Biotin-Thiamine-Responsive Basal Ganglia Disease

Mendelian MONDO:0011841 Pathograph 18 Basal Ganglia Disorder Hereditary Neurological Disease Neurometabolic Disorder

Biotin-thiamine-responsive basal ganglia disease is a rare autosomal recessive neurometabolic disorder caused by biallelic SLC19A3 variants that impair thiamine transporter 2 function. It typically presents with subacute encephalopathy, seizures, dysarthria or dysphagia, and movement disorder, often after febrile illness, with characteristic bilateral basal ganglia MRI abnormalities that may extend to thalamic, cortical, and subcortical regions. Early high-dose thiamine and biotin can reverse symptoms and prevent progression, whereas delayed diagnosis is associated with severe neurologic disability or death.

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1
Mappings
1
Definitions
1
Inheritance
3
Pathophys.
2
Histopath.
15
Phenotypes
18
Pathograph
1
Genes
3
Treatments
1
Differentials
1
References
1
Deep Research
🔗

Mappings

MONDO
MONDO:0011841 biotin-responsive basal ganglia disease
skos:exactMatch Orphanet ORPHA:65284
ORPHA:65284 maps exactly to MONDO:0011841 and defines the current biotin-thiamine-responsive basal ganglia disease scope.
📘

Definitions

1
Treatable SLC19A3-related basal ganglia encephalopathy
BTBGD is defined as an SLC19A3-related, treatable encephalopathy with confusion, seizures, movement disorder, and bilateral basal ganglia lesions.
OTHER
Show evidence (2 references)
ORPHA:65284 SUPPORT Other
"A rare genetic neurological disorder characterized by subacute encephalopathy with confusion, seizures, and movement disorder, often following a history of febrile illness."
Orphanet provides the concise disease definition and core clinical presentation.
PMID:27905264 SUPPORT Human Clinical
"Biotin-thiamine-responsive basal ganglia disease (BTBGD) is an autosomal recessive neurometabolic disorder caused by mutations in the SLC19A3 gene."
A family study and literature review defines BTBGD by its SLC19A3 genetic cause and neurometabolic phenotype.
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
BTBGD is caused by biallelic pathogenic variants in SLC19A3.
Autosomal recessive inheritance
Show evidence (2 references)
ORPHA:65284 SUPPORT Other
"Autosomal recessive"
Orphanet records autosomal recessive inheritance.
PMID:36657988 SUPPORT Human Clinical
"Biotin thiamine responsive basal ganglia disease (BTRBGD) is an inherited autosomal recessive disorder that results from the inability of thiamine to cross the blood-brain barrier."
Clinical case report and review states the autosomal recessive inheritance and thiamine-transport basis.
⚙

Pathophysiology

3
SLC19A3 thiamine transporter deficiency
Pathogenic SLC19A3 variants reduce thiamine transporter 2 function, limiting thiamine transport into and within the central nervous system.
SLC19A3 link
thiamine transport link ↓ DECREASED
thiamine transmembrane transporter activity link ↓ DECREASED
blood brain barrier link
Downstream
Stress-triggered cerebral thiamine-transport failure Mutant SLC19A3 limits the adaptive thiamine-transport response needed during physiologic stress.
Show evidence (2 references)
PMID:24372704 SUPPORT In Vitro
"Biotin-thiamine-responsive basal ganglia disease (BTBGD) is a potentially treatable disorder caused by mutations in the SLC19A3 gene, encoding the human thiamine transporter 2."
Cell/tissue study states the causal gene and thiamine transporter 2 function.
PMID:36657988 SUPPORT Human Clinical
"Biotin thiamine responsive basal ganglia disease (BTRBGD) is an inherited autosomal recessive disorder that results from the inability of thiamine to cross the blood-brain barrier."
Clinical review links disease mechanism to impaired thiamine entry across the blood-brain barrier.
Stress-triggered cerebral thiamine-transport failure
Febrile illness, acidosis, hypoxia, and other stressors fail to induce adequate SLC19A3 upregulation in patient cells, reducing adaptive thiamine availability when neuronal demand is high.
cellular response to hypoxia link ⚠ ABNORMAL thiamine transport link ↓ DECREASED
brain link
Downstream
Basal ganglia and gray-matter injury Cerebral thiamine-transport failure produces Wernicke-like injury with basal ganglia vulnerability.
Lactic acidosis Severe infantile presentations may include elevated lactate/lactic acidosis during metabolic decompensation.
Show evidence (2 references)
PMID:24372704 SUPPORT In Vitro
"exposure of fibroblasts to stress factors such as acidosis or hypoxia markedly upregulated SLC19A3 in control cells, but failed to elevate SLC19A3 expression in the patient's fibroblasts."
Patient fibroblast data show failure of stress-induced SLC19A3 upregulation.
PMID:24372704 SUPPORT In Vitro
"They also suggest that episodes of encephalopathy are caused by a substantially reduced capacity of mutant neuronal cells to increase SLC19A3 expression, necessary to adapt to stress conditions."
Authors connect impaired stress adaptation to encephalopathic episodes.
Basal ganglia and gray-matter injury
Impaired cerebral thiamine transport injures basal ganglia and other gray matter regions, producing bilateral basal ganglia lesions, Wernicke-like pathology, seizures, encephalopathy, and movement disorder.
neuron link
basal ganglion link brain link
Downstream
Subacute encephalopathy Cerebral gray-matter injury manifests clinically as acute or subacute encephalopathy.
Confusion The encephalopathic gray-matter injury state includes confusion or altered mental status.
Seizures Injured cerebral networks during BTBGD episodes are associated with seizures.
Movement disorder and dystonia Basal ganglia injury produces extrapyramidal movement disorder and dystonia.
Cogwheel rigidity Basal ganglia dysfunction in classic BTBGD produces extrapyramidal cogwheel rigidity.
Hyperreflexia BTBGD can include corticospinal or upper-motor-neuron signs such as hyperreflexia during classic presentations.
Dysphagia BTBGD encephalopathic CNS injury can include bulbar dysfunction with dysphagia.
Dysarthria BTBGD encephalopathic CNS injury can include dysarthria.
Ataxia Wernicke-like gray-matter involvement can present with ataxia in adult BTBGD.
Bilateral basal ganglia MRI abnormalities Basal ganglia lesions are visible as characteristic bilateral MRI signal abnormalities.
Show evidence (2 references)
PMID:24372704 SUPPORT Human Clinical
"These results demonstrate ubiquitously reduced thiamine transporter function in the cerebral gray matter, and neuropathological alterations similar to Wernicke's disease in BTBGD."
Human brain tissue findings support reduced transporter function and Wernicke-like gray-matter pathology.
PMID:28677371 SUPPORT Human Clinical
"The central nervous system lesions found in the patients displayed almost clearly a specific pattern for SLC19A3 defect, as previously proposed in diagnostic criteria."
Neuropathology/MRI study supports a specific SLC19A3-related CNS lesion pattern.
✶

