vessel, cerebrovascular arteriopathies: considering intracranial aneurysms, ce

16 Pages·2012·0.37 MB·English

REVIEW
CURRENT Shared associations of nonatherosclerotic, large-
O
PINION
vessel, cerebrovascular arteriopathies: considering
intracranial aneurysms, cervical artery dissection,
moyamoya disease and fibromuscular dysplasia
Andrew M. Southerlanda,b, James F. Meschiac, and Bradford B. Worralla,b,d
Purposeofreview
With ongoingadvancements innoninvasivevascular imaging and high-throughputgenomics, we have
the opportunity to reclassify the cerebrocervical disorders bythese shared associations, rather thantheir
downstream events, andto better understandetiology, mechanism and preventive treatments going
forward.
Recent findings
Thecommon nonatherosclerotic, large-vessel arteriopathies affecting the cerebrovasculature include
intracranial aneurysms, cervical artery dissection, fibromuscular dysplasia and moyamoya disease.
Together, these entities contribute toa highincidence ofdevastating cerebrovascular outcomes, including
ischemic stroke and subarachnoid hemorrhage, leading tolong-term physical and cognitive disability
frequently inyoungotherwise healthy adults. Inaddition to wellreported clinical overlap, these polygenic
phenotypes share epidemiological characteristics, environmental risk and acommon pathological
weakening of the arterialwall.
Summary
Wereviewed bothpast andpresent studiesrelating these shared associations, includingreported
candidate geneanalyses and genome-wide association data.Wealso catalogue recent descriptions
of novelarteriopathic syndromes that add tothe growinglist ofmonogenic connective tissue disease
affecting the arterial wall,and further informourunderstanding of morecommon polygenic phenotypes.
Wealso placethese cerebrocervical arteriopathies inthe contextof othersystemic nonatherosclerotic,
large-vessel vasculardisease (e.g.aortic aneurysm and dissection).
Keywords
aneurysm, arteriopathy, artery dissection, fibromuscular dysplasia, genetic,moyamoya
INTRODUCTION aneurysms,cervicalarterydissection(CeAD),moya-
moya disease and fibromuscular dysplasia (FMD).
Cerebrovascular disease has long been categorized
Current clinical classification systems (WHO) [4],
by clinicoanatomic characteristics: ischemic vs.
TOAST [5], Causative Classification System [6]) fre-
hemorrhagic, thrombotic vs. embolic, and so
on. Rapid advancements in noninvasive vascular quentlylumptheseasminoritycausesofstroke[7].
imaging and high throughput genomics create the
opportunity to reclassify neurovascular disorders
aDepartment of Neurology, bDepartment of Public Health Sciences,
byconsideringtheminthecontextofsharedassoci-
UniversityofVirginia,Charlottesville,Virginia,cDepartmentofNeurology,
ations. This strategy allowed reconceptualizing
Mayo Clinic, Jacksonville, Florida and dCenter for Public Health
small vessel disease through a shared pathogenesis Genomics,UniversityofVirginia,Charlottesville,Virginia,USA
encompassing lacunar stroke, hypertensive hemor-
Correspondence toBradfordB. Worrall,UVAHealth System,Depart-
rhage, leukoariosis and deep cerebral microbleeds mentofNeurology,#800394,Charlottesville,VA22908,USA.Tel:+1
[1,2&,3]. 4349242783;e-mail:[email protected]
Common nonatherosclerotic, large-vessel cere- CurrOpinNeurol2013,26:13–28
brocervical arteriopathies include intracranial DOI:10.1097/WCO.0b013e32835c607f
1350-7540(cid:1)2013WoltersKluwerHealth|LippincottWilliams&Wilkins www.co-neurology.com
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Cerebrovascular disease
key components of the ECM include the elastic
KEY POINTS
lamina, fibroblasts, proteoglycans and fibrillin,
defective in Marfan syndrome [9]. Ultrastructure
(cid:1) Among arteriopathic connective tissue disorders,
of the arterial wall demonstrates numerous poten-
monogenic and polygenic phenotypes share common
clinical, pathological and genetic associations. tial targets for congenital weakening (Fig. 1) [10].
These well described and other more recently
(cid:1) Thecommon nonatherosclerotic, large-vessel,
definedmonogenicconnectivetissuedisorderspre-
cerebrocervical arteriopathies includeintracranial
disposetoarteriopathy(Table1)[11–13,14&,15&,16–
aneurysms, cervical artery dissection(CeAD),
28,29&,30–36,37&,38,39,40&,41–44,45&,46,47].
moyamoya disease and fibromuscular dysplasia (FMD),
collectively responsible fora large numberof incident Prevalence ranges broadly from one in 400
strokes amongyoung and healthy adults. for autosomal dominant polycystic kidney disease
(ADPKD) [48,49] to disorders described in single
(cid:1) These arteriopathies sharepathogenesis stemmingfrom
families. Connective tissue disorders such as
loss of structuralintegrity inthe arterial wall; specific
Loeys–Dietz[50]and‘multisystemicsmoothmuscle
alterations includefunctional transformation ofsmooth
musclecells (SMCs), degradation ofthe elastic dysfunction syndrome’ [43] that predispose to
laminae, functional changesincollagen deposition arteriopathy continue to be described.
and inflammation.
(cid:1) Appreciating shared associations among these Common (polygenic) large-vessel
arteriopathies will guide future etiological research and
arteriopathies
hopefully informpotential therapeutic targets to prevent
downstream cerebrovascular events inthe future. The relationship between monogenic connective
tissue disease and polygenic phenotypes is unclear.
