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Intracranial vessel stenosis in a young patient with an MYH11 mutation: A case report and review of two prior cases
Journal Pre-proof Intracranial vessel stenosis in a young patient with an MYH11 mutation: A case report and review of two prior cases Anthony Larson, B.S., Lorenzo Rinaldo, M.D., Ph.D., Waleed Brinjikji, M.D., James Klaas, M.D., Giuseppe Lanzino, M.D. PII:
S1878-8750(20)30329-6
DOI:
https://doi.org/10.1016/j.wneu.2020.02.054
Reference:
WNEU 14329
To appear in:
World Neurosurgery
Received Date: 17 January 2020 Accepted Date: 8 February 2020
Please cite this article as: Larson A, Rinaldo L, Brinjikji W, Klaas J, Lanzino G, Intracranial vessel stenosis in a young patient with an MYH11 mutation: A case report and review of two prior cases, World Neurosurgery (2020), doi: https://doi.org/10.1016/j.wneu.2020.02.054. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier Inc. All rights reserved.
Intracranial vessel stenosis in a young patient with an MYH11 mutation: A case report and review of two prior cases Authors: Anthony Larson, B.S.a; Lorenzo Rinaldo, M.D., Ph.D.b; Waleed Brinjikji, M.D.a; James Klaas, M.D.c; Giuseppe Lanzino, M.D.a,b a
Department of Radiology, Mayo Clinic, 200 1st St. SW, Rochester MN, USA 55905
b
Department of Neurosurgery, Mayo Clinic, 200 1st St. SW, Rochester MN, USA 55905
c
Department of Neurology, Mayo Clinic, 200 1st St. SW, Rochester MN, USA 55905
Corresponding author: Anthony Larson 200 1st St. SW Rochester MN, 55905 [email protected] Dr. Lorenzo Rinaldo [email protected] Dr. Waleed Brinjikji [email protected] Dr. Giuseppe Lanzino [email protected] Dr. James Klaas [email protected]
Key words: intracranial stenosis, MYH11, Moyamoya, ACTA2, moyamoya Short Title: Intracranial vessel stenosis in a patient with an MYH11 mutation Declaration of Interests: None Abbreviations: TAAD=Thoracic aortic aneurysm and/or aortic dissection PDA=Patent ductus arteriosus SMC=Smooth muscle cell TIA=Transient ischemic attack MRA=Magnetic resonance angiogram CNS=Central nervous system ACA=Anterior Cerebral Artery ICA=Internal Carotid Artery MCA= Middle Cerebral Artery SAH=Subarachnoid hemorrhage SDH=Subdural hematoma MMD=Moyamoya disease
Background The MYH11 gene codes for smooth muscle myosin heavy chain which has a critical function in maintaining vascular wall stability. Patients with this mutation most commonly have aortic and cardiac defects. Documented involvement of intracranial vessels is exceptional.
Case Description and Results A 29-year-old female with a history of patent ductus arteriosus (PDA) and aortic dissection was found to have incidental bilateral stenosis of the terminal Internal Carotid Arteries (ICAs) as well as the proximal Anterior Cerebral Arteries (ACAs), Middle Cerebral Arteries (MCAs) and Posterior Cerebral Arteries (PCAs) on magnetic resonance angiography (MRA) that was obtained for unrelated symptoms. There was no evidence of basal collateral formation, and a generalized “straightening” of the vessels was observed. These angiographic findings have been typically observed in patients with ACTA2 mutations. As such, genetic testing was pursued which uncovered the presence of an MYH11 mutation. 51-month follow-up imaging demonstrated that the intracranial stenosis remained stable without evidence of basal collateral formation. She has not experienced any neurological events during the follow-up interval.
Conclusion Intracranial vessel involvement in patients with MYH11 mutations is rare. Vigilant cerebrovascular monitoring should be practiced in this population so as to guide appropriate management. Reporting of similar cases is important to improve our understanding of the development of idiopathic intracranial stenosis in young individuals.
Introduction The MYH11 gene codes for smooth muscle myosin heavy chain, a vital contractile protein component within smooth muscle cells that is implicated in maintaining blood vessel wall stability.1 As such, patients with mutations in this gene locus often present with vessel wall abnormalities, most commonly thoracic aortic aneurysm and/or aortic dissection (TAAD) and PDA.1 In addition to compromise of vessel wall integrity, focal areas of smooth muscle cell (SMC) hyperplasia can be observed leading to marked luminal narrowing.1, 2 Though several pathological implications of MYH11 mutations are now known, the effect that this gene mutation has on the intracerebral vasculature remains uncertain. To our knowledge, only two prior cases documenting cerebrovascular manifestations of MYH11 mutations have been published.3, 4 Here, we present the case of a patient with an MYH11 mutation found to have incidental intracranial stenosis.
