Succinate semialdehyde dehydrogenase (ALDH5A1, encoding SSADH deficiency is a defect of 4-aminobutyric acid (GABA) degradation that manifests in humans as 4-hydroxybutyric (gamma-hydroxybutyric, GHB) aciduria. It is characterized by a non-specific neurological disorder including psychomotor retardation, language delay, seizures, hypotonia and ataxia. The current therapy, vigabatrin (VGB), is not uniformly successful. Here we report the development of Aldh5a1-deficient mice. At postnatal day 16-22 Aldh5a1-/- mice display ataxia and develop generalized seizures leading to rapid death. We observed increased amounts of GHB and total GABA in urine, brain and liver homogenates and detected significant gliosis in the hippocampus of Aldh5a1-/- mice. We found therapeutic intervention with phenobarbital or phenytoin ineffective, whereas intervention with vigabatrin or the GABAB receptor antagonist CGP 35348 (ref. 2) prevented tonic-clonic convulsions and significantly enhanced survival of the mutant mice. Because neurologic deterioration coincided with weaning, we hypothesized the presence of a protective compound in breast milk. Indeed, treatment of mutant mice with the amino acid taurine rescued Aldh5a1-/- mice. These findings provide insight into pathomechanisms and may have therapeutic relevance for the human SSADH deficiency disease and GHB overdose and toxicity.

Succinic semialdehyde dehydrogenase (SSADH) catalyzes the NADP-dependent oxidation of succinic semialdehyde to succinate, the final step of the GABA shunt pathway. SSADH deficiency in humans is associated with excessive elevation of GABA and c-hydroxybutyrate (GHB). Recent studies of SSADH-null mice show that elevated GABA and GHB are accompanied by reduced glutamine, a known precursor of the neurotransmitters glutamate and GABA. In this study, cerebral metabolism was investigated in urethane-anesthetized SSADH-null and wild-type 17-day-old mice by intraperitoneal infusion of [1,[6][7][8][9][10][11][12][13] C incorporated per gram of brain tissue) for glutamate-(C4,C3), glutamine-C4, succinate-(C3/2), and aspartate-C3 in SSADH-null cortex, whereas Ala-C3 was higher and GABA-C2 unchanged.13 C Labeling from [2-13 C]acetate, a glial substrate, was lower mainly in glutamine-C4 and glutamate-(C4,C3). GHB was labeled by both substrates in SSADH-null mice consistent with GABA as precursor. Our findings indicate that SSADH deficiency is associated with major alterations in glutamate and glutamine metabolism in glia and neurons with surprisingly lesser effects on GABA synthesis.

Therapeutic intervention for human succinic semialdehyde dehydrogenase (SSADH) deficiency (␥-hydroxybutyric aciduria) has been limited to vigabatrin (VGB). Pharmacologically, VGB should be highly effective due to 4-aminobutyrate-transaminase (GABA-transaminase) inhibition, lowering succinic semialdehyde and, thereby, ␥-hydroxybutyric acid (GHB) levels. Unfortunately, clinical efficacy has been limited. Because GHB possesses a number of potential receptor interactions, we addressed the hypothesis that antagonism of these interactions in mice with SSADH deficiency could lead to the development of novel treatment strategies for human patients. SSADH-deficient mice have significantly elevated tissue GHB levels, are neurologically impaired, and die within 4 weeks postnatally. In the current report, we compared oral versus intraperitoneal administration of VGB, CGP 35348 [3-aminopropyl(diethoxymethyl)phosphinic acid, a GABA B receptor antagonist], and the nonprotein amino acid taurine in rescue of SSADH-deficient mice from early death. In addition, we assessed the efficacy of the specific GHB receptor antagonist NCS-382 (6,7,8,9-tetrahydro-5-[H]benzocycloheptene-5-ol-6-ylideneacetic acid) using i.p. administration. All interventions led to significant lifespan extension (22-61%), with NCS-382 being most effective (50 -61% survival). To explore the limited human clinical efficacy of VGB, we measured brain GHB and ␥-aminobutyric acid (GABA) levels in SSADH-deficient mice receiving VGB. Whereas high-dose VGB led to the expected elevation of brain GABA, we found no parallel decrease in GHB levels. Our data indicate that, at a minimum, GHB and GABA B receptors are involved in the pathophysiology of SSADH deficiency. We conclude that taurine and NCS-382 may have therapeutic relevance in human SSADH deficiency and that the poor clinical efficacy of VGB in this disease may relate to an inability to decrease brain GHB concentrations.

