forming small vascular channels are frequently observed around the circle of Willis. d. Presence of reticular conglomerates of small vessels is common in the pia mater. Autopsy cases without cerebral angiography should refer to 4. 1. Definite case: adults, either 1 and 3 or 2 and 3; children, either 1-a and 1-b or 2-a and 2-b with sever stenosis at the terminal portion of the ICA on the opposite side. 2. Probable case: fulfills 3 and either 1-a and 1-b or 2-a and 2-b. ICA- internal carotid artery, ACA- anterior cerebral artery, MCA- middle cerebral artery, MRI- magnetic resonance imaging, MRA- magnetic resonance ­angiography.

TA B L E 1 2 3 - 5    Genetic Types of CCM (http://omim.org/entry/116860; Accessed June 20, 2011) Phenotype

Location

Phenotype MIM Number

Gene/Locus

Gene/Locus MIM Number

CCM-1; Cerebral cavernous malformations-1 CCM-2; Cerebral cavernous malformations-2 CCM-3; Cerebral cavernous malformations-3

7q21.2

116860

CCM1

604214

7p13

603284

C7orf22

607929

3q26.1

603285

PDCD10

609118

genes CCM-1, CCM-2 and CCM-3 (Table 123-5). The prevalence of CCM has been estimated from 0.17 to 0.55 per 100000 in general population (119). CCMs are slow-flow, sinusoid blood vessels, lacking smooth muscle cells and elastic lamina. They are lined with endothelial cells that do not have tight junctions, which make them prone to intracranial hemorrhage (120). Blood at various stages of thrombosis usually fills CCM vessels forming mulberry-like shapes. Even in the absence of obvious hemorrhage, all lesions are surrounded by the deposits of hemosiderin (119). More than half of CCMs are familial (121). Multilocus linkage analysis revealed that CCM1 is present in 40%, CCM2 in 20%, and CCM3 in 40% of inherited cases. CCM genes products, respectively CCM1/Krit1, CCM2/macaverinin, and CCM3/PDCD10, are specifically expressed in endothelium, neurons, and astrocytes (121). Based on immunohistochemical staining, Pagenstechaer and colleagues showed loss of expression of

CCM-coded proteins, limited only to endothelial cell within cavernous malformation. Additionally, their results demonstrated endothelial cell mosaicism within cavernous tissue (122). 123.4.16.1.1 Clinical Presentation.  If not symptomatic (47% of cases), CCM presents typically with epileptic seizures (25%), intracranial hemorrhage (12%), or focal neurologic deficits including headaches (15%) (120). The hemorrhage rate in patients with CCM has been estimated to be 0.7%–4.2% (123). The five-year annual rates of hemorrhage among patients presenting with hemorrhage, with symptoms not related to hemorrhage and an incidental finding, were respectively 6.19%, 2.18%, and 0.33% (124). Risk of recurrent hemorrhage decreases over time from 19.8% in the first year to 5% in the fifth year (120). 123.4.16.1.2 Diagnosis and Treatment.  MR imaging with T2-weighted gradient-echo imaging is currently the gold standard imaging technique for detecting both

CHAPTER 123  Genetics of Stroke

14

sporadic and familial CCMs (125). Currently, surgical removal is the only treatment option in CCM. After careful patient selection, surgery significantly improves patient’s neurological condition, from 5.9 NIHSS score after the first episode to 1.7 NIHSS score after 40 months postoperative follow-up (126). Experimental results have shown that mutations in two CCM (KRIT1 and OSM) genes cause RhoA activation. Treatment aimed at blocking activated RhoA may potentially stop the ­disease (127). 123.4.16.2 HHT – Hereditary Hemorrhagic Telangiectasia (ENG, ACVRL1 and SMAD4).  Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia. Rendu, Osler, and Weber independently gave the original description of HHT in the nineteenth century, hence the eponymous Rendu–Osler– Weber syndrome. So far, based on the affected gene/ locus, five types of HTT have been described. (Table 123-6). Telangiectasias are characterized by the presence of multiple arteriovenous malformations (AVMs) of different sizes. AVMs lack intervening capillaries that result in direct connections between arteries and veins (128). They are usually found in in the skin, mucosa, and viscera. Although the prevalence of HHT is estimated from one per 5000 to one per 10, 000, it may be underdiagnosed due to variable phenotypes and diagnostic limitations (129). Each of the genes in HHT1, HHT2 and JHPT encodes a protein involved in TGF-β superfamily signaling. The genes within chromosomal regions in HHT3 and HHT4 types remain to be discovered. Endoglin (ENG)—HHT1—is expressed predominantly on endothelial cells, syncytiotrophoblasts, activated monocytes, and tissue macrophages. ENG is a coreceptor from the TGF-β family and binds TGFB1 and TGFB3 proteins (128). Activin A receptor type II-like 1 (ACVRL1)— HHT2—codes for the activin receptor-like kinase (ALK) 1, which is a type I receptor from the TGFβ super family ligands. ALK1 is expressed on endothelial, lung, and