Forexample,only1–2%ofintracranialaneurysmor
CeAD cases prove to be syndromic [51–53], with
We reconsider these large-vessel cerebrocervical the majority being spontaneous or idiopathic not
arteriopathiesonthebasisofsharedclinicalcharac- manifestingovertsignsofcollagenvasculardisease.
teristics,pathogenesisandgeneticrisk,dichotomiz- This discrepancy likely stems from low penetrance
ingbetweenmonogenicandpolygenicphenotypes. variantsandadditionalnongeneticfactorsdiscussed
here.
MONOGENIC ARTERIOPATHIC
CONNECTIVE TISSUE DISORDERS Intracranial aneurysms
Of the structural elements of the arterial wall, Saccular intracranial aneurysms represent the most
comprising intima, media and adventitia, tensile prevalent cerebral large-vessel, nonatherosclerotic
strength relies primarily on smooth muscle cell arteriopathy with rupture leading to subarachnoid
(SMC) integrity and collagen type III (COL3A1), hemorrhage (SAH), associated with high mort-
the principal component of the extracellular ality and morbidity. Most commonly occurring at
matrix (ECM) and the defective gene product in bifurcations with a predilection for the anterior
vascular Ehlers-Danlos IV (vEDS) [8]. Additional circulation,biomechanicalweakeninginthearterial
Intima Endothelial cells
Internal elastic lamina
Media Elastic fibers
Smooth muscle cells
Adventitia
Fibroblasts
Collagen fibers
FIGURE 1. Ultrastructure of the arterial wall. Representative of an intracranial artery; extracranial arteries also have an
external elastic lamina betweenthe media–adventitia. Reprinted withpermission from [10].
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Nonatherosclerotic cerebrocervical vasculopathies Southerland etal.
Table 1. Monogenic syndromeswith overlapping cerebrocervical andextra-cerebral arteriopathies
Name(abbreviation; Cerebrocervical Extra-cerebral
OMIMlisting) Gene/locus Inheritance arteriopathy arteriopathy Otherfeatures
VascularEhlers-Danlos COL3A1 AD IA,CeAD TAA,AAA, Jointanddermalmanifestations,
typeIV(vEDS; aorticdissection pronetospontaneousrupture
OMIM130050) ofbowelandlargearteries
Marfansyndrome Fibrillin-1(FBN1) AD IA,CeAD[11] TAA,AAA,aortic Hallmarkskeletal,ocularand
(MFS;OMIM154700) dissection cardiovascularfeatures.
Arachnodactylyand
subluxationofthelenses
Arterialtortuosity SLC2A10[12] AR IA,CeAD TAA,AAA Generalizedtortuosityand
syndrome(ATS; elongationofallmajor
OMIM208050) arteries,softskin,jointlaxity,
severekeratoconus
Adultpolycystic PKD1 AD IA,CeAD TAA,AAA,aortic Renalcysts,livercysts
kidneydisease(PKD1; dissection
OMIM173900)
Adultpolycystickidney Unknown[13] AD IA Unknown Renalcysts,livercysts
disease(PKD3;
OMIM600666)
Loeys-Dietzsyndrome TGFBR1 AD A,CeAD TAA,AAA,aortic Triadofarterialtortuosity
type1A(LDS1A; dissection,other andaneurysms,hypertelorism,
OMIM608967) vesseldissection bifiduvula/cleftpalate;
pregnancycomplications
Loeys-Dietzsyndrome TGFBR2 AD IA,CeAD TAA,AAA,aortic IndistinguishablefromLDS1A
type1B(LDS1B; dissection,other
OMIM610168) vesseldissection
Loeys-Dietzsyndrome TGFBR1 AD IA,CeAD TAA,AAA,aortic Phenotypicallysimilarto
type2A(LDS2A; dissection,other vEDS,bifiduvulaisusually
OMIM610380) vesseldissection onlycraniofacialfeature
Loeys-Dietzsyndrome TGFBR2 AD IA,CeAD TAA,AAA,aortic IndistinguishablefromLDS2A
type2B(LDS2B; dissection,other
OMIM610380) vesseldissection
Loeys-Dietzsyndrome SMAD3 AD IA,CeAD TAA,AAA,aortic Previouslyknownas
type3(LDS3; dissection,other aneurysm–osteoarthritis
OMIM613795) vesseldissection syndrome[15&];
[14&] congenitalheartdisease
Loeys-Dietzsyndrome TGFB2 AD IA,CeAD TAA,AAA Skeletalmanifestations,
type4(LDS4; bicuspidaorticvalve,
OMIM614816) arterialtortuosity,
arachnodactyly,scoliosis,
clubfeetandthinskinwith
easybruisingandstriae
Osteogenesisimperfecta COL1A1 AD CeAD,FMD[16] TAA,AAA Multiplebonefractures,
type1(OI1;OMIM166200) hearingloss,bluesclera
Alpha-1antitrypsin SERPINA1 AR FMD[17–21] None Emphysema,liverdisease
deficiency(OMIM
613490)
Psuedoxanthomaelasticum ATP-bindingcassette AR,pseudo- IA,[23];CeAD ?AAA[25] Mineralizedandfragmented
(PXE;OMIM264800) subfamilyCmember6 dominant [24] elasticfibersintheskin,
(ABCC6)[22]; vascularwallsandBurch