Histopathology

2
Necrotic and hemorrhagic basal ganglia lesions
Post-mortem BTBGD brain tissue can show mixed acute, subacute, and chronic neuropathologic injury with cystic/necrotic putamen lesions, hemorrhagic caudate lesions, cortical-layer hemorrhage, and Wernicke-like gray-matter alterations.
Show evidence (2 references)
PMID:24372704 SUPPORT Human Clinical
"Post-mortem analysis of the brain of one brother showed a mixture of acute, subacute and chronic changes with cystic and necrotic lesions and hemorrhage in the putamen, and hemorrhagic lesions in the caudate nucleus and cortical layers."
Post-mortem human brain analysis documents necrotic and hemorrhagic basal ganglia/cortical lesions.
PMID:24372704 SUPPORT Human Clinical
"neuropathological alterations similar to Wernicke's disease in BTBGD."
The same study links BTBGD pathology to Wernicke-like gray-matter injury.
SLC19A3-specific central nervous system lesion pattern
Neuropathology and MRI studies support a recognizable central nervous system lesion pattern in patients with SLC19A3 variants.
Show evidence (1 reference)
PMID:28677371 SUPPORT Human Clinical
"The central nervous system lesions found in the patients displayed almost clearly a specific pattern for SLC19A3 defect, as previously proposed in diagnostic criteria."
Dedicated neuropathology/MRI study supports a specific SLC19A3-related CNS lesion pattern.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Biotin-Thiamine-Responsive Basal Ganglia Disease Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

15
Digestive 1
Dysphagia Dysphagia (HP:0002015)
Show evidence (1 reference)
PMID:27905264 SUPPORT Human Clinical
"The disease is characterized by subacute encephalopathy with confusion, dysphagia, dysarthria, and seizures."
Clinical review lists dysphagia among characteristic findings.
Metabolism 1
Lactic acidosis Lactic acidosis (HP:0003128)
Show evidence (2 references)
PMID:27896110 SUPPORT Human Clinical
"Four different phenotypes have been described; infantile lactic acidosis with encephalopathy"
Full-text review identifies infantile lactic acidosis with encephalopathy as one recognized BTBGD presentation.
PMID:27896110 SUPPORT Human Clinical
"Biochemical analysis revealed elevated blood lactate at 3.8 mmol/L (nl 0.6-2.2)"
Patient biochemical testing documents elevated blood lactate.
Nervous System 10
Subacute encephalopathy Encephalopathy (HP:0001298)
Temporal: SUBACUTE
Show evidence (2 references)
ORPHA:65284 SUPPORT Other
"A rare genetic neurological disorder characterized by subacute encephalopathy with confusion, seizures, and movement disorder, often following a history of febrile illness."
Orphanet definition directly identifies subacute encephalopathy.
PMID:27905264 SUPPORT Human Clinical
"The disease is characterized by subacute encephalopathy with confusion, dysphagia, dysarthria, and seizures."
Clinical review identifies subacute encephalopathy with associated neurologic features.
Confusion Confusion (HP:0001289)
Show evidence (1 reference)
ORPHA:65284 SUPPORT Other
"A rare genetic neurological disorder characterized by subacute encephalopathy with confusion, seizures, and movement disorder, often following a history of febrile illness."
Orphanet lists confusion within the defining presentation.
Seizures Seizure (HP:0001250)
Show evidence (2 references)
ORPHA:65284 SUPPORT Other
"A rare genetic neurological disorder characterized by subacute encephalopathy with confusion, seizures, and movement disorder, often following a history of febrile illness."
Orphanet lists seizures in the defining presentation.
PMID:35532649 SUPPORT Human Clinical
"We report a 49-year-old lady presenting with rapidly progressive cognitive impairment, seizures, hypersomnolence, ataxia, and generalized dystonia of 3 weeks duration."
Adult BTBGD case confirms seizures in a genetically confirmed patient.
Movement disorder and dystonia Dystonia (HP:0001332)
Show evidence (2 references)
ORPHA:65284 SUPPORT Other
"A rare genetic neurological disorder characterized by subacute encephalopathy with confusion, seizures, and movement disorder, often following a history of febrile illness."
Orphanet lists movement disorder in the defining presentation; dystonia is a specific movement-disorder manifestation supported by the clinical case.
PMID:35532649 SUPPORT Human Clinical
"We report a 49-year-old lady presenting with rapidly progressive cognitive impairment, seizures, hypersomnolence, ataxia, and generalized dystonia of 3 weeks duration."
Genetically confirmed adult BTBGD case documents generalized dystonia.
Hyperreflexia Hyperreflexia (HP:0001347)
Show evidence (1 reference)
PMID:24260777 SUPPORT Human Clinical
"hyperreflexia, ankle clonus, and Babinski responses are common."
GeneReviews lists hyperreflexia among common classic BTBGD neurologic signs.
Dysarthria Dysarthria (HP:0001260)
Show evidence (1 reference)
PMID:27905264 SUPPORT Human Clinical
"The disease is characterized by subacute encephalopathy with confusion, dysphagia, dysarthria, and seizures."
Clinical review lists dysarthria among characteristic findings.
Ataxia Ataxia (HP:0001251)
Show evidence (1 reference)
PMID:35532649 SUPPORT Human Clinical
"We report a 49-year-old lady presenting with rapidly progressive cognitive impairment, seizures, hypersomnolence, ataxia, and generalized dystonia of 3 weeks duration."
Genetically confirmed adult BTBGD case documents ataxia.
Bilateral basal ganglia MRI abnormalities Abnormal basal ganglia morphology (HP:0002134)
Show evidence (4 references)
ORPHA:65284 SUPPORT Other
"Imaging may reveal bilateral lesions in the basal ganglia."
Orphanet describes the bilateral basal ganglia imaging pattern.
PMID:27905264 SUPPORT Human Clinical
"Children presenting with unexplained encephalopathy and MRI abnormalities including bilateral signal alteration of caudate nucleus and putamen should raise the suspicion for BTBGD"
Review highlights bilateral caudate and putamen signal alteration as a diagnostic clue.
PMID:35532649 SUPPORT Human Clinical
"The magnetic resonance imaging (MRI) of the brain revealed T2-hyperintensities in the basal ganglia, thalamus, cortical, subcortical regions with striatal necrosis suggestive of BTBGD"
Adult case report documents thalamic, cortical, and subcortical involvement in addition to basal ganglia abnormalities.
+ 1 more reference
Cognitive impairment Cognitive impairment (HP:0100543)
Show evidence (1 reference)
PMID:35532649 SUPPORT Human Clinical
"We report a 49-year-old lady presenting with rapidly progressive cognitive impairment, seizures, hypersomnolence, ataxia, and generalized dystonia of 3 weeks duration."
Genetically confirmed adult BTBGD case documents rapidly progressive cognitive impairment.
Hypersomnolence Drowsiness (HP:0002329)
Show evidence (1 reference)
PMID:35532649 SUPPORT Human Clinical
"We report a 49-year-old lady presenting with rapidly progressive cognitive impairment, seizures, hypersomnolence, ataxia, and generalized dystonia of 3 weeks duration."
Genetically confirmed adult BTBGD case documents hypersomnolence during the acute episode.
Other 3
Cogwheel rigidity Cogwheel rigidity (HP:0002396)
Show evidence (1 reference)
PMID:24260777 SUPPORT Human Clinical
"Dystonia and cogwheel rigidity are nearly always present"
GeneReviews states that cogwheel rigidity is nearly always present in classic BTBGD.
Ankle clonus Ankle clonus (HP:0011448)
Show evidence (1 reference)
PMID:24260777 SUPPORT Human Clinical
"hyperreflexia, ankle clonus, and Babinski responses are common."
GeneReviews lists ankle clonus among common classic BTBGD neurologic signs.
Babinski sign Babinski sign (HP:0003487)
Show evidence (1 reference)
PMID:24260777 SUPPORT Human Clinical
"hyperreflexia, ankle clonus, and Babinski responses are common."
GeneReviews lists Babinski responses among common classic BTBGD neurologic signs.
🧬

