High Prevalence of Cerebral Venous Sinus Thrombosis in Seven Chinese Patients with Cystathionine β-Synthase Deficiency

Cystathionine β-synthase (CBS) deficiency is a rare autosomal recessive genetic disorder that disrupts homocysteine metabolism, leading to severe hyperhomocysteinemia (HHCY). This condition manifests with multi-system complications, including intellectual disability, ocular abnormalities, skeletal deformities, and thrombotic events. While the global prevalence of thrombotic complications in CBS deficiency ranges between 23% and 42%, this study highlights a striking predominance of cerebral venous sinus thrombosis (CVST) in seven Chinese patients, emphasizing the need for heightened clinical suspicion and routine thrombophilia screening in this population.

Clinical Presentation and Diagnostic Findings

The study retrospectively analyzed seven patients from five unrelated Chinese families diagnosed with CBS deficiency between July 2016 and July 2019. Five patients presented with acute vascular events, primarily CVST, while two asymptomatic siblings were identified through family screening. Among the symptomatic cases, three developed secondary epilepsy due to CVST, and two exhibited additional atrial thrombosis. Neurological symptoms such as headaches, seizures, and focal deficits were common, aligning with venous infarction patterns observed on neuroimaging. Notably, CVST was the sole clinical feature in two patients (Patients 5 and 7), underscoring the variability in disease presentation.

Ocular abnormalities, including congenital lens dislocation, myopia, and strabismus, were present in five patients, typically emerging during childhood. Skeletal features such as osteoporosis, kyphoscoliosis, and arachnodactyly (Marfanoid habitus) were documented in three patients, while neuropsychiatric manifestations like intellectual disability, behavioral abnormalities, and hyperpigmentation affected four individuals. These systemic findings highlight the pleiotropic nature of CBS deficiency and the challenges in early diagnosis, particularly when initial symptoms are nonspecific.

Biochemical and Genetic Profiling

All patients exhibited markedly elevated plasma total homocysteine (Hcy) levels ranging from 48 to 242 μmol/L (normal: 0–15 μmol/L), accompanied by significantly increased methionine concentrations (127–438 μmol/L; normal: 8–50 μmol/L). Severe deficiencies in vitamin B12 (<50 pg/mL) and folate (<1 ng/mL) were consistently observed, contributing to the metabolic derangements. Urine organic acid analyses ruled out other inherited metabolic disorders, confirming CBS deficiency as the primary diagnosis.

Genetic sequencing revealed considerable heterogeneity across the cohort, identifying eight distinct CBS mutations. The most prevalent mutation, c.833T>C (p.I278T), occurred in two patients, with Patient 5 harboring a homozygous variant. Compound heterozygous mutations were present in six patients, including three novel variants exclusive to Chinese populations: c.949A>G, c.407T>C, and c.551T>C. Family segregation analysis confirmed autosomal recessive inheritance, with parents being heterozygous carriers. These findings contrast with mutation spectra reported in non-Chinese cohorts, suggesting ethnic-specific genetic profiles in CBS deficiency.

Treatment Responses and Clinical Outcomes

First-line therapy involved high-dose B vitamin supplementation (mecobalamin 0.5–1.5 mg/day, folic acid 5–15 mg/day, vitamin B6 30–60 mg/day), which normalized Hcy levels in Patients 5 and 7 within one month. Pyridoxine responsiveness was assessed by escalating vitamin B6 doses (300–600 mg/day) for two weeks. Patients 3 and 4 demonstrated significant Hcy reduction (100 μmol/L despite six months of betaine (3–6 g/day) and methionine-restricted diets.

Anticoagulation therapy (unfractionated heparin followed by warfarin) achieved partial recanalization of venous sinuses in all CVST cases, with no recurrence during follow-up (median 16 months, range 6–36 months). However, Patient 4 succumbed to hemorrhagic stroke two years post-diagnosis, likely attributable to medication non-adherence and psychological comorbidities. This fatal outcome underscores the importance of comprehensive management addressing both metabolic and psychosocial factors.

Genotype-Phenotype Correlations

The c.833T>C mutation, associated with pyridoxine responsiveness in Patients 5 and 7, correlated with later-onset vascular-predominant disease lacking multisystem involvement. Conversely, novel mutations c.551T>C and c.949A>G (compound heterozygous in Patients 3 and 4) demonstrated partial pyridoxine sensitivity, reducing Hcy levels to 32–41 μmol/L. In contrast, c.407T>C and c.919G>A mutations (Patients 1, 2, 6) conferred complete pyridoxine resistance, necessitating aggressive dietary and betaine therapies. These observations align with previous reports linking mutation location (particularly within the CBS catalytic domain) to enzymatic residual activity and therapeutic response.

Implications for Clinical Practice

This cohort illustrates CVST as a cardinal feature of CBS deficiency in Chinese patients, distinct from Western populations where arterial thromboses predominate. Key recommendations include:

1. Universal Hcy Screening: For unexplained thrombotic events, particularly CVST, paired with assessment for syndromic features (ectopia lentis, skeletal anomalies).
2. Early Genetic Testing: Prioritize CBS sequencing in HHCY cases with normal methylenetetrahydrofolate reductase (MTHFR) status.
3. Therapeutic Stratification: Pyridoxine trials should precede long-term management, with dose escalation to 600 mg/day before declaring non-responsiveness.
4. Lifelong Surveillance: Regular monitoring of Hcy, coagulation parameters, and vascular imaging, even in responsive patients, to mitigate thrombotic risks.

The identification of three China-specific mutations (c.949A>G, c.407T>C, c.551T>C) expands the CBS variant database and facilitates population-specific carrier screening. Furthermore, the survival of CVST patients with appropriate anticoagulation contrasts with historical mortality rates, emphasizing advances in acute stroke care.

Conclusion

This study provides critical insights into the phenotypic spectrum and genetic architecture of CBS deficiency in China, bridging gaps in ethnic-specific disease understanding. The high CVST prevalence demands increased diagnostic vigilance, while genotype-guided therapy optimization may improve outcomes in this metabolically complex disorder. Future research should explore long-term neurological sequelae and cost-effective screening protocols for at-risk populations.

doi:10.1097/CM9.0000000000001013

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