FV 754. Newborn Screening, a Disease-Modifying Intervention for Glutaric Aciduria Type 1

Background: Glutaric aciduria type 1 (GA1, OMIM #231670) is a rare inherited neurometabolic disorder of L-lysine, L-hydroxylysine, and L-tryptophan metabolism due to deficiency of glutaryl-CoA dehydrogenase resulting in accumulation of glutaryl-CoA, glutaric acid (GA), and 3-hydroxyglutaric acid (3-OH-GA), especially within the brain. Two arbitrarily defined biochemical subgroups, low (LE) and high excretors (HE), have been described according to the amount of urinary GA. Untreated individuals commonly present with a complex, predominantly dystonic movement disorder (MD) following acute or insidious onset of striatal damage. Implementation of GA1 into national newborn screening (NBS) programs has improved the neurologic short-term outcome. However, it is unclear whether NBS changes the long-term outcome and which outcome variables are predictive.

Aims: To investigate the long-term neurologic and nonneurologic outcomes in patients treated and prospectively followed after positive NBS, to identify major disease-modifying effects of interventional and noninterventional parameters, and to evaluate the overall benefit of the NBS program for GA1 patients.

Methods: This prospective, observational, multicenter study with a cumulative follow-up time of 710.6 years includes 87 patients identified by NBS, four patients missed by NBS and three mothers with GA1 identified by positive NBS results of their unaffected children. Clinical and biochemical follow-up parameters were assessed prospectively. Neurologic manifestations were separated into major motor symptoms, that is, manifestation of a MD, and minor motor symptoms, that is, fine motor deficits and/or delayed achievement of motor milestones in the absence of MD.

Results: The study population comprises 98.3% of individuals with GA1 identified by NBS in Germany between 1999 and 2016. Overall, cumulative sensitivity of NBS is 95.6% but is lower (84%) for patients with LE phenotype. Neurologic outcome of patients missed by NBS is as poor as in the pre-NBS era, while the clinical phenotype of diagnosed patients depends on the quality of therapeutic interventions rather than noninterventional variables (gender, biochemical subtype, and migration). Presymptomatic start of treatment according to recent guideline recommendations (AWMF no. 027-018), that is, low lysine diet and carnitine supplementation for maintenance treatment and intermittent emergency treatment during episodes likely to induce catabolism, clearly improves the neurologic outcome (MD: 7% of patients), while delayed emergency treatment results in acute-onset MD (100%), and deviations from maintenance treatment increase the risk of insidious onset MD (50%) and, less pronounced, minor motor symptoms. Patients with severe MD have a much lower life expectancy (n = 5; median age at death, 3.3 years) than those being asymptomatic or having mild or moderate MD (p < 0.001). Nonadherence to recommended emergency treatment has a major negative impact on survival (p = 0.0036). Independent of the neurologic phenotype, kidney function tends to decline with age, a nonneurologic manifestation not predicted by any variable included in this study.

Conclusion: NBS is a beneficial, disease-modifying intervention for GA1. However, improved neurologic outcome critically depends on adherence to recommended therapy regimen while kidney dysfunction does not appear to be impacted by recommended therapy.