2. Academic Validation
  3. Identification and targeted management of a neurodegenerative disorder caused by biallelic mutations in SLC5A6

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

  • NPJ Genom Med. 2019 Nov 14;4:28. doi: 10.1038/s41525-019-0103-x.
Alicia B Byrne 1 2,  Peer Arts 1,  Steven W Polyak 2 3,  Jinghua Feng 2 4,  Andreas W Schreiber 2 3 4,  Karin S Kassahn 3 5,  Christopher N Hahn 1 2 5 6,  Dylan A Mordaunt 7,  Janice M Fletcher 5,  Jillian Lipsett 8,  Drago Bratkovic 6 7,  Grant W Booker 3,  Nicholas J Smith # 6 9,  Hamish S Scott # 1 2 4 5 6
Affiliations

Affiliations

  • 1 1Genetics and Molecular Pathology Research Laboratory, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, SA Australia.
  • 2 2School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia.
  • 3 3School of Biological Sciences, University of Adelaide, Adelaide, SA Australia.
  • 4 4ACRF Cancer Genomics Facility, Centre for Cancer Biology, An alliance between SA Pathology and the University of South Australia, Adelaide, SA Australia.
  • 5 5Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, SA Australia.
  • 6 6School of Medicine, University of Adelaide, Adelaide, SA Australia.
  • 7 7South Australian Clinical Genetics Service, Women's and Children's Hospital, North Adelaide, SA Australia.
  • 8 8Department of Surgical Pathology, SA Pathology, North Adelaide, SA Australia.
  • 9 9Department of Neurology, Women's and Children's Hospital, North Adelaide, SA Australia.
  • # Contributed equally.
PMID: 31754459 DOI: 10.1038/s41525-019-0103-x
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.

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