Letter to the Editor. Cerebral arteriopathy and the ACTA2 mutation

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  • Mayo Clinic, Rochester, MN
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TO THE EDITOR: We congratulate the authors of the article by Tschoe et al.1 which illustrates two siblings who possessed identical de novo ACTA2 Arg258Cys substitutions, yet demonstrated clinically and radiographically distinct cerebrovascular phenotypes (Tschoe C, Kim TE, Fargen KM, Wolfe SQ. Cerebral arteriopathy in ACTA2 mutations: a spectrum of disease highlighted by a case of variable penetrance in two siblings. J Neurosurg Pediatr. 2021;27[4]:446–451). This is a well-done and intriguing report. As mentioned by the authors, the literature describes the cerebrovascular phenotypical manifestations of patients in the context of ACTA2 mutations to have 1) a pattern of paraclinoid bilateral internal carotid artery (ICA) stenosis similar to that seen in moyamoya angiopathy, 2) lack of basal or leptomeningeal collaterals, and 3) a generalized “straightening” of the cerebral arteries.2–4 The cases in the current report by Tschoe et al., however, demonstrate that cerebrovascular phenotypes in the context of ACTA2 Arg258Cys mutations do not always manifest in this typical pattern of disease, likely due to variable penetrance of this particular mutation.

Patients with mutations in the ACTA2 gene with concomitant intracranial vascular manifestations have been described as early as 2009.5 More recently, other gene mutations that code for smooth muscle contractile proteins have been demonstrated to be associated with cerebrovascular pathology as well, namely the MYH11 gene.6 To our knowledge, only 3 prior cases of MYH11 mutations with concomitant cerebrovascular pathology have been reported. In each separate case, a distinct cerebrovascular phenotype was described. Keylock et al.6 reported the case of a patient with a moyamoya-type angiopathy with bilateral ICA stenosis and basal collateralization. In contrast, a patient presented by Ravindra et al.7 possessed minimal stenosis with delayed middle cerebral artery filling along with a de novo aneurysm.7 We have recently reported a case of a patient with an MYH11 mutation (IVS28 c.3858+ 1G>A [IVS28+1G>A]) who was found to have a similar phenotype to that described in patients with ACTA2 mutations, including bilateral stenosis of the distal ICA and straightening of the cerebral arteries without evidence of collateral vessel formation.8 This patient, however, was negative for an ACTA2 mutation. Interestingly, all 3 reported cases of MYH11 mutations with cerebrovascular pathology had distinct mutations within the MYH11 gene, which may explain the differences in phenotype.

These cases as demonstrated by Tschoe et al.1 in the context of previously reported cases of ACTA2 mutations implicate that 1) clinicians caring for patients with ACTA2 mutations should have a low threshold for cerebrovascular evaluation, and 2) patients possessing ACTA2 mutations with cerebrovascular involvement may not always have similar phenotypes. Furthermore, ACTA2 mutations in addition to MYH11 mutations may both manifest in similar cerebrovascular phenotypes, as noted in our prior report and in one of the patients presented by Tschoe et al. Further work is therefore necessary to elucidate the underlying pathogenesis of smooth muscle protein mutations and the consequent cerebrovascular phenotypes.

Disclosures

The authors report no conflict of interest.

References

  • 1

    Tschoe C, Kim TE, Fargen KM, Wolfe SQ. Cerebral arteriopathy in ACTA2 mutations: a spectrum of disease highlighted by a case of variable penetrance in two siblings. J Neurosurg Pediatr. 2021;27(4):446451.

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  • 2

    Munot P, Saunders DE, Milewicz DM, et al. . A novel distinctive cerebrovascular phenotype is associated with heterozygous Arg179 ACTA2 mutations. Brain. 2012;135(8):25062514.

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  • 3

    Rutledge WC, Choudhri O, Walcott BP, et al. . Indirect and direct revascularization of ACTA2 cerebral arteriopathy: feasibility of the superficial temporal artery to anterior cerebral artery bypass with posterior auricular artery interposition graft: case report. J Neurosurg Pediatr. 2016;18(3):339343.

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  • 4

    Amans MR, Stout C, Fox C, et al. . Cerebral arteriopathy associated with Arg179His ACTA2 mutation. J Neurointerv Surg. 2014;6(9):e46.

  • 5

    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):617627.

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  • 6

    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):136138.

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  • 7

    Ravindra VM, Karsy M, Schmidt RH, et al. . 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):463470.

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  • 8

    Larson A, Rinaldo L, Brinjikji W, et al. . Intracranial vessel stenosis in a young patient with an MYH11 mutation: a case report and review of 2 prior cases. World Neurosurg. 2020;137(243):246.

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Response

No response was received from the authors of the original article.

Contributor Notes

Correspondence Anthony S. Larson: lars4689@umn.edu.

INCLUDE WHEN CITING Published online May 14, 2021; DOI: 10.3171/2021.2.PEDS2182.

Disclosures The authors report no conflict of interest.

  • 1

    Tschoe C, Kim TE, Fargen KM, Wolfe SQ. Cerebral arteriopathy in ACTA2 mutations: a spectrum of disease highlighted by a case of variable penetrance in two siblings. J Neurosurg Pediatr. 2021;27(4):446451.

    • Search Google Scholar
    • Export Citation
  • 2

    Munot P, Saunders DE, Milewicz DM, et al. . A novel distinctive cerebrovascular phenotype is associated with heterozygous Arg179 ACTA2 mutations. Brain. 2012;135(8):25062514.

    • Search Google Scholar
    • Export Citation
  • 3

    Rutledge WC, Choudhri O, Walcott BP, et al. . Indirect and direct revascularization of ACTA2 cerebral arteriopathy: feasibility of the superficial temporal artery to anterior cerebral artery bypass with posterior auricular artery interposition graft: case report. J Neurosurg Pediatr. 2016;18(3):339343.

    • Search Google Scholar
    • Export Citation
  • 4

    Amans MR, Stout C, Fox C, et al. . Cerebral arteriopathy associated with Arg179His ACTA2 mutation. J Neurointerv Surg. 2014;6(9):e46.

  • 5

    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):617627.

    • Search Google Scholar
    • Export Citation
  • 6

    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):136138.

    • Search Google Scholar
    • Export Citation
  • 7

    Ravindra VM, Karsy M, Schmidt RH, et al. . 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):463470.

    • Search Google Scholar
    • Export Citation
  • 8

    Larson A, Rinaldo L, Brinjikji W, et al. . Intracranial vessel stenosis in a young patient with an MYH11 mutation: a case report and review of 2 prior cases. World Neurosurg. 2020;137(243):246.

    • Search Google Scholar
    • Export Citation

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