placental cells (128). MADH4—JHPT—encodes the transcription factor Smad4. Mutations in Smad4 cause juvenile polyposis/HHT syndrome by disturbing TGF / BMP pathway (128). 123.4.16.2.1 Clinical Presentation.  Main HHT symptoms include epistaxis, telangiectasia, gastrointestinal (GI) bleeding, pulmonary AVM (PAVM), cerebral system HHT complications, and hepatic vascular abnormalities. The age of AVM development or AVM symptom onset varies and is organ-specific. AVMs in the brain are usually present at birth, whereas those in liver and in lungs develop or grow over time (128). Nasal bleeding is the major manifestation of mucous telangiectases and, in HHT, is the main reason to seek medical attention. On average, epistaxis starts at the age of 12 years but may range from infancy to adulthood. It affects more than 95% of patients (130). Telangiectases of the face, oral cavity, or hands develop as often as epistaxis, but later in life. Onethird of affected patients develop telangiectases before the age of 20 years, with remaining two-thirds developing symptoms before the age of 40 years (131). The color of the telangiectases may range from pink to red, and the size may vary from pinhead-size lesions to larger, sometimes raised purple lesions. Telangiectases may be distinguished from petechiae and angiomata by blanching upon pressure and recurrent immediate refill (128). GI bleeding due to AVM affects 15–45% of patients with HHT and begins after the age of 50 years. If prolonged, this can lead to anemia and the need for transfusion. Telangiectases usually develop in upper GI tract; however, other localizations are also possible (128). Although 74% of HHT patients develop hepatic vascular abnormalities, only 8% are symptomatic (128). Three different types of vascular malformations may be observed in the liver: hepatic artery to hepatic veins, hepatic artery to portal veins, and portal veins to hepatic veins (130).

TA B L E 1 2 3 - 6    Genetic Types of HHT (http://omim.org/entry/187300; Accessed June 20, 2011) Phenotype

Location

Phenotype MIM Number

Gene/Locus

Gene/Locus MIM Number

Telangiectasia, hereditary ­hemorrhagic, type 1- HHT1 Telangiectasia, hereditary ­hemorrhagic, type 2- HHT2 Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome - JHPT Telangiectasia, hereditary ­hemorrhagic, type 3- HHT3 Telangiectasia, hereditary ­hemorrhagic, type 4- HHT4

9q34.11

187300

ENG

131195

12q13.13

600376

ACVRL1

601284

18q21.2

175050

MADH4

600993

5q31.3-q32

601101

7p14

610655

5:139,500,000– 149,800,000a 7:28,800,000– 43,300,000a

aThe

Genome Reference Consortium Human genome build 37 (GRCh37), from NCBI.

CHAPTER 123  Genetics of Stroke Prevalence of PAVMS ranges from 15 to 59%, depending on the method used for detection (128). Patients with ENG gene mutations seams to have higher incident of PAVMS compared with ACVRL1 mutation carriers (129). PAVMS frequently cause neurological complications. TIA, ischemic stroke or brain abscess were found in 30–40% of patients with PAVMs. Other pulmonary complications include massive hemoptysis or hemothorax and pulmonary hypertension (132). AVMs may be found in the brain and less frequently in the spine; overall, CNS vessel malformation rate ranges from 10 to 23% in HHT patients (130). Based on a retrospective study, bleeding risk is approximately 0.5% per year (130). The wide spectrum of CNS symptoms includes headaches, acute or subacute hemorrhage, back pain, acute or progressive paraparesis/tetraparesis, sciatic pain, and sphincter disturbance. 123.4.16.2.2 Diagnosis and Treatment.  The Curacao criteria (Table 123-5) have been established for the HHT in 1999 (133) and are as follows: (1) spontaneous recurrent epistaxis; (2) multiple telangiectases at characteristic sites; (3) family history; and (4) visceral lesions. If at least three criteria are present, the diagnosis is definite. Diagnosis is possible or suspected if two criteria are present, and unlikely if less than two criteria are present. Mutations in ACVRL1, ENG and MADH4 genes are found in 90% of definite HHT patients. Genetic tests are currently used to diagnose asymptomatic patients and to avoid complications (130). Epistaxis may be treated surgically with steroids and with antifibrinolytic drugs. Cutaneous and labial telangiectases may be treated with laser therapy. GI treatments have not been successful, and transplantation is the only treatment option for hepatic involvement (130). Because lung and brain AVMs may cause serious complications, they should be treated before they become symptomatic. Screening for brain AVMs should first include contrastenhanced MR imaging and, if necessary, should be evaluated with angiography. Surgery is the first brain AVM treatment option; however, due to difficult localization, this may not be possible. Therefore, in certain situation, surgery should be replaced by stereotactic radiosurgery or by embolization (130).

