Clinical characteristics.

Biotin-thiamine-responsive basal ganglia disease (BTBGD) may present in childhood, early infancy, or adulthood.

• The classic presentation of BTBGD occurs in childhood (age 3-10 years) and 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 stress. Simple partial or generalized seizures are easily controlled with anti-seizure medication.
• An early-infantile Leigh-like syndrome / atypical infantile spasms presentation occurs in the first three months of life with poor feeding, vomiting, acute encephalopathy, and severe lactic acidosis.
• An adult-onset Wernicke-like encephalopathy presentation is characterized by acute onset of status epilepticus, ataxia, nystagmus, diplopia, and ophthalmoplegia in the second decade of life.

Prompt administration of biotin and thiamine early in the disease course results in partial or complete improvement within days in the childhood and adult presentations, but most with the infantile presentation have had poor outcome even after supplementation with biotin and thiamine.

Diagnosis/testing.

The diagnosis of BTBGD is established in a proband with biallelic pathogenic variants in SLC19A3 identified by molecular genetic testing.

Management.

Treatment of manifestations: Biotin (5-10 mg/kg/day) and thiamine (up to 40 mg/kg/day with a maximum of 1500 mg daily) 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. Anti-seizure medication is used to control seizures. Treatment of dystonia is symptomatic and includes administration of trihexyphenidyl or L-dopa. Rehabilitation, physiotherapy, occupational therapy, and speech therapy as needed and adaptation of educational programs to meet individual needs. Education of the family regarding the importance of lifelong adherence to medical therapy.

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

Surveillance: Clinical review of neurologic status every six months; annual assessment of developmental progress and educational needs; social support and care coordination each visit.

Agents/circumstances to avoid: Infections, stress, profuse exercise, and trauma.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives (e.g., sibs ) of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment with biotin and thiamine and preventive measures (avoidance of stress and trauma).

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 testing and preimplantation genetic testing for pregnancies at increased risk are possible if the SLC19A3 pathogenic variants in the family have been identified.

Suggestive Findings

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

• Acute/subacute encephalopathy with seizures, extrapyramidal manifestations (dystonia, cogwheel rigidity, dysarthria, dysphagia), and pyramidal tract signs (quadriparesis, hyperreflexia) typically in a child age three to ten 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:
  • Swelling and bilateral and symmetric increased T₂-weighted 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 / apparent diffusion coefficient MRI
  • Chronic changes including atrophy and necrosis of caudate and putamen with diffuse cerebral cortical and (to a lesser extent) cerebellar atrophy [Yamada et al 2010]
  • Spinal cord involvement (seen in 1 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.
  * In the early-onset form, high lactate levels in the blood and CSF; high alanine, leucine, and isoleucine in the plasma; and elevated excretion of α-ketoglutarate in the urinary organic acid assays can be observed.
• Family history consistent with autosomal recessive inheritance. Note: (1) Presumably affected (but undiagnosed) sibs may have had unexplained coma or encephalopathy. (2) Consanguinity has been reported in a large number of families [Alfadhel et al 2013, Tabarki et al 2013].

Establishing the Diagnosis

The diagnosis of BTBGD is established in a proband with biallelic pathogenic (or likely pathogenic) variants in SLC19A3 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic SLC19A3 variants of uncertain significance (or of one known SLC19A3 pathogenic variant and one SLC19A3 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of biotin-thiamine-responsive basal ganglia disease is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of biotin-thiamine-responsive basal ganglia disease has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

To date, 135 individuals have been identified with a pathogenic variant in SLC19A3 [Alfadhel et al 2019]. The following description of the phenotypic features associated with biotin-thiamine-responsive basal ganglia disease (BTBGD) is based on this report. While the classic presentation of BTBGD occurs in childhood, early infantile-onset and adult-onset presentations are reported as well.

Classic BTBGD usually presents in children of preschool 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].

Classic BTBGD is most commonly characterized by recurrent acute/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 a 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.

Seizures are mainly simple partial or generalized seizures and are easily controlled with anti-seizure medication. Infantile spasms also occur [Yamada et al 2010].

Administration of biotin and thiamine early in the disease course results in 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.

The early-infantile Leigh-like syndrome / atypical infantile spasms presentation is characterized by the occurrence in the first three months of life of poor feeding, vomiting, acute encephalopathy, and severe lactic acidosis. Four individuals with atypical infantile spasms have been described [Yamada et al 2010]. Most individuals in this group have had poor outcome or even death (even after supplementation with biotin and thiamine).

Adult Wernicke-like encephalopathy is characterized by acute onset of status epilepticus, ataxia, nystagmus, diplopia, and ophthalmoplegia in the second decade of life [Kono et al 2009]. Affected individuals show dramatic response to high dose of thiamine.

Prevalence

The disorder is pan ethnic; however, it is most prevalent in Saudi Arabia. The carrier frequency of a pathogenic variant in SLC19A3 is 1:500 in Saudi newborns [Alfadhel et al 2019].

