Cerebral Thiamine-Transporter-Deficiency (SLC19A3) – A Rare But Treatable Cause Of An Acute Necrotizing Encephalopathy

Aims: The term Acute Necrotizing Encephalopathy (ANE) describes a group of mostly rapid progressive encephalopathies with characteristic symmetric lesions in basalganglia and thalamus, which often debut as a result of a virus-infection in healthy children. In the following we describe two siblings, who presented with ANE. In this family a rare deficiency of the cerebral thiamine-transporter (hTHTR2) has been verified.

Methods: We conducted detailed physical examinations as well as brain MRI. Molecular genetic analyses consist of amplifying and sequencing of DNA-fragments, copy number assays, RNA isolation out of fibroblasts, reverse transcription of RNA and sequencing of cDNA. Wild type-cDNA and patient-cDNA have been transfected in HEK293-cells to perform a thiamine-assay.

Results: A former healthy 3 ½ year old boy developed progressive loss of consciousness with apraxia and epileptic seizures. T2-weighted MRI showed bilateral hyperintensities in striatum and subcortical areas. Neurometabolic and infectiologic examinations produced normal results. The patient survived with severe residual symptoms. His brother developed similar symptoms at the age of 13. He died in consequence of an aspiration during status epilepticus. The autopsy disclosed necrotic lesions in brainstem and subcortical without any inflammatory signs. In moleculargenetic analysis two novel heterozygous mutations in SLC19A3 were identified. After diagnosis the initiation of biotin- and thiamine-therapy leads to a considerable improvement of the surviving brothers symptoms.

Conclusion: Mutations in SLC19A3 are up to now in just a few patients worldwide described. These mutations are a cause of an ANE with high therapeutic relevance. At least in some of the patients with so called biotin-responsive basalganglia disease progression can be prevented by treatment with biotin and thiamine. Already existing symptoms may also be improved. Therefore a probatory therapy with biotin and thiamine should be considered in all patients with suspected ANE.