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Dr/ Ayman Al-maltDr/ Ayman Al-maltAssistant Lecturer Of NeurologyAssistant Lecturer Of Neurology

Faculty of medicineFaculty of medicine Tanta universityTanta university..

Stroke, or ‘‘brain attack,’’ is defined as a focal neurological deficit lasting for more than 24 hours with no cause other than that of vascular origin.

Ischemic stroke is responsible for about 80% of all strokes, intracerebral hemorrhage for 15% and subarachnoid hemorrhage for 5%.

A transient ischemic attack (TIA) has the same complex symptoms as stroke, but with a resolution of these symptoms within 24 hours .

INTRODUCTION

Since introduction of thrombolytic therapy in acute ischemic stroke; The American Heart Association and American Stroke

Association (AHA/ASA) 2009 Guidelines shift from the time-based definition of TIA to a tissue-based definition in 2002(3) with a new

definition for TIA as "a brief episode of neurological dysfunction caused by focal

brain or retinal ischemia, with clinical symptoms typically lasting less than one hour

and without evidence of acute infarction"

INTRODUCTION

Stroke is considered to be one of the important global health problems as 15

million people worldwide suffer a stroke annually; of those, 5 million die and another

5 million are left permanently disabled, placing a burden on family and

community(5). Stroke is the third commonest cause of

mortality after cardiac disease, cancer and the first cause of disability(6).

INTRODUCTION

Risk Factors Risk Factors Non Modifiable risk Non Modifiable risk

factors:factors: AgeAge Gender maleGender male Race Race (African-American)(African-American)

GeneticsGenetics ( mono or ( mono or polygenetic)polygenetic)

Modifiable risk factors High BPHigh BP Cigarette smokingCigarette smoking Alcohol intakeAlcohol intake Heart diseaseHeart disease Atrial fibrillationAtrial fibrillation DiabetesDiabetes blood Cholesterolblood Cholesterol Sedentary lifestyleSedentary lifestyle Obesity, StressObesity, Stress

• IS and HS have an important genetic background. IS and HS have an important genetic background.

• The causation of stroke is multifactorial (a The causation of stroke is multifactorial (a combination of environmental and genetic risk combination of environmental and genetic risk factors) and the genetic part is very complex factors) and the genetic part is very complex (polygenic, multiple genes play a role). (polygenic, multiple genes play a role).

• Many common risk factors for stroke like DM and Many common risk factors for stroke like DM and hypertension are partly inherited, so many genetic hypertension are partly inherited, so many genetic loci contribute more or less to the stroke phenotype. loci contribute more or less to the stroke phenotype.

• Here, we will review genetic factors that play a role Here, we will review genetic factors that play a role in IS and HS , with a focus on monogenic forms of in IS and HS , with a focus on monogenic forms of stroke that can serve as a model to study the more stroke that can serve as a model to study the more common phenotypes. common phenotypes.

Genetic factors and ischemic stroke

Genetic Factors of ischemic strokeSingle Gene Disorders:• CADASIL• Fabry’s disease• Sickle cell disease• Homocystenuria• MELAS• Moyamoya disease• Connective tissue disorders• Miscellaneous

Multifactorial Stroke Disorders:• Rennin-Angiotensin-Aldosterone system.• Haemostatic system.• Phosphdiesterase 4D• ALOX5 AP and the Leukotriene pathway.

Single-gene disorders associated with IS

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy.

1- AD small-vessel disease mutations in NOTCH3. 2- The clinical phenotype comprises migraine recurrent strokes and TIAs, dementia, and psychiatric disturbance with onset usually in the third to sixth decade.3- About a 1/3 of patients develop migraine with aura. NOTCH3 encodes a cell-surface receptor, which has a role in arterial development and is expressed on vascular smooth-muscle cells. Ch19

1- CADASIL

1- CADASIL

MRI similar to those for sporadic small-vessel disease. A relatively unique and diagnostically important feature of CADASIL, is bilateral involvement of the anterior temporal white matter and external capsule .

MRI of a CADASIL patient showing white matter hyperintensitie of the centrum semiovale and lacunar infarctions.

1- CADASIL

FD is an X-linked systemic disorder

deficiency of lysosomal enzyme α-galactosidase A.

progressive accumulation of glycosphingolipids,

in the myocardium, renal epithelium, skin, eye, and

vasculature.

Onset is typically in childhood or adolescence

C/P acroparaesthesia, angiokeratoma, or

hypohidrosis ,hearing loss being common signs.

2- Fabry’s Disease

Systemic complications involving the kidneys, heart,

and brain usually follow in mid-adulthood.

