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Objective: Untreated individuals with glutaric aciduria type 1 (GA1) commonly present with a complex, predominantly dystonic movement disorder (MD) following acute or insidious onset striatal damage. Implementation of GA1 into newborn screening (NBS) programs has improved the short-term outcome. It remains unclear, however, whether NBS changes the long-term outcome and which variables are predictive., Methods: This prospective, observational, multicenter study includes 87 patients identified by NBS, 4 patients missed by NBS, and 3 women with GA1 identified by positive NBS results of their unaffected children., Results: The study population comprises 98.3% of individuals with GA1 identified by NBS in Germany during 1999-2016. Overall, cumulative sensitivity of NBS is 95.6%, but it is lower (84%) for patients with low excreter phenotype. The neurologic outcome of patients missed by NBS is as poor as in the pre-NBS era, and the clinical phenotype of diagnosed patients depends on the quality of therapeutic interventions rather than noninterventional variables. Presymptomatic start of treatment according to current guideline recommendations clearly improves the neurologic outcome (MD: 7% of patients), whereas delayed emergency treatment results in acute onset MD (100%), and deviations from maintenance treatment increase the risk of insidious onset MD (50%). Independent of the neurologic phenotype, kidney function tends to decline with age, a nonneurologic manifestation not predicted by any variable included in this study., Interpretation: NBS is a beneficial, disease-changing intervention for GA1. However, improved neurologic outcome critically depends on adherence to recommended therapy, whereas kidney dysfunction does not appear to be impacted by recommended therapy. Ann Neurol 2018;83:970-979., (© 2018 American Neurological Association.)

Objective: To evaluate the effect of treatment according to current evidence-based recommendations on the neurological outcome of patients with glutaric aciduria type I (GA-I)., Methods: Fifty-two patients identified by newborn screening (NBS) in Germany from 1999 to 2009 were followed prospectively. Neurological outcome was assessed by the occurrence of an acute encephalopathic crisis and the severity of a movement disorder (MD) with predominant dystonia superimposing on axial hypotonia. Outcome was evaluated in relation to therapy and therapy-independent parameters., Results: Outcome was best in GA-I patients who were treated in full accordance with treatment recommendations (n=37; 5% MD). Deviations from recommended basic metabolic treatment (low-lysine diet, carnitine) resulted in an intermediate outcome (n=9; 44% MD), whereas disregard of emergency treatment recommendations was associated with a poor outcome (n=6; 100% MD). Treatment regimens deviating from recommendations significantly increased the risk for MD (odds ratio [OR], 35; 95% confidence interval [CI], 5.88-208.39) and acute encephalopathic crises (OR, 51.32; 95% CI, 2.65-993.49). Supervision by a metabolic center improved the outcome (18% vs 57% MD; OR, 6.17; 95% CI, 1.15-33.11), whereas migrational background and biochemical phenotype (high versus low excretor status) had no significant effect., Interpretation: Follow-up of neonatally diagnosed patients with GA-I in Germany clearly demonstrates that the inclusion of this rare disease in the NBS disease panel has significantly improved the neurological outcome of affected individuals. The establishment of and adherence to evidence-based treatment recommendations, and supervision by experienced metabolic centers helps to minimize the number of patients who do not benefit from NBS.