SLC19A3 – Leigh Syndrome

SLC19A3 (thiamine transporter-2) encodes a high-affinity thiamine transporter critical for cellular thiamine uptake. Pathogenic biallelic variants in SLC19A3 underlie Leigh syndrome, a subacute necrotizing encephalomyelopathy characterized by symmetrical basal ganglia and brainstem lesions. The disorder follows an autosomal recessive inheritance pattern and manifests with acute encephalopathy (HP:0006846), generalized dystonia (HP:0007325), and epileptic spasms (HP:0011097), often during infancy or early childhood. Phenotypic overlap with Wernicke encephalopathy underscores the importance of considering SLC19A3 testing in Leigh-like presentations (PMID:24099834).

Case series include a discovery of a homozygous c.20C>A (p.Ser7Ter) founder variant in 17 additional Moroccan patients, confirming pathogenicity across three independent families (PMID:23423671). A novel adolescent case with homozygous c.517A>G (p.Asn173Asp) variant also segregated with disease in one family (PMID:24099834). In four children from different backgrounds, thiamine and biotin supplementation led to clinical and radiological improvements, highlighting therapeutic responsiveness (PMID:24957181). In a consanguineous Tunisian family, the c.1264A>G (p.Thr422Ala) variant resulted in oxidative stress and 42% mtDNA depletion, corroborating a loss-of-function mechanism (PMID:37642897).

To date, at least 25 pathogenic SLC19A3 variants have been reported, including nonsense (e.g., c.20C>A (p.Ser7Ter)), splice-site, frameshift, and missense changes. The c.20C>A (p.Ser7Ter) variant acts as a founder allele in Moroccan patients, whereas missense substitutions such as p.Thr422Ala recur in diverse populations. Most variants result in complete loss of transporter function or impaired thiamine binding, consistent with a recessive haploinsufficiency model. Deep intronic and regulatory variants remain uncommon.

In vitro assays demonstrate that pathogenic missense variants, including p.Thr422Ala and p.Gly23Val, abrogate thiamine transport activity without affecting membrane localization, confirming transporter deficiency (PMID:16790503). SLC19A3 knockout mice exhibit significantly reduced intestinal thiamine uptake and decreased plasma thiamine levels, phenocopying the human biochemical defect (PMID:19879271). These data support a loss-of-function mechanism leading to diminished intracellular thiamine availability. Concordance between biochemical assays, molecular docking, and cellular models further strengthens the disease association.

Early recognition of SLC19A3-related Leigh syndrome is critical, as high-dose thiamine, with or without biotin, can dramatically reverse neurologic decline if initiated promptly. Brain MRI findings of bilateral dorsal striatum and medial thalamic lesions may guide differential diagnosis. Molecular diagnosis enables presymptomatic treatment and family counseling. Given the autosomal recessive inheritance, carrier screening and prenatal testing are feasible. Domain-specific variant effects may underlie phenotypic variability, warranting further genotype-phenotype studies.

Integrating genetic and functional evidence, biallelic loss-of-function variants in SLC19A3 are determined to cause autosomal recessive Leigh syndrome with definitive clinical validity. Genetic evidence is rated as strong based on over 20 probands and multi-family segregation, and functional evidence is moderate given robust in vitro and in vivo data. While additional regulatory and deep-intronic variants remain to be fully characterized, current knowledge supports early genetic testing to inform targeted thiamine therapy. Key take-home: SLC19A3 testing should be integrated into the diagnostic workup of Leigh syndrome for timely, potentially lifesaving treatment.

References

• Brain | 2013 | Exome sequencing reveals a novel Moroccan founder mutation in SLC19A3 as a new cause of early-childhood fatal Leigh syndrome PMID:23423671
• BMJ case reports | 2013 | Treatable Leigh-like encephalopathy presenting in adolescence. PMID:24099834
• Orphanet journal of rare diseases | 2014 | Thiamine transporter-2 deficiency: outcome and treatment monitoring. PMID:24957181
• American journal of physiology. Cell physiology | 2006 | Biotin-responsive basal ganglia disease-linked mutations inhibit thiamine transport via hTHTR2: biotin is not a substrate for hTHTR2. PMID:16790503
• Gastroenterology | 2010 | Impaired intestinal vitamin B1 (thiamin) uptake in thiamin transporter-2-deficient mice. PMID:19879271
• Metabolic brain disease | 2023 | Vitamin B1 deficiency leads to high oxidative stress and mtDNA depletion caused by SLC19A3 mutation in consanguineous family with Leigh syndrome. PMID:37642897

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