Fabry's disease is surprisingly common in young

stroke patients. both large-artery disease and small-

vessel disease (posterior circulation).

ERT with recombinant α-galactosidase.

2- Fabry’s Disease

3- Sickle Cell Disease3- Sickle Cell Disease

SCD is the most common cause of stroke in children

ch11p15.5.

The disease can be caused by the homozygous state for

haemoglobin S (HbS) or by the compound heterozygous

state with haemoglobin C (HbC) or α-thalassaemia.

About 25% of patients with HbS/HbS (highest between 2

years and 5 years) and 10% of those with HbS/HbC will

have a stroke by the age of 45 years.

Conversely, the risk of HS 1% is highest in 3rd

decade.

Clinically overt strokes 11% are typically due to

large-artery disease, characterised by intimal

thickening, proliferation of fibroblasts and smooth-

muscle cells, and eventually thrombus formation.

Silent small recurrent infarcts located in subcortical

regions, and attributed to small-vessel disease. ( 22%)

3- Sickle Cell Disease3- Sickle Cell Disease

4- Homocystinuria

Homocystinuria encompasses a group of mostly AR

enzyme deficiencies, which cause high (>100μmol/L)

plasma concentrations of homocysteine and

homocystinuria. Ch 21

deficiency of cystathionine beta-synthase (CBS), a

key enzyme in the degradation of homocysteine.

50% of untreated patients with CBS deficiency have

a thromboembolic event by the age of 30 years

The disease should be considered in any child with

stroke, mental retardation, a traumatic (mostly

downward) dislocation of the ocular lenses, or skeletal

abnormalities.

Homocystinuria must be distinguished from milder

(15–100μmol/L) hyperhomocysteinaemia, which is a

risk factor for stroke in the general population and is

associated with deficient dietary B6, B12, or folate.

4- Homocystinuria

Homocystinuria can cause stroke (atherosclerosis

and thromboembolism but also through small-vessel

disease and arterial dissection).

Around a half of the patients with CBS deficiency

respond to B6. Those who respond tend to have a later

onset, a milder phenotype, and a better prognosis than

non-responders.

4- Homocystinuria

advanced age, tobacco use, excess coffee intake, low

dietary folate intake, and low vitamin B intake. Higher

homocysteine levels are also associated with diabetes

mellitus, malignancies, hypothyroidism, lupus,

inflammatory bowel disease, and certain medication

use such as metformin, methotrexate, anticonvulsants,

theophylline, and levodopa.

Acquired Causes Of Hyperhomocysteinemia

5- MELAS Syndrome

The syndrome of mitochondrial myopathy,

encephalopathy, lactic acidosis, and stroke-like episodes

is associated with several mutations in mitochondrial

DNA.

MELAS is associated with various symptoms,

however, monosymptomatic cases with stroke as the

sole manifestation exist.

The cerebral lesions underlying stroke-like episodes

in MELAS differ from typical ischaemic infarcts; the

cortex is almost invariably involved.

In many cases, lesions are not limited to vascular

territories and there are no embolic or stenotic lesions

on angiography. Also, diffusion-weighted MRI may

show an increase in the apparent diffusion coefficient

within acute lesions, suggesting vasogenic rather than

cytotoxic oedema.

5- MELAS Syndrome

Serial diffusion-weighted MRI

obtained during stroke-like

episodes of a patient .

He had recurrent attacks of

throbbing headache, sparkling

phenomena, alternating

hemiparesis and homonemous

hemianopia

5- MELAS SYNDROME

Moyamoya disease is a chronic progressive syndrome that is characterised by bilateral occlusion of the terminal carotid artery in association with telangiectatic vessels at the base of the brain.

The disease is uncommon in non-Asian populations whereas its prevalence in Japan 3-5/ 100 000.The most frequent manifestations in childhood are TIS, IS, and epileptic seizures. Rupture of telangiectatic vessels causes ICH. adult type: 30 years (HS). Juvenile type 5 years (IS).

6- Moyamoya disease

About 10% of moyamoya cases occur as familial cases, but the pattern of inheritance is not clear. autosomal dominant Moyamoya disease has been linked to genetic loci on chromosomes 3p, 8q, and 17q

moyamoya-like changes have been described in association with a variety of single-gene disorders, including sickle-cell disease, SLE, pseudoxanthoma elasticum, and neurofibromatosis type 1.

6- Moyamoya disease

IS is a well-known complication of several heritable CT disorders.Marfan's syndrome is an AD ch 15 systemic disorder affecting the musculoskeletal system, CVS, and the eye. The diagnosis is usually established on clinical grounds whereas the role of genetic testing is limited.

