No abstract

Invasive infections of the central nervous system or digestive tract caused by commensal fungi of the genus Candida are rare and life-threatening. The known risk factors include acquired and inherited immunodeficiencies, with patients often displaying a history of multiple infections. Cases of meningo-encephalitis and/or colitis caused by Candida remain unexplained. We studied five previously healthy children and adults with unexplained invasive disease of the central nervous system, or the digestive tract, or both, caused by Candida spp. The patients were aged 39, 7, 17 37, and 26 years at the time of infection and were unrelated but each born to consanguineous parents of Turkish (two patients), Iranian, Moroccan or Pakistani origin. Meningo-encephalitis was isolated in three patients, associated with colitis in a fourth patient, and the fifth patient suffered from isolated colitis. Inherited CARD9 deficiency was recently reported in otherwise healthy patients with other forms of severe disease caused by Candida, Trichophyton, Phialophora, and Exophiala, including meningo-encephalitis, but not colitis, caused by Candida and Exophiala. We therefore sequenced CARD9 in the five patients. All were found to be homozygous for rare and deleterious mutant CARD9 alleles: R70W and Q289* for the three patients with isolated C. albicans meningo-encephalitis, R35Q for the patient with meningo-encephalitis and colitis caused by C. glabrata, and Q295* for the patient with C. albicans colitis. Regardless of their levels of mutant CARD9 protein, the patients’ monocyte-derived dendritic cells responded poorly to CARD9-dependent fungal agonists (curdlan, heat-killed C. albicans, Saccharomyces cerevisiae and Exophiala dermatitidis). Invasive infections of the CNS or digestive tract caused by Candida in previously healthy children and even adults may be caused by inherited CARD9 deficiency.

No abstract

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...

No abstract

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.

This paper reviews the clinical presentation of 217 patients with urea cycle defects, including 121 patients with neonatal-onset forms and 96 patients with late-onset forms. Long-term outcome of these patients is also reported with the severity of the neonatal forms of these disorders, mostly for ornithine carbamoyltransferase-deficient males. Patients with late-onset forms may present at any age and carry a 28% mortality rate and a subsequent risk of subsequent disabilities.

No abstract