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Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025.

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Biotin-Thiamine-Responsive Basal Ganglia Disease

Synonyms: Biotin-Responsive Basal Ganglia Disease (BBGD), BTBGD, BTRBGD, Thiamine Metabolism Dysfunction Syndrome 2, Thiamine Transporter-2 Deficiency

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

Author Information and Affiliations

Initial Posting: ; Last Update: January 9, 2025.

Estimated reading time: 23 minutes

Summary

Clinical characteristics.

Biotin-thiamine-responsive basal ganglia disease (BTBGD) may present in early infancy, childhood, or adulthood. Early-infantile BTBGD presents before age three months with vomiting, feeding difficulties, encephalopathy, hypotonia, seizures, and respiratory failure. Classic BTBGD presents between ages three and ten years with recurrent subacute encephalopathy manifesting as confusion, seizures, ataxia, supranuclear facial palsy, external ophthalmoplegia, and/or dysphagia that, 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. Adult Wernicke-like encephalopathy BTBGD, described in three individuals to date, presents after age ten years with acute onset of status epilepticus, ataxia, nystagmus, diplopia, and ophthalmoplegia.

Prompt administration of biotin and thiamine early in the disease course results in partial or complete improvement within days in classic and adult BTBGD; however, most infants with early-infantile BTBGD have a poor outcome.

Diagnosis/testing.

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

Management.

Targeted therapies: Biotin (5-10 mg/kg/day) and thiamine (up to 40 mg/kg/day with a maximum of 1,500 mg daily) are given orally as early in the disease course as possible and are continued lifelong. During acute decompensations thiamine may be increased to double the regular dose and given intravenously. Disease manifestations typically resolve within days in classic and adult BTBGD.

Supportive care: Acute encephalopathic episodes may require care in an ICU to manage seizures and increased intracranial pressure; thiamine may be increased to double the regular dose and given intravenously. Anti-seizure medication is used to control seizures. Treatment of dystonia is symptomatic and includes administration of trihexyphenidyl or levodopa. Rehabilitation, physical therapy, 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.

Surveillance: At each visit, review neurologic status and assess developmental progress, educational needs, social support, and need for care coordination.

Agents/circumstances to avoid: Avoid use of sodium valproate to treat epilepsy. Use of ACTH to treat epileptic spasms can induce status dystonicus.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an affected individual to identify as early as possible those who would benefit from prompt initiation of treatment with biotin and thiamine and information about agents/circumstances to avoid.

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

Genetic counseling.

BTBGD is inherited in an autosomal recessive manner. 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. Once the SLC19A3 pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members and prenatal/preimplantation genetic testing for BTBGD are possible.

GeneReview Scope

Biotin-Thiamine-Responsive Basal Ganglia Disease (BTBGD): Included Phenotypes
  • Early-infantile BTBGD
  • Classic (childhood) BTBGD
  • Adult Wernicke-like encephalopathy BTBGD

Diagnosis

No consensus clinical diagnostic criteria for biotin-thiamine-responsive basal ganglia disease (BTBGD) have been published; however, suggested criteria for the diagnosis of inherited thiamine defects with prominent neurologic involvement have been proposed [Ortigoza-Escobar et al [2017].

Suggestive Findings

BTBGD should be suspected in probands with the following clinical, laboratory, and imaging findings (by phenotype) and family history.

Early-Infantile (Leigh-Like) BTBGD (age <3 months)

Clinical findings

  • Vomiting
  • Feeding difficulties
  • Irritability
  • Encephalopathy
  • Hypotonia
  • Seizures, infantile spasms
  • Respiratory failure

Laboratory findings

  • Elevated lactate concentrations in blood and cerebrospinal fluid (CSF)
  • Elevated blood alanine, leucine, and isoleucine concentrations
  • Increased alpha-ketoglutarate in urinary organic acid analysis
  • Low free thiamine in CSF and/or fibroblasts [Ortigoza-Escobar et al 2016]

Note: Oxidative phosphorylation (OXPHOS) abnormalities, found exclusively in early-infantile BTBGD, are associated with poor outcomes, including high mortality rates [Wang et al 2021].

Brain MRI findings. During the acute stage, MRI reveals swelling of the basal nuclei, thalami, cerebral white matter and cortex, pons, and midbrain.

