Biotin-thiamine-responsive basal ganglia disease

Last revised by Ashesh Ishwarlal Ranchod on 26 Feb 2023

Biotin-thiamine-responsive basal ganglia disease (BTBGD) is a rare neurometabolic syndrome caused by defective thiamine transporter 2 (THTR2) activity due to mutations in the solute carrier family 19 member 3 gene (SLC19A3). 

The presentation of biotin-thiamine-responsive basal ganglia disease is variable and has been documented to occur at any point from birth to early adulthood. Symptom onset is most often between 3 and 10 years of age. The disease is pan-enthnic; however, most of the reported cases in the literature are from Arab population, particularly from Saudi Arabia with an estimated prevalence of 1 in 1,000,000 1.

Children affected by biotin-thiamine-responsive basal ganglia disease typically present with intermittent subacute encephalopathy. Movement disorder, cognitive deficits, and seizures are classical. In addition, palsies affecting nerves to the head and neck cause deficits in facial expression, eye movement, mastication and swallowing. Interestingly, acute episodes of encephalopathy often follow a febrile illness or significant stress. 

Left untreated, biotin-thiamine-responsive basal ganglia disease may progress to severe incapacitation, coma, and death.

In some cases, biotin-thiamine-responsive basal ganglia disease presents insidiously with slowly progressive, chronic dystonia, seizures, and developmental delay 2

Thiamine is vital for energy metabolism in the brain, with thiamine deficiency causing a multitude of neurological deficits. Specifically, in addition to biotin-thiamine-responsive basal ganglia disease, there are five disease phenotypes associated with variants in SLC19A3

  • Wernicke-like encephalopathy
  • infantile spasms-psychomotor retardation-progressive brain atrophy-basal ganglia disease syndrome
  • Leigh syndrome with leukodystrophy
  • thiamine metabolism dysfunction syndrome 3
  • thiamine-responsive encephalopathy

In humans, there is no biological pathway for thiamine synthesis and so normal cellular function is almost exclusively dependent on uptake by thiamine transporter 1 (THTR1) and THTR2. 

MRI of an acute episode demonstrates severe vasogenic edema. Atrophy, necrosis and gliosis are observed at follow-up. These findings have been described in all reported cases of biotin-thiamine-responsive basal ganglia disease 3. Abnormal signal intensity signifying loss or impairment of nervous tissue is classically observed within the head of the caudate with complete or partial involvement of the putamen. Lesions may also be observed diffusely throughout the cortex. The thalami, brainstem, cerebellum, and spinal cord are less frequently affected.

Treatment with high-dose biotin and thiamine supplementation early in disease progression rapidly evokes a complete, or at least partial, response in many patients. 

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