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A case of hemichorea in RNF213-related vasculopathy

Abstract

Background

Internal carotid artery (ICA) stenosis has been recently reported to cause hemichorea, mainly in East Asia. The East Asian-specific p.R4810K variant of RNF213, a susceptibility gene for moyamoya disease (MMD), accounts for up to 25% of sporadic ischemic stroke with ICA stenosis cases in East Asia. However, as RNF213-related vasculopathy does not meet the diagnostic criteria for MMD, the creation of a new disease category has been suggested. Here, we report the first case of hemichorea in RNF213-related vasculopathy.

Case presentation

An 81-year-old woman was admitted to our hospital with choreic movements in the periphery of the right extremities at rest. Though head magnetic resonance imaging showed no fresh or old cerebral infarction, 123I-iodoamphetamine-single photon emission computed tomography showed cerebral blood flow of < 80% in the anterior territory of the left middle cerebral artery (MCA) in a resting state and cerebrovascular reactivity of < 10% in the broader area supplied by the left MCA after acetazolamide challenge. Head magnetic resonance angiography and digital subtraction angiography revealed left ICA C1 portion stenosis with compromised collateral vessels. Involuntary movements resolved with haloperidol administration within 3 days, without apparent recurrence from continuation of the medication for a year. Genetic testing revealed the presence of the heterozygous RNF213 p.R4810K variant.

Conclusions

Chorea is thought to be caused by damage to circuitry connecting the basal ganglia with the cerebral cortex, as found in cases of MMD, which possess aberrant vessels in the basal ganglia. However, aberrant vessels and cerebral infarctions were not observed in the basal ganglia in the current case, decreasing the likelihood of a role in chorea. Alternatively, as RNF213 regulates vascular endothelial function and angiogenesis, dysregulation may impair the neurovascular unit and damage basal ganglia circuitry, contributing to the development of chorea. This case may renew interest in the concept of RNF213-related vasculopathy and the pathophysiological mechanisms behind chorea in ICA stenosis.

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Background

Chorea is characterized by abrupt involuntary movements resulting from a continuous flow of random muscle contractions [1]. Internal carotid artery (ICA) stenosis rarely causes chorea but has been recently reported to cause hemichorea. These reports emanate mainly from East Asia [2,3,4,5,6,7,8,9,10,11] (Table 1), though the reason for the regional difference is not clear. Nonetheless, chorea is found relatively frequently in 3.3–4.2% of patients with ICA stenosis caused by rare moyamoya disease (MMD) [12]. MMD shows a characteristic ‘East-West gradient’ geographical pattern of the disease prevalence because of the East Asian-specific RNF213 p.R4810K variant [13]. Furthermore, this nonsynonymous p.R4810K variant accounts for up to 25% of sporadic ischemic stroke with ICA stenosis in East Asia, even without meeting the diagnostic criteria of MMD [14], which has led to a novel disease concept of RNF213-related vasculopathy [13]. Here, we report the first case of hemichorea in a RNF213-related vasculopathy other than MMD, which may help define the clinical spectrum of RNF213-related vasculopathy.

Table 1 Cases of hemichorea caused by internal carotid artery stenosis, which did not meet the diagnostic criteria of moyamoya disease

Case presentation

An 81-year-old woman noticed choreic movements in the periphery of the right lower extremity at rest, which gradually became more frequent. One month later, she also noticed involuntary movements in the periphery of the right upper extremity and was admitted to our hospital. On admission, she displayed involuntary, irregular, and nonrhythmic movements in the periphery of the right extremities without other neurological deficits. She had a medical history of hypertension and dyslipidemia but no family history of cerebrovascular disorders or chorea. Blood and cerebrospinal fluid tests and cervical and lumbar spine magnetic resonance imaging (MRI) were normal. Head MRI showed no fresh or old cerebral infarction (Fig. 1a). However, 123I-iodoamphetamine-single photon emission computed tomography showed cerebral blood flow < 80% in the anterior territory of left middle cerebral artery (MCA) in a resting state (Fig. 1b) and cerebrovascular reactivity < 10% in the broader area supplied by the left MCA after acetazolamide challenge (Fig. 1c). Head magnetic resonance angiography (MRA) and digital subtraction angiography revealed left ICA C1 portion stenosis with poor collateral vessels (Fig. 1d, e). She refused recommended extracranial-intracranial bypass surgery; however, the involuntary movements resolved with haloperidol administration within 3 days, without apparent recurrence from continuation of the medication for a year. Follow-up head MRI and MRA taken 1 year later showed no interval changes (Fig. 2a, b). Genetic testing performed with Taqman probes (TaqMan SNP Genotyping Assays; Applied Biosystems) using a 7300/7500 Real-Time PCR System (Applied Biosystems) [15] revealed the presence of the heterozygous RNF213 p.R4810K variant.

