O-19: GLP-1 receptor agonists in Wolfram syndrome: clinical experience from a pediatric case series
P Bruzzi, F Candia, M Villanova, G Frontino, S F Madeo, L Lucaccioni, V Trevisani, L Iughetti, B PredieriAbstract
Introduction
Wolfram syndrome type 1 (WS1) is a rare autosomal recessive neurodegenerative disorder due to WFS1 variants. It classically includes non-autoimmune insulin-dependent diabetes, optic atrophy, diabetes insipidus and deafness, but shows marked phenotypic heterogeneity. GLP-1 receptor agonists (GLP-1RAs) may reduce ER stress and exert anti-apoptotic effects, suggesting a disease-modifying role.
Objectives
To describe clinical variability and assess the impact of GLP-1RA therapy in pediatric WS1
Methods
We report 3 female adolescents with genetically confirmed WS1 followed at our center
Results
Patients 1 and 2 (sisters; compound heterozygous variants c.2020G>A, c.316-2A>G) developed childhood-onset non-autoimmune diabetes with preserved β-cell function. Patient 1 showed a mild disease onset (isolated glycosuria, intermittent hyperglycemia), making the progression consistent with a MODY-like pattern. Both patients later experienced metabolic control deterioration and extra-pancreatic features began slightly to emerge (renal cysts, steatosis, initial optic atrophy). GLP-1RA therapy, introduced in both patients, reduced insulin requirement (0.94–0.84 to 0.44 IU/kg/day) and markedly improved metabolic control [time in range (TIR) 33% to 92% and 28% to 83% within 1 month, respectively].
Patient 3 (homozygous variant c.2099G>A; c.2141_2164dup) had a more severe clinical course, with diabetes onset at 5 years (autoantibody-negative; C-peptide 0.2 ng/ml) and early multisystem involvement (optic atrophy, hearing loss, growth hormone deficiency, attention deficit disorder). GLP-1RA improved TIR (74% to 86%) and reduced insulin requirement (1.31 to 0.72 IU/kg/day).
Conclusions
This case series highlights marked WS1 phenotypic variability, even within families, supporting genotype–phenotype correlations and the need to consider WS1 in the differential diagnosis of atypical non-autoimmune diabetes. GLP-1RAs show promising metabolic benefits and may represent an emerging strategy targeting ER stress–related neurodegeneration.