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Rafael Artuch - One of the best experts on this subject based on the ideXlab platform.
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op6 2631 decreased free thiamine in cerebro spinal fluid and fibroblasts is a sensitive marker of thiamine transporter 2 deficiency in leigh syndrome patients
European Journal of Paediatric Neurology, 2015Co-Authors: J Ortigoza D Escobar, Mercedes Casado, J A Mayr, Alfonso Ribes, Angela Arias, Mercedes Serrano, Mireia Tondo, Niklas Darin, Marta Moleroluis, Rafael ArtuchAbstract:Objectives Thiamine transporter-2 (hTHTR2) deficiency due to SLC19A3 mutations is a potentially reversible cause of Leigh syndrome for which no biochemical markers are currently available. Our aim was to assess the sensitivity of thiamine quantification in cerebrospinal fluid (CSF) and fibroblasts from patients with Leigh encephalopathy and SLC19A3 defects as compared with other causes of Leigh syndrome. Methods Thiamine vitamers (free-thiamine, thiamine monophosphate (TMP) and thiamine diphosphate (TDP)) were analyzed by HPLC-fluorescence detection in whole-blood and cerebrospinal fluid (CSF) samples from 106 and 38 paediatric controls, respectively. Results were compared with patients with Leigh syndrome due to SLC19A3 defects (N=6) and mitochondrial respiratory chain defects (N=9). In all but one SLC19A3 patient, samples were collected before thiamine supplementation. Thiamine vitamers were also analyzed by HPLC in fibroblasts from SLC19A3 patients (N=3) and patients with other metabolic defects (N=6). Results A negative correlation between thiamine isoforms and age was detected in whole-blood and CSF, thus three reference intervals were established for free-thiamine and two intervals for TMP and TDP. Free-thiamine was severely reduced in five non-treated SLC19A3 patients CSF, but not TMP and TPP. The SLC19A3 patient under thiamine supplementation showed thiamine values above reference range. Nine Leigh patients with mitochondrial defects showed normal o slightly reduced values for CSF thiamine. In SLC19A3 patient's fibroblasts, a reduction in free-thiamine was detected as compared with control sample. These values normalized after thiamine was added to the culture medium. Conclusion SLC19A3 patients show a profound deficiency of free-thiamine in the CSF that allows their identification from other causes of Leigh syndrome. SLC19A3 is essential to maintain CSF thiamine homeostasis and to prevent brain damage. Thiamine overload can supply the SLC19A3 defect and restore thiamine values in fibroblasts and CSF, probably by an alternative transport system.
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OP6 – 2631: Decreased free-thiamine in cerebro spinal fluid and fibroblasts is a sensitive marker of thiamine transporter 2 deficiency in Leigh syndrome patients
European Journal of Paediatric Neurology, 2015Co-Authors: J.d. Ortigoza Escobar, Marta Molero-luis, Mercedes Casado, J A Mayr, Alfonso Ribes, Angela Arias, Mercedes Serrano, Mireia Tondo, Niklas Darin, Rafael ArtuchAbstract:Objectives Thiamine transporter-2 (hTHTR2) deficiency due to SLC19A3 mutations is a potentially reversible cause of Leigh syndrome for which no biochemical markers are currently available. Our aim was to assess the sensitivity of thiamine quantification in cerebrospinal fluid (CSF) and fibroblasts from patients with Leigh encephalopathy and SLC19A3 defects as compared with other causes of Leigh syndrome. Methods Thiamine vitamers (free-thiamine, thiamine monophosphate (TMP) and thiamine diphosphate (TDP)) were analyzed by HPLC-fluorescence detection in whole-blood and cerebrospinal fluid (CSF) samples from 106 and 38 paediatric controls, respectively. Results were compared with patients with Leigh syndrome due to SLC19A3 defects (N=6) and mitochondrial respiratory chain defects (N=9). In all but one SLC19A3 patient, samples were collected before thiamine supplementation. Thiamine vitamers were also analyzed by HPLC in fibroblasts from SLC19A3 patients (N=3) and patients with other metabolic defects (N=6). Results A negative correlation between thiamine isoforms and age was detected in whole-blood and CSF, thus three reference intervals were established for free-thiamine and two intervals for TMP and TDP. Free-thiamine was severely reduced in five non-treated SLC19A3 patients CSF, but not TMP and TPP. The SLC19A3 patient under thiamine supplementation showed thiamine values above reference range. Nine Leigh patients with mitochondrial defects showed normal o slightly reduced values for CSF thiamine. In SLC19A3 patient's fibroblasts, a reduction in free-thiamine was detected as compared with control sample. These values normalized after thiamine was added to the culture medium. Conclusion SLC19A3 patients show a profound deficiency of free-thiamine in the CSF that allows their identification from other causes of Leigh syndrome. SLC19A3 is essential to maintain CSF thiamine homeostasis and to prevent brain damage. Thiamine overload can supply the SLC19A3 defect and restore thiamine values in fibroblasts and CSF, probably by an alternative transport system.
