Identification of LDLR mutation in cerebral venous sinus thrombosis co-existing with dural arteriovenous fistulas: a case report

Cerebral venous sinus thrombosis (CVST) and dural arteriovenous fistula (DAVFs) are both rare cerebrovascular diseases. The co-existence of CVST and DAVFs is even rarer. Previous clinical studies have suggested that CVST is closely associated with DAVFs and may account for the subsequent occurrence of DAVFs. CVST can result from inherited thrombophilia, an inherited predisposition to thrombosis, which includes factor V Leiden mutation, protein C and S deficiency, sickle cell disease, and prothrombin 20,210 gene mutation [1]. Here, we present a patient who carried a heterozygous mutation in the low-density lipoprotein receptor (LDLR) gene and suffered from both CVST and DAVFs.

The swift advancement of dementia is a rare neurological manifestation, typically necessitating an exhaustive assessment, especially for potentially reversible causes. In the case of this 51-year-old male patient who presented with progressive dementia, his brain MRI revealed bilateral diffuse white matter hyperintensity across the cerebral hemispheres. A plausible pathogenic mechanism suggests that the DAVFs in the right sigmoid sinus and an occlusion in the left transverse sinus increase venous pressure. This elevation in pressure might contribute to venous hypertensive encephalopathy and the rapid deterioration of cognitive abilities, as documented in prior reports [3].

DAVFs, referring to pathologic shunts between meningeal arteries and dural venous sinuses or veins, are potentially associated with CVST. However, it remains unclear whether DAVFs cause CVST or develop as a result of CVST [1, 3]. In this case, follow-up interviews indicated that despite early embolization of DAVFs, the patient’s intracranial pressure remained elevated due to CVST. These observations suggest that CVST might lead to the formation of DAVFs.

CVST is a rare clinical condition with various predisposing factors. Over 85% of the diagnosed cases have at least one identified risk factor, including acquired and genetic prothrombotic conditions. Common acquired risks include neurosurgical procedures, adjacent infections, trauma, pregnancy, puerperium, antiphospholipid syndrome, obesity, malignancy, exogenous hormones, oral contraception, and COVID-19. The genetic risks refer to inherited thrombophilia conditions, such as hyperhomocysteinemia, antithrombin III deficiency, protein C or protein S deficiency, factor V Leiden mutation, and G20210A prothrombin gene mutation. The cause of CVST remains unidentified in approximately 15% of patients. Identifying the exact cause of CVST in each patient is essential but complex. No clear etiologies or risk factors for CVST were initially found in this case. Then, whole genome exome sequencing revealed a heterozygous mutation in the LDLR gene (NM_000527:exon12:c.C1747T:p.H583Y). To our knowledge, this is the first report of an LDLR gene mutation possibly associated with the development of CVST and subsequent DAVFs.

Previous studies have demonstrated a significant correlation between LDLR gene mutations and coronary and cerebral artery thrombosis [4, 5]. The relationship between the LDLR mutation and venous thrombosis has also been reported. A whole exome sequencing study conducted on patients with sickle cell disease identified a patient with heterozygous mutations in the LDLR gene who also had a history of deep venous thrombosis [6]. The LDLR mutations in the patient led to altered expression of specific proteins associated with thrombosis, including factor VIII and anticardiolipin antibodies. Increasing evidence has shown that a high plasma level of factor VIII is an independent risk factor for venous thrombosis [7]. Kyrle et al. showed that factor VIII levels exceeding 150 mcg/L are associated with a 5-fold increase in the risk of venous thrombosis [8]. Furthermore, Bovenschen et al. observed an approximately 4.2-fold rise in factor VIII levels in LDLR-deficient mice [9]. LDLR has also been identified as contributing to factor VIII homeostasis [9]. Additionally, Ochoa et al. showed that individuals carrying the anticardiolipin antibody exhibited a significantly lower LDLR gene expression level than the control group [10].

In conclusion, this case report posits that the mutation of the LDLR gene could induce a prothrombotic state, potentially facilitating the gradual onset of CVST and the ensuing formation of DAVFs. More extensive research is essential to determine the relative risk and prevalence of LDLR gene mutations in patients diagnosed with DAVF and CVST. Given the paucity of existing literature on the correlation between LDLR mutations and CVST and the absence of related animal studies, our findings call for validation through more comprehensive investigations, encompassing both animal experiments and clinical studies.