|Ahead of print
The frequency of factor V Leiden and prothrombin mutations in children with cerebral palsy showing evidence of vascular thrombo-Embolic events seen on magnetic resonance imaging
Ender Karaca1, Ayse Nur Buyru2, Adnan Yuksel1
1 Department of Medical Genetics, Istanbul University Cerrahpasa Medical Faculty, Istanbul, Turkey
2 Department of Medical Biology, Istanbul University Cerrahpasa Medical Faculty, Istanbul, Turkey
Yesilyurt cad. Bora sitesi, Ünal apt. No 12 Daire 5, Florya, Istanbul
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Thrombophilic risk factors play an important role in the pathogenesis of cerebral palsy (CP). Factor V Leiden (fVL) mutation is the most common cause of hereditary thrombophilia associated with CP. Objective: To determine the prevalence and relationship of fVL (G1691A) and prothrombin (G20210A) mutations in CP patients with and without evidence of thromboembolic events as seen on MRI. Materials and Methods: Twenty-one children with CP showing evidence of vascular thromboembolic events seen on magnetic resonance imaging (MRI) (Group 1) and 68 children with CP with no evidence of vascular thromboembolic events seen on MRI (Group 2) were studied to identify the presence of fVL (G1691A) and prothrombin (G20210A) mutations. Results: The prevalence of the fVL (G1691A) mutation was 9.52 and 4.41% in groups 1 and 2 respectively, while the prevalence of the prothrombin (G20210A) mutation was 4.79 and 2.94% in groups 1 and 2 respectively. There were no statistically differences in the prevalence of fVL (P = 0.58) and prothrombin mutations (P = 0.55) between CP patients with and without any evidence of vascular thromboembolic events as seen on MRI. Conclusions: Similar studies including more homogenous groups could contribute to greater understanding of the risk factors that lead to developing CP.
Keywords: Cerebral palsy, factor v leiden mutation, prothrombin gene mutation, vascular thromboembolic event on MRI
|How to cite this URL:|
Karaca E, Buyru AN, Yuksel A. The frequency of factor V Leiden and prothrombin mutations in children with cerebral palsy showing evidence of vascular thrombo-Embolic events seen on magnetic resonance imaging. J Pediatr Neurosci [Epub ahead of print] [cited 2022 Dec 6]. Available from: https://www.pediatricneurosciences.com/preprintarticle.asp?id=51366
| Introduction|| |
Cerebral palsy (CP) is the most common cause of chronic disability in childhood and its incidence is seen as one in 2-2.5 live births.  It is characterized by aberrant control of movement or posture caused by a nonprogressive brain insult in early life.  CP has multiple etiology with perinatal asphyxia and prematurity being important in its pathogenesis, however, it is usually triggered by other risk factors. , Among these factors, genetic prothrombotic risk factors play an important role in the pathogenesis of infantile thrombosis and stroke.
The relationship between CP and thrombophilia has not been completely defined yet. The most commonly reported thrombophilia risk factors for CP are factor V Leiden (fVL) (G1691A) and prothrombin (G20210A) mutations. ,,,,
The aim of this study is to determine the frequency and the relationship of fVL (G1691A) and prothrombin (G20210A) mutations in CP patients with and without any evidence of thromboembolic events seen on MRI.
| Materials and Methods|| |
This study includes 89 patients that were referred to our clinic after being diagnosed with CP in the period spanning the last five years (2003-2008). The ages of the patients ranged from five months to 15 years. They were diagnosed with CP on the basis of their medical histories and neurological examinations; degenerative disorders were considered to be exclusion criteria.
All patients and their families were interviewed in detail (demographic characteristics, consanguinity, pregnancy, delivery, birth measurements, perinatal events etc.). They were all investigated for possible neurologic disorders and coagulopathies.
In addition to neurologic evaluation in the first examination, they were also referred to Orthopedia and Physical Medicine clinics. All patients underwent cerebral magentic resonance imaging (MRI) and some of them also underwent metabolic tests. The patients were separated into two groups according to their MRI findings of vascular thrombosis. Patients with evidence of vascular thromboembolic events were assigned to Group 1 (21 patients with a mean age of 7.28 (5.9 ± 4.0) years). The MRI of these patients showed well-defined focal encephalomalacic regions contrary to the inferior, medial, posterior cerebral arteries, or their major division sites. Group 2 (68 patients with a mean age of 6.35 (6.3 ± 4.2) years) included patients without any evidence of thromboembolism on their MRI. The MRI of these patients (group 2) showed different outcomes as normal, periventricular leukomalacia, heterotropia, and cerebral atrophy.
