NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Biotin-Thiamine-Responsive Basal Ganglia Disease

Synonyms: BTBGD, Biotin-Responsive Basal Ganglia Disease, Thiamine Transporter-2 Deficiency

, MD, , MD, and , MD, MHSc, FCCMG.

Author Information

Initial Posting: .

Summary

Clinical characteristics.

Biotin-thiamine-responsive basal ganglia disease (BTBGD) is characterized by recurrent subacute encephalopathy manifest as confusion, seizures, ataxia, dystonia, supranuclear facial palsy, external ophthalmoplegia, and/or dysphagia which - if left untreated - can eventually lead to coma and even death. Dystonia and cogwheel rigidity are nearly always present; hyperreflexia, ankle clonus, and Babinski responses are common. Hemiparesis or quadriparesis may be seen. Episodes are often triggered by febrile illness or mild trauma or surgery. Less frequently, BTBGD presents as chronic or slowly progressive dystonia, seizures, and/or psychomotor delay. Although onset is usually in childhood (ages three to ten 10 years), it is extremely variable, ranging from the newborn period to adulthood. Prompt administration of biotin and thiamine early in the disease course results in partial or complete improvement within days.

Diagnosis/testing.

Brain MRI shows symmetric and bilateral increased T2 signal intensity in the central part of caudate head and part or all of the putamen, as well as involvement of the globi pallidi, thalami, infra-and supratentorial brain cortex, brain stem, and cerebellum. During acute crises, severe vasogenic edema can be observed; chronic changes include atrophy, necrosis, and gliosis in the affected regions. The diagnosis of BTBGD is confirmed by identification of biallelic SLC19A3 pathogenic variants.

Management.

Treatment of manifestations: Biotin (5-10 mg /kg/day) and thiamine (in doses ranging from 300-900mg) are given orally as early in the disease course as possible and are continued lifelong. Symptoms typically resolve within days. Acute encephalopathic episodes may require care in an ICU to manage seizures and increased intracranial pressure; during acute decompensations thiamine may be increased to double the regular dose and be given intravenously. Treatment of dystonia is symptomatic and includes administration of L-dopa. Rehabilitation, physiotherapy, occupational therapy, and speech therapy as needed. Adaptation of educational programs to meet individual needs.

Prevention of primary manifestations: Prompt administration of biotin and thiamine early in the disease course.

Surveillance: Evaluation every six months by the treating subspecialists.

Agents/circumstances to avoid: Stress, trauma.

Evaluation of relatives at risk: If the pathogenic variants have been identified in an affected family member, perform molecular genetic testing on at-risk relatives (e.g., sibs of the proband) in order to begin thiamine and biotin therapy as soon as possible in all individuals with biallelic SLC19A3 pathogenic variants, even those who are asymptomatic.

Pregnancy management: Affected women should continue thiamine and biotin during pregnancy.

Genetic counseling.

BTBGD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.

Diagnosis

Biotin-thiamine-responsive basal ganglia disease (BTBGD) is suspected in individuals with the following:

  • Acute/subacute encephalopathy with seizures, extra pyramidal manifestations (dystonia, cogwheel rigidity, dysarthria, dysphagia), and pyramidal tract signs (quadriparesis, hyperreflexia) typically in a child age 3-10 years and usually preceded by febrile illness or some other stress. Cerebellar signs, supranuclear facial nerve palsy, external ophthalmoplegia, and ataxia are variably present.
  • Brain MRI showing the following:
    • Bilateral and symmetric increased T2 signal intensity in the caudate nucleus, putamen, thalamus, infra-and supratentorial brain cortex, and brain stem [Ozand et al 1998]
    • Vasogenic edema during acute crises as demonstrated by diffusion-weighted imaging (DWI)/apparent diffusion coefficient (ADC) MRI
    • Chronic changes including diffuse cerebral cortical and (to a lesser extent) cerebellar atrophy, and gliosis in the affected regions [Yamada et al 2010]
    • Spinal cord involvement (seen in one affected individual) [Alfadhel et al 2013]
  • Normal laboratory investigations, including tandem mass spectrometry of blood; urine gas chromatography-mass spectrometry (GC-MS); serum concentrations of lactic acid,* ammonia, biotin, and thiamine; serum biotinidase enzyme activity; urine amino acids; plasma amino acids; liver enzymes; coagulation profile; lipid profile; and cerebrospinal fluid (CSF) cell count, protein, glucose, and cultures

    * Serum concentration of lactic acid may be high in the acute stage.
  • Family history consistent with autosomal recessive inheritance. Note: (1) Presumably affected (but undiagnosed) sibs may have had unexplained coma or encephalopathy. (2) To date, consanguinity has been reported in a large portion of families [Alfadhel et al 2013, Tabarki et al 2013].