15

123.4.17 CAA – Cerebral Amyloid Angiopathies Cerebral amyloid angiopathy (CAA) is a process of progressive pathological deposition of amyloid proteins in arterial and arteriole walls and less frequently in veins and capillaries of the CNS. Amyloid deposits damage the vessel wall and activate matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) (134). CAA may occur as sporadic, familial, or hereditary disease. Familial and hereditary forms of CAA are described in Table 123-7. Deposited pathologic proteins are products of large-protein proteolysis. The most common form of CAA is due to Aβ deposition—product of amyloid precursor protein (APP) proteolysis. Other less common proteins include both ABri and ADan, which are products of amyloid Bri precursor protein (ABriPP) proteolysis, mutant cystatine C (Acys), mutated transthyretin (ATTR), mutated gelsolin (AGel) and disease-associated prion protein (PrP) (134). Based on Aβ form of CAA, in initial stages, cerebrovascular amyloid appears around smooth muscle of tunica media and adventitia, then gradually infiltrates, and finally replaces the smooth muscle cells (135). CAA is generally assumed to be a risk factor for ICH, ischemic stroke, and white matter lesions. Nevertheless, in sporadic cases, CAA may not suffice to explain the incidence of hemorrhage (134).

123.5 CVT – CEREBRAL VENOUS THROMBOSIS (FVL, PROTHROMBIN) Cerebral venous thrombosis (CVT) is a rare cause of stroke due to the thrombosis of the dural sinus and/or cerebral veins. CVT affects approximately 5 persons per million annually accounting for 0.5 to 1% of all strokes (19). CVT is more common (78%) in patients under 50 years of age (19). The acute phase of CVT-case fatality is around 4%, whereas overall death or dependency rate is around 15% (18). There are multiple predisposing causes of CVT (Table 123-8). All are linked to the Virchow triad of alterations in blood flow, vascular endothelial injury, or alterations in the constitution of the blood. Other causes of CVT

TA B L E 1 2 3 - 7    Familial and Hereditary forms of Cereberal Amyloid Angiopathy (http://omim.org; Accessed June 20, 2011) Location

Phenotype

21q21.3

Cerebral amyloid angiopathy, Dutch, Italian, Iowa, Flemish, Arctic variants Cerebral amyloid angiopathy, Icelandic type Dementia, familial British Dementia, familial Danish Amyloidosis, hereditary, transthyretin-related Prion protein-related cerebral amyloid ­angiopathy

20p11.21 13q14.2 13q14.2 18q12.1 20p13

Phenotype OMIM Number

Gene/Locus

Gene/Locus OMIM Number

605714

APP

104760

105150 176500 117300 105210 176640

CST3 ITM2B ITM2B TTR PRNP

604312 603904 603904 176300

16

CHAPTER 123  Genetics of Stroke

TA B L E 1 2 3 - 8    CVT Risk Factors (19) Condition

Prevalence, %

OR (95% CI; p-value)

Prothrombotic conditions Protein C deficiency Protein S deficiency Antiphospholipid and anticardiolipin antibodies Mutation G20210A of factor II Resistance to activated protein C and factor V Leiden Hyperhomocysteinemia Pregnancy and puerperium Oral contraceptives

34.1 N/A N/A 5.9 N/A

NA 11.1 (1.87 to 66.05; P=0.009) 12.5 (1.45 to 107.29; P=0.03) 8.8 (1.3 to 57.4; NA) 9.3(5.9 to 14.07) 3.4 (2.3 to 5.1) 4.6 (1.6 to 12.0; NA) NA 5.6 (4.0 to 7.9; NA)

4.5 21 54.3

N/A – not available.

