Thread by @WorldStrokeEd

#WeekendLecture
#GeneticsAndStroke

#Genetics is involved in several #stroke related conditions, such as small vessel disease #SVD, aneurysms, dissections, cavernomas, and intracranial #hemorrhages

Check this 🧵!
Prepared by @J_Rosales_MD
Edited by @interneurona

#Weekendlecture

#Genetic & #SVD
🧬🧠

✅1,5% of cerebral #SVD are #monogenic disorders
✅AR, AD or X-linked
☝🏼Absence of family history doesn't rule out diagnosis because of
👉de novo mutation
👉reduced expression or
👉incomplete penetrance
✅ahajournals.org/doi/10.1161/ST…

#Weekendlecture

#Genetic & #SVD

When to #suspect?🕵️‍♀️

✅early onset stroke without vascular RFs
✅systemic features and neuroimaging of an specific monogenic disorder
✅consanguinity
✅negative work up for other causes of SVD

👉ahajournals.org/doi/10.1161/ST…

#Weekendlecture
#Genetic & #SVD

👉#CADASIL most common SVD caused by single gene mutation
✅Autosomal dominant
✅Prevalence 2-4/100 000
☝️#NOTCH3 mutation, most frequent in hot spot,3-4 exons
🚬 and HTN are associated with earlier age of stroke onset

👉thelancet.com/journals/laneu…

#Weekendlecture
#Genetic & #SVD
#CADASIL
External capsule/anterior temporal lobes hyperintensities ☝️highly suggestive of but not specific
CADASIL #scale help to select patient to genetic testing
Skin biopsy👉57% Se bit.ly/3oukOT7
✅Gold Standard NOTCH3 genetic test

#Weekendlecture
#Genetic & #SVD
Less frequent SVD
#Fabry pulvinar sign, dolicobasilar,ICH
#CARASIL alopecia, lumbar pain
#COL4A1_2 ⬆️ICH risk;aneurysms,dissections
#PADMAL pons
#CARASAL brainstem, ICH, CN involvement, sicca
#RVCL-S: retinal/ liver/renal
👉bit.ly/3uzFSc1

#Weekendlecture
#Genetic & #CCM

☝️Genes👉Functional loss, CCM1 (KRIT1)/CCM2 (MGC4607)/CCM3, most agressive (PDCD10)
👉Prev: 1/3300 to 1/3800
👉20% of all CCMs are familial:
✅AD with incomplete penetrance
✅Multiple CCM
bit.ly/3B7yNlx

#Weekendlecture
#Genetic & #CCM

✅Extra neurological manifestations:
~5% #retinal cavernomas, choroidal hemangiomas,
~9% hyperkeratotic #cutaneous lesions
✅Diagnosis: sequencing analysis if negative deletion/duplication analysis for the 3 genes

bit.ly/3B9xO3Z

#Weekendlecture
#Genetic & #Dissections

✅60% of sCAD had abnormalities in skin connective tissue, but
👉#CAD occurs in pts w/ known CTD ~2%, mainly Ehlers-Danlos bit.ly/3A6Cp5Q
👉Most studies looking for mutations/genetics associations are (-)ve bit.ly/3Dc0IRB

#Weekendlecture
#Genetic & #Dissections #CAD

Syndromic vs nonsyndromic
👉#Ehlers_Danlos type IV, #Marfan #Loeys_Dietz vs isolated dissection
🕵️Extraneuro signs, multiple dissection, joint hypermobility, pectus excavatum, aorta disorders
👉Diagnosis: gene panel or exome sequence

#Weekendlecture
#Genetic & #Aneurysm

👉If 1-2 family members have IA, risk of 1st degree relatives >30yo is ~9.8%
👉Pts w/familial history of SAH (~10%)
✅SAH at younger age
✅⬆️risk of multiple IA vs sporadics
☝️Majority of IA heritability is polygenic.
bit.ly/3FeSnP6

#Weekendlecture
#Genetic & #Aneurysm

#Endothelial cell appear to be the target
✅Genetic predisposition for HBP and 🚬 are independent genetic causes of IA
☝️In recent #GWA 17 loci were found and 11 potential genes go.nature.com/2Yhon3S

#Weekendlecture
#Genetic & #ICH

👉Heritability of #ICH estimated at 44% (73% lobar vs 34% deep)
👉Mechanisms involved: #amyloid deposition, lipid metabolism, coagulation, inflammation
Polygenic, but most strong association #ApoE
bit.ly/3FfnBFB

#Weekendlecture
#Genetic & #ICH

✅APOE Ɛ 2- 4 ⬆️risk of first and recurrent lobar ICH
#Familial CAA: APP, CST3, BRI, TTR, ITM2B, GSN, PRNP, and ITM2B genes
#Lobar ICH: APOE Ɛ2, Ɛ4, GPX1. Deep APOE Ɛ4, 1q22, COL4A2, TIMP-1, TIMP-2, MMP-2, MMP-9, ACE

nature.com/articles/nrneu…

#WeekendLecture
#GeneticsAndStroke

Thank you for reading!!
And thanks again to @J_Rosales_MD for preparing this weekend material