Biotin-thiamine-responsive basal ganglia disease (BTBGD) is confirmed in individuals with biallelic SLC19A3 pathogenic variants (see Table 1).

Sequencing of SLC19A3 is likely to identify pathogenic variants on both alleles and therefore provide molecular confirmation of BTBGD in most individuals with typical clinical and radiologic findings. Although large exon or whole-gene deletions have not been reported, apparent heterozygosity for a single pathogenic variant in SLC19A3 identified by sequence analysis in a typically affected individual may indicate compound heterozygosity for a second unidentified pathogenic variant and warrants deletion analysis.

Table 1.

Summary of Molecular Genetic Testing Used in Biotin-Thiamine-Responsive Basal Ganglia Disease

Gene 1Test MethodVariants Detected 2Pathogenic Variant Detection Frequency by Test Method 3
SLC19A3Sequence analysis 4Sequence variants42/46 5
Deletion/duplication analysis 6Exon or whole-gene deletions/duplicationsUnknown, none reported 7
1.
2.

See Molecular Genetics for information on allelic variants.

3.

The ability of the test method used to detect a pathogenic variant that is present in the indicated gene

4.

Examples of pathogenic variants detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.
6.

Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7.

No deletions or duplications involving SLC19A3 have been reported to cause BTBGD.

Clinical Characteristics

Clinical Description

Biotin-thiamine-responsive basal ganglia disease (BTBGD) usually presents in children of preschool age or early school age (i.e., ages 3-10 years). In one report onset was at age one month [Pérez-Dueñas et al 2013] and in another at age 20 years [Debs et al 2010].

Most commonly BTBGD is characterized by recurrent subacute onset of encephalopathy manifest as confusion, generalized seizures, ataxia, dystonia, supranuclear facial palsy, external ophthalmoplegia, and dysphagia, eventually leading to coma and even death. This encephalopathy may be associated with variable degree of raised intracranial pressure. Dystonia and cogwheel rigidity are nearly always present. Hyperreflexia, ankle clonus, and Babinski responses are common. Hemiparesis or quadriparesis may be seen. Episodes are often triggered by febrile illness, mild trauma, or stress.

Less frequently, BTBGD presents as a chronic or slowly progressive condition characterized by dystonia, seizures, and psychomotor delay.

Seizures are mainly simple partial or generalized seizures and are easily controlled with antiepileptic drugs. Infantile spasms also occur [Yamada et al 2010].

Administration of biotin and thiamine early in the disease course results in partial or complete clinical improvement within days (see Management). Lifelong treatment is required. Treatment initiated later in the disease course or lack of treatment may result in death or chronic neurologic sequelae including dystonia, quadriparesis, epilepsy, or mild intellectual disability may ensue.

Prevalence

Prevalence is unknown.

The disease is pan ethnic; however, it is most prevalent in Saudi Arabia.

Genotype-Phenotype Correlations

Genotype-phenotype correlations are poor. Despite having the same pathogenic variants, children from the same family have extremely variable outcomes, ranging from normal to severely handicapped [Alfadhel et al 2013].

Differential Diagnosis

Additional disorders in the differential diagnosis:

In its chronic stage BTBGD shares clinical features with several conditions including Wilson disease, juvenile Huntington disease, and torsion dystonia (DYT1); however, BTBGD can be differentiated by its acute to subacute presentation.

See Thiamine-responsive dysfunction syndrome: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with biotin-thiamine responsive basal ganglia disease (BTBGD), the following evaluations are recommended:

  • Neurologic evaluation by a pediatric neurologist
  • Assessments by specialists in rehabilitation medicine, physiotherapy, occupational therapy, and speech therapy
  • Psychology evaluation for assessment of IQ
  • Clinical genetics consultation

Treatment of Manifestations

Appropriate treatment includes the following:

  • ICU care during acute encephalopathic episode, including treatment of seizures and increased intracranial pressure
  • Biotin and thiamine therapy. Biotin is given as 5-10 mg /kg and thiamine as 300-900 mg orally. (Note: In one report 20mg/kg/day in a neonate was used.)