Genotype-Phenotype Correlations

SLC19A3 genotype-phenotype correlations are poorly defined; however:

• Biallelic predicted loss-of-function variants are more likely to present early and develop into the severe Leigh-like phenotype.
• Compound heterozygosity for one missense variant and one predicted loss-of-function variant has been associated with the classic childhood form of BTBGD.
• The founder Saudi variant, c.1264A>G (p.Thr422Ala), is associated with the classic childhood form.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with BTBGD, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

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 optional surgery

Surveillance

Agents/Circumstances to Avoid

Infections, stress, profuse exercise, and trauma should be avoided as they can precipitate acute attacks.

Use of sodium valproate for epilepsy should be avoided.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives (e.g., sibs) of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment with biotin and thiamine and preventive measures (avoidance of stress and trauma).

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 in the US and EU Clinical Trials Register in Europe 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).

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., presumed to be carriers of one SLC19A3 pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an SLC19A3 pathogenic variant and allow reliable recurrence risk assessment. (De novo variants are known to occur at a low but appreciable rate in autosomal recessive disorders [Jónsson et al 2017].)
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an SLC19A3 pathogenic variant, each sib of an affected individual has at conception 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.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. an affected individual's reproductive partner also has BTBGD or is a carrier, 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 relatives requires prior identification of the SLC19A3 pathogenic variants in the family.

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/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While use of prenatal testing is a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

SLC19A3 encodes thiamine transporter 2 (hTHTR2). A second gene, SLC19A2, encodes the thiamine transporter 1 (hTHTR1). Thiamine enters the cytosol by either hTHTR1 or hTHTR2 and is converted into thiamine pyrophosphate (TPP, the active form) by thiamine pyrophosphokinase 1 (TPK1).

TPP is:

• An essential cofactor for transketolase in the cytoplasm;
• Transported into mitochondria, where it binds to pyruvate dehydrogenase and stimulates conversion of pyruvate to acetyl-CoA;
• A cofactor for α-ketoglutarate and branched-chain α-ketoacid dehydrogenase, entering the tricarboxylic acid cycle for energy production and biosynthesis.

Mechanism of disease causation. Biotin-thiamine-responsive basal ganglia disease (BTBGD) results from loss of hTHTR2 function.

Acknowledgments

We would like to thank the PSMMC pediatric neurology team (S Al Shafi, S Al Shahwan, K Hundallah, A AlGhamdi, W Hakami).

Revision History

• 20 August 2020 (sw) Revision: SLC5A6-related biotin-responsive infantile-onset neurodegeneration added to Differential Diagnosis
• 16 April 2020 (ha) Comprehensive update posted live
• 21 November 2013 (me) Review posted live
• 28 May 2013 (aah) Original submission

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]
• Alfadhel M, Umair M, Almuzzaini B, Alsaif S, AlMohaimeed SA, Almashary MA, Alharbi W, Alayyar L, Alasiri A, Ballow M, AlAbdulrahman A, Alaujan M, Nashabat M, Al-Odaib A, Altwaijri W, Al-Rumayyan A, Alrifai MT, Alfares A, AlBalwi M, Tabarki B. Targeted SLC19A3 gene sequencing of 3000 Saudi newborn: a pilot study toward newborn screening. Ann Clin Transl Neurol. 2019;6:2097-103. [PMC free article: PMC6801173] [PubMed: 31557427]
• Byrne AB, Arts P, Polyak SW, Feng J, Schreiber AW, Kassahn KS, Hahn CN, Mordaunt DA, Fletcher JM, Lipsett J, Bratkovic D, Booker GW, Smith NJ, Scott HS. Identification and targeted management of a neurodegenerative disorder caused by biallelic mutations in SLC5A6. NPJ Genom Med. 2019;4:28. [PMC free article: PMC6856110] [PubMed: 31754459]
• Calvo S, Jain M, Xie X, Sheth SA, Chang B, Goldberger OA, Spinazzola A, Zeviani M, Carr SA, Mootha VK. Systematic identification of human mitochondrial disease genes through integrative genomics. Nat Genet. 2006;38:576-82. [PubMed: 16582907]
• 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]
• Flønes I, Sztromwasser P, Haugarvoll K, Dölle C, Lykouri M, Schwarzlmüller T, Jonassen I, Miletic H, Johansson S, Knappskog PM, Bindoff LA, Tzoulis C. Novel SLC19A3 promoter deletion and allelic silencing in biotin-thiamine-responsive basal ganglia encephalopathy. PLoS One. 2016;11:e0149055. [PMC free article: PMC4749299] [PubMed: 26863430]
• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389-97. [PMC free article: PMC9314484] [PubMed: 35834113]
• Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519-22. [PubMed: 28959963]
• 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]
• Ramsay J, Morton J, Norris M, Kanungo S. Organic acid disorders. Ann Transl Med. 2018;6:472. [PMC free article: PMC6331355] [PubMed: 30740403]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207. [PMC free article: PMC7497289] [PubMed: 32596782]
• 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]