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Case Reports
. 2016 Feb 10;11(2):e0149055.
doi: 10.1371/journal.pone.0149055. eCollection 2016.

Novel SLC19A3 Promoter Deletion and Allelic Silencing in Biotin-Thiamine-Responsive Basal Ganglia Encephalopathy

Irene Flønes  1   2 , Paweł Sztromwasser  3   4   5 , Kristoffer Haugarvoll  1   2 , Christian Dölle  1   2 , Maria Lykouri  1   2 , Thomas Schwarzlmüller  2   6 , Inge Jonassen  5 , Hrvoje Miletic  7   8   9 , Stefan Johansson  3   4   10 , Per M Knappskog  3   4   10 , Laurence A Bindoff  1   2 , Charalampos Tzoulis  1   2
Affiliations
Case Reports

Novel SLC19A3 Promoter Deletion and Allelic Silencing in Biotin-Thiamine-Responsive Basal Ganglia Encephalopathy

Irene Flønes et al. PLoS One. .

Abstract

Background: Biotin-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 results: In 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.

Conclusions: We 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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Neuroimaging findings.
A: axial T2 weighted MRI of patient 2 taken during an episode with seizures, increasing encephalopathy and exacerbation of the dystonia. Images show bilateral high T2-signal changes and swelling in the putamen and caudate head. In addition there are multiple cortical lesions preferentially occurring in the depths of sulci, which is typical of BBGD. B: axial T2 and coronal T2-FLAIR weighted MRI of patient 1 taken during an episodic exacerbation show a similar pattern with bilateral striatal and multiple cortical lesions. The signal abnormalities regressed completely on later scans (not shown). C (upper lane): FDG-PET scan of the brain of patient 1 taken ~5 years later shows multiple foci of decreased glucose metabolism that correlate to the localization of the transient cortical signal changes on MRI. The striatum shows minimal uptake consistent with severe neuronal loss. A normal scan is shown in the lower lane for comparison.
Fig 2
Fig 2. Genetic and molecular findings.
A: coverage analysis of whole-genome sequencing data in patient 3 shows a clear regional drop in sequencing depth (red line) corresponding to the 45,049 bp deletion in the 5’-UTR of the SLC19A3 gene. The two arrows mark the position of the break-points. Coverage in the same region of a control is shown in the bottom lane for comparison. The blue diagram depicts the SLC19A3 gene in a 3’-5’ alignment. Vertical rectangulars show the proportional position of the exons. B: Western blot analysis in frontal cortex homogenate of patient 1 using two primary antibodies (left and right panel) shows an increase of SLC19A3 protein immunoreactivity in the patient (P) compared to two age and gender matched controls (C1, C2).
See this image and copyright information in PMC

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References

    1. Subramanian VS, Marchant JS, Said HM. Biotin-responsive basal ganglia disease-linked mutations inhibit thiamine transport via hTHTR2: biotin is not a substrate for hTHTR2. American journal of physiology Cell physiology. 2006;291(5):C851–9. - PubMed
    1. Ozand PT, Gascon GG, Al Essa M, Joshi S, Al Jishi E, Bakheet S, et al. Biotin-responsive basal ganglia disease: a novel entity. Brain: a journal of neurology. 1998;121 (Pt 7):1267–79. - PubMed
    1. Tabarki B, Alfadhel M, AlShahwan S, Hundallah K, AlShafi S, AlHashem A. Treatment of biotin-responsive basal ganglia disease: Open comparative study between the combination of biotin plus thiamine versus thiamine alone. European journal of paediatric neurology: EJPN: official journal of the European Paediatric Neurology Society. 2015;19(5):547–52. - PubMed
    1. Tabarki B, Al-Hashem A, Alfadhel M. Biotin-Thiamine-Responsive Basal Ganglia Disease. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, et al., editors. GeneReviews(R). Seattle (WA)1993. - PubMed
    1. Zeng WQ, Al-Yamani E, Acierno JS Jr., Slaugenhaupt S, Gillis T, MacDonald ME, et al. Biotin-responsive basal ganglia disease maps to 2q36.3 and is due to mutations in SLC19A3. American journal of human genetics. 2005;77(1):16–26. - PMC - PubMed

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This work was supported (authors CT and PMK) by grants from the Regional Health Authority of Western Norway (Helse Vest, http://www.helse-vest.no/en/Sider/default.aspx, grant no 911903 and 911810), and the Bergen Research Foundation bioinformatics grant. These grants covered the expenses for the genetic tests and analyses.

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