Glutaric aciduria type 1: a clinician's view of progress.

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. Using quantitative neuron counts and cell-specific stains, the authors broaden our knowledge about the basal ganglia lesions associated with GA1. They show that striatal large cholinergic interneurons are lost in addition to medium spiny neurons, challenging the notion that the medium spiny neurons are uniquely vulnerable in GA1. In addition they demonstrate an activation/proliferation of microglia in the post-injury period that regresses over time. Together, these observations raise the possibility that acute striatal necrosis in GA1 is a form of pan-coagulative necrosis, as occurs in genuine cerebral ischaemia (Auer and Sutherland, 2002). In such injuries, the whole brain or large subregions may be affected by a common insult, but selective vulnerability arises due to regional particulars of blood supply and/or cell type. Thus, while medium spiny neurons may be more vulnerable to injury (Calabresi et al., 2000) they are not uniquely so, and neuronal necrosis in GA1 may not be so ‘selective’ as previously assumed (Strauss and Morton, 2003). At a gross level, the authors try to address an important paradox: despite the fact that MR images of affected neonates and infants suggest atrophy of specific cortical regions and the axonal intermediate zone, these same brains are consistently heavy at post-mortem (Fig. 1). This implies that the MRI appearance cannot simply reflect brain atrophy, and casts doubt on the term ‘frontotemporal hypoplasia’ to describe the young GA1 brain (Strauss et al., 2003). While physical distortion of the frontal and temporal cortex is often noted post-mortem (Kimura et al., 1994; Soffer et al., 1992), histological evidence of cortical atrophy is never found. Increased brain weight may reflect cerebral hypercellularity or, more likely, a poorly understood abnormality of intracranial fluid dynamics. If the material accounting for increased brain weight is water, where is it located, what is its source, and how does it communicate with other intracranial fluid compartments? These simple questions are difficult to answer. Finding correct solutions may be the key to explaining the puzzling constellation of hydrodynamic abnormalities seen in young GA1 brains: congenital ventriculomegaly and communicating hydrocephalus, middle cranial fossa arachnoid cysts, subdural collections of cerebrospinal fluid and/or blood, and T2and diffusion-weighted signal enhancement in certain subcortical white matter regions (Strauss et al., 2003). Perhaps the most important contribution of the paper is to corroborate the finding of previous studies (Goodman et al., 1977; Kölker et al., 2003) that brain glutaric acid (GA) is very high in patients with GA1, and exceeds plasma andCSFlevelsbyone to twoordersofmagnitude.At the wholeorgan level, only two scenarios could account for this. Either