Deep Intronic NPC1 Variants in Niemann-Pick Disease Type C: A Pediatric Case Report and Systematic Review

We report a 16-year-old girl with progressive ataxia, gaze palsy, and psychotic symptoms suggestive of Niemann-Pick disease type C (NPC). Despite strong clinical and biochemical evidence, including elevated N-palmitoyl-O-phosphocholine-serine (PPCS or lysosphingomyelin-509 [lyso-SM-509]), conventional genetic testing was inconclusive. RNA sequencing of fibroblasts revealed a homozygous NPC1 intronic variant (c.3246-25A > G) causing aberrant splicing. Miglustat was initiated, leading to clinical stabilization. A systematic literature review identified 12 patients with intronic splice-altering variants located outside the canonical splice donor and acceptor regions, including variants situated more than 20 bp from exon-intron boundaries, predominantly affecting NPC1. Most patients presented with juvenile- or adult-onset disease and showed heterogeneous biomarker profiles. This case highlights the diagnostic utility of RNA sequencing in unsolved NPC cases and emphasizes its role in uncovering cryptic pathogenic variants, enabling timely diagnosis and treatment. Intronic variants should be considered in genetically elusive but clinically compatible NPC presentations.