RARE DISEASE
Biotin-thiamine-responsive basal ganglia disease
Biotin-thiamine-responsive basal ganglia disease
Biotin-thiamine-responsive basal ganglia disease
Synonyms: BBGD, BTBGD, Biotin-responsive basal ganglia disease
Synonyms: BBGD, BTBGD, Biotin-responsive basal ganglia disease
Synonyms: BBGD, BTBGD, Biotin-responsive basal ganglia disease
Drug discovery
3
drugs
With orphan designations
Overview
Biotin-thiamine-responsive basal ganglia disease (BTBGD) is a rare autosomal recessive neurometabolic disorder caused by SLC19A3 gene mutations, impairing thiamine transport. It manifests with subacute encephalopathy, dystonia, seizures, and dysarthria, often triggered by febrile illness or stress. Diagnosis relies on characteristic basal ganglia lesions on MRI and genetic confirmation. Early treatment with high-dose biotin and thiamine halts progression and reverses symptoms, though lifelong supplementation is required [1][2][6].
Therapies
Immediate initiation of high-dose biotin (1–10 mg/kg/day) and thiamine (10–40 mg/kg/day), with dose escalation (up to 75 mg/kg/day) for refractory cases [5][9][15]
Lifelong maintenance therapy; IV thiamine during acute crises [8][15]
Avoidance of triggers (e.g., alcohol, febrile illness) and contraindicated drugs (metformin, verapamil) [8][9]
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
33 drug discovery papers about Biotin-thiamine-responsive basal ganglia disease, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
33 drug discovery papers about Biotin-thiamine-responsive basal ganglia disease, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2024-08-22 | Derivation of two iPSC lines (KAIMRCi004-A, KAIMRCi004-B) from a Saudi patient with Biotin-Thiamine-responsive Basal Ganglia Disease (BTBGD) carrying homozygous pathogenic missense variant in the SCL19A3 gene.
The neurometabolic disorder known as biotin-thiamine-responsive basal ganglia disease (BTBGD) is a rare autosomal recessive condition linked to bi-allelic pathogenic mutations in the SLC19A3 gene. BTBGD is characterized by progressive encephalopathy, confusion, seizures, dysarthria, dystonia, and severe disabilities. Diagnosis is difficult due to the disease's rare nature and diverse clinical characteristics. The primary treatment for BTBGD at this time is thiamine and biotin supplementation, while its long-term effectiveness is still being investigated. In this study, we have generated two clones of induced pluripotent stem cells (iPSCs) from a 10-year-old female BTBGD patient carrying a homozygous mutation for the pathogenic variant in exon 5 of the SLC19A3 gene, c.1264A > G (p.Thr422Ala). We have confirmed the pluripotency of the generated iPS lines and successfully differentiated them to neural progenitors. Because our understanding of genotype-phenotype correlations in BTBGD is limited, the establishment of BTBGD-iPSC lines with a homozygous SLC19A3 mutation provides a valuable cellular model to explore the molecular mechanisms underlying SLC19A3-associated cellular dysfunction. This model holds potential for advancing the development of novel therapeutic strategies.
2024-03-06 | Derivation of two iPSC lines (KAIMRCi004-A, KAIMRCi004-B) from a Saudi patient with Biotin-Thiamine-Responsive Basal Ganglia disease (BTBGD) carrying homozygous pathogenic missense variant in the SCL19A3 gene
Abstract The neurometabolic disorder known as biotin-thiamine-responsive basal ganglia disease (BTBGD) is a rare autosomal recessive condition linked to bi-allelic pathogenic mutations in the SLC19A3 gene. BTBGD is a neurological disorder characterized by progressive encephalopathy, confusion, seizures, dysarthria, dystonia, and severe disabilities. Diagnosis is difficult due to the disease's rare nature and diverse clinical characteristics. The primary treatment for BTBGD at this time is thiamine and biotin supplementation, while its long-term effectiveness is still being investigated. Despite the lack of knowledge related to genotype-phenotype correlations, the derivation of BTBGD-iPSC lines carrying a homozygous mutation in SLC19A3 constitutes a unique cell model to examine the molecular mechanisms underlying the cellular dysfunctions caused by SLC19A3 pathogenic variant and could promote the development of novel therapeutic agents.
