UNASSIGNED: Biotin-thiamine-responsive basal ganglia disease (BTBGD) is a rare, autosomal recessive neurometabolic disorder caused by mutations in the SLC19A3 gene and characterized by recurrent sub-acute episodes of encephalopathy. Patients with BTBGD have classical neuroimaging findings and a dramatic response to high doses of thiamine.
UNASSIGNED: To highlight the advantages of administering a higher dose of thiamine for patients with BTBGD who have not shown improvement with the standard recommended dosage.
UNASSIGNED: Herein, we report on two Saudi girls with classical clinical and radiological findings of BTBGD. Hallmark symptoms in these patients included an acute onset of ataxia, tremor, slurred speech, dystonia, and dysphagia. The initial routine laboratory workups were unremarkable. Brain magnetic resonance imaging revealed extensive hyperintense signals in the bilateral basal ganglia, which suggested the diagnosis of a BTBGD. Hence started empirically on biotin 10 mg/kg/day and thiamine 40 mg/kg/day, but there was no noticeable improvement. After increasing the thiamine to 75 mg/kg/day the patients started to improve significantly. Genetic testing was requested and came positive for the mutation of the SLC19A3 gene. After two months of initiating the management, thiamine was reduced to 30 mg/kg/day. Subsequent follow-ups showed complete improvement in their condition with no apparent long-term sequel or relapse.
UNASSIGNED: we conclude that administration of thiamine at a dosage of up to 40 mg/kg/day may not be sufficient in treating certain patients with BTBGD. Thus, considering a significantly higher dosage could potentially contribute to achieving remission.

UNASSIGNED: The occurrence of thiamine metabolism dysfunction syndrome (THMD), a rare autosomal recessive condition, may be linked to various mutations found in the TPK1 and SLC19A3 genes. The disease chiefly manifests through ataxia, muscle hypotonia, abrupt or subacute onset encephalopathy, and a decline in developmental milestones achieved during the early stages of infancy. We present findings from an investigation that involved two individuals from Iran, both of whom experienced seizures along with ataxia and hypotonia. The underlying genetic causes were found with the use of next-generation sequencing (NGS) technology, which has facilitated the detection of causal changes in a variety of genetic disorders.
UNASSIGNED: The selection of cases for this study was based on the phenotypic and genetic information that was obtainable from the Center for Comprehensive Genetic Services. The genetic basis for the problems observed among the participants was determined through the application of whole-exome sequencing (WES). Subsequently, sanger sequencing was employed as a means of validating any identified variations suspected to be causative.
UNASSIGNED: The first patient exhibited a homozygous mutation in the TPK1 gene, NM_022445.4:c.224 T > A:p.I75 N, resulting in the substitution of isoleucine for asparagine at position 75 (p.I75 N). In our investigation, patient 2 exhibited a homozygous variant, NM_025243.4:c.1385dupA:pY462X, within the SLC19A3 gene.
UNASSIGNED: Collectively, when presented with patients showcasing ataxia, encephalopathy, and basal ganglia necrosis, it is essential to account for thiamine deficiency in light of the potential advantages of prompt intervention. At times, it may be feasible to rectify this deficiency through the timely administration of thiamine dosages. Accordingly, based on the results of the current investigation, these variations may be useful for the diagnosis and management of patients with THMD.

Biotin-thiamine-responsive basal ganglia disease (BTBGD) is a rare, inherited neurometabolic disorder caused by mutations in the SLC19A3 gene and characterized by recurrent sub-acute episodes of encephalopathy that are often triggered by infections. Patients with BTBGD have classical neuroimaging findings and a dramatic response to high doses of thiamine. Herein, we report a 2 and a half-year-old Saudi girl presented with an acute onset of ataxia, slurred speech, and dysphagia, which was preceded by a history of accidental ingestion of around 20 mL of ethyl alcohol that is used in formulating perfumes 1 day earlier. Her older brother had a similar clinical presentation and was diagnosed with BTBGD. The patient was fully alert and spoke in full sentences with dysarthria. She was unable to walk unassisted. Investigation revealed a positive toxicity test for ethyl alcohol (10 mg/dL), and brain magnetic resonance imaging showed basal ganglia changes consistent with BTBGD. The dramatic response to high doses of thiamine suggested SLC19A3 as a strong candidate gene, and Sanger sequencing revealed a homozygous (NM_025243.4): c.1264A>G (p.Thr422Ala) mutation. Patients with BTBGD should be cautious and aware of ethyl alcohol products, which can lead to a BTBGD crisis. The administration of a high dose of thiamin may be required in patients who have not responded to the recommended dose. Further clinical research is required to determine the optimal doses.

