title: Elevated plasma succinate in PTEN, SDHB, and SDHD mutation-positive individuals.
abstract: OBJECTIVE
  Cowden syndrome results from germline mutations in the gene for phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and from variants in succinate dehydrogenase B and D subunits. We hypothesized that succinate accumulation may be common among individuals with SDH variants/mutations and those with PTEN mutations.
  
  
  METHODS
  Urine and blood were collected from individuals meeting full or partial Cowden syndrome diagnostic criteria or those with paraganglioma (PGL) or a known susceptibility paraganglioma-associated gene mutation, and succinate was measured. PTEN, SDHB, SDHC, and SDHD genes were sequenced from genomic DNA.
  
  
  RESULTS
  Elevated plasma succinate was observed in 13/21 (62%) individuals with germline PTEN, SDHB, or SDHD mutations as compared with 5/32 (16%) controls (P < 0.001), in 10/15 (67%) individuals with pathogenic PTEN mutations but in <20% of mutation-negative individuals meeting identical criteria, and in individuals with mutations in SDHB (1/1, 100%) and SDHD (2/5, 40%).
  
  
  CONCLUSIONS
  Our data suggest that mutations in PTEN, SDHB, and SDHD reduce catalytic activity of succinate dehydrogenase, resulting in succinate accumulation, and identify a common biochemical alteration in these two patient populations (PTEN and SDHx mutation positive individuals). Plasma organic acid analysis may provide an effective and inexpensive screening method to determine when more expensive gene sequencing of PTEN and SDH genes is warranted.
authors.affiliation: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Hobert
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Mester
authors.forename: Jessica
authors.initials: J
authors.lastname: Moline
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002264:Carboxylic Acids / Q000097:blood / Q000652:urine; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D018095:Germ-Line Mutation; D006223:Hamartoma Syndrome, Multiple / Q000097:blood* / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D010235:Paraganglioma / Q000175:diagnosis / Q000235:genetics; D017422:Sequence Analysis, DNA; D013385:Succinate Dehydrogenase / Q000235:genetics*; D019802:Succinic Acid / Q000097:blood* / Q000652:urine
chemical_list: D002264:Carboxylic Acids; D008565:Membrane Proteins; C108096:SDHC protein, human; C491545:SDHD protein, human; D019802:Succinic Acid; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human