Mucopolysaccharidosis IIIA (MPS-IIIA) is a severe inborn error of metabolism caused by mutations in the sulfamidase gene (SGSH), which encodes a lysosomal enzyme involved in the metabolism of heparan sulfate (HS). Defective sulfamidase activity leads to the accumulation of HS within lysosomes, resulting in lysosomal dysfunction and ultimately leading to neurodegeneration and dementia in affected children. However, preceding dementia, individuals often exhibit severe and debilitating autistic-like behaviors, including self-injury, stereotypic behaviors, and social impairment. These autistic symptoms are often resistant to conventional antipsychotic medications, which can increase the risk of extrapyramidal side effects, representing un unmet urgent medical need.Recently, we discovered that the autistic-like behaviors observed in young MPS-IIIA mice are attributed to increased proliferation of mesencephalic dopamine neurons during embryogenesis (De Risi et al., 2021, Nature Communications). This leads to overactivation of the D1-direct striatal pathway at the expense of the D2-indirect pathway. Building upon these findings, we are currently investigating various dopaminergic drugs in both preclinical and clinical settings, aiming to rebalance the observed D1-D2 activation imbalance and alleviate autistic-like behaviors in MPS-IIIA. Given that mutations in the SGSH gene are associated with autism spectrum disorder (ASD) and that HS function plays a crucial role in core synaptic organizing complexes such as neurexin and neuroligin (mutated in autism), these findings may have broader implications for pharmacological management of autism.This work is supported by Sanfilippo Children's foundation, Sanfilippo Fighters and Cure Sanfilippo Foundation.