A Multisystem Perspective of Pediatric Cell Trafficking Disorders: Within the Cells, Beneath the Signs

Cell trafficking disorders(CTDs) are rare, heterogeneous inherited conditions marked by impaired intracellular transport mechanisms such as vesicular trafficking, cytoskeletal dynamics, and organelle interactions. Although clinical awareness is increasing, CTDs are often underdiagnosed due to phenotypic overlap with mitochondrial, lysosomal, and glycosylation disorders. We retrospectively analyzed 14 pediatric patients with molecularly confirmed CTDs at a single center. Clinical, biochemical, imaging, and genetic findings were reviewed to explore genotype-phenotype relationships and shared clinical features. The cohort included 8 females and 6 males, with a median diagnostic age of 29 months (range: 1-86 months). Common initial symptoms were developmental delay, hypotonia, seizures, and hepatosplenomegaly. MRI abnormalities were noted in 7 patients. Elevated serum lactate and dicarboxylic aciduria were observed in 9 and 6 patients, respectively. Creatine kinase was raised in several cases, prominently in one with TANGO2 deficiency. Elevated AST (n = 12) and ALT (n = 5) indicated mild hepatic involvement. Immunological abnormalities included immunoglobulin deficiency (n = 3) and protein C/S deficiency (n = 4). Recurrently mutated genes were AP4M1 and NPC1 (n = 2 each); others included BSCL2, PACS1, RAB3GAP1, STXBP1, TANGO2, HERC1, KIF1A, ATP1A3, VPS13B, and NLGN3. Two novel variants were identified: AP4M1 c.929 + 1G>T and NPC1 c.145A>T. This case series highlights the clinical and biochemical convergence of genetically diverse CTDs, emphasizing the role of trafficking defects in neurodevelopmental and systemic dysfunction. Expanding diagnostic panels to include trafficking-related genes and adopting a mechanism-based classification may improve early recognition and tailored management of these complex disorders.