Genetic Associations

1
Biallelic SLC19A3 pathogenic variants (Biallelic SLC19A3 pathogenic variants cause BTBGD.)
Show evidence (2 references)
ORPHA:65284 SUPPORT Other
"SLC19A3 | solute carrier family 19 member 3 | hgnc:16266 | Disease-causing germline mutation(s) in"
Orphanet records SLC19A3 as disease-causing.
PMID:27896110 SUPPORT Human Clinical
"Whole exome sequencing (WES) was performed at Baylor College of Medicine, Medical Genetics Laboratory and confirmed compound heterozygous frameshift mutations in the SLC19A3 gene in trans"
Patient sequencing identified biallelic SLC19A3 frameshift variants in trans.
💊

Treatments

3
High-dose thiamine and biotin supplementation
Action: vitamin supplementation MAXO:0001129
Agent: thiamine ↗ biotin ↗
Immediate high-dose thiamine and biotin supplementation is the core disease-specific therapy and should be started when BTBGD is suspected.
Mechanism Target:
BYPASSES SLC19A3 thiamine transporter deficiency — High-dose thiamine increases substrate availability despite reduced SLC19A3 transporter function.
Show evidence (1 reference)
PMID:27896110 SUPPORT Human Clinical
"This treatment strategy is supported by in vitro studies suggesting that high doses of thiamine and biotin restore insufficient thiamine transport by overexpression of SLC19A3 gene"
Human clinical case report/review cites in vitro support that high-dose vitamins restore insufficient SLC19A3-mediated thiamine transport.
MODULATES Stress-triggered cerebral thiamine-transport failure — Early vitamin supplementation supports thiamine availability during stress-triggered episodes.
Show evidence (1 reference)
PMID:27905264 SUPPORT Human Clinical
"Children presenting with unexplained encephalopathy and MRI abnormalities including bilateral signal alteration of caudate nucleus and putamen should raise the suspicion for BTBGD and be started immediately on biotin and thiamine regimen since the prognosis of the disease is affected by the..."
Clinical review supports immediate vitamin treatment during suspected encephalopathic episodes.
Target Phenotypes: Encephalopathy ↗ Confusion ↗ Seizure ↗ Dysphagia ↗ Dysarthria ↗ Dystonia ↗ Ataxia ↗ Abnormal basal ganglia morphology ↗
Show evidence (3 references)
ORPHA:65284 SUPPORT Other
"The disease usually becomes symptomatic in childhood and is life-threatening if left untreated, but symptoms can be reversed and progression prevented by treatment with high doses of biotin and thiamine."
Orphanet directly supports high-dose biotin and thiamine as disease-modifying treatment.
PMID:35532649 SUPPORT Human Clinical
"High doses of biotin and thiamine are the mainstay of the treatment to achieve a favorable outcome."
Adult case report and review supports high-dose vitamin treatment.
PMID:36657988 SUPPORT Human Clinical
"It is considered a treatable condition if vitamin supplementation, most commonly with thiamine and biotin, is initiated early."
Child neurology review emphasizes early thiamine/biotin supplementation.
Avoidance of sodium valproate and ACTH
Action: Pharmacotherapy NCIT:C15986
Sodium valproate should be avoided for epilepsy treatment in BTBGD, and ACTH used for epileptic spasms can induce status dystonicus.
Target Phenotypes: Seizure ↗ Dystonia ↗
Show evidence (1 reference)
PMID:24260777 SUPPORT Human Clinical
"Avoid use of sodium valproate to treat epilepsy. Use of ACTH to treat epileptic spasms can induce status dystonicus."
GeneReviews explicitly lists sodium valproate and ACTH as agents/circumstances to avoid in BTBGD.
Genetic counseling
Action: genetic counseling MAXO:0000079
Families benefit from counseling about autosomal recessive recurrence risk and targeted SLC19A3 testing for relatives.
Show evidence (1 reference)
PMID:27896110 SUPPORT Human Clinical
"early supplementation with biotin and/or thiamine can improve the devastating progression of this condition and allow for appropriate genetic counseling."
Case report explicitly links molecular diagnosis and treatment recognition to genetic counseling.
🔬

Biochemical Markers

1
Blood lactate elevation (INCREASED)
Context: Infantile BTBGD may present with lactic acidosis with encephalopathy, and affected patients can show elevated blood lactate during the diagnostic evaluation.
Pathograph Readouts
Readout Of Lactic acidosis Positive Diagnostic
Elevated blood lactate is the biochemical measurement underlying the lactic acidosis phenotype in infantile BTBGD presentations.
Show evidence (1 reference)
PMID:27896110 SUPPORT Human Clinical
"Biochemical analysis revealed elevated blood lactate at 3.8 mmol/L (nl 0.6-2.2)"
Patient testing directly documents elevated blood lactate.
Show evidence (2 references)
PMID:27896110 SUPPORT Human Clinical
"Four different phenotypes have been described; infantile lactic acidosis with encephalopathy"
Full-text review identifies infantile lactic acidosis with encephalopathy as a recognized presentation.
PMID:27896110 SUPPORT Human Clinical
"Biochemical analysis revealed elevated blood lactate at 3.8 mmol/L (nl 0.6-2.2)"
Patient biochemical testing directly documents elevated lactate.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Biotin-Thiamine-Responsive Basal Ganglia Disease:

Leigh syndrome MONDO:0009723
Overlapping Features BTBGD can mimic Leigh syndrome clinically and radiographically, especially with infantile basal ganglia lesions and lactic-acidosis-like presentations.
Show evidence (1 reference)
PMID:27896110 SUPPORT Human Clinical
"Our report adds to the genotype-phenotype correlation, highlighting the clinical importance of considering SLC19A3 gene defects as part of the differential diagnosis for Leigh syndrome."
Case report directly identifies Leigh syndrome as an important differential diagnosis.
{ }