MF is caused by mutations in a gene (FBN1)FBN1 encodes fibrillin 1, an extracellular matrix protein.

6- Connective t issue Disorders

MF Fibrillin 1 is expressed in many tissues, including the heart and elastic arteries.

CV complications of the disease include TIAs, IS, and subdural haematoma. neurovascular manifestations were associated with cardiac sources of embolism, in particular prosthetic heart valves, mitral valve prolapse, and AF, whereas there was no association with aortic disease or cerebral artery dissection.

7- Connective t issue Disorders

Ehlers-Danlos syndrome type IV, the vascular type, is an AD disorder resulting from mutations in COL3A1, the gene for collagen type III. The disorder may be suspected on the basis of the associated clinical features and can be confirmed by mutational screening or biochemical studies on cultured fibroblasts (synthesis of an abnormal type III procollagen). The mutational spectrum is broad and neomutations are common. About 50% of the cases have no apparent FH.

7- Connective t issue Disorders

CV complications are common and include intracranial aneurysms, arterial dissection, and spontaneous rupture of large and medium-sized arteries.

IS has also been recognised as a complication of osteogenesis imperfecta and pseudoxanthoma elasticum, which is associated with stenotic lesions of the distal carotid artery and with small-vessel disease.

7- Connective t issue Disorders

IS can occur as a complication of several heritable cardiomyopathies and dysrhythmias, haemoglobinopathies, coagulopathies, and dyslipidaemias, and vasculopathies (herdiatry endotheliopathy with retinopathy , nephropathy and stroke).

8- Miscellaneous

Common Multifactorial Stroke And Genetic Risk Factors For IS

The genetic contribution to common multifactorial stroke seems to be polygenic. Most likely, there are many alleles with small effect sizes. It is increasingly recognised that the effects of some alleles are limited to one or few stroke subtypes and that effect sizes may vary depending on sex and ethnic origin.Most previous studies investigating genetic risk factors for human stroke have taken a candidate gene approach using case–control methodologies.

difficulties: sample characteristics small number and study design, could explain much of the inconsistency between studies.

Most common 1- Renin-angiotensin-aldosterone system 2- Inflammatory genes3- Haemostatic system 4- Phosphodiesterase 4D5- ALOX5AP and the leukotriene pathway5- ALOX5AP and the leukotriene pathway

Common Multifactorial Stroke And Genetic Risk Factors For Ischaemic Stroke

RAAS contributes to the risk of ischaemic stroke. Among the various sequence variations in RAAS, the insertion/deletion (I/D) polymorphism ACE is the most extensively studied. ACE produces angiotensin II and catabolises bradykinin thereby affecting vascular tone, endothelial function, and smooth-muscle-cell proliferation. RAAS has a well-documented effect on systemic blood pressure. Thus, the I/D polymorphism has become a strong candidate for cardiovascular risk.

1- Renin-angiotensin-aldosterone system

Among the most widely investigated genes are

those involved in inflammation (eg, interleukin

1, interleukin 6, TNFα, toll-like receptor 4, P-

selectin and E-selectin, C-reactive protein), lipid

metabolism (eg, apolipoprotein E, paraoxonase,

epoxide hydrolase), nitric oxide release, and

extracellular matrix (matrix

metalloproteinases).

2- Inf lammatory genes

Prothrombotic states, such as APC resistance and the

underlying Factor V Leiden polymorphism , are an

established risk factor for VTE but their role in IS is

still debated.

factor V Leiden polymorphism, the prothrombin

G20210A polymorphism, and the PAI1 polymorphism

all confer a small but significant risk for IS.

3- Haemostatic system

1- Increased levels of natural procoagulantsFactor V Leiden mutation (APC resistance)Prothrombin 20210 mutationFVIII, FIX, FXI, FVII, VWF

2- Decreased levels natural anticoagulantsAntithrombin (AD Ch1)Protein C (AD Ch1)Protein S (ADch3)Tissue Factor Pathway Inhibitor (TFPI)

Inherited Causes of Thrombosis

3- Abnormalities of FibrinolysisPlasminogen deficiency Type IPlasminogen deficiency Type IIDecreased levels of tissue plasminogen activator (tPA)Increased levels of plasminogen activator inhibitor (PAI-1)

Inherited Causes of Thrombosis

prothrombotic states might be responsible for stroke

in some younger patients and in those with additional

risk factors.

However, there is less evidence for a role of

prothrombotic states in unselected patients with

common multifactorial stroke.