Niklas Darin - One of the best experts on this subject based on the ideXlab platform.
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free thiamine is a potential biomarker of thiamine transporter 2 deficiency a treatable cause of leigh syndrome
Brain, 2016Co-Authors: Juan Dario Ortigozaescobar, Angela Arias, Mercedes Serrano, Angels Garciacazorla, Mireia Tondo, Alfonso Oyarzabal, M V Hernandez, Niklas Darin, Marta Moleroluis, Judit GarciavilloriaAbstract:Thiamine transporter-2 deficiency is caused by mutations in the SLC19A3 gene. As opposed to other causes of Leigh syndrome, early administration of thiamine and biotin has a dramatic and immediate clinical effect. New biochemical markers are needed to aid in early diagnosis and timely therapeutic intervention. Thiamine derivatives were analysed by high performance liquid chromatography in 106 whole blood and 38 cerebrospinal fluid samples from paediatric controls, 16 cerebrospinal fluid samples from patients with Leigh syndrome, six of whom harboured mutations in the SLC19A3 gene, and 49 patients with other neurological disorders. Free-thiamine was remarkably reduced in the cerebrospinal fluid of five SLC19A3 patients before treatment. In contrast, free-thiamine was slightly decreased in 15.2% of patients with other neurological conditions, and above the reference range in one SLC19A3 patient on thiamine supplementation. We also observed a severe deficiency of free-thiamine and low levels of thiamine diphosphate in fibroblasts from SLC19A3 patients. Surprisingly, pyruvate dehydrogenase activity and mitochondrial substrate oxidation rates were within the control range. Thiamine derivatives normalized after the addition of thiamine to the culture medium. In conclusion, we found a profound deficiency of free-thiamine in the CSF and fibroblasts of patients with thiamine transporter-2 deficiency. Thiamine supplementation led to clinical improvement in patients early treated and restored thiamine values in fibroblasts and cerebrospinal fluid. * Abbreviations : free-T : free-thiamine TMP : thiamine monophosphate TDP : thiamine diphosphate TPK : thiamine pyrophosphokinase hTHTR2 : thiamine transporter-2
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op6 2631 decreased free thiamine in cerebro spinal fluid and fibroblasts is a sensitive marker of thiamine transporter 2 deficiency in leigh syndrome patients
European Journal of Paediatric Neurology, 2015Co-Authors: J Ortigoza D Escobar, Mercedes Casado, J A Mayr, Alfonso Ribes, Angela Arias, Mercedes Serrano, Mireia Tondo, Niklas Darin, Marta Moleroluis, Rafael ArtuchAbstract:Objectives Thiamine transporter-2 (hTHTR2) deficiency due to SLC19A3 mutations is a potentially reversible cause of Leigh syndrome for which no biochemical markers are currently available. Our aim was to assess the sensitivity of thiamine quantification in cerebrospinal fluid (CSF) and fibroblasts from patients with Leigh encephalopathy and SLC19A3 defects as compared with other causes of Leigh syndrome. Methods Thiamine vitamers (free-thiamine, thiamine monophosphate (TMP) and thiamine diphosphate (TDP)) were analyzed by HPLC-fluorescence detection in whole-blood and cerebrospinal fluid (CSF) samples from 106 and 38 paediatric controls, respectively. Results were compared with patients with Leigh syndrome due to SLC19A3 defects (N=6) and mitochondrial respiratory chain defects (N=9). In all but one SLC19A3 patient, samples were collected before thiamine supplementation. Thiamine vitamers were also analyzed by HPLC in fibroblasts from SLC19A3 patients (N=3) and patients with other metabolic defects (N=6). Results A negative