Report of the Largest Chinese Cohort With SLC19A3 Gene Defect and Literature Review

Abstract

Thiamine metabolism dysfunction syndrome 2 (THMD2) is a rare metabolic disorder caused by SLC19A3 mutations, inherited in autosomal recessive pattern. As a treatable disease, early diagnosis and therapy with vitamin supplementation is important to improve the prognosis. So far, the reported cases were mainly from Saudi Arab regions, and presented with relatively simple clinical course because of the hot spot mutation (T422A). Rare Chinese cases were described until now. In this study, we investigated 18 Chinese THMD2 patients with variable phenotypes, and identified 23 novel SLC19A3 mutations, which expanded the genetic and clinical spectrum of the disorder. Meanwhile, we reviewed all 146 reported patients from different countries. Approximately 2/3 of patients presented with classical BTBGD, while 1/3 of patients manifested as much earlier onset and poor prognosis, including infantile Leigh-like syndrome, infantile spasms, neonatal lactic acidosis and infantile BTBGD. Literature review showed that elevated lactate in blood and CSF, as well as abnormal OXPHOS activities of muscle or skin usually correlated with infantile phenotypes, which indicated poor outcome. Brainstem involvement on MRI was more common in deceased cases. Thiamine supplementation is indispensable in the treatment of THMD2, whereas combination of biotin and thiamine is not superior to thiamine alone. But biotin supplementation does work in some patients. Genotypic-phenotypic correlation remains unclear which needs further investigation, and biallelic truncated mutations usually led to more severe phenotype.

Child Neurology: Infantile Biotin Thiamine Responsive Basal Ganglia Disease

“…In retrospective cohorts of infantile BTRBGD, all patients presented with encephalopathy consisting of irritability, crying, and/or depressed level of consciousness. 5 They are also more likely to have concomitant hypotonia, ophthalmoplegia, dysphagia, and lactic acidosis compared with childhood BTRBGD. 5 Owing to its nonspecific clinical presentation and low incidence, BTRBGD is often mistaken for other conditions, especially early in the course of the illness.…”

“…1,3 Mutations in the SLC19A3 gene cause a rare recessive metabolic condition called BTRBGD, characterized by early onset encephalopathy, bulbar dysfunction, dystonia/ hypotonia, ataxia, and seizures that are often triggered by a febrile illness. 2,5 BTRBGD is considered a treatable condition if vitamin supplementation is started early. Treatment consists of a combination of high dose biotin (1-10 mg/kg/d) and thiamine (10-40 mg/kg/d).…”

“…With an estimated disease prevalence of BTRBGD from SLC19A3 mutations of 1 in 215,000, 8 there are few reports of BTRBGD in the literature, especially describing cases with neonatal or infantile onset. 5,[9][10][11][12][13][14][15] Given its rarity, the genotypephenotype correlation is not completely known. However, in contrast to the classical childhood-and adult-onset BTRBGD phenotypes, which often respond more effectively to supplementation, 5 infantile BTRBGD unfortunately portends a more severe phenotype with increased morbidity and mortality, despite vitamin supplementation.…”

Next-generation sequencing of Tunisian Leigh syndrome patients reveals novel variations: impact for diagnosis and treatment

“…To date there is a total of 62 disease-causing variants identified in the SLC19A3 gene with our findings, which are associated with a wide spectrum of disorders from mild-to-severe clinical manifestations. Among these variants 37 are missense, 18 truncating mutations (nonsense or frameshift), four gross deletions of either exons, promoter region or the whole gene and 2 splicing mutations [ 32 ]. A novel homozygous missense variant c.958G>C (p.Glu320Gln) was found in four Japanese patients with a clinical presentation and radiological traits that were classified as LS.…”

“…Considering a case with adult-onset Wernicke’s-like encephalopathy a compound heterozygous variants Glu320 Gln combined with Lys44Glu were identified leading to a mild clinical manifestation [ 31 ]. Other than that, the hot spot variant identified Thr422Ala in the Saudi Arabian result in a somewhat mild phenotypes with a good prognosis [ 32 , 34 ]. As for the truncated variants, a Turkish patient harbored the SLC19A3 homozygous frameshift variant c.982del (p.Ala328Leufs*10), resulting in a truncated protein.…”