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Background Adenoma detection rate (ADR) has recently been used as a quality measure for screening colonoscopy. We hypothesize that the adenoma detection rate (ADR) will increase with each decade of life after 50 years. Objective The aim of this study is to define age-based goals for adenoma detection rate and advanced neoplasia to improve the quality of colonoscopy. Methods Utilizing the Clinical Outcomes Research Initiative (CORI) database, patients who underwent screening colonoscopy between 2005-2006 were identified. Pathology of polyp findings was reviewed and the ADR and the prevalence of advanced neoplasia were calculated based on age and gender. Results There were 7,756 (44.9%) polypectomies performed on 17,275 patients between 2005-2006. 56.3% (4,363) of these polyps were adenomas or more advanced lesions. The ADR was higher in men than women and increased with age. The ADR in men under age 50 was 24.7 [95% CI 18.2-31.2]; 50-59 years: 27.8 [26.5-29.1]; 60-69 years: 33.6 [31.7-35.4]; 70-79 years: 34.3 [31.5-37.1]; > 80 years: 40.0 [32.9-47.1]. The ADR in women under 50 years old was 12.6 [6.8-18.4]; 50-59 years: 17.0 {15.9-18.1]; 60-69 years: 22.4 {20.8-24.0]; 70-79 years: 26.1 {23.7-28.5]; > 80 years: 26.9 [21.4-32.5]. Limitations The CORI database offers access to demographic information as well as endoscopy and pathology data but there is limited clinical information about patients in the database. Conclusion Adenoma detection rate, and importantly, the rate of advanced neoplasia, increased with each decade of life over 50 and are higher in men than women in each decade of life.

Metabolite profiling in succinate semialdehyde dehydrogenase (SSADH; Aldh5a1 -/-) deficient mice previously revealed elevated c-hydroxybutyrate (GHB) and total GABA in urine and total brain and liver extracts. In this study, we extend our metabolic characterization of these mutant mice by documenting elevated GHB and total GABA in homogenates of mutant kidney, pancreas and heart. We quantified b-alanine (a GABA homolog and putative neurotransmitter) to address its potential role in pathophysiology. We found normal levels of b-alanine in urine and total homogenates of mutant brain, heart and pancreas, but elevated concentrations in mutant kidney and liver extracts. Amino acid analysis in mutant total brain homogenates revealed no abnormalities except for significantly decreased glutamine, which was normal in mutant liver and kidney extracts. Regional amino acid analysis (frontal cortex, parietal cortex, hippocampus and cerebellum) in mutant mice confirmed glutamine results. Glutamine synthetase protein and mRNA levels in homogenates of mutant mouse brain were normal. We profiled organic acid patterns in mutant brain homogenates to assess brain oxidative metabolism and found normal concentrations of Kreb's cycle intermediates but increased 4,5-dihydroxyhexanoic acid (a postulated derivative of succinic semialdehyde) levels. We conclude that SSADH-deficient mice represent a valid metabolic model of human SSADH deficiency, manifesting focal neurometabolic abnormalities which could provide key insights into pathophysiologic mechanisms. Keywords: b-alanine, 4,5-dihydroxyhexanoic acid, GABA, c-hydroxybutyrate, glutamine, succinate semialdehyde dehydrogenase. Succinic semialdehyde dehydrogenase (SSADH; succinatesemialdehyde:NAD + oxidoreductase, EC 1.2.1.24) deficiency (4-hydroxybutyric aciduria) is a rare autosomal recessively inherited defect of the GABA degradative pathway (Fig. 1) . Clinical findings in patients are heterogeneous, featuring psychomotor retardation, hypotonia, absence of developed speech, ataxia and occasionally seizures (Gibson et al. 1998). Current therapeutic intervention is limited to vigabatrin, an antiepileptic which acts pharmacologically through inhibition of GABA-transaminase ( Fig. 1) (Gibson et al. 1995(Gibson et al. , 1997. Unfortunately, vigabatrin Received November 19, 2001; revised manuscript received December 14, 2001; accepted December 19, 2001.Address correspondence and reprints requests to K. Michael Gibson, Biochemical Genetics Laboratory, Oregon Health & Science University, Genetics Laboratories, 2525 SW 3rd Avenue, Portland, OR 97201, USA. E-mail: gibsonm@ohsu.edu Abbreviations used: DHHA, 4,5-dihydroxyhexanoic acid; GHB, c-hydroxybutyrate or 4-hydroxybutyrate; GS, glutamine synthetase; SSADH, succinate semialdehyde dehydrogenase; tBA, total b-alanine, representing free and esterified b-alanine; TCA, tricarboxylic acid cycle; tGABA, total GABA, representing free and esterified GABA.

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