BACKGROUND: Metachromatic leukodystrophy (MLD) is a rapidly progressive leukodystrophy that leads to severe disability and early death if untreated. Autologous hematopoietic stem and progenitor cell gene therapy (HSPC-GT, atidarsagene autotemcel, arsa-cel) for early onset subtypes and allogenic hematopoietic stem cell transplantation (HSCT) for late onset disease substantially alters disease progression for early onset disease when administered before symptom onset, creating a strong rationale for newborn screening (NBS). At the same time, NBS technique for MLD in dried blood spots has recently been demonstrated to be robust and highly accurate. The aim was to give real-world results from the world's first NBS pilots for clinical management and treatment of identified children. METHODS: Between September 2021 and July 2025, 359,282 newborns underwent NBS for MLD in two different laboratories in Germany and Austria using a three-tier algorithm integrating sulfatide quantification, arylsulfatase A (ARSA) activity measurement, and ARSA sequencing. Screen-positive infants underwent a predefined care pathway including standardized confirmatory diagnostics, genotype-based and biochemical prediction of disease onset, clinical assessment and management guiding early treatment and surveillance at the qualified treatment center (QTC) in Tübingen. RESULTS: Nine newborns screened positive and all were confirmed to have MLD (detection rate approximately 1 per 40,000). Based on genotype and leukocyte ARSA enzyme activity, disease onset prediction was possible in all of them. Seven infants were classified as having pre-symptomatic early-onset MLD and were referred for HSPC-GT. All treated infants showed preserved neurological function up to 30 months after treatment (median 18.5 months). Two infants predicted to develop late-onset MLD entered structured surveillance for treatment with HSCT and have remained clinically asymptomatic for CNS signs of disease. No false-positive or known false-negative results were observed. CONCLUSION: These results from our pilot programs demonstrate that NBS enables reliable early identification of MLD and support streamlined care pathways leading to timely intervention. Importantly, this study provides real-world evidence illustrating that NBS for MLD can enable timely, pre-symptomatic treatment and structured surveillance within standard national healthcare systems. These findings further substantiate the value of NBS for MLD at a critical moment as several countries consider national implementation of MLD screening.