Source YAML

click to show 
name: Biotin-Thiamine-Responsive Basal Ganglia Disease
creation_date: "2026-05-07T13:45:22Z"
updated_date: "2026-05-19T04:01:29Z"
description: >-
  Biotin-thiamine-responsive basal ganglia disease is a rare autosomal
  recessive neurometabolic disorder caused by biallelic SLC19A3 variants that
  impair thiamine transporter 2 function. It typically presents with subacute
  encephalopathy, seizures, dysarthria or dysphagia, and movement disorder,
  often after febrile illness, with characteristic bilateral basal ganglia MRI
  abnormalities that may extend to thalamic, cortical, and subcortical regions.
  Early high-dose thiamine and biotin can reverse symptoms and prevent
  progression, whereas delayed diagnosis is associated with severe neurologic
  disability or death.
category: Mendelian
disease_term:
  preferred_term: biotin-thiamine-responsive basal ganglia disease
  term:
    id: MONDO:0011841
    label: biotin-responsive basal ganglia disease
parents:
- Basal Ganglia Disorder
- Hereditary Neurological Disease
- Neurometabolic Disorder
synonyms:
- BBGD
- BTBGD
- BTRBGD
- Biotin-responsive basal ganglia disease
- Thiamine-responsive encephalopathy
- Thiamine metabolism dysfunction syndrome 2
notes: >-
  ORPHA:65284 is the primary structured disease record used for the disease
  scope. ORPHA:199348 is an older/narrower thiamine-responsive encephalopathy
  record that maps to the same MONDO concept and supports the SLC19A3-gene and
  thiamine-responsive phenotype relationship. Phenotype frequencies are not
  asserted because the cached Orphanet records do not provide HPO frequency
  rows and the cited clinical literature is heterogeneous.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0011841
      label: biotin-responsive basal ganglia disease
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:65284
    mapping_justification: >-
      ORPHA:65284 maps exactly to MONDO:0011841 and defines the current
      biotin-thiamine-responsive basal ganglia disease scope.
external_assertions:
- name: Orphanet biotin-thiamine-responsive basal ganglia disease record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:65284
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=65284
  description: >-
    Orphanet's ORPHA:65284 structured record supplies the disease definition,
    synonyms, inheritance, onset, prevalence, disease-gene assertion, and
    exact MONDO mapping used in this entry.
  evidence:
  - reference: ORPHA:65284
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0011841 | Exact"
    explanation: Orphanet maps ORPHA:65284 exactly to the MONDO concept used here.
  - reference: ORPHA:65284
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SLC19A3 | solute carrier family 19 member 3 | hgnc:16266 | Disease-causing germline mutation(s) in"
    explanation: Orphanet records SLC19A3 as the disease-causing gene for ORPHA:65284.
- name: Orphanet thiamine-responsive encephalopathy record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:199348
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=199348
  description: >-
    ORPHA:199348 is a thiamine-responsive encephalopathy record with SLC19A3
    and OMIM:607483 cross-references that overlaps the BTBGD disease concept.
  evidence:
  - reference: ORPHA:199348
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Thiamine-responsive encephalopathy is a Wernicke-like encephalopathy characterized by seizures responsive to high doses of thiamine."
    explanation: The older Orphanet record supports the thiamine-responsive encephalopathy phenotype.
  - reference: ORPHA:199348
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SLC19A3 | solute carrier family 19 member 3 | hgnc:16266 | Disease-causing germline mutation(s) in"
    explanation: ORPHA:199348 also records SLC19A3 as the disease-causing gene.
definitions:
- name: Treatable SLC19A3-related basal ganglia encephalopathy
  definition_type: OTHER
  description: >-
    BTBGD is defined as an SLC19A3-related, treatable encephalopathy with
    confusion, seizures, movement disorder, and bilateral basal ganglia lesions.
  evidence:
  - reference: ORPHA:65284
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A rare genetic neurological disorder characterized by subacute encephalopathy with confusion, seizures, and movement disorder, often following a history of febrile illness.
    explanation: Orphanet provides the concise disease definition and core clinical presentation.
  - reference: PMID:27905264
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biotin-thiamine-responsive basal ganglia disease (BTBGD) is an autosomal recessive neurometabolic disorder caused by mutations in the SLC19A3 gene.
    explanation: A family study and literature review defines BTBGD by its SLC19A3 genetic cause and neurometabolic phenotype.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    BTBGD is caused by biallelic pathogenic variants in SLC19A3.
  evidence:
  - reference: ORPHA:65284
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal recessive"
    explanation: Orphanet records autosomal recessive inheritance.
  - reference: PMID:36657988
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biotin thiamine responsive basal ganglia disease (BTRBGD) is an inherited autosomal recessive disorder that results from the inability of thiamine to cross the blood-brain barrier.
    explanation: Clinical case report and review states the autosomal recessive inheritance and thiamine-transport basis.
prevalence:
- population: Worldwide
  percentage: <1 per 1,000,000
  notes: Orphanet classifies BTBGD as ultra-rare worldwide.
  evidence:
  - reference: ORPHA:65284
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | ORPHANET"
    explanation: Orphanet reports worldwide point prevalence below one per million.
progression:
- phase: Acute/subacute presentation
  age_range: Infancy to adulthood
  notes: >-
    The disorder may present as infantile, childhood, or adult Wernicke-like
    encephalopathy, commonly with acute or subacute worsening after illness or
    other physiologic stress.
  evidence:
  - reference: ORPHA:65284
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Infancy"
    explanation: Orphanet records infantile onset.
  - reference: ORPHA:65284
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Childhood"
    explanation: Orphanet records childhood onset.
  - reference: ORPHA:65284
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Adult"
    explanation: Orphanet records adult onset.
  - reference: PMID:36657988
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BTRBGD can present as an infantile form, classical childhood form, or adult Wernicke-like encephalopathy.
    explanation: Review summarizes the three recognized age-related presentations.
- phase: Outcome depends on treatment timing
  age_range: Any symptomatic age
  notes: >-
    Delay in recognition and vitamin treatment is associated with severe
    residual disability or death, while early treatment can stabilize or improve
    neurologic signs.
  evidence:
  - reference: PMID:27905264
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We studied six patients in this article in which three died before a diagnosis was established, one was diagnosed lately and is currently severely affected, and two were diagnosed early and are currently stable on treatment.
    explanation: Family data directly support the treatment-timing effect on clinical outcome.
genetic:
- name: Biallelic SLC19A3 pathogenic variants
  gene_term:
    preferred_term: SLC19A3
    term:
      id: hgnc:16266
      label: SLC19A3
  association: Biallelic SLC19A3 pathogenic variants cause BTBGD.
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: ORPHA:65284
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SLC19A3 | solute carrier family 19 member 3 | hgnc:16266 | Disease-causing germline mutation(s) in"
    explanation: Orphanet records SLC19A3 as disease-causing.
  - reference: PMID:27896110
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing (WES) was performed at Baylor College of Medicine, Medical Genetics Laboratory and confirmed compound heterozygous frameshift mutations in the SLC19A3 gene in trans
    explanation: Patient sequencing identified biallelic SLC19A3 frameshift variants in trans.
pathophysiology:
- name: SLC19A3 thiamine transporter deficiency
  description: >-
    Pathogenic SLC19A3 variants reduce thiamine transporter 2 function,
    limiting thiamine transport into and within the central nervous system.
  genes:
  - preferred_term: SLC19A3
    term:
      id: hgnc:16266
      label: SLC19A3
  molecular_functions:
  - preferred_term: thiamine transmembrane transporter activity
    term:
      id: GO:0015234
      label: thiamine transmembrane transporter activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: thiamine transport
    term:
      id: GO:0015888
      label: thiamine transport
    modifier: DECREASED
  locations:
  - preferred_term: blood brain barrier
    term:
      id: UBERON:0000120
      label: blood brain barrier
  evidence:
  - reference: PMID:24372704
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Biotin-thiamine-responsive basal ganglia disease (BTBGD) is a potentially treatable disorder caused by mutations in the SLC19A3 gene, encoding the human thiamine transporter 2.
    explanation: Cell/tissue study states the causal gene and thiamine transporter 2 function.
  - reference: PMID:36657988
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biotin thiamine responsive basal ganglia disease (BTRBGD) is an inherited autosomal recessive disorder that results from the inability of thiamine to cross the blood-brain barrier.
    explanation: Clinical review links disease mechanism to impaired thiamine entry across the blood-brain barrier.
  downstream:
  - target: Stress-triggered cerebral thiamine-transport failure
    causal_link_type: DIRECT
    description: Mutant SLC19A3 limits the adaptive thiamine-transport response needed during physiologic stress.
    evidence:
    - reference: PMID:24372704
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        exposure of fibroblasts to stress factors such as acidosis or hypoxia markedly upregulated SLC19A3 in control cells, but failed to elevate SLC19A3 expression in the patient's fibroblasts.
      explanation: Patient fibroblast data directly support impaired stress-induced SLC19A3 upregulation downstream of the transporter defect.
    - reference: PMID:24372704
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        They also suggest that episodes of encephalopathy are caused by a substantially reduced capacity of mutant neuronal cells to increase SLC19A3 expression, necessary to adapt to stress conditions.