correlation between thiamine isoforms and age was detected in whole-blood and CSF, thus three reference intervals were established for free-thiamine and two intervals for TMP and TDP. Free-thiamine was severely reduced in five non-treated SLC19A3 patients CSF, but not TMP and TPP. The SLC19A3 patient under thiamine supplementation showed thiamine values above reference range. Nine Leigh patients with mitochondrial defects showed normal o slightly reduced values for CSF thiamine. In SLC19A3 patient's fibroblasts, a reduction in free-thiamine was detected as compared with control sample. These values normalized after thiamine was added to the culture medium. Conclusion SLC19A3 patients show a profound deficiency of free-thiamine in the CSF that allows their identification from other causes of Leigh syndrome. SLC19A3 is essential to maintain CSF thiamine homeostasis and to prevent brain damage. Thiamine overload can supply the SLC19A3 defect and restore thiamine values in fibroblasts and CSF, probably by an alternative transport system.
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OP6 – 2631: Decreased free-thiamine in cerebro spinal fluid and fibroblasts is a sensitive marker of thiamine transporter 2 deficiency in Leigh syndrome patients
European Journal of Paediatric Neurology, 2015Co-Authors: J.d. Ortigoza Escobar, Marta Molero-luis, Mercedes Casado, J A Mayr, Alfonso Ribes, Angela Arias, Mercedes Serrano, Mireia Tondo, Niklas Darin, Rafael ArtuchAbstract:Objectives Thiamine transporter-2 (hTHTR2) deficiency due to SLC19A3 mutations is a potentially reversible cause of Leigh syndrome for which no biochemical markers are currently available. Our aim was to assess the sensitivity of thiamine quantification in cerebrospinal fluid (CSF) and fibroblasts from patients with Leigh encephalopathy and SLC19A3 defects as compared with other causes of Leigh syndrome. Methods Thiamine vitamers (free-thiamine, thiamine monophosphate (TMP) and thiamine diphosphate (TDP)) were analyzed by HPLC-fluorescence detection in whole-blood and cerebrospinal fluid (CSF) samples from 106 and 38 paediatric controls, respectively. Results were compared with patients with Leigh syndrome due to SLC19A3 defects (N=6) and mitochondrial respiratory chain defects (N=9). In all but one SLC19A3 patient, samples were collected before thiamine supplementation. Thiamine vitamers were also analyzed by HPLC in fibroblasts from SLC19A3 patients (N=3) and patients with other metabolic defects (N=6). Results A negative correlation between thiamine isoforms and age was detected in whole-blood and CSF, thus three reference intervals were established for free-thiamine and two intervals for TMP and TDP. Free-thiamine was severely reduced in five non-treated SLC19A3 patients CSF, but not TMP and TPP. The SLC19A3 patient under thiamine supplementation showed thiamine values above reference range. Nine Leigh patients with mitochondrial defects showed normal o slightly reduced values for CSF thiamine. In SLC19A3 patient's fibroblasts, a reduction in free-thiamine was detected as compared with control sample. These values normalized after thiamine was added to the culture medium. Conclusion SLC19A3 patients show a profound deficiency of free-thiamine in the CSF that allows their identification from other causes of Leigh syndrome. SLC19A3 is essential to maintain CSF thiamine homeostasis and to prevent brain damage. Thiamine overload can supply the SLC19A3 defect and restore thiamine values in fibroblasts and CSF, probably by an alternative transport system.
Angela Arias - One of the best experts on this subject based on the ideXlab platform.