Fig. 1
figure1

Hemichorea developed in a case of RNF213-related vasculopathy showing no ischemic stroke on an MRI fluid-attenuated inversion recovery image (a) but reduced cerebral blood flow in a resting state (b, arrowheads) and after acetazolamide challenge (c) of 123I-iodoamphetamine-single photon emission computed tomography with unilateral intracranial stenosis of the left internal carotid artery on MRA (d) and digital subtraction angiography (e, arrowhead)

Fig. 2
figure2

Follow-up head MRI fluid-attenuated inversion recovery image (a) and MRA (b) taken one year later showed no interval changes, including unilateral intracranial stenosis of the left internal carotid artery (b, arrowhead)

Discussion and conclusions

We detail a case of unilateral intracranial ICA stenosis presenting with hemichorea. This case did not meet the diagnostic criteria of MMD [14] because of the presence of unilateral intracranial stenosis of ICA without aberrant vessels in the basal ganglia; however, the patient was found to carry the RNF213 p.R4810K variant, which has been strongly associated with MMD [16]. We and others have reported this variant as a key factor in ischemic stroke with intracranial arterial stenosis, a common stroke subtype found in East Asian cases, and termed ‘RNF213-related vasculopathy’ [13, 16]. This report may indicate a possible explanation of why ICA stenosis leads to chorea more predominantly in East Asia and potentially widens the disease spectrum of RNF213-related vasculopathies through inclusion of chorea as an additional clinical symptom. As with MMD, previous reports have suggested a predominance of hemichorea in ICA stenosis in East Asian cases, which we have termed the ‘East-West gradient’ [11], possibly indicating the importance of not only hemodynamic change, but also the ethnicity-specific RNF213 p.R4810K variant, in hemichorea development. Chorea is thought to be caused by damage to circuitry connecting the basal ganglia with the cerebral cortex [1], as found in cases of MMD with aberrant vessels in the basal ganglia [12]. However, aberrant vessels were not observed in the basal ganglia in the current case, decreasing likelihood of a role in chorea. Alternatively, as RNF213 encodes a protein containing two ATPases associated with diverse cellular activities and an E3 ligase domain that regulate vascular endothelial function and angiogenesis [17], dysfunctional RNF213 may directly damage neural circuitry, contributing to development of chorea. Indeed, we recently reported endothelial cell specific RNF213 mutant (human p.R4810K orthologue) transgenic mice had delayed recovery of cerebral blood flow, more profoundly in the basal ganglia than the cerebral cortex, after cerebral hypoperfusion induced by carotid artery stenosis [18]. Therefore, endothelial damage and resultant neural dysfunction in the basal ganglia may be associated with chorea. Additional cases will be required to uncover the mechanism of the genotype-phonotype association, which may be being obscured by the low penetrance of RNF213 variant and susceptibility to environmental factors [15, 19, 20].

In conclusion, this case may expand and renew the disease concept of RNF213-related vasculopathy and elaborate on the pathophysiological mechanisms behind chorea in ICA stenosis.

Availability of data and materials

Not applicable.

Abbreviations

ICA:

Internal carotid artery

MMD:

Moyamoya disease

MCA:

Middle cerebral artery

MRI:

Magnetic resonance imaging

MRA:

Magnetic resonance angiography

References

  1. 1.

    Cardoso F, Seppi K, Mair KJ, Wenning GK, Poewe W. Seminar on choreas. Lancet Neurol. 2006;5(7):589–602. https://doi.org/10.1016/s1474-4422(06)70494-x.

    Article  PubMed  Google Scholar 

  2. 2.

    Morigaki R, Uno M, Suzue A, Nagahiro S. Hemichorea due to hemodynamic ischemia associated with extracranial carotid artery stenosis. Report of two cases. J Neurosurg. 2006;105(1):142–7. https://doi.org/10.3171/jns.2006.105.1.142.

    Article  PubMed  Google Scholar 

  3. 3.

    Waterston JA, Brown MM, Butler P, Swash M. Small deep cerebral infarcts associated with occlusive internal carotid artery disease. A hemodynamic phenomenon? Arch Neurol. 1990;47(9):953–7. https://doi.org/10.1001/archneur.1990.00530090023007.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Galea I, Norwood F, Phillips MJ, Shearman C, McMonagle P, Gibb WR. Pearls & Oy-sters: resolution of hemichorea following endarterectomy for severe carotid stenosis. Neurology. 2008;71(24):e80–2. https://doi.org/10.1212/01.wnl.0000336975.80810.74.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Fukui T, Hasegawa Y, Seriyama S, Takeuchi T, Sugita K, Tsukagoshi H. Hemiballism-hemichorea induced by subcortical ischemia. Can J Neurol Sci. 1993;20(4):324–8.

    CAS  Article  Google Scholar 

  6. 6.

    Kim DW, Ko Y, Jang SH, Yoon SJ, Oh GS, Lee SJ, et al. Acute hemichorea as an unusual presentation of internal carotid artery stenosis. J Mov Disord. 2013;6(1):17–20. https://doi.org/10.14802/jmd.13004.

    Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Pareés I, Pujadas F, Hernández-Vara J, Lorenzo-Bosquet C, Cuberas G, Munuera J, et al. Reversible hemichorea associated with extracranial carotid artery stenosis. J Neurol Sci. 2011;300(1–2):185–6. https://doi.org/10.1016/j.jns.2010.08.068.

