Riboflavin transporter deficiency associated with a homozygous nonsense slc52a3 variant: first genotype–phenotype correlation and literature review

Erick L. Cuevas-García, Universidad Juárez Autónoma de Tabasco, División Académica de Ciencias de la Salud, Villahermosa, Tabasco, Mexico.
Tania I. Alejandro-León, Universidad Juárez Autónoma de Tabasco, División Académica de Ciencias de la Salud, Villahermosa, Tabasco, Mexico.
José O. Cornelio-Nieto, Department of Pediatric Neurology, Hospital Regional de Alta Especialidad del Niño Dr. Rodolfo Nieto Padrón, Villahermosa, Tabasco, Mexico
Pablo Valladares-Sánchez, Department of Pediatric Neurology, Hospital Regional de Alta Especialidad del Niño Dr. Rodolfo Nieto Padrón, Villahermosa, Tabasco, Mexico
Mario González-Medina, Department of Pediatric Neurology, Hospital Regional de Alta Especialidad del Niño Dr. Rodolfo Nieto Padrón, Villahermosa, Tabasco, Mexico
Rubicel Díaz-Martínez, Department of Genetics, Hospital Regional de Alta Especialidad del Niño Dr. Rodolfo Nieto Padrón, Villahermosa, Tabasco, Mexico

Objective: The objective of the study was to describe a rare case of riboflavin (RF) transporter deficiency (RTD) caused by a homozygous nonsense variant in SLC52A3 not previously associated with a detailed clinical phenotype, and to review the clinical features, genetic findings, and therapeutic response reported in the literature. Methods: We report the clinical, neuro-physiological, and genetic findings of an infant diagnosed with RTD. Molecular analysis was performed using next-generation sequencing, with variant confirmation by Sanger sequencing. Variant interpretation followed the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines. In addition, a narrative review of the literature was conducted, focusing on previously reported cases of SLC52A2 and SLC52A3 mutations. Results: The patient presented with progressive neuromuscular involvement, including hypotonia, dysphagia, and respiratory failure requiring ventilatory support. Genetic testing identified a homozygous nonsense variant in SLC52A3, predicted to result in loss of protein function. This vari-ant has been previously deposited in ClinVar by the testing laboratory but has not been reported in published clinical cases to date. Despite early initiation of high-dose RF supplementation, no significant clinical improvement was observed. Review of the literature suggests that missense variants are more frequently associated with partial therapeutic response, whereas severe loss-of-function variants, such as nonsense mutations, are associated with poorer outcomes. Conclusions: RTD should be considered in infants with progressive neuromuscular symptoms and respiratory compromise. Although early RF supplementa-tion remains essential, this case highlights that therapeutic response may be limited in patients harboring severe loss-of-function variants, underscoring the importance of genotype-phenotype correlations for prognosis and clinical counseling.

Keywords: Brown-Vialetto-Van Laere syndrome. SLC52A3. Polyneuropathies. Exome sequencing. Codon nonsense.