small molecules
2024-09-01 | D013 Thiamine deficiency in CSF of Huntington’s disease presymptomatic carriers evidences etiological relevance and value as predictive biomarker
Thiamine (Vit B1) deficiencies (acquired or genetic) result in encephalopathies, some of which affect particularly the striatum, like that by mutations of the brain endothelium thiamine transporter (SLC19A3=ThTr2; OMIM #607483, Biotin and thiamine-responsive basal ganglia disease). Transcriptomic analyses of brain tissue from Huntington’s disease (HD) patients and mice revealed decreased expression of SLC19A31 and TPK12 –the kinase converting thiamine into the enzyme cofactor TPP-. Accordingly, HD patients show reduced thiamine levels in CSF (TMP) and brain parenchyma (TPP).1 Furthermore, high dose thiamine-biotin administration to HD mice attenuated their oligodendrocyte maturation deficit,2 and their radiological, neuropathological, and motor phenotypes,1 thus evidencing the potential of high dose thiamine-biotin therapy for HD. The currently enrolling, multicentric clinical trial HUNTIAM (NCT04478734) is designed to rule out toxicity of high dose thiamine-biotin in HD patients, and to assess normalization of CSF thiamine after one-year treatment. Here we report that HUNTIAM patients treated for three or more months (one third of estimated enrollment) did not experience treatment-associated side effects. Initial data on potential normalization of CSF thiamine will be available soon. Remarkably, in a longitudinal cohort of HD presymptomatic carriers, we have interrogated the evolution of their CSF thiamine levels in relation to their neuropsychological, neurological, and biomarker progression. Our preliminary data show that decrease in CSF thiamine levels precedes onset of motor symptoms and that its yearly evolution correlates with that of prodromal signs (like SWRT decline). These results underscore the etiological relevance of decreased CSF thiamine content and its predictive value as disease-onset biomarker.
References
Picó S, et al. CPEB alteration and aberrant transcriptome-polyadenylation lead to a treatable SLC19A3 deficiency in Huntington9s disease. Sci Transl Med 2021;13:eabe7104. Lim RG, et al. Huntington disease oligodendrocyte maturation deficits revealed by single-nucleus RNAseq are rescued by thiamine-biotin supplementation. Nat Commun 2022;13:7791.
cell therapies
2024-08-22 | Derivation of two iPSC lines (KAIMRCi004-A, KAIMRCi004-B) from a Saudi patient with Biotin-Thiamine-responsive Basal Ganglia Disease (BTBGD) carrying homozygous pathogenic missense variant in the SCL19A3 gene.
The neurometabolic disorder known as biotin-thiamine-responsive basal ganglia disease (BTBGD) is a rare autosomal recessive condition linked to bi-allelic pathogenic mutations in the SLC19A3 gene. BTBGD is characterized by progressive encephalopathy, confusion, seizures, dysarthria, dystonia, and severe disabilities. Diagnosis is difficult due to the disease's rare nature and diverse clinical characteristics. The primary treatment for BTBGD at this time is thiamine and biotin supplementation, while its long-term effectiveness is still being investigated. In this study, we have generated two clones of induced pluripotent stem cells (iPSCs) from a 10-year-old female BTBGD patient carrying a homozygous mutation for the pathogenic variant in exon 5 of the SLC19A3 gene, c.1264A > G (p.Thr422Ala). We have confirmed the pluripotency of the generated iPS lines and successfully differentiated them to neural progenitors. Because our understanding of genotype-phenotype correlations in BTBGD is limited, the establishment of BTBGD-iPSC lines with a homozygous SLC19A3 mutation provides a valuable cellular model to explore the molecular mechanisms underlying SLC19A3-associated cellular dysfunction. This model holds potential for advancing the development of novel therapeutic strategies.