      explanation: Authors connect mutant neuronal-cell stress adaptation to encephalopathic episodes.
- name: Stress-triggered cerebral thiamine-transport failure
  description: >-
    Febrile illness, acidosis, hypoxia, and other stressors fail to induce
    adequate SLC19A3 upregulation in patient cells, reducing adaptive thiamine
    availability when neuronal demand is high.
  biological_processes:
  - preferred_term: cellular response to hypoxia
    term:
      id: GO:0071456
      label: cellular response to hypoxia
    modifier: ABNORMAL
  - preferred_term: thiamine transport
    term:
      id: GO:0015888
      label: thiamine transport
    modifier: DECREASED
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:24372704
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      exposure of fibroblasts to stress factors such as acidosis or hypoxia markedly upregulated SLC19A3 in control cells, but failed to elevate SLC19A3 expression in the patient's fibroblasts.
    explanation: Patient fibroblast data show failure of stress-induced SLC19A3 upregulation.
  - reference: PMID:24372704
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      They also suggest that episodes of encephalopathy are caused by a substantially reduced capacity of mutant neuronal cells to increase SLC19A3 expression, necessary to adapt to stress conditions.
    explanation: Authors connect impaired stress adaptation to encephalopathic episodes.
  downstream:
  - target: Basal ganglia and gray-matter injury
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Cerebral thiamine-transport failure produces Wernicke-like injury with basal ganglia vulnerability.
    evidence:
    - reference: PMID:24372704
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These results demonstrate ubiquitously reduced thiamine transporter function in the cerebral gray matter, and neuropathological alterations similar to Wernicke's disease in BTBGD.
      explanation: Human brain/tissue findings support gray-matter thiamine-transporter failure and Wernicke-like neuropathology.
  - target: Lactic acidosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Severe infantile presentations may include elevated lactate/lactic acidosis during metabolic decompensation.
    intermediate_mechanisms:
    - metabolic decompensation during infantile encephalopathic presentations
    evidence:
    - reference: PMID:27896110
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Four different phenotypes have been described; infantile lactic acidosis with encephalopathy
      explanation: Clinical review links lactic acidosis with the infantile encephalopathic BTBGD presentation, supporting an indirect edge.
    - reference: PMID:27896110
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Biochemical analysis revealed elevated blood lactate at 3.8 mmol/L (nl 0.6-2.2)
      explanation: Patient biochemical testing documents lactate elevation during evaluation of BTBGD.
- name: Basal ganglia and gray-matter injury
  description: >-
    Impaired cerebral thiamine transport injures basal ganglia and other gray
    matter regions, producing bilateral basal ganglia lesions, Wernicke-like
    pathology, seizures, encephalopathy, and movement disorder.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: basal ganglion
    term:
      id: UBERON:0002420
      label: basal ganglion
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:24372704
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These results demonstrate ubiquitously reduced thiamine transporter function in the cerebral gray matter, and neuropathological alterations similar to Wernicke's disease in BTBGD.
    explanation: Human brain tissue findings support reduced transporter function and Wernicke-like gray-matter pathology.
  - reference: PMID:28677371
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The central nervous system lesions found in the patients displayed almost clearly a specific pattern for SLC19A3 defect, as previously proposed in diagnostic criteria.
    explanation: Neuropathology/MRI study supports a specific SLC19A3-related CNS lesion pattern.
  downstream:
  - target: Subacute encephalopathy
    causal_link_type: DIRECT
    description: Cerebral gray-matter injury manifests clinically as acute or subacute encephalopathy.
    evidence:
    - reference: ORPHA:65284
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        A rare genetic neurological disorder characterized by subacute encephalopathy with confusion, seizures, and movement disorder, often following a history of febrile illness.
      explanation: Orphanet defines BTBGD by subacute encephalopathy in the setting of this basal ganglia disease.
  - target: Confusion
    causal_link_type: DIRECT
    description: The encephalopathic gray-matter injury state includes confusion or altered mental status.
    evidence:
    - reference: ORPHA:65284
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        A rare genetic neurological disorder characterized by subacute encephalopathy with confusion, seizures, and movement disorder, often following a history of febrile illness.
      explanation: Orphanet lists confusion as part of the BTBGD encephalopathic presentation.
  - target: Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Injured cerebral networks during BTBGD episodes are associated with seizures.
    evidence:
    - reference: ORPHA:65284
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        A rare genetic neurological disorder characterized by subacute encephalopathy with confusion, seizures, and movement disorder, often following a history of febrile illness.
      explanation: Orphanet lists seizures within the defining encephalopathic presentation.
    - reference: PMID:35532649
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report a 49-year-old lady presenting with rapidly progressive cognitive impairment, seizures, hypersomnolence, ataxia, and generalized dystonia of 3 weeks duration.
      explanation: Adult BTBGD case documents seizures together with acute neurologic deterioration.
  - target: Movement disorder and dystonia
    causal_link_type: DIRECT
    description: Basal ganglia injury produces extrapyramidal movement disorder and dystonia.
    evidence:
    - reference: ORPHA:65284
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        A rare genetic neurological disorder characterized by subacute encephalopathy with confusion, seizures, and movement disorder, often following a history of febrile illness.
      explanation: Orphanet identifies movement disorder as part of the defining basal ganglia disease presentation.
    - reference: PMID:35532649
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report a 49-year-old lady presenting with rapidly progressive cognitive impairment, seizures, hypersomnolence, ataxia, and generalized dystonia of 3 weeks duration.
      explanation: Adult BTBGD case documents generalized dystonia during the episode.
  - target: Cogwheel rigidity
    causal_link_type: DIRECT
    description: Basal ganglia dysfunction in classic BTBGD produces extrapyramidal cogwheel rigidity.
    evidence:
    - reference: PMID:24260777
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Dystonia and cogwheel rigidity are nearly always present"
      explanation: GeneReviews states that cogwheel rigidity is nearly always present in classic BTBGD.
  - target: Hyperreflexia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: BTBGD can include corticospinal or upper-motor-neuron signs such as hyperreflexia during classic presentations.
    evidence:
    - reference: PMID:24260777
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "hyperreflexia, ankle clonus, and Babinski responses are common."
      explanation: GeneReviews lists hyperreflexia among common classic BTBGD neurologic signs.
  - target: Dysphagia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: BTBGD encephalopathic CNS injury can include bulbar dysfunction with dysphagia.
    evidence:
    - reference: PMID:27905264
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The disease is characterized by subacute encephalopathy with confusion, dysphagia, dysarthria, and seizures.
      explanation: Clinical review links dysphagia to the BTBGD encephalopathic presentation.
  - target: Dysarthria
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: BTBGD encephalopathic CNS injury can include dysarthria.
    evidence:
    - reference: PMID:27905264
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The disease is characterized by subacute encephalopathy with confusion, dysphagia, dysarthria, and seizures.
      explanation: Clinical review links dysarthria to the BTBGD encephalopathic presentation.
  - target: Ataxia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Wernicke-like gray-matter involvement can present with ataxia in adult BTBGD.
    evidence:
    - reference: PMID:35532649
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report a 49-year-old lady presenting with rapidly progressive cognitive impairment, seizures, hypersomnolence, ataxia, and generalized dystonia of 3 weeks duration.
      explanation: Adult BTBGD case documents ataxia with rapidly progressive neurologic involvement.
  - target: Bilateral basal ganglia MRI abnormalities
    causal_link_type: DIRECT
    description: Basal ganglia lesions are visible as characteristic bilateral MRI signal abnormalities.
    evidence:
    - reference: ORPHA:65284
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Imaging may reveal bilateral lesions in the basal ganglia."
      explanation: Orphanet directly supports bilateral basal ganglia imaging abnormalities.
    - reference: PMID:35532649
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The magnetic resonance imaging (MRI) of the brain revealed T2-hyperintensities in the basal ganglia, thalamus, cortical, subcortical regions with striatal necrosis suggestive of BTBGD
      explanation: Adult case report documents MRI-visible basal ganglia and broader gray-matter injury.
histopathology:
- name: Necrotic and hemorrhagic basal ganglia lesions
  description: >-
    Post-mortem BTBGD brain tissue can show mixed acute, subacute, and chronic
    neuropathologic injury with cystic/necrotic putamen lesions, hemorrhagic
    caudate lesions, cortical-layer hemorrhage, and Wernicke-like gray-matter
    alterations.
  context: SLC19A3-mutant central nervous system tissue
  evidence:
  - reference: PMID:24372704
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Post-mortem analysis of the brain of one brother showed a mixture of acute, subacute and chronic changes with cystic and necrotic lesions and hemorrhage in the putamen, and hemorrhagic lesions in the caudate nucleus and cortical layers.