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free thiamine is a potential biomarker of thiamine transporter 2 deficiency a treatable cause of leigh syndrome
Brain, 2016Co-Authors: Juan Dario Ortigozaescobar, Angela Arias, Mercedes Serrano, Angels Garciacazorla, Mireia Tondo, Alfonso Oyarzabal, M V Hernandez, Niklas Darin, Marta Moleroluis, Judit GarciavilloriaAbstract:Thiamine transporter-2 deficiency is caused by mutations in the SLC19A3 gene. As opposed to other causes of Leigh syndrome, early administration of thiamine and biotin has a dramatic and immediate clinical effect. New biochemical markers are needed to aid in early diagnosis and timely therapeutic intervention. Thiamine derivatives were analysed by high performance liquid chromatography in 106 whole blood and 38 cerebrospinal fluid samples from paediatric controls, 16 cerebrospinal fluid samples from patients with Leigh syndrome, six of whom harboured mutations in the SLC19A3 gene, and 49 patients with other neurological disorders. Free-thiamine was remarkably reduced in the cerebrospinal fluid of five SLC19A3 patients before treatment. In contrast, free-thiamine was slightly decreased in 15.2% of patients with other neurological conditions, and above the reference range in one SLC19A3 patient on thiamine supplementation. We also observed a severe deficiency of free-thiamine and low levels of thiamine diphosphate in fibroblasts from SLC19A3 patients. Surprisingly, pyruvate dehydrogenase activity and mitochondrial substrate oxidation rates were within the control range. Thiamine derivatives normalized after the addition of thiamine to the culture medium. In conclusion, we found a profound deficiency of free-thiamine in the CSF and fibroblasts of patients with thiamine transporter-2 deficiency. Thiamine supplementation led to clinical improvement in patients early treated and restored thiamine values in fibroblasts and cerebrospinal fluid. * Abbreviations : free-T : free-thiamine TMP : thiamine monophosphate TDP : thiamine diphosphate TPK : thiamine pyrophosphokinase hTHTR2 : thiamine transporter-2
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op6 2631 decreased free thiamine in cerebro spinal fluid and fibroblasts is a sensitive marker of thiamine transporter 2 deficiency in leigh syndrome patients
European Journal of Paediatric Neurology, 2015Co-Authors: J Ortigoza D Escobar, Mercedes Casado, J A Mayr, Alfonso Ribes, Angela Arias, Mercedes Serrano, Mireia Tondo, Niklas Darin, Marta Moleroluis, Rafael ArtuchAbstract:Objectives Thiamine transporter-2 (hTHTR2) deficiency due to SLC19A3 mutations is a potentially reversible cause of Leigh syndrome for which no biochemical markers are currently available. Our aim was to assess the sensitivity of thiamine quantification in cerebrospinal fluid (CSF) and fibroblasts from patients with Leigh encephalopathy and SLC19A3 defects as compared with other causes of Leigh syndrome. Methods Thiamine vitamers (free-thiamine, thiamine monophosphate (TMP) and thiamine diphosphate (TDP)) were analyzed by HPLC-fluorescence detection in whole-blood and cerebrospinal fluid (CSF) samples from 106 and 38 paediatric controls, respectively. Results were compared with patients with Leigh syndrome due to SLC19A3 defects (N=6) and mitochondrial respiratory chain defects (N=9). In all but one SLC19A3 patient, samples were collected before thiamine supplementation. Thiamine vitamers were also analyzed by HPLC in fibroblasts from SLC19A3 patients (N=3) and patients with other metabolic defects (N=6). Results A negative correlation between thiamine isoforms and age was detected in whole-blood and CSF, thus three reference intervals were established for free-thiamine and two intervals for TMP and TDP. Free-thiamine was severely reduced in five non-treated SLC19A3 patients CSF, but not TMP and TPP. The SLC19A3 patient under thiamine supplementation showed thiamine values above reference range. Nine Leigh patients with mitochondrial defects showed normal o slightly reduced values for CSF thiamine. In SLC19A3 patient's fibroblasts, a reduction in free-thiamine was detected as compared with control sample. These values normalized after thiamine was added to the culture medium. Conclusion SLC19A3 patients show a profound deficiency of free-thiamine in the CSF that allows their identification from other causes of Leigh syndrome. SLC19A3 is essential to maintain CSF thiamine homeostasis and to prevent brain damage. Thiamine overload can supply the SLC19A3 defect and restore thiamine values in fibroblasts and CSF, probably by an alternative transport system.
