Genetic Stroke Syndrome

1. GENETIC STROKE SYNDROMES
DR.SARATH MENOR.R, MD(Med.),DNB(Med.),MNAMS
DEPT. OF NEUROSCIENCES
AIMS,KOCHI

2. OUTLINE
 Monogenic Disorders
 Clinico-radiological profile
 Genetic Determinants
 Treatment options

3. INTRODUCTION-STROKE
 Multifactorial
 Cryptogenic Stroke & FH of stroke - look for
Inherited Syndrome
 Recognition of clinical phenotypes
 Specific genetic testing
 Prognostic & Rx implications

4. MONOGENIC SYNDROMES
FABRY DISEASE
 Young stroke
 Vertebrobasilar occlusion
 Dolichoectasia of cerebral vessels
 WM abnormalities on brain MRI
 TIA
 Vertigo
 Sensori neural deafness
 Cognitive disturbances

5. PNS
 Small fibre PN
 Painful acroparesthesia
 Hypohydrosis
 Impaired temperature sensations
 Intestinal dysmotility
 NCV /EMG-may be normal

6. OTHER PRESENTATIONS
 Conduction abnormalities
 Cardiomyopathies
 Renal failure
 Angiokeratomas
 Corneal dystrophy

7. 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

8. RADIOLOGY
 Hyper intensity in pulvinar region on T1W
 MRA-tortous cerebral vessels

9. 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

10. Axial diffusion-weighted MRI
sequence obtained at
the level of the thalami. Multifocal,
bihemispheric regions of restricted
diffusion are seen with notable
involvement of the calcarine cortex and
splenium of the corpus callosum.
Infarction of the splenium resulted in
the disconnection syndrome alexia
without agraphia, evident on
neurologic examination

11. 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).

12. 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.

13. 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

14. 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)

15. 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

16. 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

17. RX
 TCD ->200cm/sec- Exchange transfusion-HbS <30%
 Hydroxy urea- increase HbF
 Exchange transfusion + Iron chelation - better outcome

18. 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

19.  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

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

21.  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

22.  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

23. RX
 No specific rx
 Antiplatelet therapy and migraine prophylaxis
 Control of HTN,DM,DLP

24. 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

26. RETINAL VASCULOPATHY WITH CEREBRAL
LEUKODYSTROPHY
 cerebroretinal vasculopathy syndrome;
 hereditary vascular retinopathy;
 hereditary endotheliopathy, retinopathy,
nephropathy, and stroke (HERNS)

27.  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

28. 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 and
indocyanine green angiography with
corresponding color photographs of
the retina show views of the macula of
the right eye (GYI). Periarteriolar
narrowing and sheathing, focal
leakage, telangiectasias, and cotton
wool spots are present

29.  Mutations in the TREX1 gene
 TREX1 encodes a DNA exonuclease
 Inheritance is autosomal dominant
 The proliferative retinopathy may respond to intravitreal
bevacizumab

30. 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

31.  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.

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

33.  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 seizures
Statin avioded-- myopathy

34. 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

35.  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”

36. 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)

37.  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.

38. Associations
 nonatherosclerotic large vessel arteriopathies –
- cervical artery dissection
- fibromuscular dysplasia,
- intracranial aneurysms.
 secondary to atherosclerosis, radiation, sickle cell
disease - termed moyamoya syndrome.

39. 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

40. 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

41.  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

42. 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.

43.  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

44.  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

45. SINGLE-GENE DISORDERS ASSOCIATED WITH IS

47. 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

48. INHERITED CAUSES OF THROMBOSIS
 1- Increased levels of natural
procoagulants
 Factor V Leiden mutation (APC resistance)
 Prothrombin 20210 mutation
 FVIII, FIX, FXI, FVII, VWF
 2- Decreased levels natural
anticoagulants
 Antithrombin (AD Ch1)
 Protein C (AD Ch1)
 Protein S (ADch3)
 Tissue Factor Pathway Inhibitor (TFPI)

49. 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 lumenischemia
(cerebral infarction, “incomplete” infarction, and
leukoencephalopathy) or g

50.  AD,Chr21
DutchBritish,Icelandic
type.Associatedwith
cerebral lobar hge.
MRI of a patient with
hereditary CAA showing
multiple microbleeds and
hemorrhages.

51. THANK YOU