polymorphismsin membraneintheeye
xylosyltransferasegene,
XYLT1(608124)and
XYLT2(608125)modify
severityofPXE[22]
Microcephalic PCNT,pericentrin, ARorcompound IA,moyamoya TAA,AAA Postnataldwarfismwith
osteodysplasticprimordial 21q22[26] heterozygous microcephalyand
dwarfismtypeII(MOPD2; dysmorphia
OMIM210720)
Neuro-fibromatosis Neurofibromingene AD IA,moyamoya Coartactionofthoracic Aorticaneurysms,
type1(NF1;OMIM (NF1);17q11.2 andabdominalaorta, moyamoya[28]
162200) [27] venousandarterial
aneurysms
Grangesyndrome Unknown;unknown Unclear IA,moyamoya TAA,AAA,venous Stenosisorocclusionrenal,
(OMIM602531);arterial [16,29&,30] andarterialaneurysms abdominalandcerebral
occlusivedisease,progressive, arteries.Cerebralaneurysms,
withhypertension,heart congenitalheartdefects,
defects,bonefragility, brachydactyly,syndactyly,
andbrachysyndactyly bonefragilityandlearning
disabilities
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Cerebrovascular disease
Table 1 (Continued)
Name(abbreviation; Cerebrocervical Extra-cerebral
OMIMlisting) Gene/locus Inheritance arteriopathy arteriopathy Otherfeatures
Hereditaryangiopathywith COL4A1 AD IA[31–34] TAA,AAA,arterial Associatedwithasmall
nephropathy,aneurysms aneurysms vesselarteriopathy
andmusclecramps [35,36]andriskof
(HANAC;OMIM611773) ICH[37&]
AlportsyndromeX-linked COL4A5 AD ?CeAD,FMDand TAA,AAA[39] Progressive
(ATS;OMIM301050) moyamoya[38] glomerulonephropathy,
variablesensorineural
hearinglossandvariable
ocularanomalies
SAMS(stenosis,aneurysm, SAMHD1 ARorcompound IA,moyamoya[41] ?aorticaneurysm Cerebralvasculopathyand
moyamoyaandstroke) heterozygous earlyonsetstroke
[40&] [40&,41,42];samegene
mutatedinchilblainlupus
(CHBL2;614415)and
Aicardi-Goutieressyndrome
(AGS5;612952)
Homocyst(e)inuria CBS AR ?CeAD Aorticdissection Marfanoidphenotype
(OMIM236200)
Multisystemicsmoothmuscle ACTA2 AD ?IA,moyamoya Aorticdissection, Mydriasis,patentductus
dysfunctionsyndrome TAA,AAA arteriosus,hypotonic
(OMIM613834)a.k.a. [43,44,45&,46] bladder,malrotationand
moyamoyatype5(MYMY5; hyperperistalsisofthe
OMIM614042)andfamilial gastrointestinaltract
thoracicaorticaneurysm
type6(AAT6;OMIM611788)
CutisLaxatypeIA;(ARCL1A; FBLN5 AR IA,FMD[47] TAA,AAA,aortic Phenotypicallysimilarto
OMIM219100) dissection vEDS;multiplediverticula
(esophagus,duodenum,
ileum,bladder).Theother
hadpulmonaryemphysema
OMIM,OnlineMendelianInheritanceinMandatabase(www.ncbi.nlm.nih.gov/omim).AAA,abdominalaorticaneurysm;AD,autosomaldominant;AR,
autosomalrecessive;CeAD,cervicalarterydissection;FMD,fibromusculardysplasia;IA,intracranialaneurysm;ICH,intracerebralhemorrhage;TAA,thoracic
aorticaneurysm.
wall leads to outpouching of all three arterial (1.6:1),butroughlyequalinpatientsyoungerthan
layers.Avarietyofultrastructuraldefectsareassoci- 50 years [10,57,60,62]. Sex differences may reflect
ated with aneurysms, including alteration in the hormonal interactions with vascular wall integrity.
elastin-to-collagen ratio, SMC transformation and A recent meta-analysis confirmed an increased
migrationtotheintima,andproteindysfunctionin risk for SAH among postmenopausal women
the ECM. Yet, the hallmark pathological feature of comparedwithpremenopausalwomenofthesame
intracranialaneurysmisdegradationoftheinternal age, but failed to show a significant relationship
elastic lamina [10,54]. between hormone replacement therapy and SAH
The prevalence of intracranial aneurysm (0.5– [63,64&].
5% in autopsy series) and incidence of aneurysmal Risk for intracranial aneurysm rupture also
SAH (8–11/100000 totalling approximately 30000 differs by race and ethnicity. Several community-
cases per year in the USA) varies by region and based US cohorts demonstrate higherincidences of
population [10,55–60]. An international review of SAHinAfrican-AmericansandHispanicsthannon-
unruptured aneurysms found an overall pre- Hispanic whites [58,62,65,66]. Globally, Finland
valence of 3.2% [95% confidence interval (CI) and Japan have the highest incidence of SAH
1.9–5.2], with no difference in prevalence ratios [67–69]. Whether genetics or environmental risk
between countries, despite wide variance in SAH explains these differences remains unresolved.