    Article  PubMed  Google Scholar 

  8. 8.

    Shimizu T, Hiroki M, Yamaoka Y, Kato S, Suda M, Ide K, et al. Alternating paroxysmal hemiballism-hemichorea in bilateral internal carotid artery stenosis. Intern Med. 2001;40(8):808–12. https://doi.org/10.2169/internalmedicine.40.808.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Kodera Y, Nakayama T, Yutani S, Uesugi T, Ohnuki Y, Takizawa S. Hemichorea improved by carotid artery stenting in a 73-year-old man with hypoperfusion of the basal ganglia. Rinsho Shinkeigaku. 2015;55(5):356–9. https://doi.org/10.5692/clinicalneurol.cn-000641.

    Article  PubMed  Google Scholar 

  10. 10.

    Noda K, Ishimoto R, Hattori N, Okuma Y, Yamamoto T. Hemichorea improvement following endarterectomy for internal carotid artery stenosis. J Neurol Sci. 2016;371:45–7. https://doi.org/10.1016/j.jns.2016.10.019.

    Article  PubMed  Google Scholar 

  11. 11.

    Muguruma K, Motoda A, Sugimoto T, Kitamura T. A case of hemichorea caused by right internal carotid artery stenosis. Rinsho Shinkeigaku. 2019;59(8):509–14. https://doi.org/10.5692/clinicalneurol.cn-001276.

    Article  PubMed  Google Scholar 

  12. 12.

    Ahn ES, Scott RM, Robertson RL Jr, Smith ER. Chorea in the clinical presentation of moyamoya disease: results of surgical revascularization and a proposed clinicopathological correlation. J Neurosurg Pediatr. 2013;11(3):313–9. https://doi.org/10.3171/2012.11.PEDS12199.

    Article  PubMed  Google Scholar 

  13. 13.

    Okazaki S, Morimoto T, Kamatani Y, Kamimura T, Kobayashi H, Harada K, et al. Moyamoya disease susceptibility variant RNF213 p.R4810K increases the risk of ischemic stroke attributable to large-artery atherosclerosis. Circulation. 2019;139(2):295–8. https://doi.org/10.1161/CIRCULATIONAHA.118.038439.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Guidelines for diagnosis and treatment of moyamoya disease (spontaneous occlusion of the circle of Willis). Neurol Med Chir (Tokyo). 2012;52(5):245–66. https://doi.org/10.2176/nmc.52.245.

  15. 15.

    Liu W, Morito D, Takashima S, Mineharu Y, Kobayashi H, Hitomi T, et al. Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development. PLoS One. 2011;6(7):e22542. https://doi.org/10.1371/journal.pone.0022542.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Bang OY, Chung JW, Kim DH, Won HH, Yeon JY, Ki CS, et al. Moyamoya disease and spectrums of RNF213 vasculopathy. Transl Stroke Res. 2020;11(4):580–9. https://doi.org/10.1007/s12975-019-00743-6.

    Article  PubMed  Google Scholar 

  17. 17.

    Kamimura T, Okazaki S, Morimoto T, Kobayashi H, Harada K, Tomita T, et al. Prevalence of RNF213 p.R4810K variant in early-onset stroke with intracranial arterial stenosis. Stroke. 2019;50(6):1561–3. https://doi.org/10.1161/strokeaha.118.024712.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Morimoto T, Enmi JI, Hattori Y, Iguchi S, Saito S, Harada KH, et al. Dysregulation of RNF213 promotes cerebral hypoperfusion. Sci Rep. 2018;8(1):3607. https://doi.org/10.1038/s41598-018-22064-8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Liu W, Hitomi T, Kobayashi H, Harada KH, Koizumi A. Distribution of moyamoya disease susceptibility polymorphism p.R4810K in RNF213 in east and southeast Asian populations. Neurol Med Chir (Tokyo). 2012;52(5):299–303. https://doi.org/10.2176/nmc.52.299.

    Article  Google Scholar 

  20. 20.

    Koizumi A, Kobayashi H, Hitomi T, Harada KH, Habu T, Youssefian S. A new horizon of moyamoya disease and associated health risks explored through RNF213. Environ Health Prev Med. 2016;21(2):55–70. https://doi.org/10.1007/s12199-015-0498-7.

    CAS  Article  PubMed  Google Scholar 

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Acknowledgments

We are indebted to Dr. Ahmad Khundakar for his editorial assistance and helpful comments.

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SH was the first author, collected patient data and wrote the manuscript. MI was a major contributor in writing the manuscript. TY contributed to revision of the manuscript and genetic testing. All authors have read and approved the final manuscript.

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Correspondence to Masafumi Ihara.

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Hosoki, S., Yoshimoto, T. & Ihara, M. A case of hemichorea in RNF213-related vasculopathy. BMC Neurol 21, 32 (2021). https://doi.org/10.1186/s12883-021-02061-7

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Keywords

  • Carotid stenosis
  • Chorea
  • RNF213
  • Moyamoya disease
  • East-west gradient