Glutaric aciduria type 1 (GA1) arises from an enzymatic block in the common degradation pathway for lysine and tryptophan. It is a cause of crippling striatal necrosis during infancy (Strauss et al., 2003). Clinical experience teaches us two things about GA1. First, predicting precisely when and if basal ganglia injury will occur in an individual is presently difficult, if not impossible. Second, when such injuries ensue, we have no therapeutic instruments to stop them. Thus, to prevent injuries we need prediction, and there is ample clinical evidence that plasma and urine organic acid measurements are inadequate for this purpose (Strauss et al., 2003). Real progress in the treatment of GA1 requires a deeper understanding of the premorbid state—the set of physiological adaptations entrained by abnormal organic acid metabolism in the brain. For this knowledge to be applied physiological changes that precede the catastrophic event must be defined, so that anatomical or biochemical abnormalities causatively linked to brain injury can be monitored in the clinical setting. Such a picture does not readily emerge from in vitro experiments, which generally use isolated single cell types from a variety of non-human species assayed under non-physiological conditions (see Kölker et al., 2004, for review), cannot be reproduced consistently (Freudenberg et al., 2004), and are difficult to reconcile with the complex conditions that prevail in a living patient.

Careful post-mortem studies are an invaluable tool for understanding physiological derangements that occur in life. In this issue of Brain, Dr Funk and colleagues report on six post-mortem brains from aboriginal Ojibway–Cree GA1 patients of Northern Canada to, in their words,‘offer additional insight into the pathogenesis of the disorder...[to] help us develop an intervention strategy that could prevent the episode associated with acute striatal injury and thus minimize the devastating neurological sequelae seen in our affected patients’(italics mine). The ‘episode’—a term used to underscore their central thesis that GA1, while a systemic and lifelong disorder of organic acid metabolism, causes an age-dependent paroxysm: a sudden, destructive, and anatomically restricted injury to the brain occurring within a particular developmental period.