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OP6 – 2631: Decreased free-thiamine in cerebro spinal fluid and fibroblasts is a sensitive marker of thiamine transporter 2 deficiency in Leigh syndrome patients
European Journal of Paediatric Neurology, 2015Co-Authors: J.d. Ortigoza Escobar, Marta Molero-luis, Mercedes Casado, J A Mayr, Alfonso Ribes, Angela Arias, Mercedes Serrano, Mireia Tondo, Niklas Darin, Rafael ArtuchAbstract:Objectives Thiamine transporter-2 (hTHTR2) deficiency due to SLC19A3 mutations is a potentially reversible cause of Leigh syndrome for which no biochemical markers are currently available. Our aim was to assess the sensitivity of thiamine quantification in cerebrospinal fluid (CSF) and fibroblasts from patients with Leigh encephalopathy and SLC19A3 defects as compared with other causes of Leigh syndrome. Methods Thiamine vitamers (free-thiamine, thiamine monophosphate (TMP) and thiamine diphosphate (TDP)) were analyzed by HPLC-fluorescence detection in whole-blood and cerebrospinal fluid (CSF) samples from 106 and 38 paediatric controls, respectively. Results were compared with patients with Leigh syndrome due to SLC19A3 defects (N=6) and mitochondrial respiratory chain defects (N=9). In all but one SLC19A3 patient, samples were collected before thiamine supplementation. Thiamine vitamers were also analyzed by HPLC in fibroblasts from SLC19A3 patients (N=3) and patients with other metabolic defects (N=6). Results A negative correlation between thiamine isoforms and age was detected in whole-blood and CSF, thus three reference intervals were established for free-thiamine and two intervals for TMP and TDP. Free-thiamine was severely reduced in five non-treated SLC19A3 patients CSF, but not TMP and TPP. The SLC19A3 patient under thiamine supplementation showed thiamine values above reference range. Nine Leigh patients with mitochondrial defects showed normal o slightly reduced values for CSF thiamine. In SLC19A3 patient's fibroblasts, a reduction in free-thiamine was detected as compared with control sample. These values normalized after thiamine was added to the culture medium. Conclusion SLC19A3 patients show a profound deficiency of free-thiamine in the CSF that allows their identification from other causes of Leigh syndrome. SLC19A3 is essential to maintain CSF thiamine homeostasis and to prevent brain damage. Thiamine overload can supply the SLC19A3 defect and restore thiamine values in fibroblasts and CSF, probably by an alternative transport system.
Mireia Tondo - One of the best experts on this subject based on the ideXlab platform.
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free thiamine is a potential biomarker of thiamine transporter 2 deficiency a treatable cause of leigh syndrome
Brain, 2016Co-Authors: Juan Dario Ortigozaescobar, Angela Arias, Mercedes Serrano, Angels Garciacazorla, Mireia Tondo, Alfonso Oyarzabal, M V Hernandez, Niklas Darin, Marta Moleroluis, Judit GarciavilloriaAbstract:Thiamine transporter-2 deficiency is caused by mutations in the SLC19A3 gene. As opposed to other causes of Leigh syndrome, early administration of thiamine and biotin has a dramatic and immediate clinical effect. New biochemical markers are needed to aid in early diagnosis and timely therapeutic intervention. Thiamine derivatives were analysed by high performance liquid chromatography in 106 whole blood and 38 cerebrospinal fluid samples from paediatric controls, 16 cerebrospinal fluid samples from patients with Leigh syndrome, six of whom harboured mutations in the SLC19A3 gene, and 49 patients with other neurological