Effect of Newborn Screening and Adherence to Recommended Treatment on Clinical Outcome in Glutaric Aciduria Type 1: A Meta-analysis

Background: Glutaric aciduria type 1 (GA1) is a rare neurometabolic disorder of lysine metabolism caused by inherited deficiency of glutaryl-CoA dehydrogenase causing severe neurologic disease, i.e. acute (after an encephalopathic crisis) and insidious onset of dystonic movement disorder (MD) due to striatal damage in most untreated patients. Metabolic treatment consists of low lysine diet, oral carnitine supplementation and intermittent emergency treatment in situations likely to induce catabolism, such as infections. Implementation into national newborn screening (NBS) programs and adherence to recommended therapy are thought to improve the clinical outcome. For the first time, we investigated the effects of NBS programs worldwide by a meta-analysis.

Methods: Systematic literature search for articles published from 2000–2018 was performed using the PRISMA protocol and completed by hand search and contacting authors. Only articles reporting on more than one patient identified by NBS were included into a random effect meta-analysis. Single case reports, but not reports on case series were excluded. We investigated effects of interventional (NBS vs targeted metabolic screening, maintenance and emergency therapy) and non-interventional variables (gender, biochemical subtype, migrational background) on outcome (acute or insidious onset of MD, acute encephalopathic crisis, motor development, and mortality).

Findings: Fifteen publications reporting on NBS patients (n = 11 reporting on targeted metabolic screening) were included into quantitative synthesis. In the NBS group (n = 261 patients), 169 patients (65%) received recommended therapy; 195 patients remained asymptomatic (74.7%, 95% CI 69.7–98.3), and motor development was normal in 171 of them (88%), while 66 (25.3%) developed a MD, 39 of whom following acute encephalopathic crisis (EC). In contrast, 244 patients (62%) identified by targeted screening (n = 386) developed an EC (p<0.0001), and 285 of them (82%) showed an abnormal motor development. Mortality rates of both groups did not differ. Low lysine diet according to the guideline recommendations was superior to other forms of diet which showed a trend towards increased risk for insidious-onset dystonia (p = 0.06, relative risk 0.61, 95% CI 0.02–1.25). This effect was significant after exclusion of non-informative studies. Delayed emergency treatment increased the risk for developing acute MD. Gender, biochemical subtype and migrant background had no significant impact on outcome.

Discussion and Conclusion: This first meta-analysis of NBS programs for GA1 worldwide demonstrates a positive effect of NBS and recommended therapy on neurologic outcome while none of the evaluated non-interventional parameters had a measurable effect. Evaluation of therapy, however, is limited by the low quantity of informative studies comparing different treatment forms.

No conflict of interest has been declared by the author(s).