Note: It is recommended that treatment start with high-dose thiamine and biotin in encephalopathic infants with symmetric basal ganglia involvement on imaging (Leigh-like syndrome), even before genetic confirmation of BTBGD, as prompt treatment may improve outcomes [Maney et al 2023].

Subsequent MRIs reveal cystic degeneration of the white matter that progresses to cerebral, cerebellar, and brain stem atrophy.

Thalamic lesions are more common in early-infantile BTBGD. Neonates and young toddlers may present with extensive areas of restricted diffusion affecting the perirolandic white matter and thalami, with or without involvement of the basal ganglia [Değerliyurt et al 2019, Kelsch et al 2021].

Brain MRS findings. An elevated lactate peak or a decreased N-acetylaspartate (NAA) peak may be observed in magnetic resonance spectroscopy (MRS) of the affected areas.

Classic BTBGD (typically ages 3-10 years)

Clinical findings. Episodes of acute/subacute encephalopathy, usually preceded by a trigger such as febrile illness (including SARS-CoV-2 infection), trauma, intense exercise, ethyl alcohol ingestion, and/or vaccination, are characterized by the following:

  • Seizures
  • Extrapyramidal manifestations (dystonia, cogwheel rigidity, dysarthria, dysphagia)
  • Pyramidal tract signs (quadriparesis, hyperreflexia)
  • Variable presence of cerebellar signs (supranuclear facial nerve palsy, external ophthalmoplegia, and ataxia)

BTBGD can present with mild neurologic symptoms without encephalopathy at onset, as seen in older children with progressive cognitive deficits [Lail et al 2023].

Laboratory findings. Normal laboratory investigations include the following:

  • Tandem mass spectrometry of blood
  • Urine gas chromatography-mass spectrometry (GC-MS), urine amino acids
  • Serum concentrations of lactic acid, ammonia, and thiamine
  • Plasma amino acids, liver enzymes, coagulation profile, lipid profile
  • CSF cell count, protein, glucose, and cultures

In the acute phase of decompensation, some individuals show increased lactate concentration in blood and CSF. Additionally, in some specialized laboratories, low free thiamine concentration may be observed in CSF and/or fibroblasts [Ortigoza-Escobar et al 2016].

Brain MRI findings

  • Swelling and bilateral and symmetric increased T2-weighted signal intensity in the caudate nuclei, putamen, thalami, 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 the caudate nuclei and putamen with diffuse cerebral cortical and (to a lesser extent) cerebellar atrophy [Yamada et al 2010]
  • Brain stem involvement on MRI can be observed [Wang et al 2021].
  • Less common findings include the following:
    • Spinal cord involvement (1 individual) [Alfadhel et al 2013]
    • Severe subdural hematoma, along with basal ganglia lesions, brain stem abnormalities, and cerebral atrophy [Huang et al 2024]

Brain MRS (magnetic resonance spectroscopy) can show a lactate peak or a decreased NAA peak [Maney et al 2023], suggesting neuronal injury.

Adult Wernicke-Like Encephalopathy BTBGD (age >10 years)

Clinical findings reported to date by Oommen et al [2022] are:

  • Two Japanese males who presented in the second decade of life with status epilepticus, diplopia, nystagmus, ptosis, ophthalmoplegia, and ataxia;
  • An Indian woman who presented initially at age 49 years with rapidly progressive dementia.

Laboratory investigations are unremarkable.

Brain MRI showed high-intensity signals in the bilateral medial thalami and periaqueductal gray region.

Family History

Family history for all phenotypes is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Note: (1) Presumably affected (but undiagnosed) sibs may have had unexplained coma or encephalopathy. (2) Consanguinity has been reported in many families [Alfadhel et al 2013, Tabarki et al 2013].

Establishing the Diagnosis

The diagnosis of BTBGD is established in a proband with suggestive findings and 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, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Option 1

Single-gene testing. Sequence analysis of SLC19A3 is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.

Note: Targeted analysis for the c.1264A>G (p.Thr422Ala) founder variant can be performed first in individuals of Saudi Arabian ancestry [Alfadhel et al 2013] (see Table 6).

A multigene panel that includes SLC19A3 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

Comprehensive genomic testing does not require the clinician to determine which genes is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible. To date, the majority of SLC19A3 pathogenic variants reported (e.g., missense, nonsense, truncated variants) are within the coding region and are likely to be identified on exome sequencing. Only one intronic variant has been reported [Maney et al 2023].

