In this report, we describe the Italian cohort of CTX patients evaluated by our group in the last 40 years (more than 60 patients). Currently, in Italy 47 patients are under CDCA therapy. We report the geographic distribution, the number of patients and their clinical findings, the common CYP27A1 variants detected (i.e. regional differences/founder variants), and the clinical spectrum including some atypical findings and the frequency of familial cases. We performed deep neurophysiological, neuroimaging, bone density and vitamin D metabolism analyses together with clinical evaluations. By using a CTX model, some basic data have been acquired on the role of the dentate nucleus in eye movement, combining neuroimaging/neurophthalmologic investigations. A suspicion index has been validated in our cohort and was able to raise suspicion for the diagnosis earlier than previously. The patients received a delayed diagnosis, in adulthood, in the majority of cases. In recent years with better clinical knowledge of the disease by the neurologic, ophthalmologic and paediatric communities, the diagnosis was possible earlier, even in the neonatal period in two cases: a child, now 15 years old, is symptom free after CDCA therapy. Another case treated by liver transplantation for neonatal cholestasis at 4 months, at the age of 2 years, is healthy. We also report our experience during a period when CDCA became temporarily unavailable in Italy and patients lacked access to the drug. Finally, we report the present health care system organization for this disease within the Italian Rare Diseases Network. The therapy is completely covered by the National Health System for patients certified by a CTX Center within the Regional Rare Diseases Network.