Case Description A 29-year-old female non-smoker with a history of PDA and aortic dissection with aortic valve replacement on chronic anticoagulation therapy with warfarin presented with intermittent vertiginous sensation at times associated with vertical or horizontal diplopia. She also complained of intermittent unilateral frontal headaches of gradual onset but denied sudden-onset “thunderclap” headaches. She did not use any illicit drugs, triptans, ergotamines, or any adrenergic, serotonergic or other sympathomimetic medications. She had no history of autoimmune disease or systemic vasculitic disorders. Her family history was remarkable for coronary artery disease prematurely in her father in his 40s, as well as a transient ischemic attack (TIA) at age 53, and heterozygous factor V Leiden mutation in her mother. Four great paternal
uncles had suffered fatal myocardial infarction in their 30’s. She had no features of connective tissue disease including pectus excavatum or carinatum, extensible skin, joint hypermobility, or increased arm span. Out of concern for potential vertebrobasilar TIAs, a brain MRA was performed. This showed bilateral stenosis of the terminal portion of the ICAs, in addition to the bilateral proximal MCAs, ACAs and PCAs (Figure 1A and B.) No collateral Moyamoya vessels were evident, and no aneurysms were observed. Additionally, a generalized “straightening” of the cerebral vessels was noted (Figure 1C). No dilated surface vessels or “ivy sign” was noted. There was no evidence of thromboembolism or infarction. This angiographic phenotype has been previously documented in patients with ACTA2 gene mutations, a gene which codes for smooth muscle alpha actin, but genetic testing for this, as well as testing for Marfan syndrome and other connective tissue disorders was negative. However, genetic testing did demonstrate the presence of an MYH11 IVS28 c.3858+ 1G>A (IVS28+1G>A) mutation. This mutation occurs at a donor splice site resulting in aberrant MYH11 mRNA. Subsequent genetic testing of her family found that her mother is a carrier of the mutated MYH11 gene, and her sister, brother and youngest son are also positive for the mutation. Her sister suffered an aortic aneurysm in pregnancy, but the rest of her family remains asymptomatic. 51-month follow-up imaging did not demonstrate progression of intracranial stenosis or formation of basal collaterals (Figure 2). She has remained free of any new neurological events over this interval.
Discussion Mutations in multiple different vascular SMC contractile proteins have been shown to manifest as vascular disorders, most commonly TAAD and PDA.5 However, involvement of the
cerebral vasculature is less commonly documented. Our case provides further evidence that MYH11 mutations may involve cerebral vasculature. MYH11 is a protein encoding gene located on the short arm of chromosome 16. The protein product of this gene, smooth muscle myosin heavy chain, plays a crucial role in the contractile apparatus of vascular smooth muscle, in addition to maintaining appropriate histological organization and integrity of vascular walls.2 The exact molecular mechanism of pathogenesis in the setting of MYH11 mutations is not well understood, though multiple aberrant signaling pathways may be involved.2, 6 Intracerebral arteriopathy in the setting of an MYH11 mutation has been reported twice previously to our knowledge (Table 1). Keylock et al.3 presented the case of a 2-year-old girl who presented with an acute infarct in the left ACA/MCA territory found to have a heterozygous mutation in the MYH11 gene NM_002474:c.4604G>A(p.R1535Q). Subsequent catheter angiography demonstrated the presence of bilateral stenosis of the terminal ICAs and MCAs, in addition to showing a generalized straightening of the vessels, similar to that found in our patient here. Intriguingly, their patient had prominent basal collateralization pattern, similar to that seen in Moyamoya disease/syndrome.7 This finding was notably absent in our patient. A second case reported by Ravindra and colleagues4 involved a 6-month-old female who presented with subarachnoid hemorrhage (SAH) as a result of a multiple ruptured MCA aneurysms. Genetic testing revealed a heterozygous mutation of MYH11 on 6p13.11 (c.5273G > A). Of interest, cerebral angiography demonstrated a lack of vessel straightening and absence of basal Moyamoya collateral vessels. This phenotypic discrepancy could be due to the different mutations of the MYH11 gene present in each case. The presence of multiple aneurysms in this
