An ecological study of a newborn screening pro- gram in Ireland supports the effectiveness of interventions to drive free homocysteine to 11 mmol/L to prevent thromboembolic events.739 A study of treatment of severe hyperhomocysteine performed in Australia, the Netherlands, and Ireland on patients who had cystathionine -synthase defi- ciency (mean age, 27.8 years; range, 2.5 70 years) supported a dramatic reduction of risk of vascu- lar events relative to a historical cohort study (RR, 2. A systematic review of RCTs of agalsidase alfa or beta in patients with Anderson-Fabry disease found that the enzyme replacement therapy improved pain-related quality of life but that their effects on morbidity or mortality required further Knowledge Gaps and Future Research Specific treatments are needed for several single- gene disorders associated with high risk of stroke, including mitochondrial myopathy, encephalopa- thy, lactic acidosis, stroke-like episodes, cerebral autosomal dominant arteriopathy with subcorti- cal infarcts and leukoencephalopathy, cerebral autosomal recessive arteriopathy with subcorti- cal infarcts and leukoencephalopathy, cathep- sin-A related arteriopathy with strokes and leukoencephalopathy, retinal vasculopathy with cerebral leukodystrophy, and cases of pathogenic mutations in the COL4A1/COL4A2 genes.745 Because of the low prevalence of these condi- tions, generating high-quality evidence for thera- pies for single-gene disorders that cause stroke will be challenging but not impossible. For patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, prospective multicenter single-arm studies suggest that oral l-arginine may extend the interictal phase of stroke-like spells and intravenous l-arginine may improve headache, nausea/vomiting, impaired consciousness, and visual disturbances. 