GENETIC STROKE SYNDROMES

DR.SARATH MENOR.R, MD(Med.),DNB(Med.),MNAMS

DEPT. OF NEUROSCIENCES

AIMS,KOCHI

OUTLINE

Monogenic Disorders Clinico-radiological profile Genetic Determinants Treatment options

INTRODUCTION-STROKE

Multifactorial Cryptogenic Stroke & FH of stroke - look for

Inherited Syndrome Recognition of clinical phenotypes Specific genetic testing Prognostic & Rx implications

MONOGENIC SYNDROMESFABRY DISEASE

Young stroke Vertebrobasilar occlusion Dolichoectasia of cerebral vessels WM abnormalities on brain MRI

TIA Vertigo Sensori neural deafness Cognitive disturbances

PNS

Small fibre PN Painful acroparesthesia Hypohydrosis Impaired temperature sensations Intestinal dysmotility

NCV /EMG-may be normal

OTHER PRESENTATIONS

Conduction abnormalities Cardiomyopathies Renal failure Angiokeratomas Corneal dystrophy

PATHOPHYSIOLOGY

GLA-Lysosomal alpha galactosidase A deficiency 300 mutations X linked –men affected, women-carriers

Lysosomal storage syndrome-glycosphingolipids - globotriaosylceramide in vascular endothelium,

smooth-muscle cells, autonomic & dorsal root ganglia

Vascular occlusion ,ischemia Dolichoectasia

RADIOLOGY

Hyper intensity in pulvinar region on T1W MRA-tortous cerebral vessels

Pulvinar sign in Fabry disease. Magnetic resonance findings in the posterior thalamus (pulvinar). T1-weighted images through the thalamus in three patients with mild (A), moderate (B), and marked (C) hyperintensity

Axial diffusion-weighted MRIsequence obtained atthe level of the thalami. Multifocal,bihemispheric regions of restricteddiffusion are seen with notableinvolvement of the calcarine cortex andsplenium of the corpus callosum.

Infarction of the splenium resulted inthe disconnection syndrome alexiawithout agraphia, evident onneurologic examination

Vertebrobasilar dolichoectasia in Fabry disease. A, Magnetic resonance angiography demonstrating tortuosity of the vertebrobasilar system. B,T2-weighted MRI through the dolichoectatic vertebral-basilar junction (arrow).

DIAGNOSIS Measurement of leukocyte GLA activity Sensitivity & specificity GLA activity assay = 100% in men, & 50% of female carriers

Skin Biopsy or Skin fibroblast culture

Diagnosis of Fabry – young stroke with FH+ & post.circulation involved.

RFT,ECG,2DEcho,Urinalysis.

TREATMENT

Enzyme Replacement Therapy-Recombinant GLA

Reduce stroke risk, LV mass progression

IV infusion-agalsidase alpha 0.2mg/kg or agalsidase beta 1mg/kg every 2 weeks

Expensive

SICKLE CELL DISEASE (SCD)

Stroke in 25% in affected indv. before 45 yr age Ischemic stroke < 20 yrs, H’rghic stroke >20 yrs

age R/r stroke – between 2yr-5 yrs of age. Cognitive & behavioral changes- Silent small

recurrent infarcts located in subcortical regions

Vasocclusive crisis SCD is the most common cause of stroke in children(Indian

population)

PATHOPHYSIOLOGY

Point mutation - Val Glu,6th of beta-polypeptide Hb

Polymerisation of deoxy Hb RBC structural changes Adherence of vascular endothelium AR Non atherosclerotic cerebral vasculopathy-

stenosis & occlusion of proximal cerebral artery

DIAGNOSIS

Mean BFV in proximal MCA or distal ICA by TCD

>200cm/sec- high risk of stroke Routine screen –Annually from age of 2 yrs If >200cm/sec-rescreen 2-4 weeks

RX

TCD ->200cm/sec- Exchange transfusion-HbS <30%

Hydroxy urea- increase HbF

Exchange transfusion + Iron chelation - better outcome

CADASIL Cerebral autosomal dominant arteriopathy with subcortical

infarcts and leucoencephalopathy.

AD small-vessel disease mutations in NOTCH3.

