Diagnosis and management of glutaric aciduria type I--revised recommendations

Abstract

Glutaric aciduria type I (synonym, glutaric acidemia type I) is a rare organic aciduria. Untreated patients characteristically develop dystonia during infancy resulting in a high morbidity and mortality. The neuropathological correlate is striatal injury which results from encephalopathic crises precipitated by infectious diseases, immunizations and surgery during a finite period of brain development, or develops insidiously without clinically apparent crises. Glutaric aciduria type I is caused by inherited deficiency of glutaryl-CoA dehydrogenase which is involved in the catabolic pathways of L-lysine, L-hydroxylysine and L-tryptophan. This defect gives rise to elevated glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutarylcarnitine which can be detected by gas chromatography/mass spectrometry (organic acids) or tandem mass spectrometry (acylcarnitines). Glutaric aciduria type I is included in the panel of diseases that are identified by expanded newborn screening in some countries. It has been shown that in the majority of neonatally diagnosed patients striatal injury can be prevented by combined metabolic treatment. Metabolic treatment that includes a low lysine diet, carnitine supplementation and intensified emergency treatment during acute episodes of intercurrent illness should be introduced and monitored by an experienced interdisciplinary team. However, initiation of treatment after the onset of symptoms is generally not effective in preventing permanent damage. Secondary dystonia is often difficult to treat, and the efficacy of available drugs cannot be predicted precisely in individual patients. The major aim of this revision is to re-evaluate the previous diagnostic and therapeutic recommendations for patients with this disease and incorporate new research findings into the guideline.

Fig 1

Diagnostic algorithm for glutaric aciduria type I. a, Newborn screening for GA-I is performed using MS/MS. In low excretor cohorts with known mutations, GCDH gene mutation analysis should be considered as alternative method (dotted line). Note that in these patients treatment should be started after the identification of two disease-causing mutations (*). b, Selective screening should be initiated if the diagnosis of GA-I is suspected clinically or there is a positive family history. Note that a few patients with a low-excreting phenotype may show (intermittently) normal urinary excretion of 3-OH-GA (and GA). If an individual shows normal 3-OH-GA (and GA) concentrations in urine (or other body fluids) but presents with highly suspicious signs and symptoms for GA-I, further diagnostic studies should be considered but the decision should be made based on the individual circumstance (**). Comment on mutation and enzyme analysis: Since GCDH gene analysis is more broadly available than GCDH enzyme analysis, and the identification of two disease-causing mutations not only confirms the diagnosis but also enables accurate genetic counselling and prenatal diagnosis, we recommend starting with GCDH gene analysis. However, depending on local availability and experience, GCDH enzyme analysis could be performed first