Compound heterozygous <i>SLC19A3</i> mutations further refine the critical promoter region for biotin-thiamine-responsive basal ganglia disease

Whitford, Whitney; Hawkins, Isobel; Glamuzina, Emma; Wilson, Felicia; Marshall, Andrew; Ashton, Fern; Love, Donald R.; Taylor, Juliet; Hill, Rosamund; Lehnert, Klaus; Snell, Russell G.; Jacobsen, Jessie C.

doi:10.1101/mcs.a001909

Cited by 19 publications

(15 citation statements)

References 61 publications

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“…Also, two gross deletions affecting the gene promoter (exon 1 and flanking intronic regions) have been reported. 92,93 The most prevalent genetic alteration in patients carrying SLC19A3 defects is NM_025243: c.1264A>G; p.Thr422Ala. This mutation is present in homozygosity in patients with Arab ethnic backgrounds.…”

Section: Slc19a3: Genetic Defects and Functional Studiesmentioning

confidence: 99%

Genetic defects of thiamine transport and metabolism: A review of clinical phenotypes, genetics, and functional studies

Marcé‐Grau

Martí-Sánchez

Baide‐Mairena

et al. 2019

J of Inher Metab Disea

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Thiamine is a crucial cofactor involved in the maintenance of carbohydrate metabolism and participates in multiple cellular metabolic processes within the cytosol, mitochondria, and peroxisomes. Currently, four genetic defects have been described causing impairment of thiamine transport and metabolism: SLC19A2 dysfunction leads to diabetes mellitus, megaloblastic anemia and sensory‐neural hearing loss, whereas SLC19A3, SLC25A19, and TPK1‐related disorders result in recurrent encephalopathy, basal ganglia necrosis, generalized dystonia, severe disability, and early death. In order to achieve early diagnosis and treatment, biomarkers play an important role. SLC19A3 patients present a profound decrease of free‐thiamine in cerebrospinal fluid (CSF) and fibroblasts. TPK1 patients show decreased concentrations of thiamine pyrophosphate in blood and muscle. Thiamine supplementation has been shown to improve diabetes and anemia control in Rogers' syndrome patients due to SLC19A2 deficiency. In a significant number of patients with SLC19A3, thiamine improves clinical outcome and survival, and prevents further metabolic crisis. In SLC25A19 and TPK1 defects, thiamine has also led to clinical stabilization in single cases. Moreover, thiamine supplementation leads to normal concentrations of free‐thiamine in the CSF of SLC19A3 patients. Herein, we present a literature review of the current knowledge of the disease including related clinical phenotypes, treatment approaches, update of pathogenic variants, as well as in vitro and in vivo functional models that provide pathogenic evidence and propose mechanisms for thiamine deficiency in humans.

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Section: Slc19a3: Genetic Defects and Functional Studiesmentioning

confidence: 99%

Genetic defects of thiamine transport and metabolism: A review of clinical phenotypes, genetics, and functional studies

Marcé‐Grau

Martí-Sánchez

Baide‐Mairena

et al. 2019

J of Inher Metab Disea

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“…9 It may explain why individuals harboring SLC19A3 gene mutations develop neurological symptoms and pathology, without having a systemic thiamine deficiency. 10 Furthermore, the effect of thiamine and thiamine diphosphate on a poorlymyelinated developing brain is very different form the clinical picture of thiamine deficiency in the mature brain. Glutamate excitotoxicity has been proposed as a major cause of thiamine deficiency-related neurodegeneration but selective neuronal vulnerability may occur in different stages of the brain maturation.…”

Section: Introductionmentioning

confidence: 99%

Biotin-Thiamine Responsive Encephalopathy: Report of an Egyptian Family with a Novel SLC19A3 Mutation and Review of the Literature

et al. 2018

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Biotin-thiamine responsive basal ganglia disease (BTRBGD) is an autosomal recessive neurometabolic disorder with poor genotype-phenotype correlation, caused by mutations in the SLC19A3 gene on chromosome 2q36.6. The disease is characterized by three stages: stage 1 is a sub-acute encephalopathy often triggered by febrile illness; stage 2 is an acute encephalopathy with seizures, loss of motor function, developmental regression, dystonia, external ophthalmoplegia, dysphagia, and dysarthria; stage 3 is represented by chronic or slowly progressive encephalopathy. Clinical and biochemical findings, as well as the magnetic resonance imaging (MRI) pattern, resemble those of Leigh's syndrome, so that BTRBGD can be misdiagnosed as a mitochondrial encephalopathy.Here we report the clinical and radiological phenotypes of two siblings diagnosed with BTRBGD in which a novel SLC19A3 mutation (NM_025243.3: c.548C > T; p.Ala183Val) was found by whole exome sequencing (WES) of the family members.

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“…Numerous homozygous as well as compound heterozygous variants have been reported before in different regions of SLC19A3 in human patients suffering from thiamine metabolism dysfunction syndrome-2 [ 19 ]. SLC19A3 is a member of solute carrier family 19 and encodes thiamine transporter 2.…”

Section: Discussionmentioning

confidence: 99%

SLC19A3 Loss-of-Function Variant in Yorkshire Terriers with Leigh-Like Subacute Necrotizing Encephalopathy

Drögemüller

Letko

Matiasek

et al. 2020

Genes

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Sporadic occurrence of juvenile-onset necrotizing encephalopathy (SNE) has been previously reported in Yorkshire terriers. However, so far, no causative genetic variant has been found for this breed-specific form of suspected mitochondrial encephalomyopathy. Affected dogs showed gait abnormalities, central visual defects, and/or seizures. Histopathological analysis revealed the presence of major characteristics of human Leigh syndrome and SNE in Alaskan huskies. The aim of this study was to characterize the genetic etiology of SNE-affected purebred Yorkshire terriers. After SNP genotyping and subsequent homozygosity mapping, we identified a single loss-of-function variant by whole-genome sequencing in the canine SLC19A3 gene situated in a 1.7 Mb region of homozygosity on chromosome 25. All ten cases were homozygous carriers of a mutant allele, an indel variant in exon 2, that is predicted to lead to a frameshift and to truncate about 86% of the wild type coding sequence. This study reports a most likely pathogenic variant in SLC19A3 causing a form of SNE in Yorkshire terriers and enables selection against this fatal neurodegenerative recessive disorder. This is the second report of a pathogenic alteration of the SLC19A3 gene in dogs with SNE.

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Compound heterozygous SLC19A3 mutations further refine the critical promoter region for biotin-thiamine-responsive basal ganglia disease

Cited by 19 publications

References 61 publications

Genetic defects of thiamine transport and metabolism: A review of clinical phenotypes, genetics, and functional studies

Genetic defects of thiamine transport and metabolism: A review of clinical phenotypes, genetics, and functional studies

Biotin-Thiamine Responsive Encephalopathy: Report of an Egyptian Family with a Novel SLC19A3 Mutation and Review of the Literature

SLC19A3 Loss-of-Function Variant in Yorkshire Terriers with Leigh-Like Subacute Necrotizing Encephalopathy

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