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Vineta Fellman - One of the best experts on this subject based on the ideXlab platform.
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a turkish bcs1l mutation causes GRACILE like disorder
Turkish Journal of Pediatrics, 2016Co-Authors: Esra Serdaroglu, Heike Kotarsky, Sahin Takci, Onur Cil, Eda Utine, Sule Yigit, Vineta FellmanAbstract:A full-term growth-restricted female newborn (1790 g), presented with lactic acidosis (12.5 mmol/L) after birth. She had renal tubulopathy, cholestasis and elevated serum ferritin concentration (2819 ng/ml). Two similarly affected sisters had died before 3 months of age. Mitochondrial disorder was suspected since the disease resembled the Finnish GRACILE Syndrome, caused by a homozygous mutation (c.232A>G) in BCS1L. Thus, we sequenced the BCS1L gene, encoding the assembly factor for respiratory chain complex III. The patient had a homozygous mutation (c.296C>T; p.P99L), for which both parents were heterozygous. In four previously published patients of Turkish origin, the same homozygous mutation resulted in complex III deficiency, tubulopathy, encephalopathy, and liver failure. The p.P99L mutation seems to be specific to Turkish population and leads to GRACILE-like or Leigh-like condition. Assembly defects in complex III should be investigated in the affected tissues, since fibroblasts may not exhibit the deficiency. (Less)
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1036 GRACILE Syndrome in a turkish newborn infant caused by a homozygous mutation p99l in complex iii assembly factor bcs1l
Archives of Disease in Childhood, 2012Co-Authors: Erkin Serdaroglu, Heike Kotarsky, Vineta Fellman, Sahin Takci, Onur Cil, Eda Utine, Sule YigitAbstract:Background and Aim GRACILE Syndrome, a neonatal, autosomally recessive disorder found in Finland, featuring growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis and early death, is caused by a homozygous mutation (S78G) in BCS1L, the assembly factor for respiratory chain complex III. We investigated a newborn Turkish girl with similar symptoms. Her two sisters with low birth weight, metabolic acidosis, cholestasis and renal Fanconi Syndrome, had died at 18 and 105 days age, respectively. Methods and results The girl was born to healthy nonconsanguineous parents. She was growth retarded (1789 g at term), developed tachypnea and metabolic acidosis on day one. Lactic acidosis, jaundice with direct hyperbilirubinemia, nonspecific aminoaciduria, high phosphaturia, proteinuria and glucosuria were detected. Serum iron (190 mcg/dl), ferritin (2819 ng/ml) and transferrin saturation (99.4%) were increased. Metabolic, cardiologic and sonographic workup were otherwise normal. Because of similarities with GRACILE Syndrome, the BCS1L gene was investigated. The Finnish SNP was not found, but gene sequencing revealed a homozygous mutation resulting in an amino acid exchange (P99L) in the protein. Conclusions The studied infant had a GRACILE-like disorder caused by a different mutation than that in newborns of Finnish ancestors. Most likely the two diseased siblings had the same homozygous BCS1L mutation that previously has been published in three other newborns or Turkish origin. We proposed that P99L-mutation in BCS1L is a Turkish genotype resulting in GRACILE Syndrome phenotype, and should be investigated in Turkish newborns with the typical clinical features.