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

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

Gene 1MethodProportion of Pathogenic Variants 2 Identified by Method
SLC19A3 Sequence analysis 3~95% 4
Gene-targeted deletion/duplication analysis 5~5% 4, 6
1.
2.

See Molecular Genetics for information on variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

A 45-kb deletion including the promoter region but no coding exons of SLC19A3 has been reported [Flønes et al 2016].

Clinical Characteristics

Clinical Description

Biotin-thiamine-responsive basal ganglia disease (BTBGD), resulting from the inability of thiamine to cross the blood-brain barrier, comprises three age-related phenotypes: early-infantile BTBGD (presenting by age 3 months), classic (childhood) BTBGD (ages 3-10 years), and adult Wernicke-like encephalopathy BTBGD (age >10 years). To date, more than 169 individuals have been identified with biallelic pathogenic variants in SLC19A3 [Wang et al 2021]. The following descriptions of the phenotypic features associated with BTBGD is based on this report.

Early-infantile BTBGD is characterized by poor feeding, vomiting, acute encephalopathy, and severe lactic acidosis. One child had exaggerated eye opening and paroxysmal tonic downgaze [Maney et al 2023]. Four infants had atypical infantile spasms [Yamada et al 2010]. Most children in this group have had poor outcome or even death (even after supplementation with biotin and thiamine). Of note, the child reported by Maney et al [2023] showed partial response to vitamin supplementation.

Classic BTBGD usually presents between ages three and ten years; however, exceptions include onset in one infant at age one month [Pérez-Dueñas et al 2013, Kobayashi et al 2022] and one adult at age 20 years [Debs et al 2010].

Most commonly, classic BTBGD is characterized by recurrent acute/subacute onset of encephalopathy, often triggered by febrile illness, mild trauma, or stress, manifesting as confusion, seizures, ataxia, dystonia, supranuclear facial palsy, external ophthalmoplegia, and/or dysphagia. The encephalopathy may be associated with 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.

Seizures are mainly simple partial or generalized 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, Targeted Therapies). 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, and/or mild intellectual disability.

Adult Wernicke-like encephalopathy BTBGD 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 doses of thiamine (see Management, Targeted Therapies).

Prevalence

Biotin-thiamine-responsive basal ganglia disease (BTBGD) is pan ethnic.

Of note, homozygosity for the Saudi Arabian founder variant c.1264A>G (p.Thr422Ala) accounts for 52% (76/146) of BTBGD in that population (see Table 6).

The carrier frequency of the SLC19A3 c.1264A>G (p.Thr422Ala) pathogenic variant in the Saudi Arabian population is 1:500 [Alfadhel et al 2019].

Genotype-Phenotype Correlations

Although genotype-phenotype correlations remain unclear, the following have been observed:

Differential Diagnosis

Genetic disorders of interest in the differential diagnosis of infants, children, and adults presenting with acute or subacute encephalopathy are listed in Table 2.

Table 2.

Genes of Interest in the Differential Diagnosis of Acute Biotin-Thiamine-Responsive Basal Ganglia Disease

Gene(s)DisorderMOI
>350 genes 1Mitochondrial disorders incl Leigh syndrome 2 (See Primary Mitochondrial Disorders Overview, Mitochondrial DNA-Associated Leigh Syndrome Spectrum, & Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview.)AR
AD
Mat
XL
ATP7B Wilson disease AR
BCKDHA
BCKDHB
DBT
IVD
MCEE
MMAA
MMAB
MMADHC
MMUT
PCCA
PCCB 3		Organic acid disorders (e.g., IVA, MMA, MSUD, PA) 3AR
GCH1 GTP cyclohydrolase 1-deficient dopa-responsive dystonia AD
HTT Juvenile Huntington disease (See Huntington Disease.)AD
SLC25A19 SLC25A19-related thiamine metabolism dysfunction AR
SLC5A6 Infantile-onset biotin-responsive neurodegeneration (OMIM 618973)AR
SPR Sepiapterin reductase deficiency AR
TH Tyrosine hydroxylase-deficient dopa-responsive dystonia (See Tyrosine Hydroxylase Deficiency.)AR
TPK1 TPK1-related thiamine metabolism dysfunction syndrome (OMIM 614458)AR

AD = autosomal dominant; AR = autosomal recessive; IVA = isovaleric acidemia; Mat = maternal; MMA = methylmalonic acidemia; MOI = mode of inheritance; MSUD = maple syrup urine disease; PA = propionic acidemia

1.
2.