risk [61&]. Data regarding aneurysm size and risk for rup-
Nonmodifiableriskfactorspotentiallyaffecting tureconflict.TheInternationalStudyofUnruptured
the risk of aneurysm growth and rupture include IAs (ISUIA) reported an overall low risk of SAH for
age, sex, race/ethnicity and genomics. Aneurysm small (<10mm) unruptured aneurysms [70,71],
rupture most commonly occurs between 40 and yet the majority of ruptured aneurysms are less
60 years, peaking in the sixth decade [55,57]. than 10mm [72]. Aneurysms may experience a
Incidence of SAH is higher in women overall peak period for growth and rupture risk related to
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Nonatherosclerotic cerebrocervical vasculopathies Southerland etal.
hemodynamics,vascularwallintegrityandenviron- Cervical artery dissection
mentalriskfactors,especiallysmoking[73–75,76&], Cervicalarterydissection – dissectionofthecarotid
accounting for variance in SAH risk among or vertebral arteries – accounts for approximately
aneurysms of the same size and across populations 20% of ischemic stroke in adults aged 18–50 years
with the same intracranial aneurysm prevalence. [89,90].AnnualincidenceofCeADisreportedas2–
The high early rerupture risk (50% by 6 months) 4/100000,likelyanunderestimateduetodiagnostic
contrasting with low rates of long-term recurrence bias [91,92].
(3% annually) further supports the notion of peak Most CeAD occurs spontaneously, although
vulnerability [77–79]. minor neck trauma or exertion, ranging from
Familialclusteringofintracranialaneurysmand coughing to riding a roller coaster, is frequently
SAH is found in 10–15% [80], likely an underesti- associated [93&,94]. Shear forces are likely only an
mate due to ascertainment bias [81]. Nevertheless, environmental trigger in genetically or physio-
those with two or more affected family members logically predisposed individuals [95&]. Maximum
have a four-fold risk of harbouring an intracranial wall stress on the cervical arteries occurs with 908
aneurysm compared with the general population lateralrotationor458rotationwithhyperextension
[48,53]. Case–control analyses and linkage studies [96&]. Carotid dissections typically occur at a
identified several candidate genes for intracranial susceptible segment several centimeters distal to
aneurysm [10]. A large genome-wide association the bifurcation, anchored by the trunk proximally
study(GWAS)ofintracranialaneurysminEuropean andpetrousbonedistally[96&].Vertebraldissections
and Japanese populations revealed significant typically involve the vulnerable V2/V3 junction
associationswithsequencevariantsinchromosome where the artery exits the C2 transverse foramen
8q11 and 9p21 [82], which were replicated in 406 andentersthedura[97].Additionalphysiologicalor
familial cases from the Familial Intracranial Aneur- environmental associations include hypertension,
ysm(FIA)Study[83].FurtherdatafromFIAsupport low cholesterol, increased height with low weight,
the association of these two regions in familial infectionorsystemicinflammation,migraine,peri-
and sporadic disease [84&&] and reinforce a strong partumandaseasonalvariationwithfallandwinter
interaction with smoking, the greatest modifiable peaks [89,98&,99&,100–102].
risk factor for aneurysmal rupture [83]. Table 2 CeAD mostly occurs between 30 and 50 years
summarizes currently associated variants for intra- of age, with median age 5–10 years younger in
cranial aneurysm risk [82,83,84&&,85–88]. women than men [98&,103,104]. A transient peak
Table 2. Genome-wide associations forintracranial aneurysms
Locus Nearestgene Study Cohort Putativefunction Associations(OMIM)
11q24–25 FAA1 Ozturketal.[85], Familial(European) Fattyacidmetabolism TAA,AAA
Worralletal.
(linkage)[86]
9p21 CDKN2BAS/ANRI Bilguvaretal.[82], Familialþsporadic NoncodingRNA, CAD,AAA,LAA,DMII
Dekaetal.[83], (European,Japanese) P15(INK4b),
Yasunoetal.[87], P16(INK4a)
Foroudetal.[84&&]
8q11-12 SOX17 Bilguvaretal.[82], Familialþsporadic Endothelialcell Congenitalkidneyand
Dekaetal.[83], (European,Japanese) metabolism urinarytractanomalies
Yasunoetal.[87],
Foroudetal.[84&&]
2q33 PLCL1 Bilguvaretal.[82] European(Finnish,Dutch) VEGFR2signalling
Japanese
10q24 CNNM2 Yasunoetal.[87] European(Finnish,Dutch, CyclinM2 CAD,HTN,renaltubular
German)Japanese malabsorptionofmagnesium
13q13 STARD13,KL(klotho) Yasunoetal.[87] European(Finnish,Dutch, FGFreceptorspecificity, Carcinomas,CKD,
German)Japanese acceleratedageing hypocalcinosis
18q11 RBBP8 Yasunoetal.[87] European(Finnish,Dutch, Retinoblastomabinding Tumourigenesis
German)Japanese protein,DNArepair
4q31 EDNRA Yasunoetal.[88] Finnish,Japanese Endothelinreceptor HTN,CHF,migraine
OMIM,OnlineMendelianInheritanceinMandatabase(www.ncbi.nlm.nih.gov/omim).AAA,abdominalaorticaneurysm;CAD,coronaryartery
disease;CHF,congestiveheartfailure;CKD,chronickidneydisease;DMII,typeIIdiabetesmellitus;HTN,hypertension;TAA,thoracicaorticaneurysm.
