title: Stroke in young patients with hyperhomocysteinemia due to cystathionine beta-synthase deficiency.
abstract: BACKGROUND
  Although hyperhomocyst(e)inemia (Hyper-Hcy) may predispose to atherosclerosis and venous thrombosis, the mechanisms of stroke associated with Hyper-Hcy are not defined.
  
  
  METHODS
  Clinical and biochemical phenotypes and genetic features of three unrelated patients with premature stroke and severe Hyper-Hcy due to cystathionine beta-synthase (CBS) deficiency are described. Plasma Hcy and amino acids were measured by fluorescence polarization immune assay and ion exchange chromatography. Analysis of the CBS and methylenetetrahydrofolate reductase genes was performed by restriction enzyme digestion and sequence analysis.
  
  
  RESULTS
  Two of the three index cases had no known diagnosis of homocystinuria and initially presented with embolic cerebral and retinal infarction in mid-adulthood. Mechanisms of cerebrovascular disease were carotid intraluminal thrombosis, arterial dissection, and possible cardiac embolism. Family screening revealed additional members with clinically silent homocystinuria and severe Hyper-Hcy. Excluding tall stature in two individuals, all had mild phenotypes, without classic findings of CBS deficiency. Plasma total and free Hcy, methionine, and urine Hcy were elevated. Genotyping revealed heterozygous CBS mutations (I278T, D444N, G307S) in affected individuals.
  
  
  CONCLUSIONS
  Artery-to-artery embolism and dissection may cause stroke in young adults with homocystinuria. The results also support a rationale for screening for Hyper-Hcy in young adults with stroke without a phenotype suggestive of classic homocystinuria.
authors.affiliation: Stroke Service, Department of Neurology, VBK 802, Massachusetts General Hospital, Fruit St., Boston, MA 02114, USA. pikelly@partners.org
authors.forename: P J
authors.initials: PJ
authors.lastname: Kelly
authors.forename: K L
authors.initials: KL
authors.lastname: Furie
authors.forename: J P
authors.initials: JP
authors.lastname: Kistler
authors.forename: M
authors.initials: M
authors.lastname: Barron
authors.forename: E H
authors.initials: EH
authors.lastname: Picard
authors.forename: R
authors.initials: R
authors.lastname: Mandell
authors.forename: V E
authors.initials: VE
authors.lastname: Shih
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D019943:Amino Acid Substitution; D002478:Cells, Cultured; D002544:Cerebral Infarction / Q000097:blood / Q000175:diagnosis / Q000209:etiology*; D003541:Cystathionine beta-Synthase / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006579:Heterozygote; D006710:Homocysteine / Q000097:blood; D006801:Humans; D020138:Hyperhomocysteinemia / Q000097:blood / Q000175:diagnosis / Q000209:etiology* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009154:Mutation; D015356:Retinal Artery Occlusion / Q000097:blood / Q000175:diagnosis / Q000209:etiology; D020521:Stroke / Q000175:diagnosis / Q000201:enzymology / Q000209:etiology*
chemical_list: D006710:Homocysteine; D003541:Cystathionine beta-Synthase