Evaluation of thrombophilic gene mutation and hyperhomocysteinemia in children with ischemic stroke

Year 2020, , 101 - 105, 15.06.2020

Aslı Kıbrıs , Eda Sünnetçi Silistre , Betül Biner Orhaner

https://doi.org/10.16948/zktipb.553407

Abstract

Abstract

Introduction: Although a variety of
potential inherited and acquired aetiologies have been defined as a risk factor
for ischemic stroke (IS) in paediatric patients, we aimed to revisit the
influence of prothrombin G20210A (PT), methylenetetrahydrofolate reductase
C677T (MTHFR-C677T) and hyperhomocysteinemia on the initial stroke episode.

Materials and Methods: This retrospective
cross-sectional survey was conducted between 2003-2004. Paediatric patients who
had been admitted and/or followed up with the diagnosis of IS constituted the
patient group (Group I). Nineteen children who were followed up in the healthy
children policlinics were elected for control group (Group II). Thrombophilic
gene mutation analysis was performed through enzymatic polymerase chain
reaction. The homocysteine level was quantified through a chemical immunoassay
method.

Results: There was no significant difference between the
groups in terms of age [10 (1-18), p=0.98], gender (p=1.0), and ethnicity
(p=0.27). The family history of IS that suggested hereditary thrombophilia was
significantly higher in Group I (p<0.001). Additionally, it showed a 2,38 times greater risk of
ischemic stroke. The rate of neither PT (p=1.0) nor MTHFR-C677T (p=0.19) were
considerably higher in group I. While homocysteine level was higher in group I
(12,6 versus 7.5 µmol/L, p=0.014), the rate of hyperhomocysteinemia was near-significant
(p=0.09). In multi-variate analysis, none of the variables revealed a significant
impact on the IS.

Conclusions: Limited number of patient count
was the major limitation of the current study. The co-existence of clinical and genetic factors seems
to be more determinant than that of a genetic mutation per se.

Keywords: Methylenetetrahydrofolate reductase, Prothrombin
G20210A thrombophilia, Hyperhomocysteinemia, Cerebral stroke, Hereditary
thrombophilia. 

Keywords

Methylenetetrahydrofolate reductase, Prothrombin G20210A thrombophilia, Hyperhomocysteinemia, Cerebral stroke

İskemik inmeli çocuklarda trombofilik gen mutasyonu ve hiperhomosisteinemi’nin araştırılması

Abstract

Özet

Giriş: Pediatrik hastalarda iskemik inme (İİ) için birçok
kalıtımsal ve kazanılmış sebepler potansiyel risk faktörü olarak tanımlanmış
olsa da biz, protrombin G20210A (PT) ve metilentetrahidrofolat redüktaz C677T
(MTHFR-C677T) ve hiperhomosisteinemi’nin ilk İİ atağına etkisini tekrar
değerlendirmeyi amaçladık.

Gereç ve Yöntem: Bu geriye-dönük kesitsel araştırma 2003-2004
yılları arasında gerçekleştirildi. İİ tanısı ile başvuran veya takip altında
olan pediatrik hastalar çalışma topluluğunu (Grup I) oluşturmaktadır. Sağlıklı
Çocuk Polikliniği takibi altında olan 19 çocuk kontrol grubu (Grup II) için
seçildi. Trombofilik gen mutasyon analizi enzimatik polimeraz zincir reaksiyonu
ile gerçekleştirildi. Homosistein düzeyi kimyasal immünoesey metodu ile
ölçüldü.

Bulgular: Gruplar arasında yaş [10 (1-18), p= 0.98], cinsiyet
(p=1.0) ve etnik köken (p=0.27) olarak anlamlı bir fark yoktu. Herediter
trombofili’yi işaret eden İİ için aile öyküsü grup I’de anlamlı olarak daha
yüksek (p<0.001) olmasına ek olarak İİ için 2,38 kat risk artışını göstermekteydi.
Ne PT (p=1.0) ne de MTHFR-C677T oranı grup I’de anlamlı olarak daha yüksekti.
Homosistein düzeyi grup I’de daha yüksek iken (12,6 ila 7.5
µmol/L, p=0.014), hiperhomosisteinemi oranı yakın-anlamlı (p=0.009) idi.
Çok-değişkenli analizde hiçbir değişken İİ üzerine belirgin etki göstermedi.

Sonuç: Sınırlı hasta sayısı mevcut araştırmanın başlıca kısıtlılığıydı.
Klinik ve genetik faktörlerin eş-zamanlı birlikte bulunmaları, tek başına
genetik mutasyon varlığından daha belirleyici görünmektedir.