Informed consent was obtained from the parents or guardians of these patients during the interview. DNA was extracted from the blood by the Qiagen, QIAamp-extraction system, according to the manufacturer's instructions. Specific polymerase chain reaction (PCR) amplification and genotyping for the fVL and protrombin gene mutations was performed on a Roche Lightcycler according to von Ahsen et al.  Genetic analysis of all children was performed to determine the presence of mutations in the fVL (G1691A) and prothrombin (G20210A) genes. An allele-specific restriction enzyme analysis was performed for confirmation of the genotypes.
The main statistical analysis package was used for all statistical analysis,. The relationship between categorical varies was evaluated with the two-tailed Fhisher's exact test; the significance level was set at P ≤ 0.05.
| Results|| |
Out of the 21 (total 89) Group 1 patients with evidence of previous thromboembolic events on MRI, 15 had spastic hemiplegia, four had spastic quadriplegia, and two were mixed type CP. The remaining 68 Group 2 patients did not show any evidence of thromboembolic event on MRI. Nineteen of these 68 patients did not show any major abnormalities on MRI, 12 showed hypoxic ischemic encephalopathy, 18 showed periventricular leukomalasia, and nine showed other findings (heterotrophy, dysplasia etc). Group 2 consisted of 13 spastic hemiplegia, 24 spastic quadriplegia, 19 spastic diplegia, seven diskinetic type, and five mixed type CP [Table 1]. Two patients (9.52%) of group 1 (consisting of 21 patients) had the fVL mutation and one patient (4.79%) showed the prothrombin mutation. Among 68 group 2 patients, three (4.41%) showed the fVL mutation and two (2.9%) showed the prothrombin mutation. Thus, a total of 3/21 patients (14.28%) (group 1) and 5/68 patients (7.35%) (group 2) showed fVL or prothrombin mutations [Table 2].
Despite the high prevalence of fVL and prothrombin gene mutations in these patients, there was no significant difference between the two groups for fVL (G1691A) ( P = 0.58) and prothrombin gene mutations (G20210A) ( P = 0.55).
| Discussion|| |
In the present study, no significant difference in the prevalence of fVL (G1691A) and prothrombin (G20210A) mutations could be shown between children with and without evidence of vascular thrombosis seen on MRI.
Various studies have been conducted in the last few years to identify the etiology of CP and many have focused on thrombophilia as an underlying factor for CP. , Thrombophilia is an acquired or hereditary hypercoagulable state that is associated with a high incidence of
thrombosis.  Its most common hereditary cause is the aforementioned fVL mutation which has a prevalence of 4-5% in white people . ,
Several studies have revealed that fVL (G1691A) and prothrombin (G20210A) mutations are associated with CP, although some did not find any correlation. ,,,,,,, In general, patient groups in these studies were not sufficiently homogenized and also, CP subtypes and underlying brain lesions of the patients were not adequately determined. Early studies in this field by Harum et al. , Steiner et al ., and Lynch et al. revealed a relationship between hemiplegic CP and fVL mutations. ,, However, studies by Smith et al. , Fattal-Valevski et al., and Yahezkely-Schildkraut et al . did not prove any correlation between fVL mutations and CP. ,, However, the incidence of fVL mutations was found to be higher in CP patients than in the control groups, even in these studies that did not show any correlation between the two factors. For example, Yalezkely-Schldkraut et al. revealed that the incidence of the fVL mutation was 27.9 and 16.4% in the CP and control groups respectively.  In contrast, in another study by Fattal-Valevski et al ., the prevalence of the fVL mutation was found to be 24.5 and 23% in the CP and control groups respectively. 
It has been postulated that the fVL mutation is a potential factor that increases the risk of cerebral thrombo-embolism and in the course of time, leads to the development of CP in newborns. ,,,, In the present study, although we found a high prevalence of the fVL mutation in patients with evidence of vascular thrombo-embolism on MRI, we could not find a significant difference between patients with and without evidence of thrombo-embolism on MRI ( P = 0.58). This lack of difference may be attributed to other risk factors (anti-cardiolipin antibodies, antiphospholipid antibodies, lipoprotein a level, anti-thrombin III activity, plasma homocysteine, protein C and S levels..etc) that were not evaluated in the present study.
Similar to our findings (prevalence of 9.52%), Reid et al . reported the frequency of the fVL mutation in CP patients with evidence of vascular thrombosis on MRI to be 10.53%.  Again, consistent with our findings, the frequency of the fVL mutation found by Reid et al . in children with evidence of vascular thrombosis was not statistically different from that in children with other brain imaging findings. 
In conclusion, similar studies including more homogenous groups could contribute to greater understanding of the risk factors that lead to the development of CP.
| Acknowledgment|| |
This study was supported by Research Centre Foundation of Istanbul University.
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[Table 1], [Table 2]