Major clinical features are developmental delay, seizures, lethargy, coma, hypotonia, vomiting, failure to thrive, hepatomegaly, respiratory distress, cardiac dysfunction, hypoglycemia, and acidosis.

3.

More than 65 organic acids are known [Ramsay et al 2018]; listed genes represent those associated with the selected organic acidemias in the Disorder column.

Note: Dopa-responsive dystonia and Wilson disease are important to consider because they are treatable.

Acquired disorders in the differential diagnosis include:

  • Wernicke encephalopathy
  • Toxic encephalopathy
  • Infectious encephalopathy
  • Inflammatory disease (including central nervous system vasculitis)
  • Acute disseminated encephalomyelitis (ADEM)

In its chronic stage, BTBGD shares clinical features with several conditions including Wilson disease, juvenile Huntington disease, and DYT1 early-onset isolated dystonia; however, BTBGD can be differentiated by its acute/subacute presentation and MRI findings.

Management

No clinical practice guidelines for biotin-thiamine-responsive basal ganglia disease (BTBGD) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

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.

Table 3.

Biotin-Thiamine-Responsive Basal Ganglia Disease: Recommended Evaluations Following Initial Diagnosis

System/ConcernEvaluationComment
Neurologic Pediatric neurologist
  • Baseline exam for tone & movement disorders incl dystonia, spasticity, & ataxia
  • Eval for seizures
Development Developmental assessment
  • To incl motor, adaptive, cognitive, & speech-language eval
  • Eval for early intervention / special education
Feeding Gastroenterology / nutrition / feeding team eval
  • To incl eval of aspiration risk & nutritional status
  • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Dysarthria Speech-language pathology assessmentFor older persons, consider need for augmentative and alternative communication (AAC).
Musculoskeletal Orthopedics / physical medicine & rehab / PT & OT evalTo incl assessment of:
  • Gross motor & fine motor skills
  • Contractures, clubfoot, & kyphoscoliosis
  • Mobility, ADL, & need for adaptive devices
  • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Genetic counseling By genetics professionals 1To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of BTBGD to facilitate medical & personal decision making
Family support
& resources 		By clinicians, wider care team, & family support organizationsAssessment of family & social structure to determine need for:

ADL = activities of daily living; BTBGD = biotin-thiamine-responsive basal ganglia disease; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy

1.

Medical geneticist, certified genetic counselor, certified advanced genetic nurse

Treatment of Manifestations

Targeted Therapies

In GeneReviews, a targeted therapy is one that addresses the specific underlying mechanism of disease causation (regardless of whether the therapy is significantly efficacious for one or more manifestation of the genetic condition); would otherwise not be considered without knowledge of the underlying genetic cause of the condition; or could lead to a cure. —ED

Treatment with oral biotin (5-10 mg/kg/day) and thiamine (≤40 mg/kg/day; maximum of 1,500 mg/day) is critical from the time of diagnosis. Treatment with thiamine alone or in combination with biotin typically shows better outcomes than biotin alone [Wang et al 2021]. Treatment within one month of disease onset significantly improves outcome compared to treatment that is delayed.

Lifelong treatment with biotin and thiamine is required. Adults with BTBGD are typically maintained on oral biotin at 600 mg daily along with oral thiamine at 1,500 mg daily.

For individuals with BTBGD who have an insufficient response to standard doses of thiamine, increasing the dose up to 75 mg/kg/day during the acute phase may significantly improve outcomes. Subsequent dose reduction to maintenance levels (e.g., 30 mg/kg/day) has been effective in preventing relapses [Aldosari 2024].

During acute decompensation, thiamine may be increased to two times the regular dose and given intravenously.

Although most individuals with the early-infantile form do not respond to thiamine treatment and eventually succumb to the disease, it is always worth trying [Wang et al 2021].

Supportive Care

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).

Table 4.