    explanation: Post-mortem human brain analysis documents necrotic and hemorrhagic basal ganglia/cortical lesions.
  - reference: PMID:24372704
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      neuropathological alterations similar to Wernicke's disease in BTBGD.
    explanation: The same study links BTBGD pathology to Wernicke-like gray-matter injury.
- name: SLC19A3-specific central nervous system lesion pattern
  description: >-
    Neuropathology and MRI studies support a recognizable central nervous
    system lesion pattern in patients with SLC19A3 variants.
  context: Brain autopsy and MRI correlation
  evidence:
  - reference: PMID:28677371
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The central nervous system lesions found in the patients displayed almost clearly a specific pattern for SLC19A3 defect, as previously proposed in diagnostic criteria.
    explanation: Dedicated neuropathology/MRI study supports a specific SLC19A3-related CNS lesion pattern.
phenotypes:
- category: Neurological
  name: Subacute encephalopathy
  description: >-
    Acute or subacute encephalopathy with confusion or altered mental status is
    the core clinical presentation.
  phenotype_term:
    preferred_term: Encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
    temporality: SUBACUTE
  evidence:
  - reference: ORPHA:65284
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A rare genetic neurological disorder characterized by subacute encephalopathy with confusion, seizures, and movement disorder, often following a history of febrile illness.
    explanation: Orphanet definition directly identifies subacute encephalopathy.
  - reference: PMID:27905264
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disease is characterized by subacute encephalopathy with confusion, dysphagia, dysarthria, and seizures.
    explanation: Clinical review identifies subacute encephalopathy with associated neurologic features.
- category: Neurological
  name: Confusion
  description: Confusion accompanies the encephalopathic episodes.
  phenotype_term:
    preferred_term: Confusion
    term:
      id: HP:0001289
      label: Confusion
  evidence:
  - reference: ORPHA:65284
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A rare genetic neurological disorder characterized by subacute encephalopathy with confusion, seizures, and movement disorder, often following a history of febrile illness.
    explanation: Orphanet lists confusion within the defining presentation.
- category: Neurological
  name: Seizures
  description: Seizures are a common component of acute BTBGD episodes.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: ORPHA:65284
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A rare genetic neurological disorder characterized by subacute encephalopathy with confusion, seizures, and movement disorder, often following a history of febrile illness.
    explanation: Orphanet lists seizures in the defining presentation.
  - reference: PMID:35532649
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a 49-year-old lady presenting with rapidly progressive cognitive impairment, seizures, hypersomnolence, ataxia, and generalized dystonia of 3 weeks duration.
    explanation: Adult BTBGD case confirms seizures in a genetically confirmed patient.
- category: Neurological
  name: Movement disorder and dystonia
  description: >-
    Movement disorder is part of the defining phenotype and may include
    generalized dystonia.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: ORPHA:65284
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A rare genetic neurological disorder characterized by subacute encephalopathy with confusion, seizures, and movement disorder, often following a history of febrile illness.
    explanation: Orphanet lists movement disorder in the defining presentation; dystonia is a specific movement-disorder manifestation supported by the clinical case.
  - reference: PMID:35532649
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a 49-year-old lady presenting with rapidly progressive cognitive impairment, seizures, hypersomnolence, ataxia, and generalized dystonia of 3 weeks duration.
    explanation: Genetically confirmed adult BTBGD case documents generalized dystonia.
- category: Neurological
  name: Cogwheel rigidity
  description: >-
    Cogwheel rigidity is nearly always present in classic BTBGD, consistent
    with extrapyramidal basal ganglia dysfunction.
  phenotype_term:
    preferred_term: Cogwheel rigidity
    term:
      id: HP:0002396
      label: Cogwheel rigidity
  evidence:
  - reference: PMID:24260777
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dystonia and cogwheel rigidity are nearly always present"
    explanation: GeneReviews states that cogwheel rigidity is nearly always present in classic BTBGD.
- category: Neurological
  name: Hyperreflexia
  description: Hyperreflexia is a common neurologic sign in classic BTBGD.
  phenotype_term:
    preferred_term: Hyperreflexia
    term:
      id: HP:0001347
      label: Hyperreflexia
  evidence:
  - reference: PMID:24260777
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hyperreflexia, ankle clonus, and Babinski responses are common."
    explanation: GeneReviews lists hyperreflexia among common classic BTBGD neurologic signs.
- category: Neurological
  name: Dysphagia
  description: Dysphagia can occur during BTBGD encephalopathic presentations.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:27905264
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disease is characterized by subacute encephalopathy with confusion, dysphagia, dysarthria, and seizures.
    explanation: Clinical review lists dysphagia among characteristic findings.
- category: Neurological
  name: Dysarthria
  description: Dysarthria can occur during BTBGD encephalopathic presentations.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:27905264
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disease is characterized by subacute encephalopathy with confusion, dysphagia, dysarthria, and seizures.
    explanation: Clinical review lists dysarthria among characteristic findings.
- category: Neurological
  name: Ataxia
  description: Ataxia has been reported in adult Wernicke-like BTBGD presentations.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:35532649
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a 49-year-old lady presenting with rapidly progressive cognitive impairment, seizures, hypersomnolence, ataxia, and generalized dystonia of 3 weeks duration.
    explanation: Genetically confirmed adult BTBGD case documents ataxia.
- category: Metabolic
  name: Lactic acidosis
  description: >-
    Infantile BTBGD presentations may include lactic acidosis or elevated blood
    lactate during encephalopathic decompensation.
  phenotype_term:
    preferred_term: Lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
  evidence:
  - reference: PMID:27896110
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four different phenotypes have been described; infantile lactic acidosis with encephalopathy
    explanation: Full-text review identifies infantile lactic acidosis with encephalopathy as one recognized BTBGD presentation.
  - reference: PMID:27896110
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biochemical analysis revealed elevated blood lactate at 3.8 mmol/L (nl 0.6-2.2)
    explanation: Patient biochemical testing documents elevated blood lactate.
- category: Radiographic
  name: Bilateral basal ganglia MRI abnormalities
  description: >-
    Brain MRI commonly shows bilateral signal abnormalities or lesions in the
    caudate nucleus, putamen, globus pallidus, and related basal ganglia
    structures, and may also show thalamic, cortical, subcortical white matter,
    brainstem, cerebellar, or cervical-spine involvement.
  phenotype_term:
    preferred_term: Abnormal basal ganglia morphology
    term:
      id: HP:0002134
      label: Abnormal basal ganglia morphology
  evidence:
  - reference: ORPHA:65284
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Imaging may reveal bilateral lesions in the basal ganglia."
    explanation: Orphanet describes the bilateral basal ganglia imaging pattern.
  - reference: PMID:27905264
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Children presenting with unexplained encephalopathy and MRI abnormalities including bilateral signal alteration of caudate nucleus and putamen should raise the suspicion for BTBGD
    explanation: Review highlights bilateral caudate and putamen signal alteration as a diagnostic clue.
  - reference: PMID:35532649
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The magnetic resonance imaging (MRI) of the brain revealed T2-hyperintensities in the basal ganglia, thalamus, cortical, subcortical regions with striatal necrosis suggestive of BTBGD
    explanation: Adult case report documents thalamic, cortical, and subcortical involvement in addition to basal ganglia abnormalities.
  - reference: PMID:27896110
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Typical MRI findings include cortical, subcortical white matter lesions, and bilateral abnormal signal intensity in the basal ganglia with less frequent involvement of thalami, brain stem, cerebellum and cervical spine
    explanation: Full-text review summarizes broader MRI involvement beyond the basal ganglia.
- category: Neurological
  name: Cognitive impairment
  description: >-
    Rapidly progressive cognitive impairment can be a prominent feature,
    particularly in adult Wernicke-like BTBGD presentations.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: PMID:35532649
    reference_title: "Biotin-Responsive Basal Ganglia Disease: Treatable Metabolic Disorder with SLC19A3 Mutation Presenting as Rapidly Progressive Dementia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a 49-year-old lady presenting with rapidly progressive cognitive impairment, seizures, hypersomnolence, ataxia, and generalized dystonia of 3 weeks duration.
    explanation: Genetically confirmed adult BTBGD case documents rapidly progressive cognitive impairment.
- category: Neurological
  name: Hypersomnolence
  description: >-
    Excessive sleepiness can accompany the acute encephalopathic presentation
    of BTBGD.
  phenotype_term:
    preferred_term: Hypersomnolence
    term:
      id: HP:0002329
      label: Drowsiness
  evidence:
  - reference: PMID:35532649
    reference_title: "Biotin-Responsive Basal Ganglia Disease: Treatable Metabolic Disorder with SLC19A3 Mutation Presenting as Rapidly Progressive Dementia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a 49-year-old lady presenting with rapidly progressive cognitive impairment, seizures, hypersomnolence, ataxia, and generalized dystonia of 3 weeks duration.
