title: Biotin-thiamine-responsive basal ganglia disease: catastrophic consequences of delay in diagnosis and treatment.
abstract: BACKGROUND
  Biotin-thiamine-responsive basal ganglia disease (BTBGD) is an autosomal recessive neurometabolic disorder caused by mutations in the SLC19A3 gene. The disease is characterized by subacute encephalopathy with confusion, dysphagia, dysarthria, and seizures.
  
  
  METHODS
  We diagnosed a family affected by BTBGD and studied them including prognosis of cases when diagnosed and treated early in the disease process. We also review the literature comprehensively and summarize all published data about this disorder.
  
  
  RESULTS
  Since its first description, a total of 89 cases (46 females and 43 males) have been published in the literature. 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. The clinical phenotype of each family member was studied in details. In addition, a genetic testing was performed using whole exome sequencing and Sanger sequencing which demonstrated a previously reported homozygous mutation in exon 5 of the SLC19A3 gene c.1264A>G (p.Thr422Ala).
  
  
  CONCLUSIONS
  BTBGD is a treatable condition if recognized early and managed appropriately. The recognition of this disorder is important to avoid incorrect diagnosis and mismanagement. 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. We present a large family affected with this disorder with severe interfamilial variability and different prognosis despite having the same mutation and same environment. A clear genotype-phenotype correlation and the clinical heterogeneity remain to be elucidated. Bad prognostic factors observed in our review include early onset of the disease, missed or delayed diagnosis, systemic involvements including respiratory failure and rhabdomyolysis, and severe neurological deficit or radiological changes at the time of diagnosis and treatment initiation. We observed during our literature review that all patients who presented since birth died despite aggressive treatment. This observation may illustrate that early presentation and disease process leads to a more catastrophic outcome.
authors.affiliation: a King Abdulaziz Medical City/King Saud bin Abdulaziz University for Health Sciences , Jeddah , Saudi Arabia.
authors.forename: Hussein
authors.initials: H
authors.lastname: Algahtani
authors.affiliation: a King Abdulaziz Medical City/King Saud bin Abdulaziz University for Health Sciences , Jeddah , Saudi Arabia.
authors.forename: Saeed
authors.initials: S
authors.lastname: Ghamdi
authors.affiliation: b King Abdullah International Medical Research Center/King Saud bin Abdulaziz University for Health Sciences , Jeddah , Saudi Arabia.
authors.forename: Bader
authors.initials: B
authors.lastname: Shirah
authors.affiliation: c King Saud bin Abdulaziz University for Health Sciences , Jeddah , Saudi Arabia.
authors.forename: Bader
authors.initials: B
authors.lastname: Alharbi
authors.affiliation: c King Saud bin Abdulaziz University for Health Sciences , Jeddah , Saudi Arabia.
authors.forename: Raghad
authors.initials: R
authors.lastname: Algahtani
authors.affiliation: d Batterjee Medical College , Jeddah , Saudi Arabia.
authors.forename: Abdulrahman
authors.initials: A
authors.lastname: Bazaid
mesh_terms: D000293:Adolescent; D001479:Basal Ganglia / Q000000981:diagnostic imaging; D001480:Basal Ganglia Diseases / Q000000981:diagnostic imaging / Q000235:genetics / Q000628:therapy; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D016206:Databases, Bibliographic / Q000706:statistics & numerical data; D005192:Family Health; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D012189:Retrospective Studies
chemical_list: D026901:Membrane Transport Proteins; C492291:SLC19A3 protein, human
keywords: Biotin–thiamine–responsive basal ganglia disease; SLC19A3; basal ganglia; biotin; thiamine; thiamine transporter-2 deficiency