title: Increased guanidino species in murine and human succinate semialdehyde dehydrogenase (SSADH) deficiency.
abstract: Mice with targeted deletion of the GABA-degradative enzyme succinate semialdehyde dehydrogenase (SSADH; Aldh5a1; OMIM 271,980) manifest globally elevated GABA and regionally decreased arginine in brain extracts. We examined the hypothesis that arginine-glycine amidinotransferase catalyzed the formation of guanidinobutyrate (GB) from increased GABA by quantifying guanidinoacetate (GA), guanidinopropionate (GP) and GB in brain extracts employing stable isotope dilution gas chromatographic-mass spectrometry. GA and GB were up to 4- and 22-fold elevated, respectively, in total and regional (cerebellum, hippocampus, cortex) brain extracts derived from SSADH(-/-) mice. Corresponding analyses of urine and cerebrospinal fluid derived from SSADH-deficient patients revealed significant (P<0.05) elevations of GA and GB in urine, as well as GB levels in CSF. These data suggest that GB may be an additional marker of SSADH deficiency, implicate additional pathways of pathophysiology, and identify the second instance of elevated GB in a human inborn error of metabolism.
authors.affiliation: Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Erwin E W
authors.initials: EE
authors.lastname: Jansen
authors.forename: Nanda M
authors.initials: NM
authors.lastname: Verhoeven
authors.forename: Cornelis
authors.initials: C
authors.lastname: Jakobs
authors.forename: Andreas
authors.initials: A
authors.lastname: Schulze
authors.forename: Henry
authors.initials: H
authors.lastname: Senephansiri
authors.forename: Maneesh
authors.initials: M
authors.lastname: Gupta
authors.forename: O Carter
authors.initials: OC
authors.lastname: Snead
authors.forename: K Michael
authors.initials: KM
authors.lastname: Gibson
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D005998:Glycine / Q000031:analogs & derivatives* / Q000134:cerebrospinal fluid / Q000378:metabolism / Q000652:urine; D006146:Guanidines / Q000134:cerebrospinal fluid / Q000378:metabolism* / Q000652:urine; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011422:Propionates / Q000134:cerebrospinal fluid / Q000378:metabolism* / Q000652:urine; D050644:Succinate-Semialdehyde Dehydrogenase / Q000172:deficiency*
chemical_list: D006146:Guanidines; D011422:Propionates; C032267:beta-guanidinobutyric acid; C493643:ALDH5A1 protein, human; D050644:Succinate-Semialdehyde Dehydrogenase; C004946:glycocyamine; D005998:Glycine; C005775:guanidinopropionic acid