Genetic stroke syndrome
-
Upload
sarath-menon -
Category
Health & Medicine
-
view
38 -
download
3
Transcript of Genetic stroke syndrome
![Page 1: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/1.jpg)
GENETIC STROKE SYNDROMES
DR.SARATH MENOR.R, MD(Med.),DNB(Med.),MNAMS
DEPT. OF NEUROSCIENCES
AIMS,KOCHI
![Page 2: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/2.jpg)
OUTLINE
Monogenic Disorders Clinico-radiological profile Genetic Determinants Treatment options
![Page 3: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/3.jpg)
INTRODUCTION-STROKE
Multifactorial Cryptogenic Stroke & FH of stroke - look for
Inherited Syndrome Recognition of clinical phenotypes Specific genetic testing Prognostic & Rx implications
![Page 4: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/4.jpg)
MONOGENIC SYNDROMESFABRY DISEASE
Young stroke Vertebrobasilar occlusion Dolichoectasia of cerebral vessels WM abnormalities on brain MRI
TIA Vertigo Sensori neural deafness Cognitive disturbances
![Page 5: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/5.jpg)
PNS
Small fibre PN Painful acroparesthesia Hypohydrosis Impaired temperature sensations Intestinal dysmotility
NCV /EMG-may be normal
![Page 6: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/6.jpg)
OTHER PRESENTATIONS
Conduction abnormalities Cardiomyopathies Renal failure Angiokeratomas Corneal dystrophy
![Page 7: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/7.jpg)
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
![Page 8: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/8.jpg)
RADIOLOGY
Hyper intensity in pulvinar region on T1W MRA-tortous cerebral vessels
![Page 9: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/9.jpg)
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
![Page 10: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/10.jpg)
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
![Page 11: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/11.jpg)
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).
![Page 12: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/12.jpg)
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.
![Page 13: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/13.jpg)
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
![Page 14: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/14.jpg)
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)
![Page 15: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/15.jpg)
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
![Page 16: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/16.jpg)
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
![Page 17: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/17.jpg)
RX
TCD ->200cm/sec- Exchange transfusion-HbS <30%
Hydroxy urea- increase HbF
Exchange transfusion + Iron chelation - better outcome
![Page 18: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/18.jpg)
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
![Page 19: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/19.jpg)
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
![Page 20: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/20.jpg)
MRI of a CADASIL patient showing white matter hyperintensitie of the centrum semiovale and lacunar infarctions
![Page 21: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/21.jpg)
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
![Page 22: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/22.jpg)
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
![Page 23: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/23.jpg)
RX
No specific rx Antiplatelet therapy and migraine prophylaxis Control of HTN,DM,DLP
![Page 24: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/24.jpg)
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
![Page 25: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/25.jpg)
![Page 26: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/26.jpg)
RETINAL VASCULOPATHY WITH CEREBRAL LEUKODYSTROPHY
cerebroretinal vasculopathy syndrome; hereditary vascular retinopathy; hereditary endotheliopathy, retinopathy,
nephropathy, and stroke (HERNS)
![Page 27: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/27.jpg)
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
![Page 28: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/28.jpg)
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
![Page 29: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/29.jpg)
Mutations in the TREX1 gene TREX1 encodes a DNA exonuclease Inheritance is autosomal dominant
The proliferative retinopathy may respond to intravitreal bevacizumab
![Page 30: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/30.jpg)
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
![Page 31: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/31.jpg)
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.
![Page 32: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/32.jpg)
MRI abnormalities involve the cerebral cortex and may cross vascular territories with sparing of the deep white matter
![Page 33: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/33.jpg)
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
![Page 34: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/34.jpg)
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
![Page 35: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/35.jpg)
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”
![Page 36: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/36.jpg)
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)
![Page 37: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/37.jpg)
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.
![Page 38: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/38.jpg)
Associations nonatherosclerotic large vessel
arteriopathies – - cervical artery dissection - fibromuscular dysplasia, - intracranial aneurysms.
secondary to atherosclerosis, radiation, sickle cell disease - termed moyamoya syndrome.
![Page 39: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/39.jpg)
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
![Page 40: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/40.jpg)
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
![Page 41: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/41.jpg)
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
![Page 42: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/42.jpg)
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.
![Page 43: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/43.jpg)
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
![Page 44: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/44.jpg)
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
![Page 45: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/45.jpg)
SINGLE-GENE DISORDERS ASSOCIATED WITH IS
![Page 46: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/46.jpg)
![Page 47: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/47.jpg)
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
![Page 48: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/48.jpg)
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)
![Page 49: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/49.jpg)
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
![Page 50: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/50.jpg)
AD,Chr21 DutchBritish,Icelandic type.Associatedwith cerebral lobar hge.
MRI of a patient with hereditary CAA showing multiple microbleeds and hemorrhages.
![Page 51: Genetic stroke syndrome](https://reader031.fdocuments.in/reader031/viewer/2022032700/55d1efffbb61ebba5f8b4768/html5/thumbnails/51.jpg)
THANK YOU