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metabolite profiles reveal energy failure and impaired beta oxidation in liver of mice with complex iii deficiency due to a bcs1l mutation
PLOS ONE, 2012Co-Authors: Heike Kotarsky, Vineta Fellman, Mina Davoudi, Riitta Karikoski, Matthias Keller, Per Leveen, David P EnotAbstract:AIMS: Liver is a target organ in many mitochondrial disorders, especially if the complex III assembly factor BCS1L is mutated. To reveal disease mechanism due to such mutations, we have produced a transgenic mouse model with c.232A>G mutation in Bcs1l, the causative mutation for GRACILE Syndrome. The homozygous mice develop mitochondrial hepatopathy with steatosis and fibrosis after weaning. Our aim was to assess cellular mechanisms for disease onset and progression using metabolomics. METHODS: With mass spectrometry we analyzed metabolite patterns in liver samples obtained from homozygotes and littermate controls of three ages. As oxidative stress might be a mechanism for mitochondrial hepatopathy, we also assessed H(2)O(2) production and expression of antioxidants. RESULTS: Homozygotes had a similar metabolic profile at 14 days of age as controls, with the exception of slightly decreased AMP. At 24 days, when hepatocytes display first histopathological signs, increases in succinate, fumarate and AMP were found associated with impaired glucose turnover and beta-oxidation. At end stage disease after 30 days, these changes were pronounced with decreased carbohydrates, high levels of acylcarnitines and amino acids, and elevated biogenic amines, especially putrescine. Signs of oxidative stress were present in end-stage disease. CONCLUSIONS: The findings suggest an early Krebs cycle defect with increases of its intermediates, which might play a role in disease onset. During disease progression, carbohydrate and fatty acid metabolism deteriorate leading to a starvation-like condition. The mouse model is valuable for further investigations on mechanisms in mitochondrial hepatopathy and for interventions. (Less)
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Metabolite Profiles Reveal Energy Failure and Impaired Beta-Oxidation in Liver of Mice with Complex III Deficiency Due to a BCS1L Mutation
2012Co-Authors: Heike Kotarsky, Mina Davoudi, Riitta Karikoski, Matthias Keller, Per Leveen, David P Enot, Vineta FellmanAbstract:Background & AimsLiver is a target organ in many mitochondrial disorders, especially if the complex III assembly factor BCS1L is mutated. To reveal disease mechanism due to such mutations, we have produced a transgenic mouse model with c.232A>G mutation in Bcs1l, the causative mutation for GRACILE Syndrome. The homozygous mice develop mitochondrial hepatopathy with steatosis and fibrosis after weaning. Our aim was to assess cellular mechanisms for disease onset and progression using metabolomics. MethodsWith mass spectrometry we analyzed metabolite patterns in liver samples obtained from homozygotes and littermate controls of three ages. As oxidative stress might be a mechanism for mitochondrial hepatopathy, we also assessed H2O2 production and expression of antioxidants. ResultsHomozygotes had a similar metabolic profile at 14 days of age as controls, with the exception of slightly decreased AMP. At 24 days, when hepatocytes display first histopathological signs, increases in succinate, fumarate and AMP were found associated with impaired glucose turnover and beta-oxidation. At end stage disease after 30 days, these changes were pronounced with decreased carbohydrates, high levels of acylcarnitines and amino acids, and elevated biogenic amines, especially putrescine. Signs of oxidative stress were present in end-stage disease. ConclusionsThe findings suggest an early Krebs cycle defect with increases of its intermediates, which might play a role in disease onset. During disease progression, carbohydrate and fatty acid metabolism deteriorate leading to a starvation-like condition. The mouse model is valuable for further investigations on mechanisms in mitochondrial hepatopathy and for interventions.
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Mitochondrial hepatopathies in the newborn period.
Seminars in Fetal & Neonatal Medicine, 2011Co-Authors: Vineta Fellman, Heike KotarskyAbstract:Mitochondrial disorders recognized in the neonatal period usually present as a metabolic crisis combined with one or several organ manifestations. Liver disorder in association with a respiratory chain deficiency may be overlooked since liver dysfunction is common in severely sick newborn infants. Lactacidosis, hypoglycemia, elevated serum transaminases and conjugated bilirubin are common signs of mitochondrial hepatopathy. Hepatosplenomegaly may occur in severe cases. A clinical picture with fetal growth restriction, postnatal lactacidosis, hypoglycemia, coagulopathy, and cholestasis, especially in combination with neurological symptoms or renal tubulopathy, should alert the neonatologist to direct investigations on mitochondrial disorder. A normal lactate level does not exclude respiratory chain defects. The most common liver manifestation caused by mutated mitochondrial DNA (deletion) is Pearson Syndrome. Recently, mutations in several nuclear DNA genes have been identified that lead to mitochondrial hepatopathy, e.g. mitochondrial depletion Syndrome caused by DGUOK, MPV17, SUCLG1, POLG1, or C10ORF2 mutations. A combination of lactacidosis, liver involvement, and Fanconi type renal tubulopathy is common when the complex III assembly factor BCS1L harbors mutations, the most severe disease with consistent genotype-phenotype correlation being the GRACILE Syndrome. Mutations in nuclear translation factor genes (TRMU, EFG1, and EFTu) of the respiratory chain enzyme complexes have recently been identified. Diagnostic work-up of neonatal liver disorder should include assessment of function and structure of the complexes as well as mutation screening for known genes. So far, treatment is mainly symptomatic.
Heike Kotarsky - One of the best experts on this subject based on the ideXlab platform.
