Sodium-dependent multivitamin transporter deficiency caused by novel SLC5A6 mutations: a clinical case and personalized mice model study.

The SLC5A6 gene encodes the sodium-dependent multivitamin transporter (SMVT), which transports biotin, pantothenate, and lipoic acid. Mutations of the SLC5A6 gene result in a hereditary syndrome whose symptoms range from early-onset, life-threatening systemic disorder to relatively mild, late-onset motor neuropathy. We describe a clinical case of a patient with previously unknown compound heterozygous missense mutations R280W and P437Q in the SLC5A6 gene. The patient exhibited a severe metabolic disorder accompanied by an elevated blood concentration of 3-hydroxyisovalerylcarnitine (C5OH), likely explained by biotin deficiency. However, treatment with biotin was unsuccessful. To determine the pathogenicity of these new missense SLC5A6 mutations, we created a personalized mouse model matching the patient's genotype. The P437Q mutation appears to be hypofunctional, whereas R280W is lethal when homozygous. The mouse model recapitulated the physiological and biochemical manifestations of SLC5A6 mutations in humans, including increased mortality, reduced weight and strength, and elevated blood C5OH concentration. It allowed us to model the consequences of biotin treatment, which likely exacerbated the pathology by competing with pantothenate for a barely functional transporter, thereby increasing blood fatty acyl carnitine concentrations, indicative of fatty acid oxidation deficiency. We recommend analyzing the SLC5A6 gene sequence in all cases of elevated C5OH that are not explained by mutations in other known genes in the biotin pathway before prescribing treatment.