SLC19A3 – Biotin-Responsive Basal Ganglia Disease

Biotin-responsive basal ganglia disease (BBGD) is an autosomal recessive neurometabolic disorder caused by biallelic variants in the SLC19A3 gene, which encodes the thiamine transporter hTHTR2. Patients typically present in infancy or early childhood with subacute encephalopathy, movement disorders, and characteristic bilateral basal ganglia lesions on MRI. High-dose biotin and thiamine supplementation halts disease progression and induces clinical reversal.

The first linkage of BBGD to chromosome 2q36.3 and to SLC19A3 was demonstrated in consanguineous Saudi families (LOD=5.9), identifying missense variants c.67G>C (p.Gly23Arg) and c.1264A>G (p.Thr422Ala) (PMID:15871139). Subsequent case reports and series have confirmed autosomal recessive inheritance with segregation in extended pedigrees.

Clinically, BBGD manifests with acute or subacute encephalopathy, confusion, seizures, generalized dystonia (HP:0001332), dysarthria (HP:0001260), dysphagia (HP:0002015), and characteristic T2-hyperintensities in the caudate and putamen. Age of onset ranges from neonatal lactic acidosis to adult-onset dementia, underscoring phenotypic heterogeneity.

The variant spectrum now exceeds 30 distinct pathogenic alleles, including missense, nonsense, splice-site, frameshift, and promoter deletions, with a hotspot p.Thr422Ala in Middle Eastern populations. To date, >89 patients have been reported across diverse ethnicities (PMID:27905264), and segregation of pathogenic alleles has been confirmed in at least 2 additional affected relatives in an extended family study (PMID:27749535).

Functional assays demonstrate that p.Gly23Arg and p.Thr422Ala variants abolish thiamine transport via hTHTR2 without affecting biotin uptake (PMID:16790503). In vivo, Slc19a3-deficient mice exhibit significantly reduced intestinal thiamine absorption and lower blood thiamine levels, validating a loss-of-function mechanism (PMID:19879271).

Overall, the extensive clinical, genetic, segregation, and functional data fulfill ClinGen criteria for a Definitive association between SLC19A3 and BBGD. Early molecular diagnosis enables prompt biotin and thiamine therapy, which can completely reverse neurological deficits. Key take-home: SLC19A3 testing should be performed in any patient with unexplained subacute encephalopathy and bilateral basal ganglia lesions to facilitate life-saving treatment.

References

• American Journal of Human Genetics | 2005 | Biotin-responsive basal ganglia disease maps to 2q36.3 and is due to mutations in SLC19A3 PMID:15871139
• Neurological Research | 2017 | Biotin-thiamine-responsive basal ganglia disease: catastrophic consequences of delay in diagnosis and treatment PMID:27905264
• Medicine | 2016 | A case report of biotin-thiamine-responsive basal ganglia disease in a Saudi child: Is extended genetic family study recommended? PMID:27749535
• American Journal of Physiology. Cell Physiology | 2006 | Biotin-responsive basal ganglia disease-linked mutations inhibit thiamine transport via hTHTR2: biotin is not a substrate for hTHTR2 PMID:16790503
• Gastroenterology | 2010 | Impaired intestinal vitamin B1 (thiamin) uptake in thiamin transporter-2-deficient mice PMID:19879271

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