Novel biallelic variants expand the SLC5A6-related phenotypic spectrum

Abstract

The sodium (Na+):multivitamin transporter (SMVT), encoded by SLC5A6, belongs to the sodium:solute symporter family and is required for the Na+-dependent uptake of biotin (vitamin B7), pantothenic acid (vitamin B5), the vitamin-like substance α-lipoic acid, and iodide. Compound heterozygous SLC5A6 variants have been reported in individuals with variable multisystemic disorder, including failure to thrive, developmental delay, seizures, cerebral palsy, brain atrophy, gastrointestinal problems, immunodeficiency, and/or osteopenia. We expand the phenotypic spectrum associated with biallelic SLC5A6 variants affecting function by reporting five individuals from three families with motor neuropathies. We identified the homozygous variant c.1285 A > G [p.(Ser429Gly)] in three affected siblings and a simplex patient and the maternally inherited c.280 C > T [p.(Arg94*)] variant and the paternally inherited c.485 A > G [p.(Tyr162Cys)] variant in the simplex patient of the third family. Both missense variants were predicted to affect function by in silico tools. 3D homology modeling of the human SMVT revealed 13 transmembrane helices (TMs) and Tyr162 and Ser429 to be located at the cytoplasmic facing region of TM4 and within TM11, respectively. The SLC5A6 missense variants p.(Tyr162Cys) and p.(Ser429Gly) did not affect plasma membrane localization of the ectopically expressed multivitamin transporter suggesting reduced but not abolished function, such as lower catalytic activity. Targeted therapeutic intervention yielded clinical improvement in four of the five patients. Early molecular diagnosis by exome sequencing is essential for timely replacement therapy in affected individuals.

Sodium-dependent multivitamin transporter defects: a rare cause of recurrent vomiting and faltering growth

“…A more recent case series of five individuals from three families, including three siblings and two singletons, with biallelic variants in SLC5A6 demonstrated a much milder phenotypical variant with later presentations all old than 6 years of age 6. The predominant symptom in these children was pleomorphic motor neuropathies that had both axonal and demyelinating features.…”

“…Though rare, the identification of this mutation is increasing and may improve as whole exome sequencing becomes more readily used. All patients treated with vitamin supplementation have clinically improved, so early identification and treatment of the condition is of importance to prevent progressive end organ damage 2 4–6. Due to the small number of cases, prognosis remains guarded.…”

A new case of sodium‐dependent multivitamin transporter defect occurring as a life‐threatening condition responsive to early vitamin supplementation and literature review

“…Specific treatment regimens are currently based on the regimen published by Subramanian et al (2017) and the regimen used in biotinidase deficiency (Saleem & Soos, 2023;Tankeu et al, 2023). Holling et al (2022) have treated their patients with specific motor neuropathies with higher doses of biotin, pantothenic acid, and αlipoic acid leading to motor improvement. Those patients were older than the others described in literature and no information about specific adverse effects of high doses of these vitamins was reported in their study.…”

The vitamin B5/coenzyme A axis: A target for immunomodulation?

“…Cellular absorption of Pan requires SMVT that also mediates the internalization of biotin and lipoic acid [68]. Interestingly, mild cases of SMVT deficiency due to compound heterozygous variants in SLC5A6 are responsible for metabolic or bone defects, anemia, and immunodeficiency that could be rescued by biotin, Pan, and lipoate substitution [69]. Historically, pantothenate supplementation has been used to enhance wound healing by increasing epithelial cell renewal and viability.…”