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a turkish bcs1l mutation causes GRACILE like disorder
Turkish Journal of Pediatrics, 2016Co-Authors: Esra Serdaroglu, Heike Kotarsky, Sahin Takci, Onur Cil, Eda Utine, Sule Yigit, Vineta FellmanAbstract:A full-term growth-restricted female newborn (1790 g), presented with lactic acidosis (12.5 mmol/L) after birth. She had renal tubulopathy, cholestasis and elevated serum ferritin concentration (2819 ng/ml). Two similarly affected sisters had died before 3 months of age. Mitochondrial disorder was suspected since the disease resembled the Finnish GRACILE Syndrome, caused by a homozygous mutation (c.232A>G) in BCS1L. Thus, we sequenced the BCS1L gene, encoding the assembly factor for respiratory chain complex III. The patient had a homozygous mutation (c.296C>T; p.P99L), for which both parents were heterozygous. In four previously published patients of Turkish origin, the same homozygous mutation resulted in complex III deficiency, tubulopathy, encephalopathy, and liver failure. The p.P99L mutation seems to be specific to Turkish population and leads to GRACILE-like or Leigh-like condition. Assembly defects in complex III should be investigated in the affected tissues, since fibroblasts may not exhibit the deficiency. (Less)
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1036 GRACILE Syndrome in a turkish newborn infant caused by a homozygous mutation p99l in complex iii assembly factor bcs1l
Archives of Disease in Childhood, 2012Co-Authors: Erkin Serdaroglu, Heike Kotarsky, Vineta Fellman, Sahin Takci, Onur Cil, Eda Utine, Sule YigitAbstract:Background and Aim GRACILE Syndrome, a neonatal, autosomally recessive disorder found in Finland, featuring growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis and early death, is caused by a homozygous mutation (S78G) in BCS1L, the assembly factor for respiratory chain complex III. We investigated a newborn Turkish girl with similar symptoms. Her two sisters with low birth weight, metabolic acidosis, cholestasis and renal Fanconi Syndrome, had died at 18 and 105 days age, respectively. Methods and results The girl was born to healthy nonconsanguineous parents. She was growth retarded (1789 g at term), developed tachypnea and metabolic acidosis on day one. Lactic acidosis, jaundice with direct hyperbilirubinemia, nonspecific aminoaciduria, high phosphaturia, proteinuria and glucosuria were detected. Serum iron (190 mcg/dl), ferritin (2819 ng/ml) and transferrin saturation (99.4%) were increased. Metabolic, cardiologic and sonographic workup were otherwise normal. Because of similarities with GRACILE Syndrome, the BCS1L gene was investigated. The Finnish SNP was not found, but gene sequencing revealed a homozygous mutation resulting in an amino acid exchange (P99L) in the protein. Conclusions The studied infant had a GRACILE-like disorder caused by a different mutation than that in newborns of Finnish ancestors. Most likely the two diseased siblings had the same homozygous BCS1L mutation that previously has been published in three other newborns or Turkish origin. We proposed that P99L-mutation in BCS1L is a Turkish genotype resulting in GRACILE Syndrome phenotype, and should be investigated in Turkish newborns with the typical clinical features.
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metabolite profiles reveal energy failure and impaired beta oxidation in liver of mice with complex iii deficiency due to a bcs1l mutation
PLOS ONE, 2012Co-Authors: Heike Kotarsky, Vineta Fellman, Mina Davoudi, Riitta Karikoski, Matthias Keller, Per Leveen, David P EnotAbstract:AIMS: Liver is a target organ in many mitochondrial disorders, especially if the complex III assembly factor BCS1L is mutated. To reveal disease mechanism due to such mutations, we have produced a transgenic mouse model with c.232A>G mutation in Bcs1l, the causative mutation for GRACILE Syndrome. The homozygous mice develop mitochondrial hepatopathy with steatosis and fibrosis after weaning. Our aim was to assess cellular mechanisms for disease onset and progression using metabolomics. METHODS: With mass spectrometry we analyzed metabolite patterns in liver samples obtained from homozygotes and littermate controls of three ages. As oxidative stress might be a mechanism for mitochondrial hepatopathy, we also assessed H(2)O(2) production and expression of antioxidants. RESULTS: Homozygotes had a similar metabolic profile at 14 days of age as controls, with the exception of slightly decreased AMP. At 24 days, when hepatocytes display first histopathological signs, increases in succinate, fumarate and AMP were found associated with impaired glucose turnover and beta-oxidation. At end stage disease after 30 days, these changes were pronounced with decreased carbohydrates, high levels of acylcarnitines and amino acids, and elevated biogenic amines, especially putrescine. Signs of oxidative stress were present in end-stage disease. CONCLUSIONS: The findings suggest an early Krebs cycle defect with increases of its intermediates, which might play a role in disease onset. During disease progression, carbohydrate and fatty acid metabolism deteriorate leading to a starvation-like condition. The mouse model is valuable for further investigations on mechanisms in mitochondrial hepatopathy and for interventions. (Less)
