Expanded Clinical Phenotype and the Role of Untargeted Metabolomics Analysis in Confirming the Diagnosis of Sodium-Dependent Multivitamin Transporter Deficiency

The sodium-dependent multivitamin transporter (SMVT) is a ubiquitously expressed sodium-solute symporter that transports pantothenic acid, biotin, and α-lipoic acid across the intestinal epithelia and blood–brain barrier. Severe biallelic loss-of-function variants in SLC5A6 (MIM #604024) lead to SMVT deficiency (SMVTD, MIM #618973), which classically presents with developmental delay, brain atrophy, epilepsy, sensorineural hearing loss, peripheral neuropathy, and gastrointestinal, cutaneous, and immunologic abnormalities. We describe a 25-year-old female with autism spectrum disorder (ASD), intellectual disability, agenesis of the corpus callosum (ACC), and epilepsy who presented at 15 years of age with a severe metabolic crisis characterized by hyperammonemia, lactic acidosis, and rhabdomyolysis. Trio exome sequencing (ES) identified compound heterozygous variants in SLC5A6. Plasma untargeted metabolomics analysis demonstrated reduced pantothenate and coenzyme A with elevated long-chain fatty acids, indicating impaired fatty acid oxidation, functionally validating ES results, and confirming a diagnosis of SMVTD. Targeted replacement with biotin, lipoic acid, and pantothenic acid improved her neurocognitive function and metabolic control. Our patient, the oldest reported at diagnosis, expands the phenotype of SMVTD to include rhabdomyolysis, ACC, and ASD. Our study suggests that integrating ES and untargeted metabolomics in undiagnosed patients with suspected inborn errors of metabolism may help identify this ultra-rare disorder.