Glutaric aciduria type I: A translational approach to an enigmatic disease

Glutaric aciduria type I (GA-I) is an autosomal recessively inherited disorder of L-lysine, L-tryptophan and L-hydroxylysine metabolism which is biochemically characterized by the accumulation of putatively toxic glutaric and 3-hydroxyglutaric acids, and non-toxic glutarylcarnitine due to deficient activity of glutaryl-CoA dehydrogenase. The prognostic relevant event of this disease is the manifestation of a complex movement disorder with predominant dystonia superimposed on axial hypotonia. This movement disorder most often manifests during infancy or early childhood after the precipitation of acute encephalopathic crises by catabolic state but it may also develop insidiously without clinically apparent crises. Advances have been made in the description of the natural disease course and neuroradiological abnormalities demonstrating overlapping episodes of cerebral alterations including (reversible) maturational delay of the brain in utero, (irreversible) acute striatal injury during a vulnerable period of brain development and chronic progressive changes that may continue lifelong and involving extrastriatal brain regions. Neonatal identification of asymptomatic patients by tandem mass spectrometry allowing to start combined metabolic treatment in asymptomatic patients has significantly improved the neurological outcome in countries with such newborn screening programmes. In contrast, therapeutic concepts for symptomatic patients are much less effective. Post mortem studies and investigations in Gcdh-deficient mice, a transgenic mouse model for GA-I, have helped to unravel the pathomechanism. Evidence is increasing that some of the accumulating metabolites in GA-I patients are neurotoxic due to their interference with glutamatergic neurotransmission, inhibition of the 2-oxoglutarate dehydrogenase complex and impairment of the dicarboxylic acid shuttle between astrocytes and neurons. Strikingly, glutaric and 3-hydroxylgutaric acids massively accumulate in the brain of patients due to the low permeability of the blood brain barrier for dicarboxylic acids which may explain the selective neurological phenotype of GA-I. Current therapeutic concepts aim to reduce the cerebral concentrations of neurotoxic metabolites by modulating lysine influx to the brain and stimulating the formation of non-toxic glutarylcarnitine. Despite the outlined progress, the mechanism of current neuroprotective concepts is still quite hypothetical and lack a proof of principle. Our understanding has been hampered by the fact that in affected patients the biochemical effect of metabolic treatment could be determined only by using invasive methods (which would be unethical), whereas the concentrations of these biomarkers in body fluids are unlikely to correlate with the brain tissue. Therefore, a translational approach to this disease is indispensable to further unravel the mechanisms of neurologic disease and to elucidate the major principles of neuroprotective strategies.