Glutaric Aciduria is Caused by a Deficiency of a Key Enzyme in the Metabolism of Lysine

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Glutaric aciduria type 1 (GA1) is a rare organic aciduria. It is caused by deficiency of glutaryl-CoA dehydrogenase; a key enzyme in the metabolism of lysine, hydroxylisine and tryptophan. Patients can suffer selective striatal degeneration that presents as motor delay, dystonia or acute motor regression during infancy. The symptoms are due to the accumulation of toxic metabolites and can be precipitated by periods of acute illness, infectious disease, immunizations and surgery. Management of GA1 relies on preemptive diagnosis followed by protein restriction, sustained carbohydrate intake during illness and promoting renal clearance of organic acids. Because the disease is highly treatable if found before brain damage occur, newborn screening has become a pivotal part in the diagnosis of these patients. If untreated, 90% of patients will go on to develop neurological disease.

The intermediate metabolites (glutaric acid, 3-hydroxiglutaric acid (3-OH-GA), glutarylcarnitine (C5DC) and glutaconic acid) that accumulate as a result of the enzyme deficiency, can be detected by gas chromatography/mass spectrometry (GC/MS) or tandem MS. Two groups of patients have been described based on urinary metabolite excretion of glutaric acid; high and low excretors. Newborn screening usually includes identification of C5DC in a blood acylcarnitine profile followed by quantification in urine of 3-OH-GA, followed my molecular genetics confirmation (GCDH gene); in the case of low excretors the urine testing might be falsely negative.

The prevalence of the disease has been estimated at 1 in 100000 newborns but varies within populations. Some communities like the Amish or the Canadian Oji-Cree natives have a high carrier frequency (as high as 1:10)....

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...erstood source of error in the case of false positive newborn screens is the role of perinatal factors such as mode of delivery and its effects on metabolite values.

We have reasons to believe that perinatal factors could in fact affect newborn screen values. Over a span of there years there were 30 cases of positive newborn screens with elevated C5DC values in infants born at Johns Hopkins. All of them considered false positives. Close analysis of the data showed that there were a disproportionate number of cesarean sections in this group of patients as compared to the general population. We believe that there could be a relationship between the mode of delivery (C-section) and the elevated levels of C5DC in newborn screen, either as a direct consequence of the stress of the procedure, or related to the primary indication to undergo a C-section in the first place.
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