6-month-old infant confirms the vital role of MYH11 gene product in maintaining intracerebral vascular integrity. The intracranial vessel stenosis seen in this case and the previous cases of MYH11 mutations is similar to Moyamoya disease (MMD) in its anatomical distribution, in terms of proximal MCA, ACA and distal ICA involvement. Further, certain histopathological features of arterial walls in the context of MYH11 mutations are also seen in MMD. These similarities may suggest that MYH11 is a component of MMD pathogenesis. However, there are several important differences that exist. Firstly, our patient had involvement of the bilateral PCAs, a finding that is typically only seen in high Suzuki Grade MMD.7 Given that our patient would likely have a Suzuki Grade of 1 or 2,8 the involvement of the PCAs in this case is an important discrepancy between MMD and our patient with an MYH11 mutation. Secondly, no basal collaterals were seen in our patient, which are an important diagnostic feature of MMD. It is important to note that, given the low corresponding Suzuki Grade our patient would have had, the stenosis may not have been sufficient to trigger vessel collateralization, and therefore this potential difference is uncertain. Finally, the angioarchitecture in patients with MMD does not typically involve a generalized straightening of the vessels as seen in our patient. These differences highlight that, although our patient had stenosis reminiscent of that seen in MMD, a mutation in the MYH11 gene alone does not generate a complete MMD phenotype. Therefore, involvement of the MYH11 gene in MMD pathogenesis, though possible given some phenotypic similarities, remains unclear. Previous reports have found that patients with mutations in the ACTA2 gene (multisystemic smooth muscle dysfunction, which codes for smooth muscle alpha actin protein), have similar systemic vasculopathic symptoms as patients with MYH11 mutations9 including a
generalized straightening of the cerebral vessels.10 However, all prior reported cases of ACTA2 mutations with concomitant cerebrovascular arteriopathy have been without evidence of basal Moyamoya-like collateral vessels10, 11 regardless of mutation site within the ACTA2 gene.9, 11 It remains unclear as to why our patient did not develop basal collaterals, and the patient presented by Keylock and colleagues did. One potential explanation may lie in the different mutations within the MYH11 gene locus present in each case, with each unique mutation resulting in a unique phenotype. It is also possible that our patient may not have had sufficient time in order to generate such collateral circulation. With the absence of collateral formation at 51-month followup, this seems less likely. Given the less-severe intracranial stenosis seen on imaging, the likely explanation is that the stenosis was not severe enough to trigger the formation of collateral vessels. Regardless, these observations implicate that patients found to have intracranial stenosis with straightening of vessels regardless of the presence of “Moyamoya collaterals” should be screened for an MYH11 mutation in addition to an ACTA2 mutation. Furthermore, these observations could indicate that, although MYH11 and ACTA2 genes produce similar protein products involved in smooth muscle function, intracranial stenosis results from similar yet distinct pathophysiological mechanisms in each case. Given the evolving knowledge on this topic and potential association, reporting of similar cases are important to further our knowledge and channel further research in the understanding of the development of “idiopathic” intracranial stenosis in young individuals. It is reasonable to suggest that patients found to harbor the MYH11 mutation should be screened for cerebrovascular disease in order to provide appropriate management. As previously suggested,3 this carries clinical relevance since patients with known MYH11 mutations may receive anti-hypertensive treatment in order to decrease aortic wall damage, which could result in
cerebral hypoperfusion in predisposed patients. With the addition of the present case to the two prior cases reviewed here, we herein emphasize the importance of recognizing cerebral arteriopathy as a potential complication in patients with MYH11 mutations, much like in cases of patients with ACTA2 mutations.
Acknowledgements The authors have no acknowledgements
Funding No funding was received to carry out this study
References
1.
Zhu L, Vranckx R, Khau Van Kien P, et al. Mutations in myosin heavy chain 11 cause a
syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus. Nat Genet. 2006;38(3): 343-349. https://doi.org/10.1038/ng1721. 2.
Pannu H, Tran-Fadulu V, Papke CL, et al. MYH11 mutations result in a distinct vascular
pathology driven by insulin-like growth factor 1 and angiotensin II. Hum Mol Genet. 2007;16(20): 2453-2462. https://doi.org/10.1093/hmg/ddm201. 3.
Keylock A, Hong Y, Saunders D, et al. Moyamoya-like cerebrovascular disease in a child
with a novel mutation in myosin heavy chain 11. Neurology. 2018;90(3): 136-138. https://doi.org/10.1212/WNL.0000000000004828.
4.
