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.