Sertraline Treatment Can Mimic Niemann‐Pick Type C Biomarker Profile: A Diagnostic Pitfall

BACKGROUND: Oxysterols (cholestane-3β,5α,6β-triol and 7-ketocholesterol) and N-palmitoyl-O-phosphocholineserine (PPCS) are sensitive biomarkers for Niemann-Pick disease type C (NPC) screening. However, false-positive results occur, with a biomarker profile suggestive of NPC despite the absence of pathogenic variants in genes involved in NPC or other inborn errors of metabolism. OBJECTIVE: To identify causes of false-positive biomarker profiles mimicking NPC. METHODS: We conducted a multicenter retrospective study of 15 patients with false-positive oxysterols and PPCS profiles referred between 2017 and 2022 to two French NPC reference laboratories. Clinical data were collected via standardized chart review. The impact of Sertraline on NPC-like biological features was evaluated using the filipin test in fibroblasts and biomarker analysis in sertraline-treated patients. RESULTS: Thirteen of 15 patients with false-positive biomarkers were treated with sertraline. Two patients who discontinued sertraline showed normalization of biomarkers. The filipin test revealed that Sertraline disrupts intracellular cholesterol trafficking, a hallmark of NPC cellular features. Finally, among 47 sertraline-treated patients without NPC-suspicion, 26 (55%) had biomarker profile mimicking NPC. INTERPRETATION: Sertraline use is frequently associated with elevated biomarkers that mimic NPC, representing a primary cause of false-positive results in NPC screening. Genetic analysis of NPC1 and NPC2 remains essential to confirm NPC diagnosis. Most sertraline-treated patients with false-positive biomarkers presented predominantly atypical psychiatric symptoms, though one exhibited a clinical picture highly suggestive of NPC following prolonged sertraline exposure. The long-term clinical effects of sertraline use need further evaluation.