Glutaric aciduria type I: From clinical, biochemical and molecular diversity to successful therapy

The biochemical hallmark of glutaric aciduria type I (GA I) due to glutaryl -CoA dehydrogenase deficiency is the accumulation of glutaric acid, and to a lesser degree of 3-hydroxyglutaric and glutaconic acids. Abnormal metabol ites vary from gross organic aciduria to only slightly or intermittently el evated or even normal excretion of glutaric acid, making the diagnosis some times difficult. Close to 100 pathogenic mutations have been identified in the gene encoding glutaryl-CoA dehydrogenase. Specific mutations correlate with low or no excretion of glutaric acid, but there appears to be no corre lation between genotype and clinical phenotype. GA I causes unique age- and location-specific neuropathological sequelae. S tarting in the second half of gestation, maturation of the frontal and temp oral cortex is hindered, leading to the characteristic appearance of fronto temporal atrophy. Between 6 and 18 months of age, relatively mild neurologi cal symptoms may become exacerbated by fever or a catabolic state in the co urse of common infections or routine immunizations, by fasts required for s urgery, or by minor head injuries. Putamen and caudate are destroyed, resul ting in a permanent movement disorder that is similar to cerebral palsy and ranges from extreme hypotonia to choreoathetosis to rigidity with spastici ty. Recently, the underlying pathophysiology could be delineated to an envi ronmentally triggered age- and location-specific overstimulation of the NMD A 2B receptor subtype. Current therapy prevents brain degeneration in more than 90% of affected in fants who are treated prospectively. Without treatment, more than 90% of af fected children will develop severe neurological disabilities. Recognition of this disorder before the brain has been injured is essential to treatmen t. GA I may be recognized in routine neonatal screening performed with tand em mass spectrometry by an elevation of glutarylcarnitine. Where this is no t done, timely diagnosis depends on the recognition of relatively nonspecif ic physical findings such as hypotonia, irritability, macrocephaly, on the detection of suggestive abnormalities in neuroimaging and on quantitative u rinary organic acid analysis by gas chromatography - mass spectrometry.