Ravindra VM, Karsy M, Schmidt RH, Taussky P, Park MS, Bollo RJ. Rapid de novo
aneurysm formation after clipping of a ruptured middle cerebral artery aneurysm in an infant with an MYH11 mutation. J Neurosurg Pediatr. 2016;18(4): 463-470. https://doi.org/10.3171/2016.5.PEDS16115. 5.
Milewicz DM, Guo DC, Tran-Fadulu V, et al. Genetic basis of thoracic aortic aneurysms
and dissections: focus on smooth muscle cell contractile dysfunction. Annu Rev Genomics Hum Genet. 2008;9: 283-302. https://doi.org/10.1146/annurev.genom.8.080706.092303. 6.
Renard M, Callewaert B, Baetens M, et al. Novel MYH11 and ACTA2 mutations reveal
a role for enhanced TGFbeta signaling in FTAAD. Int J Cardiol. 2013;165(2): 314-321. https://doi.org/10.1016/j.ijcard.2011.08.079. 7.
Scott RM, Smith ER. Moyamoya disease and moyamoya syndrome. N Engl J Med.
2009;360(12): 1226-1237. https://doi.org/10.1056/NEJMra0804622. 8.
Suzuki J, Takaku A. Cerebrovascular "moyamoya" disease. Disease showing abnormal
net-like vessels in base of brain. Arch Neurol. 1969;20(3): 288-299. https://doi.org/10.1001/archneur.1969.00480090076012. 9.
Guo DC, Papke CL, Tran-Fadulu V, et al. Mutations in smooth muscle alpha-actin
(ACTA2) cause coronary artery disease, stroke, and Moyamoya disease, along with thoracic aortic disease. Am J Hum Genet. 2009;84(5): 617-627. https://doi.org/10.1016/j.ajhg.2009.04.007. 10.
Amans MR, Stout C, Fox C, et al. Cerebral arteriopathy associated with Arg179His
ACTA2 mutation. BMJ Case Rep. 2013;2013. https://doi.org/10.1136/bcr-2013-010997.
11.
Munot P, Saunders DE, Milewicz DM, et al. A novel distinctive cerebrovascular
phenotype is associated with heterozygous Arg179 ACTA2 mutations. Brain. 2012;135(Pt 8): 2506-2514. https://doi.org/10.1093/brain/aws172.
Figure Legends Figure 1. Intracranial stenosis in a patient with an MYH11 gene mutation. Basal Moyamoya-like collateral vessels are not visualized. (A) Axial MRA demonstrating stenosis of the proximal MCAs (arrows). (B) Coronal MRA demonstrating stenosis of the bilateral ICA termini (black arrows), ACAs (solid white arrows) and PCAs (dashed white arrows). (C) Sagittal MRA showing generalized straightening of the intracranial vessels.
Figure 2. 51-month follow-up imaging without significant changes in stenosis after accounting for differences in imaging techniques. (A) Axial MRA demonstrating persistent proximal MCA stenosis (arrows). (B) Coronal MRA demonstrating persistent stenosis of the bilateral ICA termini (black arrows), ACAs (solid white arrows) and PCAs (dashed white arrows). There is no evidence of basal collateral vessel development.
Table 1. Case summaries of MYH11 mutations with cerebrovascular manifestation.
Table 1. Study
Age/Sex
Clinical Presentation Acute left ACA/MCA infarct
MYH11 Mutation NM_002474:c.4 604G>A(p.R15 35Q)
Keylock et al.3
2 yr./F
Ravindra et 6 mo./F al.4
SAH/SDH
16p13.11 (c.5273G>A)
Present Study
Headache
IVS28 c.3858+ 1G>A (IVS28+1G>A)
29 yr./F
Angiographic features
Treatment
Follow-up Clinical/Radiographic time outcome 48 months Stable residual asymmetric tetraparesis with pseudobulbar features. Progression of bilateral intracranial stenosis with increased basal collateral formation* 3 months Improvement of R-sided hemiparesis. No radiographic follow-up
Bilateral stenosis of terminal ICA and proximal MCA with Moyamoya-like collateral formation*
Bilateral pial synangiosis
Some evidence of delayed distal MCA filling, otherwise normal appearance†
Microsurgical clipping of original ruptured aneurysm, Onyx embolization of subsequent de novo aneurysm Continuation of chronic 51 months anticoagulation and antiplatelet therapy
Stenosis of terminal ICAs, No new neurological proximal MCAs, PCAs and events. Stable intracranial ACAs. Generalized stenosis‡ ‡ straightening of vessels * Visualized on digital subtraction catheter angiography † Visualized on CTA ‡ Visualized on MRA Abbreviations: ACA=Anterior Cerebral Artery, ICA=Internal Carotid Artery, MCA=Middle Cerebral Artery, PCA=Posterior Cerebral Artery, SAH=Subarachnoid Hemorrhage, SDH=Subdural Hematoma
Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
S1878-8750(20)30329-6
DOI:
https://doi.org/10.1016/j.wneu.2020.02.054
Reference:
WNEU 14329
To appear in:
World Neurosurgery
Received Date: 17 January 2020 Accepted Date: 8 February 2020
Please cite this article as: Larson A, Rinaldo L, Brinjikji W, Klaas J, Lanzino G, Intracranial vessel stenosis in a young patient with an MYH11 mutation: A case report and review of two prior cases, World Neurosurgery (2020), doi: https://doi.org/10.1016/j.wneu.2020.02.054. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier Inc. All rights reserved.
