Association of Borna disease virus with autism spectrum disorder in Turkish children

Abstract

Aim: Autism spectrum disorders are lifelong neurodevelopmental disorders whose pathogeneses are not fully understood. Borna disease virus is a neurotropic virus that affects the central nervous system. Considering the neuropsychiatric and behavioral effects of the virus, it can be suggested that it may play a role in autism spectrum disorder. However, there are insufficient evidence to support this. In this study, we aimed to investigate the presence of Borna disease virus in patients with autism spectrum disorders and healthy controls. Methods: This case-control study, performed in children with autism spectrum disorders and a control group, included patients with autism who visited the Child and Adolescent Psychiatry outpatient clinic between December 2017 - December 2018. Borna virus positivity was assayed with the ELISA method in serum samples. Data was analyzed using SPSS version 22. Results: The study included 63 children diagnosed with autism spectrum disorder and 31 healthy controls. The age range of autism patients was 3-14 years, their mean age was 7.83 (1.96) years, and The Childhood Autism Rating Scale score was 51.09 (5.71). The seropositivity rate for Borna disease virus in the autism and healthy control groups were 25.39% and 25.80%, respectively (P=0.966). For all patients, seropositivity rate was 25.53%. Conclusion: No relationship was found between autism spectrum disorders and Borna disease virus. The clinical significance of Borna disease virus positivity in society is unknown. We conclude that Borna disease virus is not involved in the pathogenesis of autism spectrum disorders.

Keywords

• Borna disease virus
• autism spectrum disorder
• seroprevalence
• etiology

Türk çocuklarda Borna hastalığı virüsü ve otizm spektrum bozukluğu ilişkisi

Öz

Amaç: Otizm spektrum bozuklukları yaşam boyu nörogelişimsel bozukluklardır ve patogenezi günümüzde tam olarak anlaşılamamıştır. Borna hastalığı virüsü, merkezi sinir sistemini etkileyen nörotropik bir virüstür. Virüsün nöropsikiyatrik ve davranışsal etkileri göz önüne alındığında, otizm spektrum bozukluğunda rol oynayabileceği ileri sürülebilir. Ancak, bunu destekleyecek yeterli kanıt yoktur. Bu çalışmada otizm spektrum bozukluğuna sahip hastalarda ve sağlıklı kontrol grubunda Borna hastalığı virüsü varlığının araştırılması amaçlanmıştır. Yöntemler: Bu çalışma otizm spektrum bozukluğu tanısı almış ve kontrol grubundaki çocuklarda yapılan bir vaka kontrol çalışmasıdır. Çalışmaya Aralık 2017 - Aralık 2018 tarihleri arasında Çocuk ve Ergen Psikiyatri polikliniğine başvuran otizmli çocuklar dahil edilmiştir. Serum örneklerinde ELISA yöntemi ile Borna virüsü pozitifliği değerlendirilmiştir. Veriler SPSS sürüm 22 kullanılarak analiz edilmiştir. Bulgular: Çalışmaya otizm spektrum bozukluğu tanısı almış 63 çocuk ve 31 sağlıklı kontrol grubu dahil edildi. Otizm hastalarının yaş aralığı 3-14 yıl, ortalama yaş 7,83 (1,96) ve Çocukluk Otizmini Derecelendirme Ölçeği skoru ortalama 51,09 (5,71) olarak saptandı. Otizm grubunda ve sağlıklı kontrol grubunda Borna hastalığı virüsü seropozitiflik oranı sırasıyla %25,39 ve %25,80 idi (P=0,966). Tüm hastalar için seropozitiflik oranı %25,53 saptandı. Sonuç: Otizm spektrum bozukluğu ile Borna hastalığı virüsü arasında ilişki saptanmadı. Borna hastalığı virüsünün toplumdaki pozitifliğinin klinik önemi bilinmemektedir. Sonuç olarak Borna hastalığı virüsünün, otizm spektrum bozukluğunun patogenezinde rol oynadığını düşünmüyoruz.

Anahtar Kelimeler

• Borna hastalığı virüsü
• otizm spektrum bozukluğu
• seroprevalans
• etyoloji

References

1. 1. Swedo SE, Baird C. Neurodevelopmental Disorders; Autism Spectrum Disorder. In: Kupfer DJ, editor. American Psychiatric Association: Diagnostic and statistical manual of mental disorders. Arlington: American Psychiatric Publishing; 2013. pp. 50-59.
2. 2. Ekici B, Konuk FK, Dursun ŞS, Unay ÖS, Tatlı B. Neuroplay method combined with home-based Ayres sensory integration for autism: A case report. J Surg Med. 2020;4(3):246-7. doi: 10.28982/josam.613563
3. 3. Lyall K, Croen L, Daniels J, Fallin MD, Ladd-Acosta C, Lee BK, et al. The Changing Epidemiology of Autism Spectrum Disorders. Annu Rev Public Health. 2017;38:81-102. doi: 10.1146/annurev-publhealth-031816-044318
4. 4. Matsuzaki H, Iwata K, Manabe T, Mori N. Triggers for autism: genetic and environmental factors. J Cent Nerv Syst Dis. 2012;22(4):27-36. doi: 10.4137/JCNSD.S9058
5. 5. Libbey JE, Sweeten TL, McMahon WM, Fujinami RS. Autistic disorder and viral infections. J Neurovirol. 2005;11(1):1-10. doi: 10.1080/13550280590900553
6. 6. Lipkin WI, Briese T, Hornig M. Borna disease virus fact and fantasy. Virus Res. 2011;162(1-2):162-72. doi: 10.1016/j.virusres.2011.09.036
7. 7. Kinnunen PM, Palva A, Vaheri A, Vapalahti O. Epidemiology and host spectrum of Borna disease virus infections. J Gen Virol. 2013;94:247-62. doi: 10.1099/vir.0.046961-0
8. 8. Richt JA, Pfeuffer I, Christ M, Frese K, Bechter K, Herzog S. Borna disease virus infection in animals and humans. Emerg Infect Dis. 1997;3(3):343-52. doi: 10.3201/eid0303.970311

