We describe a sibling pair displaying an early infantile-onset, progressive neurodegenerative phenotype, with symptoms of developmental delay and epileptic
encephalopathy developing from 12 to 14 months of age. Using whole exome sequencing, compound heterozygous variants were identified in SLC5A6, which encodes the
sodium-dependent multivitamin transporter (SMVT)
protein. SMVT is an important transporter of the B-group
vitamins biotin, pantothenate, and lipoate. The
protein is ubiquitously expressed and has major roles in
vitamin uptake in the digestive system, as well as transport of these
vitamins across the blood-brain barrier. Pathogenicity of the identified variants was demonstrated by impaired
biotin uptake of mutant SMVT. Identification of this
vitamin transporter as the genetic basis of this disorder guided targeted therapeutic intervention, resulting clinically in improvement of the patient's neurocognitive and neuromotor function. This is the second report of biallelic mutations in SLC5A6 leading to a
neurodegenerative disorder due to impaired
biotin, pantothenate and lipoate uptake. The genetic and phenotypic overlap of these cases confirms mutations in SLC5A6 as the genetic cause of this disease phenotype. Recognition of the
genetic disorder caused by SLC5A6 mutations is essential for early diagnosis and to facilitate timely intervention by triple
vitamin (
biotin, pantothenate, and lipoate) replacement
therapy.