Intracranial vessel stenosis in a young patient with an MYH11 mutation: A case report and review of two prior cases Authors: Anthony Larson, B.S.a; Lorenzo Rinaldo, M.D., Ph.D.b; Waleed Brinjikji, M.D.a; James Klaas, M.D.c; Giuseppe Lanzino, M.D.a,b a
Department of Radiology, Mayo Clinic, 200 1st St. SW, Rochester MN, USA 55905
b
Department of Neurosurgery, Mayo Clinic, 200 1st St. SW, Rochester MN, USA 55905
c
Department of Neurology, Mayo Clinic, 200 1st St. SW, Rochester MN, USA 55905
Corresponding author: Anthony Larson 200 1st St. SW Rochester MN, 55905 [email protected] Dr. Lorenzo Rinaldo [email protected] Dr. Waleed Brinjikji [email protected] Dr. Giuseppe Lanzino [email protected] Dr. James Klaas [email protected]
Key words: intracranial stenosis, MYH11, Moyamoya, ACTA2, moyamoya Short Title: Intracranial vessel stenosis in a patient with an MYH11 mutation Declaration of Interests: None Abbreviations: TAAD=Thoracic aortic aneurysm and/or aortic dissection PDA=Patent ductus arteriosus SMC=Smooth muscle cell TIA=Transient ischemic attack MRA=Magnetic resonance angiogram CNS=Central nervous system ACA=Anterior Cerebral Artery ICA=Internal Carotid Artery MCA= Middle Cerebral Artery SAH=Subarachnoid hemorrhage SDH=Subdural hematoma MMD=Moyamoya disease
Background The MYH11 gene codes for smooth muscle myosin heavy chain which has a critical function in maintaining vascular wall stability. Patients with this mutation most commonly have aortic and cardiac defects. Documented involvement of intracranial vessels is exceptional.
Case Description and Results A 29-year-old female with a history of patent ductus arteriosus (PDA) and aortic dissection was found to have incidental bilateral stenosis of the terminal Internal Carotid Arteries (ICAs) as well as the proximal Anterior Cerebral Arteries (ACAs), Middle Cerebral Arteries (MCAs) and Posterior Cerebral Arteries (PCAs) on magnetic resonance angiography (MRA) that was obtained for unrelated symptoms. There was no evidence of basal collateral formation, and a generalized “straightening” of the vessels was observed. These angiographic findings have been typically observed in patients with ACTA2 mutations. As such, genetic testing was pursued which uncovered the presence of an MYH11 mutation. 51-month follow-up imaging demonstrated that the intracranial stenosis remained stable without evidence of basal collateral formation. She has not experienced any neurological events during the follow-up interval.
Conclusion Intracranial vessel involvement in patients with MYH11 mutations is rare. Vigilant cerebrovascular monitoring should be practiced in this population so as to guide appropriate management. Reporting of similar cases is important to improve our understanding of the development of idiopathic intracranial stenosis in young individuals.
Introduction The MYH11 gene codes for smooth muscle myosin heavy chain, a vital contractile protein component within smooth muscle cells that is implicated in maintaining blood vessel wall stability.1 As such, patients with mutations in this gene locus often present with vessel wall abnormalities, most commonly thoracic aortic aneurysm and/or aortic dissection (TAAD) and PDA.1 In addition to compromise of vessel wall integrity, focal areas of smooth muscle cell (SMC) hyperplasia can be observed leading to marked luminal narrowing.1, 2 Though several pathological implications of MYH11 mutations are now known, the effect that this gene mutation has on the intracerebral vasculature remains uncertain. To our knowledge, only two prior cases documenting cerebrovascular manifestations of MYH11 mutations have been published.3, 4 Here, we present the case of a patient with an MYH11 mutation found to have incidental intracranial stenosis.