Biotin-Thiamine-Responsive Basal Ganglia Disease: Treatment of Manifestations

Manifestation/ConcernTreatmentConsiderations/Other
Acute encephalopathy ICU care incl treatment of seizures & ↑ intracranial pressure
  • Thiamine may be ↑ to 2x regular dose & given intravenously.
  • Empiric treatment w/antimicrobial/antiviral agents recommended until infectious causes of acute/subacute encephalopathy are ruled out.
Neurologic disorder Both biotin & thiamine oral therapy (See Targeted Therapies.)
Epilepsy Standardized treatment w/ASM by experienced neurologist
  • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
  • Avoid valproate.
  • Use ACTH w/caution due to risk of status dystonicus.
  • Education of parents/caregivers 1
Developmental delay / Intellectual disability / Neurobehavioral issues See Developmental Delay / Intellectual Disability Management Issues.
Dysarthria By speech-language therapistManage communication incl augmentative & alternative communication.
Spasticity Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & fallsConsider need for positioning & mobility devices, disability parking placard.
Dystonia Symptomatic treatment incl trihexyphenidyl or levodopa
Poor weight gain / Failure to thrive
  • Feeding therapy
  • Gastrostomy tube placement may be required for persistent feeding issues.
Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia

Transition to adult care 		When independent living as an adult seems unlikely, develop realistic plans for adult life (see American Epilepsy Society Transitions from Pediatric Epilepsy to Adult Epilepsy Care).Starting by age ~18 yrs or at standardized age for affected person's country of residence
Family/Community
  • Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
  • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
  • Ongoing assessment of need for palliative care involvement &/or home nursing
  • Consider involvement in adaptive sports or Special Olympics.

ACTH = adrenocorticotropic hormone; ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy

1.

Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy Foundation Toolbox.

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

  • IEP services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine whether any changes are needed.
    • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
    • Vision consultants should be a part of the child's IEP team to support access to academic material.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Communication issues. Consider evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended at each visit.

Table 5.

Biotin-Thiamine-Responsive Basal Ganglia Disease: Recommended Surveillance

System/ConcernEvaluation
Feeding
  • Measurement of growth parameters
  • Eval of nutritional status & safety of oral intake
Neurologic
  • Monitor those w/seizures as clinically indicated.
  • Assess for new manifestations such as seizures, changes in tone, & movement disorders.
Development Monitor developmental progress & educational needs.
Musculoskeletal Physical medicine, OT/PT assessment of mobility, self-help skills
Family/Community Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).

OT = occupational therapy; PT = physical therapy

Agents/Circumstances to Avoid

Use of sodium valproate for treatment of epilepsy should be avoided.

Use of adrenocorticotropic hormone (ACTH) for epileptic spasms in individuals with BTBGD can induce status dystonicus [Hoshino & Kanemura 2022].

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an affected individual to identify as early as possible those who would benefit from prompt initiation of treatment with biotin and thiamine and avoidance of use of sodium valproate (for treatment of epilepsy) or ACTH (for treatment of infantile spasms).

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise 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 presumed to be heterozygous for an SLC19A3 pathogenic variant.
  • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an SLC19A3 pathogenic variant and to allow reliable recurrence risk assessment.
  • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017, Maney et al 2023]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • 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. Unless an affected individual's reproductive partner also has BTBGD or is a carrier (see Related Genetic Counseling Issues, Family planning), offspring will be obligate heterozygotes (carriers) for a pathogenic variant in SLC19A3.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a pathogenic variant in SLC19A3.

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 sibs for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk 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.
  • Carrier testing should be considered for the reproductive partners of individuals affected with BTBGD and individuals known to be carriers of BTBGD, particularly if consanguinity is likely and/or if both partners are of the same ancestry. An SLC19A3 founder variant has been identified in the Saudi Arabian population (see Table 6).

Prenatal Testing and Preimplantation Genetic Testing

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

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

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.

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
SLC19A3 2q36​.3 Thiamine transporter 2 SLC19A3 database SLC19A3 SLC19A3

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
607483BASAL GANGLIA DISEASE, BIOTIN-THIAMINE RESPONSIVE; BTBGD

Molecular Pathogenesis

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

Thiamine pyrophosphate 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-coenzyme A;
  • A cofactor for alpha-ketoglutarate and branched-chain alpha-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 ThTr-2 function.

Table 6.

SLC19A3 Pathogenic Variants Referenced in This GeneReview

Reference SequencesDNA Nucleotide ChangePredicted Protein ChangeComment [Reference]
NM_025243​.3
NP_079519​.1 		c.1264A>Gp.Thr422Ala

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

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

Chapter Notes

Revision History

  • 9 January 2025 (bp) Comprehensive update posted live
  • 16 April 2020 (ha) Comprehensive update posted live
  • 21 November 2013 (me) Review posted live
  • 28 May 2013 (aah) Original submission

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