Abstracts

BRAIN GABA IN SSADH DEFICIENCY

Abstract number : 2.213
Submission category :
Year : 2003
Submission ID : 4052
Source : www.aesnet.org
Presentation date : 12/6/2003 12:00:00 AM
Published date : Dec 1, 2003, 06:00 AM

Authors :
Edward J. Novotny, Robin de Graaf, Graeme F. Mason, Michael Appel, Philip Pearl, Karen L. Wong, K.M. Gibson, Douglas L. Rothman Pediatrics, Yale University, New Haven, CT; Diagnostic Imaging, Yale University, New Haven, CT; Psychiatry, Yale University, Ne

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian nervous system. Dysfunction of GABA neurotransmission has been implicated in several neurologic and psychiatric disorders. However, genetically determined disorders of GABA metabolism are rare and the most common recessively inherited disorder involves a defect in the catabolism of GABA via succinic semialdehyde dehydrogenase (SSADH)(1). Several proton MRS methods have been developed to non-invasively monitor GABA levels in the human brain [italic]in vivo [/italic](2,3). We studied five subjects with SSADH deficiency that have severe neuropsychological dysfunction and epilepsy and demonstrated major alterations in GABA and other metabolites [italic]in vivo.[/italic]
Five subjects with SSADH deficiency proven both by identification of 4-OH butyric aciduria by tandem mass spectrometry and molecular diagnostic studies were studied by the MRS protocol. The subjects included 3 male and 2 females and were between 6 and 22 years of age. A group of age- and sex-matched controls were also studied for comparison.
[underline]NMR Spectroscopy[/underline]: For the GABA MRS measurement subjects lay supine on a patient bed with their head comfortably secured with the occipital cortex apposed to an 8 cm distributed capacitance rf surface coil tuned to the 1H MRS frequency of 89.43 MHZ. Prior to the MRS measurement a T[sub]1[/sub] weighted, inversion recovery MRI of the subject[apos]s head are obtained. From the image a 1.5 x 3 x 4 cm3 volume in the occipital cortex was chosen for the GABA concentration measurement. Brain GABA was measured using a variation of a homonuclear editing pulse sequence (2). The brain GABA was quantitated by comparing the area of the GABA signal in the difference proton spectrum to the total creatine signal as previously described (2,3). In addition, the subjects had measurement of the proton signals of other amino acids and compounds in the same volume using short TE (20ms) MRS with and without macromolecule suppression.
All five subjects had marked elevation of the edited GABA signal centered at 3.01 ppm. The subjects had GABA values between 2.0 and 2.8 mM that were greater than 3 SD higher compared to controls of 1.3 [plusmn] 0.25 mM . Alterations in other amino acids were also observed.
This is the first demonstration of elevated GABA in the human brain [italic]in vivo [/italic]that was not due to pharmacological treatment. Many neurologic and psychiatric disorders associated with GABA dysfunction have significant decreases in steady-state GABA levels when compared to controls. Further investigations of these subjects by MRS will provide a better understanding of the role of GABA in neuropsychologic disorders and epilepsy.
References:
1. Jakobs, C., J. Jaeken, and K.M. Gibson, J Inherit Metab Dis, :704-15 1993
2. Rothman, D.L., et al., Proc Natl Acad Sci U S A, :5662-6 1993.
3. Novotny, E.J., Jr., et al., Epilepsia, : 462-6 1999.
[Supported by: NIH - NINDS, NIDA]