The purpose of this study was to identify the biochemical and genetic defect in L-2-hydroxyglutaric aciduria, a neurometabolic disorder characterized by the presence of elevated concentrations of L-2-hydroxyglutaric acid in urine, plasma, and cerebrospinal fluid. Evidence is provided for the existence in rat tissues of a FAD-dependent enzyme catalyzing specifically the oxidation of L-2-hydroxyglutarate to ␣-ketoglutarate. This enzyme is mainly expressed in liver and kidney but also at lower levels in heart, brain, and other tissues. Subcellular fractionation indicates that the liver enzyme is present in mitochondria, where it is bound to membranes. Based on this information, a database search led to the identification of a gene encoding a human hypothetical protein homologous to bacterial FAD-dependent malate dehydrogenases and targeted to mitochondria. The gene encoding this protein, present on chromosome 14q22.1, was found to be in a region homozygous in patients with L-2-hydroxyglutaric aciduria from two consanguineous families. Three mutations that replaced a highly conserved residue (Lys-71-Glu and Glu-176-Asp) or removed exon 9 were identified in homozygous state in patients from three distinct families and were found to cosegregate with the disease. It is concluded that L-2-hydroxyglutarate is normally metabolized to ␣-ketoglutarate in mammalian tissues and that L-2-hydroxyglutaric aciduria is caused by mutations in the gene that most likely encodes L-2-hydroxyglutarate dehydrogenase. The pathological findings observed in this metabolic disorder must therefore be due to a toxic effect of L-2-hydroxyglutarate on the central nervous system. inborn error of metabolism ͉ leukoencephalopathy ͉ ataxia A s a neurometabolic disorder, L-2-hydroxyglutaric aciduria is characterized by the presence of elevated concentrations of L-2-hydroxyglutaric acid in plasma, cerebrospinal fluid, and urine (1-3). Clinically, the affection is characterized by progressive ataxia, mental deficiency with subcortical leukoencephalopathy, and cerebellar atrophy. As of 1996, Ͼ40 patients were known worldwide (3). The disease appears to be recessively transmitted, but the enzymatic defect leading to this condition is presently unknown, largely because of poor knowledge on the origin and fate of L-2-hydroxyglutarate. A NAD-dependent dehydrogenase acting on this compound has been reported to be present in liver (4). However, this enzyme displays a very high K m for L-2-hydroxyglutarate (Ϸ10 mM), making it unsuitable to consume this substrate at physiologically relevant concentrations (probably of the order of 1 M). Furthermore, it is not deficient in patients with L-2-hydrox yglutaric aciduria (5). L-2-hydroxyglutarate dehydrogenase activity transferring its electrons to pyocyanin was partially characterized Ϸ70 years ago by Weil-Malherbe (6), who found it to be mostly active in heart, kidney, and brain. However, no oxidation of L-2-hydroxyglutarate by rat liver mitochondria was later found by Lindahl and coworkers (7). Furthermore, rat ti...
In normal conditions, albumin and immunoglobulin (Ig)G in the cerebrospinal fluid (CSF) originate from the blood, and there is no antibody production within the central nervous system. Up to 20% of CSF proteins are intrathecally synthesized, but the major fraction is blood-derived. The CSF/serum albumin quotient (QAlb) is the best marker of the blood-CSF barrier function. The corresponding immunoglobulin quotients (QIGG, QIGA, QIGM) are not linearly related to QAlb and their correlations are defined by an hyperbolic equation. This equation is used to discriminate between a blood-derived and a locally produced fraction of immunoglobulins in case of an intrathecal humoral immune response. The detection of CSF-specific oligoclonal IgG is more sensitive than the quantitative comparison between QIGG and QAlb. A further step is the determination of antibody indices and the detection of specific oligoclonal antibodies by antigen-driven immunoblots. CSF analysis remains a cornerstone for the diagnosis of various neurological disorders, including multiple sclerosis and infectious diseases of the central nervous system.
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