    Symptoms typically resolve within days. (Note: SLC19A3 encodes a second thiamine transport and some patients respond only to thiamine.)
    • Biotin and thiamine need to be given lifelong.
    • During acute decompensation thiamine may be increased to double the regular dose and given intravenously.
  • In the acute stage empiric treatment with antimicrobial/antiviral agents. Recommended until infectious causes of the acute/subacute encephalopathy are ruled out.
  • Fever control. Paramount as fever downregulates SLC19A3 and may exacerbate the disease.
  • Antiepileptic drugs for effective control of seizures
  • Symptomatic treatment of dystonia, including administration of L-dopa
  • Rehabilitation, physiotherapy, occupational therapy, and speech therapy
  • Educational programs adapted to individual needs
  • Education of the family regarding the importance of lifelong compliance with medical therapy

Prevention of Primary Manifestations

Appropriate measures include the following:

  • Prompt administration of biotin and thiamine early in the disease course (see Treatment of Manifestations)
  • Avoidance of triggers/stressors including trauma and surgery

Surveillance

Evaluation every six months by the treating subspecialists (pediatric neurologist, metabolic genetic specialist, physiotherapist, and psychologists) is appropriate.

Agents/Circumstances to Avoid

Stress and trauma should be avoided as they can precipitate acute attacks.

Evaluation of Relatives at Risk

If the pathogenic variants have been identified in an affected family member, perform molecular genetic testing on at-risk relatives (e.g., sibs of the proband) in order to begin biotin and thiamine therapy as soon as possible in all individuals with biallelic SLC19A3 pathogenic variants, even those who are asymptomatic.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Affected women should continue biotin and thiamine therapy during pregnancy. No information regarding risk to the fetus of an affected mother is available.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Routine administration of immunizations is recommended (without any specific precautions).

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Biotin-thiamine-responsive basal ganglia disease (BTBGD) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. Unless an individual with BTBGD has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for a pathogenic variant in SLC19A.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the pathogenic variants in the family have been identified.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the SLC19A3 pathogenic variants have been identified in an affected family member, prenatal testing and preimplantation genetic diagnosis for a pregnancy at increased risk for BTBGD are possible options.

Requests for prenatal testing for conditions which (like BTBGD) have treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

No specific resources for Biotin-Thiamine-Responsive Basal Ganglia Disease have been identified by GeneReviews staff.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Biotin-Thiamine-Responsive Basal Ganglia Disease : Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
SLC19A32q36​.3Thiamine transporter 2SLC19A3 databaseSLC19A3SLC19A3

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Biotin-Thiamine-Responsive Basal Ganglia Disease (View All in OMIM)

606152SOLUTE CARRIER FAMILY 19 (THIAMINE TRANSPORTER), MEMBER 3; SLC19A3
607483THIAMINE METABOLISM DYSFUNCTION SYNDROME 2 (BIOTIN- OR THIAMINE-RESPONSIVE TYPE); THMD2

Gene structure. SLC19A3 spans 32.91 kb of genomic DNA, and consists of six exons with a start codon in exon 2 and a TAA stop codon in exon 6. SLC19A3 is a member of the SLC19 (solute carrier family 19) gene family (comprising SLC19A1, SLC19A2, and SLC19A3) that is responsible for the uptake of water-soluble vitamins into cells. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. SLC19A3 pathogenic variants described in persons with BTBGD include the following (in decreasing order of frequency): c.1264A>G, c.68G>T, c.74dupT, c.980-38dupA, and c.980-14A>G [Zeng et al 2005, Debs et al 2010, Alfadhel et al 2013, Tabarki et al 2013].

Table 2.

SLC19A3 Pathogenic Allelic Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference Sequences
c.68G>Tp.Gly23ValNM_025243​.3
NP_079519​.1
c.74dupTp.Ser26LeufsTer19
c.130A>G
(218A>G)
p.Lys44Glu
c.958G>C
(1047G>C)
p.Glu320Gln
c.980-38dupA
c.980-14A>G
c.1264A>Gp.Thr422Ala

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

Table 3.

Summary of Pathogenic Genotypes Reported in BTBGD

LocationSLC19A3 GenotypesNumber of IndividualsEthnicity
Exon 5c.[1264A>G];[1264A>G] 138Saudi
Exon 3c.[958G>C ];[958G>C] 14Japanese
Exon 2c.[68G>T];[68G>T] 13Yemeni, Moroccan
Exon 2 and intron 3c.[74dupT];[980-14A>G] 22Portuguese

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Homozygous

2.

Compound heterozygous

Normal gene product. SLC19A3 encodes thiamine transporter 2 (hTHTR2).

