Increased guanidino species in murine and human succinate semialdehyde dehydrogenase (SSADH) deficiency.
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.
Jansen
Erwin E W
EE
Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, Amsterdam, The Netherlands.
Verhoeven
Nanda M
NM
Jakobs
Cornelis
C
Schulze
Andreas
A
Senephansiri
Henry
H
Gupta
Maneesh
M
Snead
O Carter
OC
Gibson
K Michael
KM
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*
D006146:Guanidines; D011422:Propionates; C032267:beta-guanidinobutyric acid; C493643:ALDH5A1 protein, human; D050644:Succinate-Semialdehyde Dehydrogenase; C004946:glycocyamine; D005998:Glycine; C005775:guanidinopropionic acid