Biotin-Thiamine-Responsive Basal Ganglia Disease via the SLC19A3 Gene

Biotin-thiamine-responsive basal ganglia disease (BTBGD) is a neurological disorder characterized by encephalopathy and neurological decline. BTBGD represents a clinical spectrum of disorders resulting from loss of the neuronal thiamine transporter hTHTR2. Disease onset can occur anytime between infancy and adulthood, with the preponderance of cases showing childhood onset. The first symptoms are often seen following febrile illness or mild trauma and include: subacute episodes of encephalopathy, seizures, ataxia, and/or confusion (Alfadhel et al. 2013; Tabarki et al. 2013). At onset, seizures are generally well controlled with medication. Additional variable symptoms include dystonia, dysarthria, dysphagia, somnolence, external ophthalmoplegia, quadriparesis, and hyperreflexia. If left untreated, severe neurodegeneration is seen, ultimately leading to severe intellectual disability, coma, respiratory insufficiency, and death. In severe cases of BTBGD, patients present during infancy with hypotonia or hyptertonia, difficulty feeding, infantile spasms, and severe psychomotor delay (Kevelam et al. 2013). In these reported cases, EEG readings showed mutlifocal spikes without hypsarrhythmia. Not only is there high phenotypic variability among patients with different SLC19A3 variants, but there can also be considerable variability in disease onset within members of the same family (Alfadhel et al. 2013).

MRI findings reveal bilateral hyperintensity of the basal ganglia (caudate nucleus and putamen) on T2-weighted sequences. Vasogenic edema is also seen on MRI during acute neurometabolic crisis. Involvement of the brain stem and cerebellar cortex and vermis has also been reported (Distelmaier et al. 2013). As the disease progresses, MRI reveals significant brain atrophy and bilateral lesions in the thalami and basal ganglia (Kevelam et al. 2013).

BTBGD is often misdiagnosed as Leigh syndrome as it shares many symptoms with this mitochondrial disorder. BTBGD patients may have lactic acidemia and a lactate peak on magnetic resonance spectroscopy, which further supports a diagnosis of Leigh syndrome (Gerards et al. 2013). However, metabolic screening in BTBGD patients is normal and there is no evidence of respiratory chain deficiency (Debs et al. 2010; Serrano et al. 2012). In addition, MRI in BTBGD patients may show vasogenic edema and diffuse cortical and subcortical changes that are not typical of Leigh syndrome (Distelmaier et al. 2013).

The BTBGD phenotype has also been likened to Wernicke's encephalopathy (WE), thiamine deficiency described in alcoholics, due to the presence of ophthalmoplegia, ataxia, and confusion.

Treatment with a high dose of biotin and additional thiamine has been shown to be effective in BTBGD patients (Tabarki et al. 2013). Patients treated shortly after onset of symptoms showed partial to complete improvement within days, whereas patients treated later into disease progression did not show a complete reversal of symptoms, but did exhibit marked improvement (Alfadhel et al. 2013). Continuous biotin-thiamine therapy is required; symptoms recur upon removal of treatment.

BTBGD is inherited in an autosomal recessive manner and is caused by pathogenic variants in the SLC19A3 gene. Pathogenic nonsense, missense, frameshift, and splice site variants in the SLC19A3 gene have been reported (Debs et al. 2010; Kevelam et al. 2013). Currently there is no clear genotype-phenotype correlation to explain why some patients with pathogenic SLC19A3 variants show a more severe course of disease than others.

SLC19A3 encodes hTHTR2, one of two thiamine transporters localized to the plasma membrane (Gerards et al. 2013). hTHTR2 is a high-affinity low capacity transporter that is expressed in neurons. Once thiamine is imported into the cell it is converted to its active form thiamine pyrophosphate, which is a cofactor for a range of enzymatic reactions.

Combined treatment with biotin and thiamine reverses disease progression in BTBGD patients with pathogenic missense and loss-of-function variants (Haack et al. 2014; Alfadhel et al. 2013). Biotin is not a known substrate of hTHTR2 and the molecular mechanism by which treatment with biotin helps compensate for defective thiamine transport is unclear.

Biotin-thiamine-responsive basal ganglia disease is a rare disorder, and clinical sensitivity cannot yet be estimated. Analytical sensitivity should be high because the great majority of pathogenic variants thus far reported are detectable by sequencing genomic DNA.

This test provides full coverage of all coding exons of the SLC19A3 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.