    explanation: Genetically confirmed adult BTBGD case documents hypersomnolence during the acute episode.
- category: Neurological
  name: Ankle clonus
  description: >-
    Ankle clonus is a common upper-motor-neuron sign in classic BTBGD.
  phenotype_term:
    preferred_term: Ankle clonus
    term:
      id: HP:0011448
      label: Ankle clonus
  evidence:
  - reference: PMID:24260777
    reference_title: "Biotin-Thiamine-Responsive Basal Ganglia Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hyperreflexia, ankle clonus, and Babinski responses are common."
    explanation: GeneReviews lists ankle clonus among common classic BTBGD neurologic signs.
- category: Neurological
  name: Babinski sign
  description: >-
    Extensor plantar responses (Babinski sign) are a common corticospinal sign
    in classic BTBGD.
  phenotype_term:
    preferred_term: Babinski sign
    term:
      id: HP:0003487
      label: Babinski sign
  evidence:
  - reference: PMID:24260777
    reference_title: "Biotin-Thiamine-Responsive Basal Ganglia Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hyperreflexia, ankle clonus, and Babinski responses are common."
    explanation: GeneReviews lists Babinski responses among common classic BTBGD neurologic signs.
biochemical:
- name: Blood lactate elevation
  presence: INCREASED
  context: >-
    Infantile BTBGD may present with lactic acidosis with encephalopathy, and
    affected patients can show elevated blood lactate during the diagnostic
    evaluation.
  biomarker_term:
    preferred_term: lactate
    term:
      id: CHEBI:24996
      label: lactate
  readouts:
  - target: Lactic acidosis
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated blood lactate is the biochemical measurement underlying the lactic acidosis phenotype in infantile BTBGD presentations.
    evidence:
    - reference: PMID:27896110
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Biochemical analysis revealed elevated blood lactate at 3.8 mmol/L (nl 0.6-2.2)
      explanation: Patient testing directly documents elevated blood lactate.
  evidence:
  - reference: PMID:27896110
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four different phenotypes have been described; infantile lactic acidosis with encephalopathy
    explanation: Full-text review identifies infantile lactic acidosis with encephalopathy as a recognized presentation.
  - reference: PMID:27896110
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biochemical analysis revealed elevated blood lactate at 3.8 mmol/L (nl 0.6-2.2)
    explanation: Patient biochemical testing directly documents elevated lactate.
diagnosis:
- name: Brain MRI for bilateral basal ganglia lesions
  description: >-
    Brain MRI helps distinguish BTBGD from other encephalopathies by detecting
    bilateral caudate, putamen, and other basal ganglia signal abnormalities,
    sometimes with thalamic and cortical-subcortical involvement.
  diagnosis_term:
    preferred_term: magnetic resonance imaging procedure
    term:
      id: MAXO:0000424
      label: magnetic resonance imaging procedure
  results: Bilateral basal ganglia lesions or signal abnormalities support BTBGD and should trigger SLC19A3 testing and immediate vitamin therapy.
  evidence:
  - reference: PMID:27905264
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Children presenting with unexplained encephalopathy and MRI abnormalities including bilateral signal alteration of caudate nucleus and putamen should raise the suspicion for BTBGD
    explanation: Review states that this MRI pattern should raise suspicion for BTBGD.
  - reference: PMID:28677371
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We confirm that the autopsy and/or MRI of the brain is sufficient to qualify a patient with an unknown neuropathological disorder directly for SLC19A3 mutations testing and a prompt trial of specific treatment.
    explanation: Neuropathology/MRI study supports MRI as a route to targeted SLC19A3 testing and treatment.
  - reference: PMID:35532649
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The magnetic resonance imaging (MRI) of the brain revealed T2-hyperintensities in the basal ganglia, thalamus, cortical, subcortical regions with striatal necrosis suggestive of BTBGD
    explanation: Adult case report supports broader MRI pattern recognition for BTBGD.
- name: Molecular genetic testing of SLC19A3
  description: >-
    Molecular testing confirms biallelic pathogenic SLC19A3 variants and helps
    distinguish BTBGD from Leigh syndrome or mitochondrial disease mimics.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  results: Biallelic pathogenic SLC19A3 variants establish the molecular diagnosis.
  evidence:
  - reference: PMID:27896110
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing (WES) was performed at Baylor College of Medicine, Medical Genetics Laboratory and confirmed compound heterozygous frameshift mutations in the SLC19A3 gene in trans
    explanation: WES established the molecular diagnosis in a BTBGD patient.
treatments:
- name: High-dose thiamine and biotin supplementation
  description: >-
    Immediate high-dose thiamine and biotin supplementation is the core
    disease-specific therapy and should be started when BTBGD is suspected.
  treatment_term:
    preferred_term: vitamin supplementation
    term:
      id: MAXO:0001129
      label: vitamin supplementation
    therapeutic_agent:
    - preferred_term: thiamine
      term:
        id: CHEBI:18385
        label: thiamine(1+)
    - preferred_term: biotin
      term:
        id: CHEBI:15956
        label: biotin
  target_mechanisms:
  - target: SLC19A3 thiamine transporter deficiency
    treatment_effect: BYPASSES
    description: High-dose thiamine increases substrate availability despite reduced SLC19A3 transporter function.
    evidence:
    - reference: PMID:27896110
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This treatment strategy is supported by in vitro studies suggesting that high doses of thiamine and biotin restore insufficient thiamine transport by overexpression of SLC19A3 gene
      explanation: Human clinical case report/review cites in vitro support that high-dose vitamins restore insufficient SLC19A3-mediated thiamine transport.
  - target: Stress-triggered cerebral thiamine-transport failure
    treatment_effect: MODULATES
    description: Early vitamin supplementation supports thiamine availability during stress-triggered episodes.
    evidence:
    - reference: PMID:27905264
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Children presenting with unexplained encephalopathy and MRI abnormalities including bilateral signal alteration of caudate nucleus and putamen should raise the suspicion for BTBGD and be started immediately on biotin and thiamine regimen since the prognosis of the disease is affected by the timing of treatment initiation.
      explanation: Clinical review supports immediate vitamin treatment during suspected encephalopathic episodes.
  target_phenotypes:
  - preferred_term: Encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
    temporality: SUBACUTE
  - preferred_term: Confusion
    term:
      id: HP:0001289
      label: Confusion
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  - preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  - preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  - preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  - preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  - preferred_term: Abnormal basal ganglia morphology
    term:
      id: HP:0002134
      label: Abnormal basal ganglia morphology
  evidence:
  - reference: ORPHA:65284
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The disease usually becomes symptomatic in childhood and is life-threatening if left untreated, but symptoms can be reversed and progression prevented by treatment with high doses of biotin and thiamine.
    explanation: Orphanet directly supports high-dose biotin and thiamine as disease-modifying treatment.
  - reference: PMID:35532649
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      High doses of biotin and thiamine are the mainstay of the treatment to achieve a favorable outcome.
    explanation: Adult case report and review supports high-dose vitamin treatment.
  - reference: PMID:36657988
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is considered a treatable condition if vitamin supplementation, most commonly with thiamine and biotin, is initiated early.
    explanation: Child neurology review emphasizes early thiamine/biotin supplementation.
- name: Avoidance of sodium valproate and ACTH
  description: >-
    Sodium valproate should be avoided for epilepsy treatment in BTBGD, and
    ACTH used for epileptic spasms can induce status dystonicus.
  role: Agents/circumstances to avoid
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  - preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:24260777
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Avoid use of sodium valproate to treat epilepsy. Use of ACTH to treat epileptic spasms can induce status dystonicus.
    explanation: GeneReviews explicitly lists sodium valproate and ACTH as agents/circumstances to avoid in BTBGD.
- name: Genetic counseling
  description: >-
    Families benefit from counseling about autosomal recessive recurrence risk
    and targeted SLC19A3 testing for relatives.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:27896110
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      early supplementation with biotin and/or thiamine can improve the devastating progression of this condition and allow for appropriate genetic counseling.
    explanation: Case report explicitly links molecular diagnosis and treatment recognition to genetic counseling.
differential_diagnoses:
- name: Leigh syndrome
  disease_term:
    preferred_term: Leigh syndrome
    term:
      id: MONDO:0009723
      label: Leigh syndrome
  description: >-
    BTBGD can mimic Leigh syndrome clinically and radiographically, especially
    with infantile basal ganglia lesions and lactic-acidosis-like presentations.
  evidence:
  - reference: PMID:27896110
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our report adds to the genotype-phenotype correlation, highlighting the clinical importance of considering SLC19A3 gene defects as part of the differential diagnosis for Leigh syndrome.
    explanation: Case report directly identifies Leigh syndrome as an important differential diagnosis.
references:
- reference: PMID:24260777
  title: Biotin-Thiamine-Responsive Basal Ganglia Disease.
  tags:
  - GeneReviews
  findings: []
📚

