A group of organic acidurias, including Canavan disease (N-acetylaspartic aciduria), glutaric aciduria type I, l-2-hydroxylgutaric aciduria and d-2-hydroxyglutaric aciduria types I and II, are characterised by a predominantly or even exclusively neurological presentation and have therefore been termed ‘cerebral’. Frequent neurological symptoms are motor and/or mental retardation or regression, extrapyramidal movement disorders and epilepsy. These symptoms are the result of acute and/or chronic pathological changes in various brain regions including grey matter (cortex, basal ganglia, cerebellum) and white matter (periventricular and subcortical). Unlike ‘classic’ organic acidurias (e.g. propionic and methylmalonic aciduria), acute metabolic decompensations with hyperammonemia, metabolic acidosis and elevated concentrations of lactate and ketone bodies are uncommon for cerebral organic acidurias. Biochemically, these diseases are characterised by accumulation of characteristic organic acids, mostly dicarboxylic acids, in body fluids. At high concentrations some of these may become neurotoxic. Since the blood–brain barrier has a low transport capacity for dicarboxylic acids, cerebral accumulation of dicarboxylic acids is facilitated. Impairment of brain energy metabolism is suggested to play a central role in the pathophysiology of this disease group. Metabolic treatment initiated in neonatally diagnosed patients with glutaric aciduria type I has significantly improved the neurological outcome, whereas current treatment strategies for the other cerebral organic acidurias are ineffective.
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