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Cerebrovascular disease
invulnerabilityseemslikely,givenhighshort-term Table3[120,121&,122&]presentsreportedcandidate
recurrenceratesofstrokeordissection((cid:2)25%),and gene variants associated with cases of CeAD
low long-term recurrence of approximately 1–2% [1,12,120].
per year [105–107]. CeAD is uncommon in the Replication has recently been completed in the
very old, perhaps reflecting a protective stiffening largest GWAS of CeAD to date – an international
of arteries over time [108]. Arterial dissections in multicenter consortium titled CADISP – Cervical
childrenmorecommonlyoccurintracranially[109], Artery Dissection and Ischemic Stroke Patients
whereaspureintracranialdissectioninadultsisrare [123].Withpublishedresultspendingandanexome
[110]. sequencing project underway, the CADISP study
Ultrastructuralabnormalitiesreflectinginherent will shed better light on the genetic associations
weakeningofthearterialwallsupportageneticcause of CeAD.
for CeAD. Histologically, this includes medial
degeneration, degradation of the external elastic
Moyamoya disease
lamina, neoangiogenesis of the vasavasorum and
extravasation of blood in the medial–adventitial Moyamoya, another poorly understood arteriopa-
border. A generalized arteriopathy is supported by thy [124&], derives its name from the characteristic
similarabnormalitiesinbothdissectedandclinically angiographic pattern [125]. The name means ‘hazy
unaffectedarteries[111,112,113&]andthat15–20% puffsofsmoke’describingthesmallvesselcollateral
ofincidentcaseshavemultivesseldissections[105]. system that develops in response to hyperplastic
AlthoughmostCeADcasesdisplaynootherpheno- stenosis and occlusion of the distal internal
typic signs [51,52], subtle indications of under- carotid and proximal vessels of the circle of Willis.
lying connective tissue disease include heritable This process may be primary moyamoya disease, a
dermal collagendefects,keloid scarring, aortic root progressive,oftenhereditarydisorder,ormoyamoya
dilatationandredundantarterialloopingorkinking syndrome secondary to vasculopathies, including
[114,115–118]. Familial CeAD is rare, associated atherosclerosis, sickle cell disease and inherited
with younger age, more commonly polyarterial thrombophilias. Although most patients with
and more likely torecur[51,114,119]. moyamoya disease are children, a second peak
Candidate gene analyses in CeAD have occurs between ages 25 and 50 years [126] with a
been underpowered and yield few significant or slight female predominance [127]. Clinical pre-
replicatedresults[120].Themostrobustassociation sentations differ by age and include cerebral
is in the methylenetetrahydrofolate reductase ischemia, intracerebral hemorrhage and cognitive
(MTHFR) variant 677TT; a meta-analysis of five impairment.
studies (N¼440 cases) revealed an increased risk Moyamoya disease, most common in Asian
for CeAD in those with the 677TT genotype with countries and in those of Asian ancestry [128],
odds ratio equal to 1.67 (95% CI 1.21–2.31) [120]. affects 3–4 per million in Asian countries and less
Table 3. Genevariants in cervical arterial dissection
Gene(variant) Locus Product/function Cohort Additionalassociations
MTHFR(C677T) 1p36 Folatemetabolism, European(Italian, Hyperhomocysteinemia,
aminoacidsynthesis German),Mexican venousthrombosis
ICAM1(469E) 19p13 Immunecellmigration European(German) Inflammation,infarctsize,SAH,
acrossvascular aneurysmgrowth
endothelium
COL3A1(3’UTR) 2q31 TypeIIIcollagen, European(German, VascularEhlers-DanlosIV,
primarycomponent Swiss)familial familialdermalconnective
ofECMandarterial tissueabnormalities
tensility
COL5A2(D1429V)a 9q34 TypeVcollagen;fibrillar European(German) ClassicalEhlers-DanlosI/II
forming;lowabundance
inECM
TGFBR2(pK372R, 3p22 RegulatesSMCmigration European(Italian) Loeys-Dietzsyndrome
pC138R)b andtransformation,
ECMmetabolism
ECM,extracellularmatrix;SAH,subarachnoidhemorrhage;SCM,smoothmusclecell.Adaptedfrom[120,121&,122&].
aGenesequencing(1/60cases);mutationnotfoundin150healthycontrols.
bGenesequencing(2/56cases);mutationnotfoundin500healthycontrols.
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Nonatherosclerotic cerebrocervical vasculopathies Southerland etal.
than 1 per million in the USA [128]. Founder degradation of the elastic laminae, abnormal
mutationshavebeenreportedinAsianpopulations collagen synthesis and segmental fibroplasia
[129,130&] and potential differences in genetic [153,154].OverallprevalenceofcervicalFMDranges
architecture may underlie moyamoya disease in from approximately 0.3 to 3.0% in consecutive
those of Asian vs. European ancestry [131&,132]. angiographic series [152,154]. Most prevalent in
Most familial cases appear to be autosomal domi- womenofEuropeandescent,FMDprimarilyaffects
nant with incomplete penetrance, although other young and middle-aged adults [155]. The largest
modes are described, and genomic imprinting has FMD registry to date (N¼447) reveals a mean age
been implicated [133]. of approximately 52 years, older than previously
Histologically,moyamoyadiseaseshowscharac- reported [156&]. A second peak occurs in children
teristic proliferation of transformed SMCs and and adolescents, but is more commonly of the
fibroblasts with thickening of the intima and intimal type, with a greater predilection for the
concomitant thinning of the media. The intimal intracranial circulation, similar to CeAD [157].
