Biotin-thiamine responsive basal ganglia disease: Identification of a pyruvate peak on brain spectroscopy, novel mutation in SLC19A3, and calculation of prevalence based on allele frequencies from aggregated next-generation sequencing data

Abstract

Biotin-thiamine responsive basal ganglia disease is an inborn error of metabolism caused by mutations in SLC19A3, encoding a transporter of thiamine across the plasma membrane. We report a novel mutation identified in the homozygous state in a patient with typical brain MRI changes. In addition, this patient had markedly elevated CSF pyruvate, a low lactate-to-pyruvate molar ratio, and an abnormal pyruvate peak at 2.4 ppm on brain magnetic resonance spectroscopy. Using aggregated exome sequencing data, we calculate the carrier frequency of mutations in SLC19A3 as 1 in 232 individuals in the general population, for an estimated prevalence of the disease of approximately 1 in 215,000 individuals. The disease is thus more frequent than previously recognized, and the presence of a pyruvate peak on spectroscopy could serve as an important diagnostic clue.

Keywords: SLC19A3; biotin-thiamine responsive basal ganglia disease; magnetic resonance spectroscopy; pyruvate; thiamine metabolism dysfunction syndrome 2; thiamine transporter-2 deficiency.

FIGURE 1

Baseline brain MRI and MRS performed at 2 years and 6 months. Axial T2 FLAIR image (a) and diffusion weighted images (b and c) demonstrates hyperintense lesions in the putamen and right caudate head with partial FLAIR signal suppression (arrows, a) and facilitated diffusion (arrows, b and c) consistent with areas of chronic encephalomalacia and necrosis. Short echo single voxel MRS (d) over the basal ganglia shows normal metabolic ratios; no abnormal pyruvate or lactate are present. Follow-up brain MRI and MRS at 3 years and 2 months. Axial T2 FLAIR (e) demonstrates acute on chronic cerebral deep gray nuclear lesions with new hyperintense lesions in the striatum (arrows) and medial thalami (arrowheads). Mixed diffusion abnormalities in the lesions (arrows, f) represent a combination of cytotoxic edema (restricted diffusion, white arrows), vasogenic edema (facilitated diffusion with mass effect, black arrows), and encephalomalacia/necrosis (facilitated diffusion without mass effect, arrowhead). Intermediate echo single voxel MRS (g) over the basal ganglia reveals an inverted lactate doublet at 1.3 ppm consistent with anaerobic metabolism and a decreased NAA to creatine ratio consistent with neuronal loss. Short echo MRS (h) over the left parietal white matter demonstrates an unusually prominent peak at 2.4 ppm consistent with pyruvate (Pyr). NAA, N-acetylaspartate; Cho, choline; Cr, creatine; MI, myoinositol