Case Description A 29-year-old female non-smoker with a history of PDA and aortic dissection with aortic valve replacement on chronic anticoagulation therapy with warfarin presented with intermittent vertiginous sensation at times associated with vertical or horizontal diplopia. She also complained of intermittent unilateral frontal headaches of gradual onset but denied sudden-onset “thunderclap” headaches. She did not use any illicit drugs, triptans, ergotamines, or any adrenergic, serotonergic or other sympathomimetic medications. She had no history of autoimmune disease or systemic vasculitic disorders. Her family history was remarkable for coronary artery disease prematurely in her father in his 40s, as well as a transient ischemic attack (TIA) at age 53, and heterozygous factor V Leiden mutation in her mother. Four great paternal
uncles had suffered fatal myocardial infarction in their 30’s. She had no features of connective tissue disease including pectus excavatum or carinatum, extensible skin, joint hypermobility, or increased arm span. Out of concern for potential vertebrobasilar TIAs, a brain MRA was performed. This showed bilateral stenosis of the terminal portion of the ICAs, in addition to the bilateral proximal MCAs, ACAs and PCAs (Figure 1A and B.) No collateral Moyamoya vessels were evident, and no aneurysms were observed. Additionally, a generalized “straightening” of the cerebral vessels was noted (Figure 1C). No dilated surface vessels or “ivy sign” was noted. There was no evidence of thromboembolism or infarction. This angiographic phenotype has been previously documented in patients with ACTA2 gene mutations, a gene which codes for smooth muscle alpha actin, but genetic testing for this, as well as testing for Marfan syndrome and other connective tissue disorders was negative. However, genetic testing did demonstrate the presence of an MYH11 IVS28 c.3858+ 1G>A (IVS28+1G>A) mutation. This mutation occurs at a donor splice site resulting in aberrant MYH11 mRNA. Subsequent genetic testing of her family found that her mother is a carrier of the mutated MYH11 gene, and her sister, brother and youngest son are also positive for the mutation. Her sister suffered an aortic aneurysm in pregnancy, but the rest of her family remains asymptomatic. 51-month follow-up imaging did not demonstrate progression of intracranial stenosis or formation of basal collaterals (Figure 2). She has remained free of any new neurological events over this interval.
Discussion Mutations in multiple different vascular SMC contractile proteins have been shown to manifest as vascular disorders, most commonly TAAD and PDA.5 However, involvement of the
cerebral vasculature is less commonly documented. Our case provides further evidence that MYH11 mutations may involve cerebral vasculature. MYH11 is a protein encoding gene located on the short arm of chromosome 16. The protein product of this gene, smooth muscle myosin heavy chain, plays a crucial role in the contractile apparatus of vascular smooth muscle, in addition to maintaining appropriate histological organization and integrity of vascular walls.2 The exact molecular mechanism of pathogenesis in the setting of MYH11 mutations is not well understood, though multiple aberrant signaling pathways may be involved.2, 6 Intracerebral arteriopathy in the setting of an MYH11 mutation has been reported twice previously to our knowledge (Table 1). Keylock et al.3 presented the case of a 2-year-old girl who presented with an acute infarct in the left ACA/MCA territory found to have a heterozygous mutation in the MYH11 gene NM_002474:c.4604G>A(p.R1535Q). Subsequent catheter angiography demonstrated the presence of bilateral stenosis of the terminal ICAs and MCAs, in addition to showing a generalized straightening of the vessels, similar to that found in our patient here. Intriguingly, their patient had prominent basal collateralization pattern, similar to that seen in Moyamoya disease/syndrome.7 This finding was notably absent in our patient. A second case reported by Ravindra and colleagues4 involved a 6-month-old female who presented with subarachnoid hemorrhage (SAH) as a result of a multiple ruptured MCA aneurysms. Genetic testing revealed a heterozygous mutation of MYH11 on 6p13.11 (c.5273G > A). Of interest, cerebral angiography demonstrated a lack of vessel straightening and absence of basal Moyamoya collateral vessels. This phenotypic discrepancy could be due to the different mutations of the MYH11 gene present in each case. The presence of multiple aneurysms in this
