A mild case of SMVT deficiency illustrating the importance of treatment response in variant classification

Abstract

Introduction Sodium-dependent multivitamin transporter (SMVT) deficiency is a recently described multivitamin-responsive IMD of which the phenotypic spectrum and response to treatment remains to be elucidated. So far, four pediatric patients have been described in three case reports with symptoms ranging from severe neurodevelopmental delay to feeding problems and failure to thrive, who demonstrated significant improvement after initiation of enhancement of targeted multivitamin treatment (biotin, pantothenic acid and lipoic acid). Case vignette of SMVT deficiency We describe a fifth case of a patient presenting at the relatively mild end of the phenotypic spectrum with failure to thrive, frequent vomiting and metabolic acidosis with hypoglycemia, and mild osteopenia, who was diagnosed with SMVT deficiency due to compound heterozygous variants in SLC5A6. Additional genetic testing of variants of unknown significance (VUS) as well as the clinical improvement in all aspects of the patient’s disease upon initiation of treatment with biotin and pantothenic acid (plus lipoate as anti-oxidant) aided in the confirmation of this diagnosis. Discussion This case report aims to enhance recognition of the broad phenotypic spectrum of SMVT deficiency due to SLC5A6 mutations, and discusses the different treatment strategies. It demonstrates how combining biochemical and genetic testing with the evaluation of (early) treatment response (i.e. using a ‘diagnostic therapeuticum’), can influence confirmation of pathogenicity of genomic variants.