Abnormal gene product. The mechanism of action of biotin remains unclear. The absence of deficient serum concentrations of biotin and thiamine and the efficacy of high doses of biotin in the treatment of biotin-thiamine-responsive basal ganglia disease (BTBGD) [Ozand et al 1998, Subramanian et al 2006] suggest that high doses of biotin increase expression of hTHTR2, thus restoring some function of the mutated receptor. On the other hand, the new understanding of the function of SCL19A3 highlights the major role of thiamine in the treatment of BTBGD.

References

Literature Cited

  • Alfadhel M, Almuntashri M, Jadah RH, Bashiri FA, Al Rifai MT, Al Shalaan H, Al Balwi M, Al Rumayan A, Eyaid W, Al-Twaijri W. Biotin-responsive basal ganglia disease should be renamed biotin-thiamine-responsive basal ganglia disease: a retrospective review of the clinical, radiological and molecular findings of 18 new cases. Orphanet J Rare Dis. 2013;8:83. [PMC free article: PMC3691666] [PubMed: 23742248]
  • Debs R, Depienne C, Rastetter A, Bellanger A, Degos B, Galanaud D, Keren B, Lyon-Caen O, Brice A, Sedel F. Biotin-responsive basal ganglia disease in ethnic Europeans with novel SLC19A3 mutations. Arch Neurol. 2010;67:126–30. [PubMed: 20065143]
  • Gerards M, Kamps R, van Oevelen J, Boesten I, Jongen E, de Koning B, Scholte HR, de Angst I, Schoonderwoerd K, Sefiani A, Ratbi I, Coppieters W, Karim L, de Coo R, van den Bosch B, Smeets H. Exome sequencing reveals a novel Moroccan founder mutation in SLC19A3 as a new cause of early-childhood fatal Leigh syndrome. Brain. 2013;136:882–90. [PubMed: 23423671]
  • Kevelam SH, Bugiani M, Salomons GS, Feigenbaum A, Blaser S, Prasad C, Häberle J, Baric I, Bakker IM, Postma NL, Kanhai WA, Wolf NI, Abbink TE, Waisfisz Q, Heutink P, van der Knaap MS. Exome sequencing reveals mutated SLC19A3 in patients with an early-infantile, lethal encephalopathy. Brain. 2013;136:1534–43. [PubMed: 23482991]
  • Kono S, Miyajima H, Yoshida K, Togawa A, Shirakawa K, Suzuki H. Mutations in a thiamine-transporter gene and Wernicke’s-like encephalopathy. N Engl J Med. 2009;360:1792–4. [PubMed: 19387023]
  • Ozand PT, Gascon GG, Al Essa M, Joshi S, Al Jishi E, Bakheet S, Al Watban J, Al-Kawi MZ, Dabbagh O. Biotin-responsive basal ganglia disease: a novel entity. Brain. 1998;121:1267–79. [PubMed: 9679779]
  • Pérez-Dueñas B, Serrano M, Rebollo M, Muchart J, Gargallo E, Dupuits C, Artuch R. Reversible lactic acidosis in a newborn with thiamine transporter-2 deficiency. Pediatrics. 2013;131:e1670-5. [PubMed: 23589815]
  • 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. Am J Physiol Cell Physiol. 2006;291:C851–9. [PubMed: 16790503]
  • Tabarki B, Al-Shafi S, Al-Shahwan S, Azmat S, Al-Hashem A. Al-Adwani, Biary N, Al-Zawahmah M, Khan S, Zuccoli G. Biotin-responsive basal ganglia disease revisited: clinical, neuroradiological, and genetic findings. Neurology. 2013;80:261–7. [PubMed: 23269594]
  • Yamada K, Miura K, Hara K, Suzuki M, Nakanishi K, Kumagai T, Ishihara N, Yamada Y, Kuwano R, Tsuji S, Wakamatsu N. A wide spectrum of clinical and brain MRI findings in patients with SLC19A3 mutations. BMC Med Genet. 2010;11:171. [PMC free article: PMC3022826] [PubMed: 21176162]
  • Zeng WQ, Al-Yamani E, Acierno JS Jr, Slaugenhaupt S, Gillis T, MacDonald ME, Ozand PT, Gusella JF. Biotin-responsive basal ganglia disease maps to 2q36.3 and is due to mutations in SLC19A3. Am J Hum Genet. 2005;77:16–26. [PMC free article: PMC1226189] [PubMed: 15871139]

Chapter Notes

Acknowledgments

We would like to thank Dr S Al Shafi Shatha and Dr Saad Al Shahwan, Division of Pediatric Neurology, PSMMC.

Revision History

  • 21 November 2013 (me) Review posted live
  • 28 May 2013 (aah) Original submission
Copyright © 1993-2018, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2018 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK169615PMID: 24260777

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Related information

  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...