6-month-old infant confirms the vital role of MYH11 gene product in maintaining intracerebral vascular integrity. The intracranial vessel stenosis seen in this case and the previous cases of MYH11 mutations is similar to Moyamoya disease (MMD) in its anatomical distribution, in terms of proximal MCA, ACA and distal ICA involvement. Further, certain histopathological features of arterial walls in the context of MYH11 mutations are also seen in MMD. These similarities may suggest that MYH11 is a component of MMD pathogenesis. However, there are several important differences that exist. Firstly, our patient had involvement of the bilateral PCAs, a finding that is typically only seen in high Suzuki Grade MMD.7 Given that our patient would likely have a Suzuki Grade of 1 or 2,8 the involvement of the PCAs in this case is an important discrepancy between MMD and our patient with an MYH11 mutation. Secondly, no basal collaterals were seen in our patient, which are an important diagnostic feature of MMD. It is important to note that, given the low corresponding Suzuki Grade our patient would have had, the stenosis may not have been sufficient to trigger vessel collateralization, and therefore this potential difference is uncertain. Finally, the angioarchitecture in patients with MMD does not typically involve a generalized straightening of the vessels as seen in our patient. These differences highlight that, although our patient had stenosis reminiscent of that seen in MMD, a mutation in the MYH11 gene alone does not generate a complete MMD phenotype. Therefore, involvement of the MYH11 gene in MMD pathogenesis, though possible given some phenotypic similarities, remains unclear. Previous reports have found that patients with mutations in the ACTA2 gene (multisystemic smooth muscle dysfunction, which codes for smooth muscle alpha actin protein), have similar systemic vasculopathic symptoms as patients with MYH11 mutations9 including a
generalized straightening of the cerebral vessels.10 However, all prior reported cases of ACTA2 mutations with concomitant cerebrovascular arteriopathy have been without evidence of basal Moyamoya-like collateral vessels10, 11 regardless of mutation site within the ACTA2 gene.9, 11 It remains unclear as to why our patient did not develop basal collaterals, and the patient presented by Keylock and colleagues did. One potential explanation may lie in the different mutations within the MYH11 gene locus present in each case, with each unique mutation resulting in a unique phenotype. It is also possible that our patient may not have had sufficient time in order to generate such collateral circulation. With the absence of collateral formation at 51-month followup, this seems less likely. Given the less-severe intracranial stenosis seen on imaging, the likely explanation is that the stenosis was not severe enough to trigger the formation of collateral vessels. Regardless, these observations implicate that patients found to have intracranial stenosis with straightening of vessels regardless of the presence of “Moyamoya collaterals” should be screened for an MYH11 mutation in addition to an ACTA2 mutation. Furthermore, these observations could indicate that, although MYH11 and ACTA2 genes produce similar protein products involved in smooth muscle function, intracranial stenosis results from similar yet distinct pathophysiological mechanisms in each case. Given the evolving knowledge on this topic and potential association, reporting of similar cases are important to further our knowledge and channel further research in the understanding of the development of “idiopathic” intracranial stenosis in young individuals. It is reasonable to suggest that patients found to harbor the MYH11 mutation should be screened for cerebrovascular disease in order to provide appropriate management. As previously suggested,3 this carries clinical relevance since patients with known MYH11 mutations may receive anti-hypertensive treatment in order to decrease aortic wall damage, which could result in
cerebral hypoperfusion in predisposed patients. With the addition of the present case to the two prior cases reviewed here, we herein emphasize the importance of recognizing cerebral arteriopathy as a potential complication in patients with MYH11 mutations, much like in cases of patients with ACTA2 mutations.
Acknowledgements The authors have no acknowledgements
Funding No funding was received to carry out this study
References
1.
Zhu L, Vranckx R, Khau Van Kien P, et al. Mutations in myosin heavy chain 11 cause a
syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus. Nat Genet. 2006;38(3): 343-349. https://doi.org/10.1038/ng1721. 2.
Pannu H, Tran-Fadulu V, Papke CL, et al. MYH11 mutations result in a distinct vascular
pathology driven by insulin-like growth factor 1 and angiotensin II. Hum Mol Genet. 2007;16(20): 2453-2462. https://doi.org/10.1093/hmg/ddm201. 3.
Keylock A, Hong Y, Saunders D, et al. Moyamoya-like cerebrovascular disease in a child
with a novel mutation in myosin heavy chain 11. Neurology. 2018;90(3): 136-138. https://doi.org/10.1212/WNL.0000000000004828.
4.
Ravindra VM, Karsy M, Schmidt RH, Taussky P, Park MS, Bollo RJ. Rapid de novo
aneurysm formation after clipping of a ruptured middle cerebral artery aneurysm in an infant with an MYH11 mutation. J Neurosurg Pediatr. 2016;18(4): 463-470. https://doi.org/10.3171/2016.5.PEDS16115. 5.