disorders. Free-thiamine was remarkably reduced in the cerebrospinal fluid of five SLC19A3 patients before treatment. In contrast, free-thiamine was slightly decreased in 15.2% of patients with other neurological conditions, and above the reference range in one SLC19A3 patient on thiamine supplementation. We also observed a severe deficiency of free-thiamine and low levels of thiamine diphosphate in fibroblasts from SLC19A3 patients. Surprisingly, pyruvate dehydrogenase activity and mitochondrial substrate oxidation rates were within the control range. Thiamine derivatives normalized after the addition of thiamine to the culture medium. In conclusion, we found a profound deficiency of free-thiamine in the CSF and fibroblasts of patients with thiamine transporter-2 deficiency. Thiamine supplementation led to clinical improvement in patients early treated and restored thiamine values in fibroblasts and cerebrospinal fluid. * Abbreviations : free-T : free-thiamine TMP : thiamine monophosphate TDP : thiamine diphosphate TPK : thiamine pyrophosphokinase hTHTR2 : thiamine transporter-2
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op6 2631 decreased free thiamine in cerebro spinal fluid and fibroblasts is a sensitive marker of thiamine transporter 2 deficiency in leigh syndrome patients
European Journal of Paediatric Neurology, 2015Co-Authors: J Ortigoza D Escobar, Mercedes Casado, J A Mayr, Alfonso Ribes, Angela Arias, Mercedes Serrano, Mireia Tondo, Niklas Darin, Marta Moleroluis, Rafael ArtuchAbstract:Objectives Thiamine transporter-2 (hTHTR2) deficiency due to SLC19A3 mutations is a potentially reversible cause of Leigh syndrome for which no biochemical markers are currently available. Our aim was to assess the sensitivity of thiamine quantification in cerebrospinal fluid (CSF) and fibroblasts from patients with Leigh encephalopathy and SLC19A3 defects as compared with other causes of Leigh syndrome. Methods Thiamine vitamers (free-thiamine, thiamine monophosphate (TMP) and thiamine diphosphate (TDP)) were analyzed by HPLC-fluorescence detection in whole-blood and cerebrospinal fluid (CSF) samples from 106 and 38 paediatric controls, respectively. Results were compared with patients with Leigh syndrome due to SLC19A3 defects (N=6) and mitochondrial respiratory chain defects (N=9). In all but one SLC19A3 patient, samples were collected before thiamine supplementation. Thiamine vitamers were also analyzed by HPLC in fibroblasts from SLC19A3 patients (N=3) and patients with other metabolic defects (N=6). Results A negative correlation between thiamine isoforms and age was detected in whole-blood and CSF, thus three reference intervals were established for free-thiamine and two intervals for TMP and TDP. Free-thiamine was severely reduced in five non-treated SLC19A3 patients CSF, but not TMP and TPP. The SLC19A3 patient under thiamine supplementation showed thiamine values above reference range. Nine Leigh patients with mitochondrial defects showed normal o slightly reduced values for CSF thiamine. In SLC19A3 patient's fibroblasts, a reduction in free-thiamine was detected as compared with control sample. These values normalized after thiamine was added to the culture medium. Conclusion SLC19A3 patients show a profound deficiency of free-thiamine in the CSF that allows their identification from other causes of Leigh syndrome. SLC19A3 is essential to maintain CSF thiamine homeostasis and to prevent brain damage. Thiamine overload can supply the SLC19A3 defect and restore thiamine values in fibroblasts and CSF, probably by an alternative transport system.