Biotin-thiamine-responsive basal ganglia disease (BTBGD) is a rare autosomal recessive neurometabolic disorder that is caused by biallelic pathogenic SLC19A3 variants and is characterized by subacute encephalopathy associated with confusion, convulsions, dysphagia, dysarthria, or other neurological manifestations.
A retrospective review of the data registry in Kuwait Medical Genetics Center for all cases diagnosed clinically and radiographically and confirmed genetically with BTBGD.
Twenty one cases from 13 different families were diagnosed with BTBGD in Kuwait. Most cases (86%) presented with confusion, dystonia, convulsions, or dysarthria, while three individuals were diagnosed pre-symptomatically during familial targeted genetic screening. Symptoms resolved completely within 2-week of treatment in two-thirds of the symptomatic cases but progressed in six of them to a variety of severe symptoms including severe cogwheel rigidity, dystonia and quadriparesis due to delayed presentation and management. Neuroradiological findings of the symptomatic cases revealed bilateral central changes in the basal ganglia. Two novel homozygous missense SLC19A3 variants were detected in a Kuwaiti and a Jordanian individuals, in addition to the previously reported Saudi founder homozygous variant, c.1264A > G; p.(Thr422Ala) in the remaining cases. Age of diagnosis ranged from newborn to 32 years, with a median age of 2-3 years. All cases are still alive receiving high doses of biotin and thiamine.
This is the first study reporting the phenotypic and genotypic spectrum of 21 individuals with BTBGD in Kuwait and describing two novel SLC19A3 variants. BTBGD is a treatable neurometabolic disease that requires early recognition and treatment initiation. This study highlights the importance of performing targeted molecular testing of the founder variant in patients presenting with acute encephalopathy in the region.

BACKGROUND: Biotin-thiamine-responsive basal ganglia disease (BTBGD) is a treatable neurometabolic disease caused by variants in SLC19A3. Typical imaging features include symmetrical involvement of the caudate nuclei and putamina.
OBJECTIVE: The study sought to explore classical BTBGD without caudate nucleus involvement, to highlight the importance of recognizing this new pattern early in the disease.
METHODS: Individuals with genetically confirmed BTBGD who harbored the same homozygous variant: NM_025243.4 (SLC19A3): c.1264A > G (p.Thr422Ala) and had atypical neuroimaging were recruited.
RESULTS: Nine patients with BTBGD had atypical neuroimaging findings on the first MRI scan. The median age at symptom onset was 3 years. All patients presented with classical clinical features of subacute encephalopathy, dystonia, ataxia, and seizures. During the acute crisis, MRI revealed bilateral and symmetric involvement of the putamina in all patients; one showed small caudate nuclei involvement. In addition, the thalami, cerebellum, and brain stem were involved in six patients, seven patients, and three patients, respectively. Treatment included a combination of high doses of thiamine and biotin. One patient died; he did not receive any vitamin supplementation. Two patients who were treated late had severe neurological sequelae, including generalized dystonia and quadriplegia. Six patients treated early had good outcomes with minimal sequelae, including mild dystonia and dysarthria. Two patients showed the classical chronic atrophic and necrotic changes already described.
CONCLUSIONS: The early atypical neuroimaging pattern of BTBGD described here, particularly the lack of caudate nucleus involvement, should not dissuade the clinician and radiologist from considering a diagnosis of BTBGD.

Recent studies have shown that human solute carrier SLC19A3 (hSLC19A3) can transport pyridoxine (vitamin B6) in addition to thiamine (vitamin B1), its originally identified substrate, whereas rat and mouse orthologs of hSLC19A3 can transport thiamine but not pyridoxine. This finding implies that some amino acid residues required for pyridoxine transport, but not for thiamine transport, are specific to hSLC19A3. Here, we sought to identify these residues to help clarify the unique operational mechanism of SLC19A3 through analyses comparing hSLC19A3 and mouse Slc19a3 (mSlc19a3). For our analyses, hSLC19A3 mutants were prepared by replacing selected amino acid residues with their counterparts in mSlc19a3, and mSlc19a3 mutants were prepared by substituting selected residues with their hSLC19A3 counterparts. We assessed pyridoxine and thiamine transport by these mutants in transiently transfected human embryonic kidney 293 cells. Our analyses indicated that the hSLC19A3-specific amino acid residues of Gln86, Gly87, Ile91, Thr93, Trp94, Ser168, and Asn173 are critical for pyridoxine transport. These seven amino acid residues were found to be mostly conserved in the SLC19A3 orthologs that can transport pyridoxine but not in orthologs that are unable to transport pyridoxine. In addition, these residues were also found to be conserved in several SLC19A2 orthologs, including rat, mouse, and human orthologs, which were all found to effectively transport both pyridoxine and thiamine, exhibiting no species-dependent differences. Together, these findings provide a molecular basis for the unique functional characteristics of SLC19A3 and also of SLC19A2.