Milewicz DM, Guo DC, Tran-Fadulu V, et al. Genetic basis of thoracic aortic aneurysms
and dissections: focus on smooth muscle cell contractile dysfunction. Annu Rev Genomics Hum Genet. 2008;9: 283-302. https://doi.org/10.1146/annurev.genom.8.080706.092303. 6.
Renard M, Callewaert B, Baetens M, et al. Novel MYH11 and ACTA2 mutations reveal
a role for enhanced TGFbeta signaling in FTAAD. Int J Cardiol. 2013;165(2): 314-321. https://doi.org/10.1016/j.ijcard.2011.08.079. 7.
Scott RM, Smith ER. Moyamoya disease and moyamoya syndrome. N Engl J Med.
2009;360(12): 1226-1237. https://doi.org/10.1056/NEJMra0804622. 8.
Suzuki J, Takaku A. Cerebrovascular "moyamoya" disease. Disease showing abnormal
net-like vessels in base of brain. Arch Neurol. 1969;20(3): 288-299. https://doi.org/10.1001/archneur.1969.00480090076012. 9.
Guo DC, Papke CL, Tran-Fadulu V, et al. Mutations in smooth muscle alpha-actin
(ACTA2) cause coronary artery disease, stroke, and Moyamoya disease, along with thoracic aortic disease. Am J Hum Genet. 2009;84(5): 617-627. https://doi.org/10.1016/j.ajhg.2009.04.007. 10.
Amans MR, Stout C, Fox C, et al. Cerebral arteriopathy associated with Arg179His
ACTA2 mutation. BMJ Case Rep. 2013;2013. https://doi.org/10.1136/bcr-2013-010997.
11.
Munot P, Saunders DE, Milewicz DM, et al. A novel distinctive cerebrovascular
phenotype is associated with heterozygous Arg179 ACTA2 mutations. Brain. 2012;135(Pt 8): 2506-2514. https://doi.org/10.1093/brain/aws172.
Figure Legends Figure 1. Intracranial stenosis in a patient with an MYH11 gene mutation. Basal Moyamoya-like collateral vessels are not visualized. (A) Axial MRA demonstrating stenosis of the proximal MCAs (arrows). (B) Coronal MRA demonstrating stenosis of the bilateral ICA termini (black arrows), ACAs (solid white arrows) and PCAs (dashed white arrows). (C) Sagittal MRA showing generalized straightening of the intracranial vessels.
Figure 2. 51-month follow-up imaging without significant changes in stenosis after accounting for differences in imaging techniques. (A) Axial MRA demonstrating persistent proximal MCA stenosis (arrows). (B) Coronal MRA demonstrating persistent stenosis of the bilateral ICA termini (black arrows), ACAs (solid white arrows) and PCAs (dashed white arrows). There is no evidence of basal collateral vessel development.
Table 1. Case summaries of MYH11 mutations with cerebrovascular manifestation.
Table 1. Study
Age/Sex
Clinical Presentation Acute left ACA/MCA infarct
MYH11 Mutation NM_002474:c.4 604G>A(p.R15 35Q)
Keylock et al.3
2 yr./F
Ravindra et 6 mo./F al.4
SAH/SDH
16p13.11 (c.5273G>A)
Present Study
Headache
IVS28 c.3858+ 1G>A (IVS28+1G>A)
29 yr./F
Angiographic features
Treatment
Follow-up Clinical/Radiographic time outcome 48 months Stable residual asymmetric tetraparesis with pseudobulbar features. Progression of bilateral intracranial stenosis with increased basal collateral formation* 3 months Improvement of R-sided hemiparesis. No radiographic follow-up
Bilateral stenosis of terminal ICA and proximal MCA with Moyamoya-like collateral formation*
Bilateral pial synangiosis
Some evidence of delayed distal MCA filling, otherwise normal appearance†
Microsurgical clipping of original ruptured aneurysm, Onyx embolization of subsequent de novo aneurysm Continuation of chronic 51 months anticoagulation and antiplatelet therapy
Stenosis of terminal ICAs, No new neurological proximal MCAs, PCAs and events. Stable intracranial ACAs. Generalized stenosis‡ ‡ straightening of vessels * Visualized on digital subtraction catheter angiography † Visualized on CTA ‡ Visualized on MRA Abbreviations: ACA=Anterior Cerebral Artery, ICA=Internal Carotid Artery, MCA=Middle Cerebral Artery, PCA=Posterior Cerebral Artery, SAH=Subarachnoid Hemorrhage, SDH=Subdural Hematoma
Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: