Neuronal ceroid lipofuscinoses (NCLs) are pediatric lysosomal storage disorders primarily affecting the central nervous system, with progressive neurodegeneration, epilepsy, vision loss and motor decline. However, a growing body of clinical and preclinical evidence suggests that extra-CNS systems — as the gastrointestinal (GI) tract — are significantly involved. In a cross-sectional study of a genetically confirmed Italian NCL cohort (n=19), we found that over 60% of caregivers reported GI symptoms, with constipation and dysphagia among the most prevalent. Using the PedsQL™ GI Symptoms Scales [1], we documented a significantly higher symptom burden in NCL patients compared to healthy peers, especially in the “Trouble Swallowing”, “Food and Drink Limits”, and “Constipation” subscales. While dysphagia and feeding limitations correlated with global functional status, constipation did not, suggesting a distinct pathophysiological mechanism. Interestingly, like what has been observed in Parkinson’s disease—where constipation and other GI symptoms may precede motor signs by years and reflect early enteric nervous system (ENS) pathology—our findings indicate that in NCLs, constipation may likewise be an early manifestation of direct ENS dysfunction rather than a consequence of CNS degeneration. Preclinical studies further support this perspective, showing ENS degeneration [2,3], intestinal dysmotility [2,3], and even microbiota alterations [4-7] across multiple NCL models. Notably, gene therapy can improve not only CNS-manifestations but also extra-CNS symptoms, including GI ones. Our data argue for the inclusion of GI endpoints in clinical monitoring and therapeutic trials and call for a broader gut–brain axis approach to understanding disease progression in NCLs.