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 α-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 α-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.

Reduced folate transport to the CNS was identified in two autism spectrum disorders, i.e., Rett syndrome and infantile low-functioning autism with neurological abnormalities. Twenty-five patients with early-onset low-functioning autism with or without neurological deficits, were evaluated for serum folate, cerebrospinal fluid (CSF) 5-methyltetrahydrofolate (5MTHF), and serum FR autoantibodies of the blocking type to determine the significance of folate receptor (FR) autoantibodies with respect to folate transport across the blood-CSF barrier. In spite of normal serum folate, CSF 5MTHF was low in 23 of 25 patients. The reduced CSF folate in 19 of these 23 patients could be explained by serum FR autoantibodies blocking the folate binding site of the membrane-attached FR on the choroid epithelial cells. Oral folinic acid supplements led to normal CSF 5MTHF and partial or complete clinical recovery after 12 months. Serum FR autoimmunity appears to represent an important factor in the pathogenesis of reduced folate transport to the nervous system among children with early-onset low-functioning autism associated with or without neurological deficits. Early detection of FR autoantibodies may be a key factor in the prevention and therapeutic intervention among this subgroup of patients with autism.

Developmental dyscalculia (DD) is a deficit in number processing and arithmetic that affects 3–6% of schoolchildren. The goal of the present study was to analyze cerebral bases of DD related to symbolic number processing. Children with DD aged 9–11 years and matched children with no learning disability history were investigated using fMRI. The two groups of children were controlled for general cognitive factors, such as working memory, reading abilities, or IQ. Brain activations were measured during a number comparison task on pairs of Arabic numerals and a color comparison task on pairs of nonnumerical symbols. In each task, pairs of stimuli that were close or far on the relevant dimension were constituted. Brain activation in bilateral intraparietal sulcus (IPS) was modulated by numerical distance in controls but not in children with DD. Moreover, although the right IPS responded to numerical distance only, the left IPS was influenced by both numerical and color distances in control children. Our findings suggest that dyscalculia is associated with impairment in areas involved in number magnitude processing and, to a lesser extent, in areas dedicated to domain-general magnitude processing.