The thiamine transporters, SLC19A2 and SLC19A3, have recently been shown to transport pyridoxine in addition to thiamine, the originally identified substrate, in our study on human orthologs. Based on these results, we characterized the rat and mouse orthologs for pyridoxine transport function. Through the assessment of pyridoxine uptake in human embryonic kidney 293 cells transiently expressing the SLC19A2/3 orthologs, we found that both rat and mouse Slc19a2 can transport pyridoxine, but rat or mouse Slc19a3 cannot. However, all SLC19A2/3 orthologs were capable of thiamine transport. We subsequently demonstrated in the rat small intestine that a carrier-mediated mechanism exists for thiamine uptake, but not for pyridoxine uptake. This is supported by the finding that rat Slc19a3, for which the human ortholog operates for the intestinal uptake of both pyridoxine and thiamine, lacks the pyridoxine transport function. Thus, SLC19A3s from different animal species exhibit differences in pyridoxine transport. Rats and mice, in which Slc19a3 lacks this function, are not suitable model animals for studies involving pyridoxine disposition and related issues.

OBJECTIVE: Adipose tissue is a specialized endocrine organ that is involved in modulating whole-body energy homeostasis and expresses a specific subset of genes, which may play a role in adipose tissue metabolism. The aim of this study was to search for novel adipose tissue-specific genes using a tissue panel of RNAseq expression profiles.
METHODS: RNAseq expression profiles from 53 human tissues were downloaded from the GTex database. SLC19A3 expression was analyzed by microarray or real-time PCR in two sets of paired subcutaneous and omental adipose tissue samples, in two studies with adipose tissue from persons with high or low body mass index (BMI), in adipose tissue from patients who underwent weight loss with a very-low caloric diet and during preadipocyte-adipocyte differentiation.
RESULTS: The RNAseq-based tissue distribution expression screen identified SLC19A3 (encoding the thiamine transporter 2) as adipose tissue-specific. SLC19A3 expression was higher in subcutaneous compared with omental adipose tissue in both sample sets (p = 0.043 and p < 0.001). Preadipocyte differentiation towards adipocytes resulted in increased SLC19A3 gene expression (p = 0.018 or less at all-time points). Subcutaneous adipose tissue expression of SLC19A3 was lower in persons with high BMI in both cohorts (p = 0.008, and p < 0.001) and increased during a weight-loss intervention (p = 0.006).
CONCLUSIONS: The specific adipose tissue expression pattern of SLC19A3, together with its regulation in obesity and during weight loss, indicate that it plays a key role in adipocyte metabolism.

Patients with Leigh syndrome (LS) sometimes develop epileptic spasms (ES). ACTH treatment for ES may be effective without serious adverse events in some patients with LS. Status dystonicus is a life-threatening disorder characterized by an acute exacerbation of generalized dystonia and often develops as a triggered event. The underlying pathophysiology of status dystonicus remains unclear. To our knowledge, there has been no reported case of status dystonicus associated with ACTH treatment. Here, we describe the first reported patient with LS, harbouring compound heterozygous mutations in SLC19A3 gene, who developed status dystonicus following initial intramuscular injection of a course of ACTH treatment for ES. Stressors can precipitate acute exacerbation in SLC19A3-related disorders. Interestingly, in this patient, external discomfort stimuli tended to induce transient hypertonia with opisthotonos. This report suggests that attention should be paid to acute exacerbation of generalized dystonia when ACTH treatment for ES is started in patients with LS, who have dystonia tend to exacerbate transiently by external discomfort stimuli.

UNASSIGNED: Biotin-thiamine-responsive basal ganglia disease (BTBGD) is an autosomal recessive neurometabolic disorder associated with pathogenic variants in SLC19A3 gene. The clinical picture includes symptoms of subacute encephalopathy (e.g. confusion, dysphagia, dysarthria, and seizures), which respond very well to early treatment with thiamine and biotin.
UNASSIGNED: A retrospective review of clinical characteristics, magnetic resonance imaging and molecular findings in 3 patients with BTBGD.
UNASSIGNED: The first symptoms in all patients occurred at 12-24 months of age and they had subacute encephalopathy, ataxia and dystonia. The baseline magnetic resonance imaging demonstrated abnormal signal intensity in the basal ganglia with atrophy and necrosis of the basal ganglia during follow-up in two patients. One patient was diagnosed and the treatment was initiated after a long period from symptoms onset and he is currently severely affected, with dystonia, quadriparesis and seizures. The other two patients were diagnosed early in life and are currently stable on treatment, without the clinical symptoms. Genetic testing demonstrated pathogenic variants in SLC19A3 gene.
UNASSIGNED: To avoid diagnostic errors and delayed or incorrect treatment, BTBGD must be recognized early. Adequate prompt treatment gives the chance of significant clinical improvement. Unexplained encephalopathy and MRI abnormalities including bilateral abnormal signal in the basal ganglia should alert the clinician to consider BTBGD in the differential, and the treatment with biotin and thiamine should be introduced immediately.