Clinical phenotype : migraine recurrent strokes & TIAs, dementia, psychiatric disturbance onset usually in the third to sixth decade. About a 1/3 of patients develop migraine with aura-early sign

NOTCH 3 encodes a cell-surface receptor, which has a role in arterial

development and is expressed on vascular smooth-muscle cells. Ch19

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

MRI abnormalities precede the onset of symptoms & useful screening tool in symptomatic & presymptomatic carriers

T2 hyperintensities involving the white matter of the anterior temporal poles (O’Sullivan sign) - 90%

Signal intensities in EC /callosum

Cerebral microbleeds-GRE sequence

Brain Atrophy

Transgenic mice expressing-a vascular NOTCH3 mutation /knockout mutation -enhanced cortical spreading depression- co prevalence of migraine with aura

Molecular genetic testing-Diagnosis

False-negative results in genetic analysis

Skin biopsy - granular osmophilic material in the

vascular basal lamina- specific for CADASIL

RX

No specific rx Antiplatelet therapy and migraine prophylaxis Control of HTN,DM,DLP

CARASIL

Onset -3rd decade Stroke, Dementia Premature alopecia- teens Cervical & lumbar spondylosis - 2nd /3rd decade Linkage analysis - mutations in the high-

temperature requirement A serine peptidase 1 (HTRA1)- gene on chromosome 10q

No disease-specific therapy

RETINAL VASCULOPATHY WITH CEREBRAL LEUKODYSTROPHY

cerebroretinal vasculopathy syndrome; hereditary vascular retinopathy; hereditary endotheliopathy, retinopathy,

nephropathy, and stroke (HERNS)

Vision and memory loss, seizures, hemiparesis, apraxia dysarthria with onset in the fourth decade followed by death - 5 to 10 years retinopathy - neovascularization of the optic disc,

retinal hemorrhages & macular edema.

50% of patients- brain MRI – enhancing tumorlike lesion with cortical sparing =

primary CNS malignancy

Small WM lesions = demyelinating disease

Sequential axial MRI = ovoid T2-hyperintense (A) and gadolinium-enhancing (B) lesion adjacent to the frontal horn of the right lateral ventricle. At 6 months, a larger lesion with surrounding edema occupied the right frontal lobe with a central zone of presumed necrosis and gadolinium enhancement (C, D). At 12 months, the lesion had reduced in size with persistent enhancement (E, F). At 18 months (not shown), the lesion further decreased in size with near resolution of the surrounding edema. Fluorescein andindocyanine green angiography with corresponding color photographs of the retina show views of the macula of the right eye (GYI). Periarteriolar narrowing and sheathing, focalleakage, telangiectasias, and cotton wool spots are present

Mutations in the TREX1 gene TREX1 encodes a DNA exonuclease Inheritance is autosomal dominant

The proliferative retinopathy may respond to intravitreal bevacizumab

MELAS

Stroke - onset before the age of 40 years, resulting in hemiparesis, hemianopia, or cortical blindness.

focal and generalized seizures, Dementia recurrent migraine like headaches muscle weakness

Short stature hearing loss Recurrent vomiting diabetes mellitus

Childhood onset Relapsing remitting progressive

Early diagnostic criteria- stroke before the age of 40 years, encephalopathy characterized by seizures or

dementia blood lactic acidosis ragged red fibers on Gomori trichrome

staining of skeletal muscle.

MRI abnormalities involve the cerebral cortex and may cross vascular territories with sparing of the deep white matter

80% of cases- A3243G mutation in the gene encoding transfer RNALEU(UUR).

mitochondrial mutations affect respiratory chain enzymes, particularly complex I.

