A prospective, longitudinal, natural history study of neurological disease trajectory in children with late-infantile or juvenile-onset GM1 gangliosidosis or GM2 gangliosidoses: the PRONTO study

Background Gangliosidoses are rare, autosomal recessive lysosomal diseases characterized by ganglioside accumulation, causing progressive neurodegeneration. Prospective natural history data are limited, particularly for late-infantile and juvenile-onset forms. Methods PRONTO was a prospective, longitudinal natural history study conducted at 13 sites in six countries (February 2022 to September 2025). Participants were aged 2–20 years and had genetically confirmed GM1 gangliosidosis or GM2 gangliosidoses and neurological symptom onset at ≥12 months of age. Assessments were conducted at baseline and every 6 months up to 24 months. Changes from baseline were assessed using Scale for the Assessment and Rating of Ataxia (SARA), functional SARA (fSARA), Inventory of Non-Ataxia Signs (INAS), swallowing function, Vineland Adaptive Behavior Scales, Third Edition (VABS-3), and Burden Scale for Family Caregivers–short version (BSFC-s). Results Thirty-one participants were enrolled. Analyses included those with data at baseline and at 24 months. SARA, fSARA, and INAS scores worsened during follow-up; at 24 months, mean changes from baseline were +2.6 ( n = 27), +1.8 ( n = 28), and +1.1 ( n = 22) points, respectively. Enteral feeding use rate increased from 13.8% (4/29) of participants at baseline to 32.1% (9/28) at 24 months. Mean change from baseline in VABS-3 Adaptive Behavior Composite was −5.4 points ( n = 14) at 24 months; BSFC-s scores showed modest changes over time. Disease progression was greater in GM2 gangliosidoses than in GM1 gangliosidosis. Conclusions PRONTO highlights the substantial neurological, functional, and caregiver burdens of late-infantile and juvenile-onset GM1 gangliosidosis and GM2 gangliosidoses over 2 years.