Objective:

To report recurrent small-vessel cerebral infarcts with progressive white-matter disease in a patient with a heterozygous Cystathionine β-Synthase (CBS) variant and mildly elevated homocysteine, and to discuss management with indefinite dual anti-platelet therapy (DAPT) plus vitamin-B supplementation.

Background:

Homozygous CBS mutations are associated with hyperhomocysteinemia and life-threatening thrombotic events; the cerebrovascular significance of heterozygous CBS variants remains uncertain.

Design/Methods:

NA

Results:

A 55-year-old man with hypertension, hyperlipidemia, and multiple infarcts beginning at age forty-one presented with worsening of prior deficits. Brain MRI showed new diffusion restriction within extensive FLAIR white-matter hyperintensities (WMH). Review of prior MRIs demonstrated marked progression to confluent WMH over ~15 years. His first stroke had been attributed to paradoxical embolism from a patent foramen ovale (PFO); despite PFO closure, infarcts recurred. Prolonged rhythm surveillance with loop recorder revealed no atrial fibrillation. A hereditary cerebral small-vessel disease panel (Invitae/Labcorp; 10-gene panel) identified a heterozygous CBS variant. Homocysteine measured 19.1 µmol/L (reference <15 µmol/L; prior 12.0 µmol/L in 2017) with normal vitamin-B levels. After completing a 21-day DAPT course, he experienced another small-vessel infarct four months later. He was then started on indefinite DAPT plus vitamin-B supplementation, with no further infarcts to date.

Conclusions:

As genetic testing becomes more accessible, integrating targeted panels alongside standard evaluations can refine diagnosis and enable individualized secondary prevention in progressive cerebral small-vessel disease. In select cases—such as heterozygous CBS variants with mildly elevated homocysteine—this may support tailored approaches like sustained DAPT plus vitamin supplementation. Further study is needed to clarify the clinical implications of variants of uncertain significance in cerebrovascular disease and to improve risk stratification and treatment selection.