hyperplasia results in narrowing and ultimately Incidental diagnosis of cerebrocervical FMD
obstruction ofthevessellumenleadingtoirregular has increased with availability of noninvasive
collateral networks [134]. Ischemia results from vascular imaging, yet the risk of cerebrovascular
compromised perfusion through stenosed large eventsremainscontroversial.Therelationshipwith
arteries and microthrombi in small vessels due to aneurysms and dissectionisclearer.Inthe USFMD
slow flow state and proinflammatory milieu [135]. registry, the coprevalence of dissection and aneur-
Recurrent hypoxia and reduced blood flow stimu- ysms was 19.7 and 17%, respectively [156&].
latesangiogenicsignalsandgrowthfactorsthatmay Of dissections, 75% involved the carotid, 21.6%
play a role in aberrant collateralization [136&]. renal and 17% vertebral arteries. Of aneurysms,
These collateral vessels are friable with reduced most were observed in the renal and carotid
structural integrity likely contributing to a higher arteries, which may also reflect pseudoaneurysms
risk of hemorrhage. as sequelae of dissection. Intracranial (11.8%) and
Five discrete genetic moyamoya disease aortic (19.7%) aneurysms likely represented true
syndromes (MYMY1–5) are currently characterized aneurysms. Nearly 25% of those in the registry
[27,43,46,133,137,138&,139&,140,141], and several reported a family history of aneurysm [156&].
additionalsyndromesmanifestmoyamoyachanges With a lack of dedicated screening, prevalence of
as part of their phenotypic spectrum [16,26,27]. intracranialaneurysmsinthosewithcerebrocervical
Moyamoya disease shares risk with other cerebral FMD may range from 7.3 to 51% [158]. In a large
and systemic vasculopathies. Table 4 demonstrates series of spontaneous CeAD, FMD is found in 15–
multiple overlaps with systemic and cerebral 20% of cases [154,159,160] (Southerland, un-
aneurysms [16,26–28,29&,30,130&,137,139&,141– published data). Although these series suggest a
144,145&,146&,147–150,151&]. higher than expected coprevalence of FMD with
Others have described a link with FMD [38]. dissections and aneurysms, diagnostic bias is likely
In contrast to FMD, which typically affects the and rates cannot be generalized to the asympto-
media,moyamoyaistypifiedbyintimalthickening. matic FMD population.
Moyamoya disease shares some pathological fea- Factors associated with FMD include smoking,
tures with FMD, CeAD and intracranial aneurysms exogenous estrogens, mechanical stress, family
primarily constituting transformation of SMCs history of early cardiovascular disease and even
and degraded elastic laminae. The frequency of human lymphocytic antigen type in a series of
moyamoya arterial changes is higher in patients renaltransplantpatients[155,161].The underlying
with CeAD and intracranial aneurysms than the cause of FMD is likely genetic, with incomplete
general population [90,126]. penetrance of a possible autosomal dominant trait
suggestedbyanumberofpedigreesshowinghigher
prevalence in first-degree relatives and identical
Fibromuscular dysplasia
twins [154,162–166]. The FMD registry reveals
Extracranial cervical FMD is second to the renal self-reported family history in 7.3%, somewhat
arteries in prevalence. FMD is characterized by lower than reported in prior series and likely an
nonatherosclerotic, alternating dilatation and con- underestimate given the lack of routine family
strictionofthearterialwall,givingabandedappear- screening [156&,162,166]. That FMD likely repre-
ance, and can involve any of the three layers; the sents a heritable systemic arteriopathy is further
medial type is most common accounting for 90% supported by familial clustering of common
of cerebrocervical cases [152]. Defective fibro- carotid wall abnormalities in cases of renal FMD
blastictransformationinSMCsleadstodownstream compared with matched controls [167,168].
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Cerebrovascular disease
Table 4. Genetics ofmoyamoya disease
Name Gene,locus Genefunction Mode Associatedfeatures
MYMY1 3p26–p24.2[137,142] Matrixmetalloproteinase AD
MYMY2 RNF213;17q25.3 Ubiquitinligaseactivity AD AssociatedwithHTN[145&]
[27,130&,139&,143,144] andATPaseactivity andimportantrolein
vascularfunction[146&]
MYMY3 Unknown;8q23[141] Unknown–TIEG,transforming AD
growthfactor-beta-inducible
earlygrowthresponse
MYMY4 BRCC3;Xq28[138&,147] Deubiquitinatingenzyme X-linkedrecessive Shortstature,hypergonadotropic
hypogonadismandfacial
dysmorphism,dilated
cardiomyopathy,premature
grayingofthehairand
early-onsetcataracts
MYMY5 ACTA2;10q23.31[43,46] Mutationspromoteincreased AD TAA,fusiformcerebralaneurysms,
SMCproliferation,leada prematureCAD.Initially
hyperplastic‘vasculo-myopathy’[44] reportedashereditarythoracic
aorticaneurysm6with
dissection(AAT6)[43]
Moyamoyadisease HLA;6q25[148–150,151&] Molecularmimicry;HLAmolecules Complex Potentialexplanationforregional
actingasreceptorsformicrobes differences
anddrugs;HLAgenesasmarkers
linkedwithdisease-relatednon-HLA
genes
Microcephalic PCNT(pericentrin); Involvedintheinitialestablishment ARorcompound Cerebralaneurysms,moyamoya
osteodysplastic 21q22[26] oforganizedmicrotubulearrays heterozygous
primordialdwarfism ofthecentrosome
typeII(MOPD2)
Neurofibromatosis NF1(neurofibromin) Tumorsuppressor,regulatorof AD Cerebralaneurysms,
type1 17q11.2[27] neurotrophin-mediatedsignalling aorticaneurysms,moyamoya
[28]
Grangesyndrome Unknown;unknown Unknown AR Stenosisorocclusionofmultiple
[16,29&,30] arteries,includingrenal,
abdominalandcerebralarteries.