Keywords

Metilentetrahidrofolat redüktaz, Protrombin G20210A trombofili, Hiperhomosisteinemi, Serebral stroke

References

• 1. Ciccone S, Cappella M, Borgna-Pignatti C. Ischemic stroke in infants and children: practical management in emergency. Stroke Res Treat. 2011;2011:736965.
• 2. Zahuranec DB, Brown DL, Lisabeth LD, Morgenstern LB. Is it time for a large, collaborative study of pediatric stroke? Stroke. 2005;36:1825-9.
• 3. Giroud M, Lemesle M, Gouyon JB, Nivelon JL, Milan C, Dumas R. Cerebrovascular disease in children under 16 years of age in the city of Dijon, France: a study of incidence and clinical features from 1985 to 1993. J Clin Epidemiol. 1995;48:1343-8.
• 4. Brankovic-Sreckovic V, Milic-Rasic V, Jovic N, Milic N, Todorovic S. The recurrence risk of ischemic stroke in childhood. Med Princ Pract. 2004;13:153-8.
• 5. Kenet G, Lutkhoff LK, Albisetti M, Bernard T, Bonduel M, Brandao L, et al. Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children: a systematic review and meta-analysis of observational studies. Circulation. 2010;121:1838-47.
• 6. Lippi G, Franchini M, Montagnana M, Salvagno GL, Targher G, Guidi GC. Inherited and acquired risk factors for arterial ischemic stroke in childhood. J Thromb Thrombolysis. 2009;27:239-48.
• 7. Van Cott EM, Laposata M, Prins MH. Laboratory evaluation of hypercoagulability with venous or arterial thrombosis. Arch Pathol Lab Med. 2002;126:1281-95.
• 8. Altuntas N, Soylu K, Suskan E, Akar N. Homocysteine levels in Turkish children. Turk J Haematol. 2004;21:79-82.
• 9. Jadaon MM. Epidemiology of Prothrombin G20210A Mutation in the Mediterranean Region. Mediterr J Hematol Infect Dis. 2011;3:e2011054.
• 10. Akar N, Misirlioglu M, Akar E, Avcu F, Yalcin A, Sozuoz A. Prothrombin gene 20210 G-A mutation in the Turkish population. Am J Hematol. 1998;58:249.
• 11. Akar N, Akar E, Deda G, Sipahi T, Ezer U. Coexistence of two prothrombotic mutations, factor V 1691 G-A and prothrombin gene 20210 G-A, and the risk of cerebral infarct in pediatric patients. Pediatr Hematol Oncol. 1999;16:565-6.
• 12. Barreirinho S, Ferro A, Santos M, Costa E, Pinto-Basto J, Sousa A, et al. Inherited and acquired risk factors and their combined effects in pediatric stroke. Pediatr Neurol. 2003;28:134-8.
• 13. Akar N, Akar E, Deda G, Sipahi T, Orsal A. Factor V1691 G-A, prothrombin 20210 G-A, and methylenetetrahydrofolate reductase 677 C-T variants in Turkish children with cerebral infarct. J Child Neurol. 1999;14:749-51.
• 14. Ridker PM, Hennekens CH, Miletich JP. G20210A mutation in prothrombin gene and risk of myocardial infarction, stroke, and venous thrombosis in a large cohort of US men. Circulation. 1999;99:999-1004.
• 15. Akar N, Akar E. Methylenetetrahydrofolate-dehydrogenase 1958 G-A (R653 Q) polymorphism in Turkish patients with venous thromboembolism. Acta Haematol. 1999;102:199-200.
• 16. Şişli E, Oto O. The Influence of Thrombophilic Gene Mutation on Recurrence of Venous Thromboembolism: A Retrospective Cross-Sectional Study. Osmangazi Journal of Medicine. 2019;41:72-80.
• 17. Ozmen F, Ozmen MM, Ozalp N, Akar N. The prevalence of factor V (G1691A), MTHFR (C677T) and PT (G20210A) gene mutations in arterial thrombosis. Ulus Travma Acil Cerrahi Derg. 2009;15:113-9.
• 18. Komitopoulou A, Platokouki H, Kapsimali Z, Pergantou H, Adamtziki E, Aronis S. Mutations and polymorphisms in genes affecting hemostasis proteins and homocysteine metabolism in children with arterial ischemic stroke. Cerebrovasc Dis. 2006;22:13-20.
• 19. Eltayeb AA, Askar GA, Abu Faddan NH, Kamal TM. Prothrombotic risk factors and antithrombotic therapy in children with ischemic stroke. Ther Adv Neurol Disord. 2015;8:71-81.
• 20. Konanki R, Gulati S, Saxena R, Gupta AK, Seith A, Kumar A, et al. Profile of prothrombotic factors in Indian children with ischemic stroke. J Clin Neurosci. 2014;21:1315-8.
• 21. Prengler M, Sturt N, Krywawych S, Surtees R, Liesner R, Kirkham F. Homozygous thermolabile variant of the methylenetetrahydrofolate reductase gene: a potential risk factor for hyperhomocysteinaemia, CVD, and stroke in childhood. Dev Med Child Neurol. 2001;43:220-5.