Rx Mitochondrial cocktail-- CoQ 10- L-carnitine- B vitamin - L-arginine

Valproate avoided- paradoxical seizuresStatin avioded-- myopathy

MOYAMOYA DISEASE

recurrent TIA, ischemic stroke & hemorrhagic stroke

In children-TIA,ischemic stroke- ppt by exercise, crying, coughing, fever, or hyperventilation

In adults- intraparenchymal and intraventricular hemorrhage

C/f Hemiparesis, aphasia, altered mentation & visual

disturbance Epilepsy

The classic angiographic appearance –stenosis & occlusion of the bilateral distal internal carotid arteries & proximal middle/ anterior cerebral arteries accompanied by a network of abnormal lenticulostriate collateral vessel- “puff of smoke”

Cerebral angiogram of the right internal carotid artery with oblique (A) and lateral (B) projections demonstrating severe tapering stenosis of the right carotid terminus (arrows) as well as severe stenosis of the M1 segment of the right middle cerebral artery with multiple small hypertrophied collateral branches extending from the region of stenosis (arrowheads)

15% cases- familial forms- mutations in RNF213 gene on chr.17q25.3.3

AD- incomplete penetrance

Non-atherosclerotic,noninflammatory vasculopathy

histopathologically- intimal hyperplasia smooth muscle cell proliferation disruption of the internal elastic lamina progressive stenosis & occlusion of affected large

vessels.

Associations nonatherosclerotic large vessel

arteriopathies – - cervical artery dissection - fibromuscular dysplasia, - intracranial aneurysms.

secondary to atherosclerosis, radiation, sickle cell disease - termed moyamoya syndrome.

RX

RCT- paucity of studies Antiplatelets Extracranial-Intracranial bypass by encephaloduroarteriosynangiosis (EDAS) &

encephaloduroarteriomyosynangiosis (EDAMS)

EDAS -attaching the dissected superficial temporal

artery to the edges of a linear dural incision

EDAMS -extension of the EDAS -superficial temporal artery in addition to the

deep temporal artery of the temporalis muscle &

middle meningeal artery

HOMOCYSTINURIA

AR enzyme deficiencies, which cause high (>100μmol/L) plasma concentrations of homocysteine and homocystinuria. Ch 21

deficiency of cystathionine beta-synthase (CBS

50% of untreated patients with CBS deficiency have a thromboembolic event by the age of 30 years

stroke, mental retardation, downward dislocation of the ocular lenses, or skeletal abnormalities by the age of 30 years

Homocystinuria-distinguished from milder (15–100μmol/L) hyperhomocysteinaemia, which is a risk factor for stroke in general &associated with deficient dietary B6, B12, or folate

CONNECTIVE TISSUE DISORDERS

Marfan's syndrome- AD ch 15 systemic disorder - musculoskeletal

system, CVS, & eye. The diagnosis- established on clinical

grounds role of genetic testing is limited.

MF - mutations in a gene (FBN1)

FBN1 encodes fibrillin 1, an extracellular matrix protein.

Ehlers-Danlos syndrome type IV, the vascular type – AD disorder- mutations in COL3A1gene-collagen

type III.

suspected on the basis of the associated clinical features & confirmed by mutational screening or biochemical studies on cultured fibroblasts (synthesis of an abnormal type III procollagen).

The mutational spectrum is broad and neo mutations

are common.

About 50% of the cases have no apparent FH

intracranial aneurysms, arterial dissection, and spontaneous rupture of large and medium-sized arteries.

Ishemic stroke-

-osteogenesis imperfecta & pseudoxanthoma elasticum, which is associated with stenotic lesions of the distal carotid artery & with small-vessel disease

SINGLE-GENE DISORDERS ASSOCIATED WITH IS

RAAS contributes to the risk of ischaemic stroke

the insertion/deletion (I/D) polymorphism ACE - most extensively studied.

ACE produces angiotensin II & catabolises bradykinin -affecting vascular tone, endothelial function, and smooth-muscle-cell proliferation.

I/D polymorphism has become a strong candidate for cardiovascular risk.

1- Renin-angiotensin-aldosterone system

INHERITED CAUSES OF THROMBOSIS 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)

AMYLOID ANGIOPATHY

, amyloid deposition occurs predominantly in the cerebral blood vessels-preference for small cerebral arteries & arterioles

amyloid-β-protein ( Abeta-related angiitis)"., cystatin transtyretin, gelsolin

vessel wall can be weakened, causing rupture & lobar HS.

CAA can also obliterate the vessel lumenischemia (cerebral infarction, “incomplete” infarction, and leukoencephalopathy) or g

AD,Chr21 DutchBritish,Icelandic type.Associatedwith cerebral lobar hge.

MRI of a patient with hereditary CAA showing multiple microbleeds and hemorrhages.

THANK YOU