A wide spectrum of clinical and brain MRI findings in patients with SLC19A3 mutations

Abstract

Background: SLC19A3 (solute carrier family 19, member 3) is a thiamin transporter with 12 transmembrane domains. Homozygous or compound heterozygous mutations in SLC19A3 cause two distinct clinical phenotypes, biotin-responsive basal ganglia disease and Wernicke's-like encephalopathy. Biotin and/or thiamin are effective therapies for both diseases.

Methods: We conducted on the detailed clinical, brain MRI and molecular genetic analysis of four Japanese patients in a Japanese pedigree who presented with epileptic spasms in early infancy, severe psychomotor retardation, and characteristic brain MRI findings of progressive brain atrophy and bilateral thalami and basal ganglia lesions.

Results: Genome-wide linkage analysis revealed a disease locus at chromosome 2q35-37, which enabled identification of the causative mutation in the gene SLC19A3. A pathogenic homozygous mutation (c.958G > C, [p.E320Q]) in SLC19A3 was identified in all four patients and their parents were heterozygous for the mutation. Administration of a high dose of biotin for one year improved neither the neurological symptoms nor the brain MRI findings in one patient.

Conclusion: Our cases broaden the phenotypic spectrum of disorders associated with SLC19A3 mutations and highlight the potential benefit of biotin and/or thiamin treatments and the need to assess the clinical efficacy of these treatments.

Figure 1

Pedigree and haplotypes in the linkage region. Squares and circles indicate males and females, respectively. The proband and affected individuals are indicated by an arrow and closed symbols, respectively. Only informative markers that define the genetic breakpoints are shown. The maximum LOD score was in the region between D2S163 to D2S2344.

Figure 2

MRIs of patients V-2, V-3, V-4 and V-6 at various ages. Areas of abnormal intensity in the thalami and basal ganglia (arrowheads) were distinct at 4 months in V-2 (A, B). The sagittal and axial views of T1- and T2-weighted images of V-2 at 1 year showed severe brain atrophy (D, E, F). The sagittal and axial views of T1- and T2-weighted images of V-3 at 7 years, 5 months (G, H, I), V-4 at 6 years, 3 months (J, K, L), and V-6 at 3 years, 5 months (M, N, O) showed severe brain atrophy, including cerebellar atrophy (I, L, O) and abnormal intensity areas in the thalami and basal ganglia.

Figure 3

Identification and characterization of a disease mutation (c.958G > C, [p.E320Q]). (A) The sequence analyses showed a G to C substitution at nucleotide position 958 in Exon 3 of SLC19A3, resulting in a substitution of glutamic acid at codon 320 for glutamine (c.958G > C, [p.E320Q]), indicated by an arrow. (B) RsaI (GTAC)-digested PCR products were run through a 1.2% agarose gel. Digestion of products containing the E320Q mutation resulted in 357- and 86-bp fragments. All patients (V-2, V-3, V-4 and V-6) were homozygous for the mutation, and their parents were heterozygous for the mutation. (C) [³H]-thiamin uptake by HEK293 cells expressing wild-type or E320Q SLC19A3. Two days after transfection, cells were incubated with 0.1 μM of [³H]-labeled thiamin (14.8 kBq:0.74TBq/mmol) for 10 min with or without 0.1 mM unlabeled thiamin. Incorporated [³H]-thiamin was measured using a liquid scintillation counter. Results are expressed as mean ± SE of specific uptake values from three independent experiments.