References & Deep Research

References

1
PMID:24260777
Biotin-Thiamine-Responsive Basal Ganglia Disease.
No top-level findings curated for this source.

Deep Research

1
Biotin-Thiamine-Responsive Basal Ganglia Disease Deep Research Fallback ▸

Biotin-Thiamine-Responsive Basal Ganglia Disease Deep Research Fallback

Date: 2026-05-07

Provider Attempts

  • timeout 90s just research-disorder falcon Biotin_Thiamine_Responsive_Basal_Ganglia_Disease terminated by signal 15 before producing an artifact.
  • timeout 90s just research-disorder openai Biotin_Thiamine_Responsive_Basal_Ganglia_Disease terminated by signal 15 before producing an artifact.

Evidence Scope Integrated

The YAML curation was built from generated Orphanet structured records and cached PubMed evidence:

  • ORPHA:65284, the primary biotin-thiamine-responsive basal ganglia disease record, supplies disease scope, synonyms, definition, inheritance, onset, prevalence, SLC19A3 gene assertion, and MONDO:0011841 exact mapping.
  • ORPHA:199348, the thiamine-responsive encephalopathy record, supports the overlapping SLC19A3-related Wernicke-like thiamine-responsive phenotype.
  • PMID:27905264 supports autosomal recessive SLC19A3 disease causation, subacute encephalopathy with dysphagia/dysarthria/seizures, bilateral caudate/putamen MRI abnormalities, and outcome dependence on early treatment.
  • PMID:24372704 supports the cellular mechanism: SLC19A3 encodes thiamine transporter 2, patient tissue shows reduced thiamine transporter function, and patient fibroblasts fail to upregulate SLC19A3 under acidosis/hypoxia.
  • PMID:27896110 supports compound heterozygous SLC19A3 variants, Leigh syndrome differential diagnosis, early thiamine/biotin supplementation, and genetic counseling.
  • PMID:28677371 supports the specific SLC19A3-related CNS lesion pattern and MRI/autopsy-triggered SLC19A3 testing with prompt specific treatment.
  • PMID:35532649 supports adult presentation with seizures, ataxia, dystonia, basal ganglia MRI abnormalities, clinical/MRI improvement after thiamine and biotin, and high-dose vitamin therapy as treatment mainstay.
  • PMID:36657988 supports autosomal recessive inheritance, blood-brain barrier thiamine transport failure, recognized infantile/childhood/adult phenotypes, and early thiamine/biotin supplementation.

No uncached web claims or hand-authored reference-cache content were used.