can be divided into acquired and genetic risks. Main (18) acquired causes comprise antithrombin III, protein C, and protein S deficiency; antiphospholipid and anticardiolipin antibodies; hyperhomocysteinemia; pregnancy and puerperium; oral contraceptives and cancer (18). The prevalence of thrombophilic symptoms in children with CVT varies between 10 and 78% (136). Both mutations in factor V Leiden gene (R506Q) due to resistance to activated protein C and prothrombin gene mutation (G20210A) causing a slight elevation of prothrombin level are independent CVT risk factors. While on oral contraceptive treatment, odds ratio for CVT is dramatically increased for G20210A mutation to 149.3 (95% CI 31.0 to 711.0) (19).

123.5.1 Clinical Presentation The wide range of presenting symptoms may be classified into to two main categories: (1) related to increased cranial pressure due to impaired venous drainage; and (2) related to focal brain injury due to venous ischemia/infarction or hemorrhage, with a number of patients presenting both mechanisms (19). The most frequent symptoms are headache, seizures, focal neurological deficits, altered consciousness, and papilledema, (18) all of which may be present isolated or in association with other symptoms.

123.5.2 Diagnosis and Treatment Diagnosis of patients suspected of CVT is based on clinical suspicion and imaging confirmation that may be supported with selected laboratory tests. Laboratory tests include routine blood work to reveal potential prothrombotic conditions and a level of D-dimers (137). Noninvasive imaging modalities include CT, MRI, and ultrasound. CT Venography (CTV) and magnetic resonance venography (MRV) are most useful. Invasive diagnostic angiographic procedures comprise cerebral angiography and direct cerebral venography (19). Anticoagulant therapy has been successfully introduced in CVT treatment in order to prevent thrombus growth, facilitate recanalization, and to prevent DVT. Both LMWH and UFH are safe and effective, with a

possible advantage of LMWH (19). Direct intrasinus thrombolytic techniques and mechanical therapies may be considered in three cases—first, if despite the use of anticoagulation clinical deterioration is present; second, if mass effect from a venous infarction occurs; and third, if ICH that causes intracranial hypertension is resistant to standard therapies (19).

123.6 GENOME-WIDE ASSOCIATION STUDIES AND GENOMICS Advances in genetics and genomics may permit new insights. In recent genome-wide association studies, a number of single-nucleotide polymorphisms have been associated with specific stroke subtypes and major strokerisk factors such as diabetes and AF, but these have yet to be replicated. Studies of messenger RNA expression have also shown promise for the development of genomic signatures for stroke classification.

123.7 SUMMARY At present, the contribution of genetic factors to stroke etiology and risk is small, involving familial predisposition, a small number of monogenic disorders such as CADASIL—the prototype genetic disorder associated with stroke—and polymorphisms associated with cerebral venous thrombosis. Possible new associations are being explored in genome-wide association studies but no markers have yet emerged.

ACKNOWLEDGMENT Dr. Baird is supported by NIH grants R01EB010087 and R21MH097639.

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Biographies  Adamski has joined Dr Baird’s group at the State University of New York (SUNY) DownDr state Medical Center in 2008. He came from the Jagiellonian University Medical College in Cracow, Poland. Dr Adamski received his medical degree and a Master of Science degree in Molecular Biology, and Biotechnology Biology from the Jagiellonian University Medical College in Cracow, Poland. Dr Adamski’s research interests are focused on genetic and immunological aspects of stroke. He studies both clinical and translational aspects of stroke.





Dr  Baird has served as the Professor and Director of the Stroke Program at the State University of New York (SUNY) Downstate Medical Center since 2007. She came from the National Institutes of Health in Bethesda, MD, where she was chief of the Stroke Neuroscience Unit and Principal Investigator at the National Institute of Neurological Disorders and Stroke. A Fellow of the Royal Australasian College of Physicians, Dr. Baird received her medical degree from the University of Melbourne, Australia, and a Master of Public Health from Harvard. After completing a Clinical Stroke Fellowship at Beth Israel Deaconess Medical Center and Harvard University in Boston, she joined the Neurology faculty at Harvard Medical School. Dr. Baird lectures worldwide and has published widely. She has performed extensive clinical and translational research. She serves on the editorial boards of a number of medical journals. Dr. Baird is a Fellow of the American Heart Association/American Stroke Association, the Royal Australasian College of Physicians and a member of the American Academy of Neurology, the American Neurological Association, the New York State Neurological Society, and the Society for Neuroscience.