A Case Report and a Review of TRAPPC4-Related TRAPPopathy

Neurodevelopmental disorder with spasticity, epilepsy and brain atrophy (NEDESBA) is a rare autosomal recessive condition, first described in 2020. It has been associated with biallelic pathogenic variants in the Trafficking Protein Particle Complex Subunit 4 (TRAPPC4) gene. This disorder belongs to the expanding group of TRAPPopathies, caused by mutations in genes encoding components of the transport protein particle (TRAPP) complex, which are essential for intracellular trafficking, autophagy and dendritic spine morphogenesis. Variants in these genes typically result in overlapping clinical features, including microcephaly, early-onset epilepsy, intellectual disability, neurodevelopmental regression, spasticity and abnormal brain MRI findings. Here, we report a 13-month-old affected male born to consanguineous parents, presenting with epileptic spasms and progressive neurodevelopmental delay. Importantly, proband also exhibits hair loss and skin rashes in early infancy. Initial metabolic screening suggested biotinidase deficiency, based on low biotin levels (0.6 nmol/min/mL; normal > 5) and overlapping clinical symptoms. However, confirmatory biochemical and enzymatic studies ruled out classic biotinidase deficiency. Whole exome sequencing revealed a homozygous splice-site variant (c.454+3A>G) in the TRAPPC4 gene, confirming the diagnosis of NEDESBA. This variant has been reported in multiple previous reports, mainly born out of consanguineous marriages. The phenotypic overlap between metabolic and genetic neurodevelopmental disorders in these cases emphasizes the critical role of early molecular testing in achieving a precise diagnosis.