Novel SERPINC1 Mutation in a Brazilian Patient with Sudden-onset Sagittal Sinus Thrombosis Caused by Congenital Antithrombin Deficiency
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A 19-year-old Brazilian man visited the emergency department of our hospital complaining of nausea and fever. He presented with left hemispatial neglect. Magnetic resonance imaging led to a diagnosis of sagittal sinus thrombosis. Blood tests showed decreased antithrombin (ATIII) activity, and ATIII deficiency was diagnosed. He was treated with heparin sodium and warfarin. Genetic counseling through medical interpreters was recommended, and the patient and his mother consented to genetic testing, which revealed a novel mutation variant of the SERPINC1 gene. Genetic counseling is important to connect patients to genetic testing, even if language barriers are present.
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Introduction
Cerebral venous sinus thrombosis is a relatively rare disease occurring in approximately 0.5%–1% of all strokes and has a young age of onset [1]. Congenital thrombophilia has been reported to account for 20%–30% of cases of cerebral venous sinus thrombosis [2], [3].
Congenital antithrombin (ATIII) deficiency is an autosomal dominant genetic disease that is recognized as a heterozygote. A previous report found that 80%–90% of ATIII-deficient patients develop thrombosis by 50–60 years old, but the first signs of onset often arise between 10–35 years old [4]. ATIII is a member of the serine protease inhibitor (SERPIN) superfamily and is located on chromosome 1q25.1 [5]. Here, we report the case of a Brazilian patient with congenital ATIII deficiency who developed sagittal sinus thrombosis and in whom a novel serpin peptidase inhibitor, clade C, member 1 (SERPINC1) gene mutation was identified by genetic testing.
Case Report
A 19-year-old Brazilian man was referred to the Emergency Department in our hospital with headache, nausea, and fever. He had been prescribed analgesics for headaches the previous day. He had been receiving treatment for autism. His mother had deep vein thrombosis and was taking edoxaban, his maternal grandmother had died of cerebral infarction, and his mother’s cousin had died of myocardial infarction at 28 years old (Fig. 1). Physical examination showed a significant shift of the midline to the right and marked left unilateral spatial neglect. Blood test results are shown in Table I.
Complete blood count | Biochemistry | Coagulation | |||
---|---|---|---|---|---|
White Blood Cells | 14,600/μL (3300–8600) | T-Bil | 0.6 mg/dL | PT (%) | 87.4% (70–130) |
Neutrophil | 77.0% | AST | 17 IU/L | PT INR | 1.07 |
Eosinophil | 1.5% | ALT | 15 IU/L | APTT | 30.4 sec (25–38) |
Basophil | 0.2% | LDH | 168 IU/L | Fibrinogen | 377 mg/dL (170–410) |
Monocyte | 8.2% | γ-GTP | 22 IU/L | D-dimer | 9.5 μg/mL (<1.0) |
Lymphocyte | 13.1% | TP | 7.5 g/dL | ATIII activity | 40.4% (75–125) |
Red Blood Cells | 544 × 104/μL (435–555) | Alb | 4.3 g/dL | ATIII antigen | 10.6 mg/dL (23.6–33.5) |
Hemoglobin | 15.2 g/dL (13.7–16.8) | BUN | 12 mg/dL | Protein S activity | 92% (64–146) |
Hematocrit | 46.4% (40.7–50.1) | Cr | 0.80 mg/dL | Protein S antigen | 114% (73–137) |
Platelets | 33.3 × 104/μL (15.8–34.8) | Na | 142 mmol/L | Protein C activity | 140% (64–146) |
Reticulocytes | 2% | K | 4.1 mmol/L | Protein C antigen | 108% (70–150) |
Cl | 105 mmol/L | ||||
Immunology | CRP | 1.77 mg/dL | |||
Anti CL-β2GP1 Ab | <1.2 | T-Cho | 226 mg/dL | ||
Anti CL IgG Ab | <4.0 | TG | 158 mg/dL | ||
LA (dRVVT) | 1.1 (<1.3) | LDL-Cho | 156 mg/dL |
Both ATIII activity and antigen were decreased at 45.3% and 10.6% of normal levels, respectively. Emergency computed tomography (CT) showed a high-density area near the parietal region of the right occipital lobe, and T2 fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) showed hyperintensity surrounding the same area, with edema (Fig. 2, panel A). Diffusion showed a signal-hyperintense area in the superior sagittal sinus, and magnetic resonance angiography (MRA) showed an area where the sagittal sinus was interrupted (Fig. 2, panel B). Sagittal sinus thrombosis was diagnosed. Anticoagulant therapy with heparin sodium was initiated, and as congenital ATIII deficiency was suspected, oral warfarin was administered. The patient was Brazilian and did not fully understand Japanese, so genetic counseling was provided through medical interpreters.