3-Haemostatic system

PDE4D gene is associated with IS in the Icelandic

population.

PDE4D ch 5q12.

PDE4D were associated with the combined

phenotype of cardiogenic and carotid stroke.

4- Phosphodiesterase 4D

PDE4D degrades second messenger cAMP, which is a

key signal transduction molecule in multiple cell types,

including vascular endothelial, smooth muscle, and

inflammatory cells.

Since associations were limited to cardiogenic and

carotid stroke it was suggested that PDE4D acts

through atherosclerosis.

4- Phosphodiesterase 4D4- Phosphodiesterase 4D

Leukotrienes are proinflammatory mediators that are implicated in the pathogenesis and progression of atherosclerosis.ALOX5AP   (arachidonate 5-l ipoxygenase-activating protein)another gene that has been discovered through genome-wide linkage analysis. ALOX5AP is associated with a 1·8-fold increased risk of MI and a 1·7-fold increased risk of IS in the Icelandic population.ALOX5AP encodes 5-lipoxygenase activating protein (FLAP), an important component of the leukotriene pathway.

5- ALOX5AP and the leukotriene pathway5- ALOX5AP and the leukotriene pathway

Genetic Factors Of Cerebral Hematoma

1. Hypertension

2. Coagulation

3. Amyloid Angiopathy

4. Herediatry Hgi Telangiectasia

5. Von Hippel Landau

6. Hamartomatous Tumour

7. Cm Avm

Not every hypertensive individual develops

hematoma, nor can every case of non-lobar

Hematoma be ascribed to hypertension.

The absence or presence of additional risk

factors probably determines whether the patient

will suffer from an IS, HS, or no stroke at all.

HTN is genetically determined.

1- Hypertension

Many candidate genes for hypertension have

been suggested including genes for renin ,

ACE, aldosterone, phospholipase, kallikrein,

endothelin, and adrenergic receptors.

Genome-wide linkage surveys have found

linkage for blood-pressure loci on almost all

chromosomes.

1- Hypertension

Disturbances of coagulation – either as a result of medication, or due to hereditary disorders of haemostasis – are important reasons for HS in up to 8% of patients.

Patients with cerebral amyloid angiopathy are at a higher risk for HS after anticoagulation or thrombolysis, especially when they are ApoE ε2 carriers.

2- Coagulation :

Hereditary disorders of haemostasis are less common causes for HS. HS is the leading cause of death in patients with fibrinogen deficiencies, and the cause of death in many patients with haemophilia A (factor VIII deficiency), and haemophilia B (factor IX deficiency). Patients with factor VII, X, V, XI and XIII deficiencies can also suffer from HS, and HS has been described in patients with platelet disorders such as congenital megakaryocyte hypoplasia and the Wiskott–Aldrich syndrome

2- Coagulation :

Amyloid is a term used to describe protein deposits with circumscript physical characteristics: β-pleated sheet configuration, apple green birefringence under polarized light after Congo red staining, fibrillary structure and high insolubility. There are many different proteins that can accumulate as amyloid, and there are many different disease processes that can lead to amyloid formation. In CAA, amyloid deposition occurs predominantly in the cerebral blood vessels, with a preference for small cerebral arteries and arterioles.

3- Amyloid Angiopathy

CAA can consist of amyloid-β-protein (Abeta-related angiitis)"., cystatin C, transthyretin, or gelsolin.Amyloid deposition in cerebral blood vessels can have several clinical consequences, but can also remain asymptomatic . The vessel wall can be weakened, causing rupture and lobar HS. CAA can also obliterate the vessel lumen, leading to ischemia (cerebral infarction, “incomplete” infarction, and leukoencephalopathy). Although CAA may contribute to the neurodegeneration of AD, a direct causal link between the 2 disorders has not been established

3- Amyloid Angiopathy

CAA is clearly a risk factor for HS, but there are many patients with amyloid angiopathy, who do not suffer from HS at all.

HS can occur in patients with cerebral CAA, but with an enormous variety of clinical presentations (eg. age at onset, age at death, occurrence of dementia).

In amyloid angiopathy the co-occurrence with other risk factors such as an ApoE genotype, the presence of hypertension, or head trauma, determines the presence or absence of a HS.

3- Amyloid Angiopathy

Amyloid AngiopathyAmyloid Angiopathy

AD ch 21 Dutch, Brit ish, Icelandic type.

Associated with cerebral lobar hge.

MRI of a patient with hereditary CAA showing

multiple microbleeds and hemorrhages.

Thank You