SSADH deficiency, a rare inborn error of human metabolism, disrupts the normal metabolism of the inhibitory neurotransmitter GABA. In response to the defect, physiologic fluids from patients accumulate GHB, a compound with numerous neuromodulatory properties. Clinical and bio-chemical findings in patients are contrasted with existing neuropharmacologic data on GHB in animals and men. We conclude that GHB contributes to the pathogenesis of SSADH deficiency; whether this effect is mediated by GHB, by GABA following metabolic interconversion, or via synergistic mechanisms by both compounds, remains to be determined. An animal model of SSADH deficiency should further define the role of GHB in the pathogenesis of SSADH deficiency, and provide a useful vehicle for the evaluation of new therapeutic intervention.

Fatty acids are a major source of metabolic fuel in man. Both mitochondria and peroxisomes are capable of fatty acid fl-oxidation (Schulz, 1985). It is generally agreed that the oxidation of medium and long chain fatty acids, which are most abundant in our daily diet, takes place predominantly in mitochondria. In contrast, peroxisomal fl-oxidafion is not so important for energy purposes, but catalyses the chainshortening of a distinct set of substrates which includes very long chain fatty acids, certain mono-and polyunsaturated fatty acids and di-and trihydroxycholestanoic acid (see Wanders et al., 1990 for review). The different physiological functions of mitochondrial and peroxisomal fl-oxidation are reflected in the widely differing clinical consequences of defects in mitochondrial and peroxisomal fl-oxidation, respectively. In recent years an increasing number of inherited diseases in man have been recognized in which there is an impairment in mitochondrial fl-oxidation (Vianey-Liaud et al., 1987). In this paper we report the identification of a new inborn error of mitochondfial fi-oxidation at the level of long chain 3-hydroxyacyl-CoA dehydrogenase in a child who presented at 5 months of age with diarrhoea and vomiting, subsequently followed by increasing lethargy which appeared to be associated with hypoketotic hypoglycaemia. MATERIALS AND METHODS Enzyme activity measurementsThe activity of 3-hydroxyacyl-CoA dehydrogenase was measured in homogenates of cultured skin fibroblasts at 37°C by following the decrease in absorbance at 311

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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.

In the present cohort with aorto-iliac aneurysm, a maximum of 58% could have been treated with an iliac side branch based on the current experience. In particular, an aneurysmal IIA seems to be a limiting factor for the use of the iliac side-branched stent graft.