9. 9. Dittrich, W, Bode L, Ludwig H, Kao M, Schneider K. Learning deficiencies in Borna disease virus infected but clinically healthy rats. Biol Psychiatry. 1989;26:818-28. doi: 10.1016/0006-3223(89)90122-4
10. 10. Hornig, M, Weissenbock H, Horscroft N, Lipkin WI. An infection based model of neurodevelopmental damage. Proc Natl Acad Sci. 1999;96:12102-7. doi: 10.1073/pnas.96.21.12102
11. 11. Ando T, Takino T, Makita K, Tajima M, Koiwa M, Hagiwara K. Seroepidemiological analysis of vertical transmission relative risk of Borna disease virus infection in dairy herds. J Vet Med Sci. 2016;78(11):1669-72. doi: 10.1292/jvms.16-0156
12. 12. Amsterdam JD, Winokur A, Dyson W, Herzog S, Gonzalez F, Rott R, et al. Borna disease virus. A possible etiologic factor in human affective disorders? Arch Gen Psychiatry. 1985;42(11):1093-6. doi: 10.1001/archpsyc.1985.01790340077011
13. 13. Carbone KM. Borna Disease Virus and Human Disease. Clin Microbiol Rev. 2001;14(3):513-27. doi: 10.1128/CMR.14.3.513-527.2001
14. 14. European Centre for Disease Prevention and Control. Acute encephalitis associated with infection with Borna disease virus 1–Germany. Stockholm: ECDC; 2018.
15. 15. Bode L, Zimmermann W, Ferszt R, Steinbach F, Ludwig H. Borna disease virus genome transcribed and expressed in psychiatric patients. Nature Med. 1995;1:232-6. doi: 10.1038/nm0395-232
16. 16. de la Torre JC, Bode L, Durrwald R, Cubitt B, Ludwig H. Sequence characterization of human Borna disease virus. Virus Res. 1996;44:33-44. doi: 10.1016/0168-1702(96)01338-x
17. 17. Sauder C, Muller A, Cubitt B, Mayer J, Steinmetz J, Trabert W, et al. Detection of Borna disease virus (BDV) antibodies and BDV RNA in psychiatric patients: evidence for high sequence conservation of human blood derived BDV RNA. J Virol. 1996;70:7713-24. doi: 10.1128/JVI.70.11.7713-7724.1996
18. 18. Kishi M, Nakaya T, Nakamura Y, Zhong Q, Ikeda K, Senjo M, et al. Demonstration of human Borna disease virus RNA in human peripheral blood mononuclear cells. FEBS Letters. 1995;3645:293-7. doi: 10.1016/0014-5793(95)00406-y
19. 19. Hirano N, Kao M, Ludwig H. Persistent, tolerant or subacute infection in Borna disease virus infected rats. J Gen Virol. 1983;64:1521-30. doi: 10.1099/0022-1317-64-7-1521
20. 20. Schopler E, Reichler RJ, De Vellis RF, Daly K. Toward objective classification of childhood autism: Childhood autism rating scale (CARS). Journal of Autism and Developmental Disorders. 1980;10(1):91-103. doi: 10.1007/BF02408436
21. 21. Cohen J. Statistical Power Analysis for the Behavioral Sciences. New York: Department of Psychology New York University; 1988.
22. 22. Pletnikov MV, Rubin SA, Vasudevan K, Moran TH, Carbone KM. Developmental brain injury associated with abnormal play behavior in neonatally Borna disease virus infected Lewis rats: a model of autism. Behavioural Brain Res. 1999;100:43-50. doi: 10.1016/s0166-4328(98)00111-9
23. 23. Lancaster K, Dietz DM, Moran TH, Pletnikov MV. Abnormal social behaviors in young and adult rats neonatally infected with Borna disease virus. Behavioural Brain Research. 2007;176:141-8. doi: 10.1016/j.bbr.2006.06.013
24. 24. Li C, Xu X, Zhang X, Cheng K, Guo Y, Jie J, et al. Activation of ERK / CREB / BDNF pathway involved in abnormal behavior of neonatally Borna virus-infected rats. Neuropsychiatr Dis Treat. 2018;15(14):3121-32. doi: 10.2147/NDT.S176399
25. 25. Hans A, Bajramovic JJ, Syan S, Perret E, Dunia I, Brahic M, et al. Persistent, noncytolytic infection of neurons by Borna disease virus interferes with ERK 1/2 signaling and abrogates BDNF-induced synaptogenesis. FASEB J. 2004;18(7):863-5. doi: 10.1096/fj.03-0764fje
26. 26. Honda T, Sofuku K, Matsunaga H, Tachibana M, Mohri I, Taniike M, et al. Prevalence of antibodies against Borna disease virus proteins in Japanese children with autism spectrum disorder. Microbiol Immunol. 2018;62:473-6. doi: 10.1111/1348-0421.12603
27. 27. Patti AM, Vulcano A, Candelori E, Donfrancesco R, Ludwig H, Bode L. Borna disease virus infection in Italian children. A potential risk for the developing brain? APMIS Suppl. 2008;124:70-3. doi: 10.1111/j.1600-0463.2008.00m12.x
28. 28. Güngör S, Anlar B, Turan N, Yılmaz H, Helps CR, Harbour DA. Antibodies to Borna disease virus in subacute sclerosing panencephalitis. Pediatr Infect Dis J. 2005;24(9):833-4. doi: 10.1097/01.inf.0000178307.70429.75