Neurodevelopmental Profile of Children With MARS1-Related Pulmonary Alveolar Proteinosis: A Cohort Study

ImportancePulmonary alveolar proteinosis (PAP) is a rare pulmonary disorder characterized by alveolar surfactant accumulation leading to respiratory impairment. MARS1 mutations lead to an early onset PAP associated in a setting of multi-organ involvement and respond to high-dose methionine supplementation. While pulmonary manifestations of MARS1-related PAP and their response to methionine are well documented, its potential impact on cognitive and adaptive functioning in pediatric patients remains poorly understood. Understanding the neurodevelopmental profile of children with MARS1-related PAP is essential for optimizing comprehensive care and long-term outcomes. ObjectiveTo characterize the neurodevelopmental profile of children with MARS1-related PAP by assessing intellectual functioning and adaptive behavior using standardized neuropsychological measures and parent-reported questionnaires. DesignObservational cohort study including 16 pediatric patients with MARS1-related PAP aged 14 months to 7.3 years, followed at the Necker-Enfants Malades Hospital (Paris, France) and treated with methionine. Intellectual functioning was assessed using the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) when age-appropriate, and adaptive behavior was evaluated via the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) through parent interviews. ResultsSixteen children with MARS1-related PAP underwent the full evaluation. Methionine was started at a median age of 6 months (IQR [5, 15]). Eight of them were able to undergo the WPPSI-IV assessment. The mean Full-Scale IQ was 72.25 (SD = 16.85), indicating borderline to mild intellectual disability relative to normative data. Adaptive behavior composite scores on the VABS-II averaged 69.75 (SD = 23.58), reflecting significant deficits across communication, daily living skills, socialization, and motor domains. The neurodevelopmental impairments were relatively homogeneous across the cohort. ConclusionsChildren with MARS1-related pulmonary alveolar proteinosis exhibit marked impairments in intellectual and adaptive functioning, suggesting a consistent neurodevelopmental profile associated with the disease, and despite methionine supplementation. These findings highlight the need for routine cognitive and developmental monitoring in pediatric PAP patients and support the development of multidisciplinary interventions addressing both respiratory and neurodevelopmental outcomes.