Cerebralaneurysms,congenital
heartdefects,brachydactyly,
syndactyly,bonefragilityand
learningdisabilities
OMIM,OnlineMendelianInheritanceinMandatabase(www.ncbi.nlm.nih.gov/omim).AD,autosomaldominant;AR,autosomalrecessive;CAD,coronaryartery
disease;HLA,humanleukocyteantigen;HTN,hypertension;SMC,smoothmusclecell;TAA,thoracicaorticaneurysm.DerivedfromOMIM.
Genomic association studies in FMD are lacking. A moyamoya and FMD, have common roots is
systematic screen of 35 patients with FMD for con- through observed associations with one another.
nective tissue genetic variants identified only two
cases with a similar phenotype that had novel var- Epidemiology
iantsinthe transforminggrowth factor breceptor1 Schievink,Mokri,andcolleaguessuggestedaunify-
genewarrantingfurtherinvestigation[169&].Table5 ing arteriopathy in a 1991 report of three families
presentstheseanalysesandothercase-reportedsyn- with CeAD and intracranial aneurysm in siblings,
dromic associations [11,17–21,163,169&,170–175]. and later confirmed a higher prevalence of intra-
The US FMD registry [176] and the ARCADIA/ cranial aneurysm among nonfamilial CeAD as well
PROFILE (Assessment of Renal and Cervical Artery [7,178]. As stated, both dissections and aneurysms
DysplasIARegisteretPROgressionofFIbromuscular are associated with FMD at higher frequencies
Lesions) [177] biorepositories are in preparation than the general population, as are intracranial
formoreformalcandidategeneandgenomicassoci- aneurysms in moyamoya disease [126]. A true co-
ation studies. prevalence between CeAD and FMD with moya-
moya disease has only been reported in isolated
casesandisdifficulttodistinguishfrommoyamoya
Shared associations among polygenic
syndrome resulting from distal carotid stenosis
phenotypes
secondary to these entities [117,168–170]. Genetic
The best argument that large-vessel cervicocerebral syndromes with coprevalence of arteriopathies
arteriopathies, including aneurysms, dissection, in the cerebral and extra-cerebral circulation exist
20 www.co-neurology.com Volume26 (cid:1) Number1 (cid:1) February2013
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Nonatherosclerotic cerebrocervical vasculopathies Southerland etal.
Table 5. Geneticinvestigations and syndromic reportsoffibromuscular dysplasia
Gene/syndrome Renal Cerebrocervical
ACE Insertionalleleassociated[170] n/a
AT1R Noassociation[170] n/a
AGT Noassociation[170] n/a
Elastin Noassociation[163] n/a
Alpha-1-antitripsin Noassociation[171];Casereport[20] Casereports[17–19,21]
ACTA2 Noassociation[172] n/a
TGFBR1 n/a Noassociation[169&]
TGFBR2 n/a Noassociation[169&]
collagen3A1 n/a Noassociation[169&]
smoothmusclea-actin2 n/a Noassociation[169&]
SMAD3 n/a Noassociation[169&]
Fibrillin(Marfansyndrome) n/a Noassociation[169&];Casereport[11]
Downsyndrome Casereport[173] n/a
Turnersyndrome n/a Casereport[174]
NeurofibromatosisI Casereport[175] n/a
n/a,notavailable.
(Table 1). These clinical and genetic observations an underdiagnosis due to a low risk of rupture or
suggest more than a coincidental, common patho- morelikelyanage-dependentcomponenttoaneur-
genesis. ysm formation. Better understanding of how the
cerebrovascularsystemagesbothmorphometrically
Age andfunctionallymayhelpunravelthepathogenesis
As mentioned, aneurysmal SAH, spontaneous of these polygenic phenotypes.
CeAD and symptomatic FMD all predominate in
adultsprimarilyrangingfrom30to50years,witha Sex
separate peak for adult cases of moyamoya. The FMD, moyamoya and aneurysmal rupture are all
reasonsforthismidlifepeakareunclear,especially more prevalent in women. Although CeAD occurs
as each entity occurs to some degree at all at roughly equal frequency by sex, women are
ages. Natural vascular stiffening or accumulating consistentlyyoungerthanmenatageofoccurrence,
atherosclerosis may explain the lower pre- have more vertebral artery involvement and more
valence among the elderly. That some traditional commonly present with multiple artery dissections
age-related vascular risk factors are inversely [98&]. Dissection and risk of aneurysm rupture are
associated with arterial dissection and aneurysm more common in the peripartum period, perhaps
rupture further supports this idea. For instance, related to hormonal shifts or an ever-changing
natural lipid deposition in the vessel wall may physiological state [103,179,180]. Limited data
fortify a congenitally weakened artery protecting suggest at least some relationship between exo-
it from downstream events such as hemorrhage genousestrogensandriskforintracranialaneurysm
or dissection. rupture, incidence of CeAD and symptomatic FMD
If these arteriopathies are genetically pre- [161,181,182].
