Identification and targeted management of a neurodegenerative disorder caused by biallelic mutations in SLC5A6

Abstract

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.

Keywords: Medical genomics; Metabolic disorders; Neurodevelopmental disorders; Personalized medicine; Translational research.

Fig. 1

Biotin, pantothenate and lipoate-dependent metabolic pathways and the effect of identified variants in SLC5A6. a Pedigree of the non-consanguineous family. b Chromatograms from Sanger sequencing of patient DNA compared to cDNA show decreased expression of the V141Afs*34 allele and stable expression of the R400T allele. c Uptake of radiolabelled biotin by HeLa cells transfected with empty vector, wild-type or mutant SMVT expression constructs. Uptake by mutant constructs is decreased compared to wild-type (p = 0.008) and not significantly different to empty vector (p > 0.05). Data show the mean and standard error of the mean (n = 4). d SCL5A6 function and e Enzymes for which the vitamins Biotin (green), Pantothenate (blue) and Alpha-lipoic acid (red) play a role as important cofactors in: the degradation pathways of the amino acids leucine, isoleucine, valine and glycine; glucose energy metabolism; the TCA cycle; and fatty acid oxidation metabolism. All pathways apart from the glycine cleavage system play a fundamental role in cellular energy production. The pathways involved with fatty acid metabolism and branch chain amino acid breakdown occur almost exclusively in the liver. BBB blood–brain barrier, BCKD Branch chain ketoacid dehydrogenase, CNS central nervous system, KDHC ketoglutarate dehydrogenase complex, PC pyruvate carboxylase, PCC propionyl-CoA carboxylase, PDHC pyruvate dehdrogenase complex, 3MCCC 3-methyl crotonyl-CoA carboxylase