2024-03-06 | Derivation of two iPSC lines (KAIMRCi004-A, KAIMRCi004-B) from a Saudi patient with Biotin-Thiamine-Responsive Basal Ganglia disease (BTBGD) carrying homozygous pathogenic missense variant in the SCL19A3 gene
Abstract The neurometabolic disorder known as biotin-thiamine-responsive basal ganglia disease (BTBGD) is a rare autosomal recessive condition linked to bi-allelic pathogenic mutations in the SLC19A3 gene. BTBGD is a neurological disorder characterized by progressive encephalopathy, confusion, seizures, dysarthria, dystonia, and severe disabilities. Diagnosis is difficult due to the disease's rare nature and diverse clinical characteristics. The primary treatment for BTBGD at this time is thiamine and biotin supplementation, while its long-term effectiveness is still being investigated. Despite the lack of knowledge related to genotype-phenotype correlations, the derivation of BTBGD-iPSC lines carrying a homozygous mutation in SLC19A3 constitutes a unique cell model to examine the molecular mechanisms underlying the cellular dysfunctions caused by SLC19A3 pathogenic variant and could promote the development of novel therapeutic agents.
small molecules
2024-09-01 | D013 Thiamine deficiency in CSF of Huntington’s disease presymptomatic carriers evidences etiological relevance and value as predictive biomarker
Thiamine (Vit B1) deficiencies (acquired or genetic) result in encephalopathies, some of which affect particularly the striatum, like that by mutations of the brain endothelium thiamine transporter (SLC19A3=ThTr2; OMIM #607483, Biotin and thiamine-responsive basal ganglia disease). Transcriptomic analyses of brain tissue from Huntington’s disease (HD) patients and mice revealed decreased expression of SLC19A31 and TPK12 –the kinase converting thiamine into the enzyme cofactor TPP-. Accordingly, HD patients show reduced thiamine levels in CSF (TMP) and brain parenchyma (TPP).1 Furthermore, high dose thiamine-biotin administration to HD mice attenuated their oligodendrocyte maturation deficit,2 and their radiological, neuropathological, and motor phenotypes,1 thus evidencing the potential of high dose thiamine-biotin therapy for HD. The currently enrolling, multicentric clinical trial HUNTIAM (NCT04478734) is designed to rule out toxicity of high dose thiamine-biotin in HD patients, and to assess normalization of CSF thiamine after one-year treatment. Here we report that HUNTIAM patients treated for three or more months (one third of estimated enrollment) did not experience treatment-associated side effects. Initial data on potential normalization of CSF thiamine will be available soon. Remarkably, in a longitudinal cohort of HD presymptomatic carriers, we have interrogated the evolution of their CSF thiamine levels in relation to their neuropsychological, neurological, and biomarker progression. Our preliminary data show that decrease in CSF thiamine levels precedes onset of motor symptoms and that its yearly evolution correlates with that of prodromal signs (like SWRT decline). These results underscore the etiological relevance of decreased CSF thiamine content and its predictive value as disease-onset biomarker.
References
Picó S, et al. CPEB alteration and aberrant transcriptome-polyadenylation lead to a treatable SLC19A3 deficiency in Huntington9s disease. Sci Transl Med 2021;13:eabe7104. Lim RG, et al. Huntington disease oligodendrocyte maturation deficits revealed by single-nucleus RNAseq are rescued by thiamine-biotin supplementation. Nat Commun 2022;13:7791.
Access all drug discovery papers and probability of success in trials forecasts:
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Drug Discovery Landscape
3 orphan drug designations for Biotin-thiamine-responsive basal ganglia disease.
3 orphan drug designations for Biotin-thiamine-responsive basal ganglia disease.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
thiamine | small molecules | FDA | — | Tilde Sciences LLC |
Biotin | small molecules | EMA | — | Lydian Limited |
biotin | small molecules | FDA | — | Tilde Sciences LLC |
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