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Metabolite Profiles Reveal Energy Failure and Impaired Beta-Oxidation in Liver of Mice with Complex III Deficiency Due to a BCS1L Mutation
2012Co-Authors: Heike Kotarsky, Mina Davoudi, Riitta Karikoski, Matthias Keller, Per Leveen, David P Enot, Vineta FellmanAbstract:Background & AimsLiver is a target organ in many mitochondrial disorders, especially if the complex III assembly factor BCS1L is mutated. To reveal disease mechanism due to such mutations, we have produced a transgenic mouse model with c.232A>G mutation in Bcs1l, the causative mutation for GRACILE Syndrome. The homozygous mice develop mitochondrial hepatopathy with steatosis and fibrosis after weaning. Our aim was to assess cellular mechanisms for disease onset and progression using metabolomics. MethodsWith mass spectrometry we analyzed metabolite patterns in liver samples obtained from homozygotes and littermate controls of three ages. As oxidative stress might be a mechanism for mitochondrial hepatopathy, we also assessed H2O2 production and expression of antioxidants. ResultsHomozygotes had a similar metabolic profile at 14 days of age as controls, with the exception of slightly decreased AMP. At 24 days, when hepatocytes display first histopathological signs, increases in succinate, fumarate and AMP were found associated with impaired glucose turnover and beta-oxidation. At end stage disease after 30 days, these changes were pronounced with decreased carbohydrates, high levels of acylcarnitines and amino acids, and elevated biogenic amines, especially putrescine. Signs of oxidative stress were present in end-stage disease. ConclusionsThe findings suggest an early Krebs cycle defect with increases of its intermediates, which might play a role in disease onset. During disease progression, carbohydrate and fatty acid metabolism deteriorate leading to a starvation-like condition. The mouse model is valuable for further investigations on mechanisms in mitochondrial hepatopathy and for interventions.
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Mitochondrial hepatopathies in the newborn period.
Seminars in Fetal & Neonatal Medicine, 2011Co-Authors: Vineta Fellman, Heike KotarskyAbstract:Mitochondrial disorders recognized in the neonatal period usually present as a metabolic crisis combined with one or several organ manifestations. Liver disorder in association with a respiratory chain deficiency may be overlooked since liver dysfunction is common in severely sick newborn infants. Lactacidosis, hypoglycemia, elevated serum transaminases and conjugated bilirubin are common signs of mitochondrial hepatopathy. Hepatosplenomegaly may occur in severe cases. A clinical picture with fetal growth restriction, postnatal lactacidosis, hypoglycemia, coagulopathy, and cholestasis, especially in combination with neurological symptoms or renal tubulopathy, should alert the neonatologist to direct investigations on mitochondrial disorder. A normal lactate level does not exclude respiratory chain defects. The most common liver manifestation caused by mutated mitochondrial DNA (deletion) is Pearson Syndrome. Recently, mutations in several nuclear DNA genes have been identified that lead to mitochondrial hepatopathy, e.g. mitochondrial depletion Syndrome caused by DGUOK, MPV17, SUCLG1, POLG1, or C10ORF2 mutations. A combination of lactacidosis, liver involvement, and Fanconi type renal tubulopathy is common when the complex III assembly factor BCS1L harbors mutations, the most severe disease with consistent genotype-phenotype correlation being the GRACILE Syndrome. Mutations in nuclear translation factor genes (TRMU, EFG1, and EFTu) of the respiratory chain enzyme complexes have recently been identified. Diagnostic work-up of neonatal liver disorder should include assessment of function and structure of the complexes as well as mutation screening for known genes. So far, treatment is mainly symptomatic.
Ilona Visapaa - One of the best experts on this subject based on the ideXlab platform.