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OP6 – 2631: Decreased free-thiamine in cerebro spinal fluid and fibroblasts is a sensitive marker of thiamine transporter 2 deficiency in Leigh syndrome patients
European Journal of Paediatric Neurology, 2015Co-Authors: J.d. Ortigoza Escobar, Marta Molero-luis, Mercedes Casado, J A Mayr, Alfonso Ribes, Angela Arias, Mercedes Serrano, Mireia Tondo, Niklas Darin, Rafael ArtuchAbstract:Objectives Thiamine transporter-2 (hTHTR2) deficiency due to SLC19A3 mutations is a potentially reversible cause of Leigh syndrome for which no biochemical markers are currently available. Our aim was to assess the sensitivity of thiamine quantification in cerebrospinal fluid (CSF) and fibroblasts from patients with Leigh encephalopathy and SLC19A3 defects as compared with other causes of Leigh syndrome. Methods Thiamine vitamers (free-thiamine, thiamine monophosphate (TMP) and thiamine diphosphate (TDP)) were analyzed by HPLC-fluorescence detection in whole-blood and cerebrospinal fluid (CSF) samples from 106 and 38 paediatric controls, respectively. Results were compared with patients with Leigh syndrome due to SLC19A3 defects (N=6) and mitochondrial respiratory chain defects (N=9). In all but one SLC19A3 patient, samples were collected before thiamine supplementation. Thiamine vitamers were also analyzed by HPLC in fibroblasts from SLC19A3 patients (N=3) and patients with other metabolic defects (N=6). Results A negative correlation between thiamine isoforms and age was detected in whole-blood and CSF, thus three reference intervals were established for free-thiamine and two intervals for TMP and TDP. Free-thiamine was severely reduced in five non-treated SLC19A3 patients CSF, but not TMP and TPP. The SLC19A3 patient under thiamine supplementation showed thiamine values above reference range. Nine Leigh patients with mitochondrial defects showed normal o slightly reduced values for CSF thiamine. In SLC19A3 patient's fibroblasts, a reduction in free-thiamine was detected as compared with control sample. These values normalized after thiamine was added to the culture medium. Conclusion SLC19A3 patients show a profound deficiency of free-thiamine in the CSF that allows their identification from other causes of Leigh syndrome. SLC19A3 is essential to maintain CSF thiamine homeostasis and to prevent brain damage. Thiamine overload can supply the SLC19A3 defect and restore thiamine values in fibroblasts and CSF, probably by an alternative transport system.
Mercedes Serrano - One of the best experts on this subject based on the ideXlab platform.
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free thiamine is a potential biomarker of thiamine transporter 2 deficiency a treatable cause of leigh syndrome
Brain, 2016Co-Authors: Juan Dario Ortigozaescobar, Angela Arias, Mercedes Serrano, Angels Garciacazorla, Mireia Tondo, Alfonso Oyarzabal, M V Hernandez, Niklas Darin, Marta Moleroluis, Judit GarciavilloriaAbstract:Thiamine transporter-2 deficiency is caused by mutations in the SLC19A3 gene. As opposed to other causes of Leigh syndrome, early administration of thiamine and biotin has a dramatic and immediate clinical effect. New biochemical markers are needed to aid in early diagnosis and timely therapeutic intervention. Thiamine derivatives were analysed by high performance liquid chromatography in 106 whole blood and 38 cerebrospinal fluid samples from paediatric controls, 16 cerebrospinal fluid samples from patients with Leigh syndrome, six of whom harboured mutations in the SLC19A3 gene, and 49 patients with other neurological disorders. Free-thiamine was remarkably reduced in the cerebrospinal fluid of five SLC19A3 patients before treatment. In contrast, free-thiamine was slightly decreased in 15.2% of patients with other neurological conditions, and above the reference range in one SLC19A3 patient on thiamine supplementation. We also observed a severe deficiency of free-thiamine and low levels of thiamine diphosphate in fibroblasts from SLC19A3 patients. Surprisingly, pyruvate dehydrogenase activity and mitochondrial substrate oxidation rates were within the control range. Thiamine derivatives normalized after the addition of thiamine to the culture medium. In conclusion, we found a profound deficiency of free-thiamine in the CSF and fibroblasts of patients with thiamine transporter-2 deficiency. Thiamine supplementation led to clinical improvement in patients early treated and restored thiamine values in fibroblasts and cerebrospinal fluid. * Abbreviations : free-T : free-thiamine TMP : thiamine monophosphate TDP : thiamine diphosphate TPK : thiamine pyrophosphokinase hTHTR2 : thiamine transporter-2
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op6 2631 decreased free thiamine in cerebro spinal fluid and fibroblasts is a sensitive marker of thiamine transporter 2 deficiency in leigh syndrome patients