Genetic testing was ultimately requested and was performed as previously reported [6]. A novel genetic mutation, c295 duplication, pAla99Glyfs*6, was identified in Exon 2 of the SERPINC1 gene (Fig. 3). Blood clotting tests of the mother and brother revealed reduced ATIII activity in the mother but normal ATIII activity in the brother. The mother was also diagnosed with congenital antithrombin deficiency.
Discussion and Conclusion
We report the case of a Brazilian patient with congenital antithrombin deficiency who developed sagittal sinus thrombosis, and genetic testing demonstrated a novel SERPINC1 mutation.
Cerebral sinus thrombosis is a relatively rare disease that occurs in approximately 0.5%–1% of all strokes and is seen predominantly in young people [1]. Congenital thrombophilia accounts for 20%–30% of all cases of cerebral sinus thrombosis, and congenital ATIII deficiency reportedly accounts for approximately 5%–10% of these cases [2], [3], [7]. Treatment is anticoagulant therapy, and heparin and warfarin are the standard drugs used, but some cases in which direct oral anticoagulants were used have been reported in recent years [8].
ATIII binds clotting factors such as thrombin to form complexes, neutralizing these factors and slowing down clotting. ATIII deficiency thus makes patients more susceptible to thrombosis [9]. ATIII deficiency is an autosomal dominant genetic disease that is recognized as a heterozygote. ATIII-deficient patients reportedly develop thrombosis by 50–60 years old in 80%–90%, but the first onset is often at 10–35 years old [4]. The clinical course of this case was considered typical for congenital antithrombin deficiency. Genetic testing was also performed, confirming a new mutation. The mother also showed reduced ATIII activity, and although she did not undergo genetic testing, the condition in the proband was thought to have been inherited from the mother.
This patient was Brazilian, and because he was worried about his ability to communicate effectively in Japanese, genetic counseling was provided through a medical interpreter. Genetic counseling is essential for genetic testing, and patients and their families should only make a decision after being provided with sufficient information. However, genetic counseling in a language other than the patient’s native language poses various problems. A report from the United States showed that Hispanic families have poor access to genetic information [10]. In addition, a survey of bi and multilingual genetic counselors reported that non-English patients have insufficient translation tools and resources, and non-English languages need to be further confirmed during training [11]. Fortunately, our hospital had employed medical interpreters who could speak Spanish or Portuguese, so although the process took longer than usual, we were able to provide genetic counseling and administer the genetic test. Our hospital has three medical interpreters on staff, meaning that even for patients who do not speak Japanese or English, explanations can be given to patients through the same interpreter during regular medical treatment, facilitating an explanation of the patient’s condition.
Here, we have reported the case of a Brazilian patient with congenital antithrombin deficiency caused by sagittal sinus thrombosis, and genetic testing demonstrated a novel SERPINC1 mutation. Even in cases where communication is difficult due to language barriers, providing genetic counseling and information using appropriate means such as medical interpreters is important, and in this case, leads to the patient agreeing to genetic testing.
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