disposed, the reasons why spontaneous CeAD The biological mechanism of a hormonal
and aneurysmal SAH are not more prevalent in influenceonriskforcerebrovasculareventsinthese
adolescents and young adults are unclear. The sep- arteriopathies remains unknown. Women have
arateagepeaksforchildrenandadultsinmoyamoya stiffer arteries than men, particularly at younger
disease, FMD and dissection highlight a potential ages, but both sexes see decreased arterial compli-
pathological variance between children and adults ancewithage[183,184].Estrogensupplementation
exemplified by the predominance of intimal FMD increases arterial compliance in postmenopausal
and intracranial dissection in children, as opposed women, as does free testosterone in older
to more medial FMD and extracranial dissection men [185,186]. Arterial compliance is increased in
in adults. Intracranial aneurysms are rarely patients with CeAD compared with age-matched
reported in children without other phenotypic controls[187,188].Arterialcomplianceinaneurysm
connective tissue disease; possible reasons include growth is clearly increased, but relationships
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Cerebrovascular disease
between compliance and rupture may be more stress.Focusonshareddiseaseamongthesearterio-
reliant on structural integrity at time-of-event. pathies should guide future association studies
Hormones may influence vessel wall physio- enlightening the search for therapeutic targets.
logy. In rat models of aortic aneurysm, men
have decreased collagen deposition and increased Environmental and physiological risk
levels of matrix metalloproteinases (MMPs), a key factors
mediator of vascular remodelling, in aortic Traditional vascular risk factors for atherosclerosis
SMCs and ECM compared with females [189,190]. including hyperlipidemia, diabetes mellitus and
Estrogen may play a protective role by lowering high BMI show an inverse relationship with both
MMP levels in the model [191]. MMP levels can arterial dissection and aneurysmal subarachnoid
be elevated in CeAD [192], but sex-stratified hemorrhage [99&,181,182,207]. Although these
differences have not been studied. associations may represent epiphenomenae, these
chronic conditions may also provide inherent pro-
Race/ethnicity tective qualities. Lower cholesterol levels including
Incidence and clinical characteristics vary by phe- treatment with lipid-lowering agents may increase
notype across ancestral populations. Investigated risk for intracerebral hemorrhage [208–211].
cohorts of CeAD and FMD mostly comprise cases Diabetes mellitus exhibits an inverse association
ofEuropeanandAsiandescent,withlimiteddatafor with abdominal aneurysm formation as well, and
populations of African descent [123,193,194]. Dis- is associated with increased collagen deposition,
section characteristics also differ by race/ethnicity; cross-linking and decreased degradation of the
Asians have a higher predilection for intracranial ECM in the arterial wall [212&,213]. The inverse
dissection and posterior circulation involvement relationship with BMI may stem from a particular
[195&]. Intracranial aneurysms exhibit consistent phenotypic profile for arteriopathic connective
prevalence throughout the world, but rupture tissue disease, although most patients with spon-
rates vary widely. For instance, rates of aneurysmal taneouslyoccurringcasesdonotexhibitaMarfan’s
SAH are highest in Japan and Finland despite no phenotype [100].
difference in prevalence of unruptured aneurysms Hypertension as a risk factor for these arterio-
compared with other countries [61&]. In the pathies is challenging to understand [99&,161,182],
United States, African-Americans and Hispanics particularlygivenitshighprevalenceinthegeneral
have higher rates of aneurysmal SAH than non- population. The higher frequency of hypertension
Hispanic whites when controlling for additional in FMD, CeAD, intracranial aneurysm rupture and
risk factors [22,26,29&,30]. Moyamoya disease, moyamoya could reflect biomechanical effects on
most prevalent in Asian populations, is reported the arterial wall or secondary alterations in the
worldwide with higher rates in those of African autonomic or renin–angiotensin systems related
descent than those of European descent [196]. to the vasculopathy itself. Although chronic
These population-based differences are vital to hypertension is associated with abdominal
understanding the genetic heterogeneity. Future aneurysms, the influence on formation of cerebral
genomicassociationstudiesshouldstrivetostratify aneurysms is less clear. Further, arterial anomalies
with broad race/ethnic representation. (kinking, redundancies and dilatations) typically
seen in hypertension are observed in non-
Disease hypertensivepatientswiththesenonatherosclerotic
Disparate pathological processes underlie these arteriopathies.
large-vessel arteriopathies likely reflecting their Smoking,ubiquitousinitsadverseeffectsonthe
polygenic origins; however, several unifying com- cerebrovascular system, also interacts with arterial
ponents stand out (Table 6) [10,54,95&,111,112, wall integrity in arteriopathic connective tissue
113&,115,152–154,192,197–206].Afunctionaltrans- phenotypes. Dermal changes in chronic smokers
formationinSMCsofthearterialmediaisacommon demonstrate its effect on the elastic properties of
denominatorforthesephenotypes.Otherprocesses, connectivetissue[214].Smokingisasignificantrisk
including degradation of the ECM and inflam- factor for aneurysmal SAH, particularly in women
mation, may be downstream results from this [182]. Smoking is more loosely associated with
unifyingevent.Structuralpatternsinthevesselwall FMD [155,161]. No similar association with CeAD
are specific to different arterial beds, and alteration has been observed; in fact, smoking might have a
of this homeostasis in different phenotypes likely potentialprotectiveeffectprovokingthepossibility
promotesarterialfragilityandinjuryinthesettingof of a differential relationship between smoking and
otherwise normal physiological or environmental differing arteriopathic phenotypes [99&,181].
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