Abstract
BackgroundBiotin-thiamine responsive basal ganglia disease is a severe, but potentially treatable disorder caused by mutations in the SLC19A3 gene. Although the disease is inherited in an autosomal recessive manner, patients with typical phenotypes carrying single heterozygous mutations have been reported. This makes the diagnosis uncertain and may delay treatment.Methods and ResultsIn two siblings with early-onset encephalopathy dystonia and epilepsy, whole-exome sequencing revealed a novel single heterozygous SLC19A3 mutation (c.337T>C). Although Sanger-sequencing and copy-number analysis revealed no other aberrations, RNA-sequencing in brain tissue suggested the second allele was silenced. Whole-genome sequencing resolved the genetic defect by revealing a novel 45,049 bp deletion in the 5’-UTR region of the gene abolishing the promoter. High dose thiamine and biotin therapy was started in the surviving sibling who remains stable. In another patient two novel compound heterozygous SLC19A3 mutations were found. He improved substantially on thiamine and biotin therapy.ConclusionsWe show that large genomic deletions occur in the regulatory region of SLC19A3 and should be considered in genetic testing. Moreover, our study highlights the power of whole-genome sequencing as a diagnostic tool for rare genetic disorders across a wide spectrum of mutations including non-coding large genomic rearrangements.
Highlights
High dose thiamine and biotin therapy was started in the surviving sibling who remains stable
We show that large genomic deletions occur in the regulatory region of SLC19A3 and should be considered in genetic testing
Biotin-thiamine-responsive basal ganglia disease (BBGD) is an autosomal recessive disorder caused by mutations in the SLC19A3 gene, encoding human thiamine transporter 2 [1]
Summary
Biotin-thiamine-responsive basal ganglia disease (BBGD) is an autosomal recessive disorder caused by mutations in the SLC19A3 gene, encoding human thiamine transporter 2 [1]. A more aggressive form of the disorder starts in early-infancy, and causes rapidly progressive encephalopathy with epilepsy, lactic acidosis, psychomotor regression and early mortality. It remains unclear whether these patients respond to therapy [6]. A later-onset Wernicke-like syndrome has been reported This commonly starts in the second decade of life with epilepsy, ataxia, nystagmus and ophtalmoplegia and MRI shows lesions of the medial thalamus and periaqueductal grey matter, mimicking Wernicke’s encephalopathy. The disease is inherited in an autosomal recessive manner, patients with typical phenotypes carrying single heterozygous mutations have been reported This makes the diagnosis uncertain and may delay treatment
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