Value of neuroimaging in metabolic diseases affecting the CNS.

Neuroimaging has become an indispensable tool in understanding the regions of susceptibility , progression of disease, and therapeutic effectiveness for the management of neurologic diseases in humans. Metabolic diseases are recognized more frequently now as the biochemical basis is understood better. In addition, and as illustrated in this issue of the AJNR [1-3] , clinicians can benefit immensely from the technologic advancements in neuroradiology. Glutaric acidemia type I (GA I) and methylmalonic acidemia are autosomal recessively inherited organic acidemias, resulting from a deficiency of mitochondrial proteins [4, 5]. The vital role of mitochondria in energy metabolism is well known. Abnormalities in the function of these organelles affect regions in which increased energy demands occur. In the infant's brain, the basal ganglia appear to be especially susceptible to such insults. Glutaryl coenzyme A (GoA) dehydrogenase is involved in an important intermediate step in the degradation of lysine and tryptophan [ 4, 6-8]. Methylmalonic acidemia (MMA) is associated with a deficiency of methylmalonyl GoA mutase, with mutations occurring at different genetic sites [5] . Marked clinical heterogeneity occurs in both disorders, and the enzyme deficiency is not always associated with serious clinical consequences. Both disorders cause progressive neurologic deterioration that is primarily extrapyramidal , with acute episodic vomiting and lethargy [4, 5, 9-11] . Neonatal or infantile onset is common to both disorders [3, 12]. However, specific neuroradiologic findings can be used to help in the differentiation of the two conditions. In GA I, CT scans have shown significant frontotemporal atrophy in both symptomatic and asymptomatic patients with white matter abnormalities that are considered pathognomonic of this disorder [13, 14]. Symptomatic patients-more than those who are asymptomatic-show severe neuroradiologic involvement. MR highlights the abnormalities of the caudate and the white matter changes [15]. Despite prominent choreoathetosis, radiologic involvement of the basal ganglia may be minimal, suggesting that neuronal function could be altered before cell death. Severe involvement of the globus pallidus occurs in MMA. This change is seen both in those with acute decompensation and in those without such episodes [1 0, 16]. It is thought to be due to cytotoxic injury from the accumulated metabolites, which specifically target the globus pallidus [17]. In addition, tissueand age-specific high energy requirements may not be met by malfunctioning mitochondria. Cytochrome c oxidase, a mitochondrial respiratory chain enzyme, is reported to be reduced secondarily in patients with methylmalonic or proprionic acidemia during acute decompensation [18] . Pathologic reports in cases of GA I document the extensive loss of neurons in the caudate and putamen and spongiform changes in the white matter with sparing of U fibers [8]. The increased cell loss, particularly in the caudate and putamen, accounts for reduced levels of 'Y-aminobutyric acid (GABA) in the brain and spinal fluid [7, 15]. The reason for the progressive atrophy of these nuclei with age is not well understood but may result from accumulation of glutaric acid, which has been shown to be toxic to striatal cells in culture [19]. The involvement of the basal ganglia in neonates and infants with GA I and MMA is of great importance to developmental neurology. The reduction of GABA as reported in GA I and the energy depletion brought about by mitochondrial involvement in both conditions could result in neuronal injury from a relative