European Journal of Paediatric Neurology, 2015Co-Authors: J Ortigoza D Escobar, Mercedes Casado, J A Mayr, Alfonso Ribes, Angela Arias, Mercedes Serrano, Mireia Tondo, Niklas Darin, Marta Moleroluis, Rafael ArtuchAbstract:Objectives Thiamine transporter-2 (hTHTR2) deficiency due to SLC19A3 mutations is a potentially reversible cause of Leigh syndrome for which no biochemical markers are currently available. Our aim was to assess the sensitivity of thiamine quantification in cerebrospinal fluid (CSF) and fibroblasts from patients with Leigh encephalopathy and SLC19A3 defects as compared with other causes of Leigh syndrome. Methods Thiamine vitamers (free-thiamine, thiamine monophosphate (TMP) and thiamine diphosphate (TDP)) were analyzed by HPLC-fluorescence detection in whole-blood and cerebrospinal fluid (CSF) samples from 106 and 38 paediatric controls, respectively. Results were compared with patients with Leigh syndrome due to SLC19A3 defects (N=6) and mitochondrial respiratory chain defects (N=9). In all but one SLC19A3 patient, samples were collected before thiamine supplementation. Thiamine vitamers were also analyzed by HPLC in fibroblasts from SLC19A3 patients (N=3) and patients with other metabolic defects (N=6). Results A negative correlation between thiamine isoforms and age was detected in whole-blood and CSF, thus three reference intervals were established for free-thiamine and two intervals for TMP and TDP. Free-thiamine was severely reduced in five non-treated SLC19A3 patients CSF, but not TMP and TPP. The SLC19A3 patient under thiamine supplementation showed thiamine values above reference range. Nine Leigh patients with mitochondrial defects showed normal o slightly reduced values for CSF thiamine. In SLC19A3 patient's fibroblasts, a reduction in free-thiamine was detected as compared with control sample. These values normalized after thiamine was added to the culture medium. Conclusion SLC19A3 patients show a profound deficiency of free-thiamine in the CSF that allows their identification from other causes of Leigh syndrome. SLC19A3 is essential to maintain CSF thiamine homeostasis and to prevent brain damage. Thiamine overload can supply the SLC19A3 defect and restore thiamine values in fibroblasts and CSF, probably by an alternative transport system.
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OP6 – 2631: Decreased free-thiamine in cerebro spinal fluid and fibroblasts is a sensitive marker of thiamine transporter 2 deficiency in Leigh syndrome patients
European Journal of Paediatric Neurology, 2015Co-Authors: J.d. Ortigoza Escobar, Marta Molero-luis, Mercedes Casado, J A Mayr, Alfonso Ribes, Angela Arias, Mercedes Serrano, Mireia Tondo, Niklas Darin, Rafael ArtuchAbstract:Objectives Thiamine transporter-2 (hTHTR2) deficiency due to SLC19A3 mutations is a potentially reversible cause of Leigh syndrome for which no biochemical markers are currently available. Our aim was to assess the sensitivity of thiamine quantification in cerebrospinal fluid (CSF) and fibroblasts from patients with Leigh encephalopathy and SLC19A3 defects as compared with other causes of Leigh syndrome. Methods Thiamine vitamers (free-thiamine, thiamine monophosphate (TMP) and thiamine diphosphate (TDP)) were analyzed by HPLC-fluorescence detection in whole-blood and cerebrospinal fluid (CSF) samples from 106 and 38 paediatric controls, respectively. Results were compared with patients with Leigh syndrome due to SLC19A3 defects (N=6) and mitochondrial respiratory chain defects (N=9). In all but one SLC19A3 patient, samples were collected before thiamine supplementation. Thiamine vitamers were also analyzed by HPLC in fibroblasts from SLC19A3 patients (N=3) and patients with other metabolic defects (N=6). Results A negative correlation between thiamine isoforms and age was detected in whole-blood and CSF, thus three reference intervals were established for free-thiamine and two intervals for TMP and TDP. Free-thiamine was severely reduced in five non-treated SLC19A3 patients CSF, but not TMP and TPP. The SLC19A3 patient under thiamine supplementation showed thiamine values above reference range. Nine Leigh patients with mitochondrial defects showed normal o slightly reduced values for CSF thiamine. In SLC19A3 patient's fibroblasts, a reduction in free-thiamine was detected as compared with control sample. These values normalized after thiamine was added to the culture medium. Conclusion SLC19A3 patients show a profound deficiency of free-thiamine in the CSF that allows their identification from other causes of Leigh syndrome. SLC19A3 is essential to maintain CSF thiamine homeostasis and to prevent brain damage. Thiamine overload can supply the SLC19A3 defect and restore thiamine values in fibroblasts and CSF, probably by an alternative transport system.