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GRACILE Syndrome a lethal metabolic disorder with iron overload is caused by a point mutation in bcs1l
American Journal of Human Genetics, 2002Co-Authors: Ilona Visapaa, Ayan Dasvarma, Jenna L Hutton, Gregory S Payne, Jouni Vesa, Marja Makarow, Vineta Fellman, Vijay Kumar, Rudy Van CosterAbstract:GRACILE (growth retardation, aminoaciduria, cholestasis, iron overload, lactacidosis, and early death) Syndrome is a recessively inherited lethal disease characterized by fetal growth retardation, lactic acidosis, aminoaciduria, cholestasis, and abnormalities in iron metabolism. We previously localized the causative gene to a 1.5-cM region on chromosome 2q33-37. In the present study, we report the molecular defect causing this metabolic disorder, by identifying a homozygous missense mutation that results in an S78G amino acid change in the BCS1L gene in Finnish patients with GRACILE Syndrome, as well as five different mutations in three British infants. BCS1L, a mitochondrial inner-membrane protein, is a chaperone necessary for the assembly of mitochondrial respiratory chain complex III. Pulse-chase experiments performed in COS-1 cells indicated that the S78G amino acid change results in instability of the polypeptide, and yeast complementation studies revealed a functional defect in the mutated BCS1L protein. Four different mutations in the BCS1L gene have been reported elsewhere, in Turkish patients with a distinctly different phenotype. Interestingly, the British and Turkish patients had complex III deficiency, whereas in the Finnish patients with GRACILE Syndrome complex III activity was within the normal range, implying that BCS1L has another cellular function that is uncharacterized but essential and is putatively involved in iron metabolism.
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abcb6 mtabc3 excluded as the causative gene for the growth retardation Syndrome with aminoaciduria cholestasis iron overload and lactacidosis
American Journal of Medical Genetics, 2002Co-Authors: Ilona Visapaa, Vineta Fellman, Lisa Lanyi, Leena PeltonenAbstract:GRACILE Syndrome (growth retardation, aminoaciduria, cholestasis, iron overload, lactacidosis, and early death; OMIM 603358) is a rare metabolic disorder with autosomal recessive mode of inheritance. So far it has been diagnosed only in patients with Finnish ancestors. The GRACILE locus has been positioned to a restricted region of chromosome 2q33-37, but the causative gene remains to be identified. The ABCB6 gene, involved in iron homeostasis, mitochondrial respiratory function, and maintenance of the stability of mitochondrial DNA, has been positioned to this same chromosomal region, and advocated in literature as a highly probable candidate gene for the Syndrome on both functional and positional grounds. We carried out sequence and quantitative expression analyses to detect potential disease-associated mutations in the ABCB6 gene. No mutations in the coding region of ABCB6 were found, and the expression level of ABCB6 in patient fibroblasts was found to be comparable to controls. Haplotype analysis of the critical DNA region provided evidence for positional exclusion also. Based on these data, ABCB6 is not the causative gene for GRACILE Syndrome.
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antenatal diagnosis of hereditary fetal growth retardation with aminoaciduria cholestasis iron overload and lactic acidosis in the newborn infant
Acta Obstetricia et Gynecologica Scandinavica, 2002Co-Authors: Vineta Fellman, Ilona Visapaa, Mihailo Vujic, Ullabritt Wennerholm, Leena PeltonenAbstract:OBJECTIVE: A prenatal diagnosis of the fetus for a mother of two previously deceased infants who died from the recently described autosomal recessive disease (OMIM 603358). The infants presented with intrauterine growth retardation, aminoaciduria, cholestasis, iron overload, severe lactic acidosis, and early death (GRACILE Syndrome). STUDY DESIGN: DNA was extracted from the fibroblasts and tissue samples of the deceased infants, parental leukocytes, and from a chorion villus biopsy in the next pregnancy. Haplotypes were determined using the relevant markers flanking the disease-associated region of chromosome 2. RESULTS: Both deceased infants were homozygous for the four critical markers. The fetal haploptypes were identical to those of the siblings and the pregnancy was terminated. The iron content of the fetal liver was increased (5000 microg/g) compared with the controls, with a marked iron accumulation in the Kupffer cells. CONCLUSIONS: Antenatal diagnosis can be performed based on linkage analysis in families with at least one affected child because the disease locus has been assigned to a restricted chromosomal region. Typical histological abnormalities may be present in early fetal life.
Leena Peltonen - One of the best experts on this subject based on the ideXlab platform.
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abcb6 mtabc3 excluded as the causative gene for the growth retardation Syndrome with aminoaciduria cholestasis iron overload and lactacidosis
American Journal of Medical Genetics, 2002Co-Authors: Ilona Visapaa, Vineta Fellman, Lisa Lanyi, Leena PeltonenAbstract:GRACILE Syndrome (growth retardation, aminoaciduria, cholestasis, iron overload, lactacidosis, and early death; OMIM 603358) is a rare metabolic disorder with autosomal recessive mode of inheritance. So far it has been diagnosed only in patients with Finnish ancestors. The GRACILE locus has been positioned to a restricted region of chromosome 2q33-37, but the causative gene remains to be identified. The ABCB6 gene, involved in iron homeostasis, mitochondrial respiratory function, and maintenance of the stability of mitochondrial DNA, has been positioned to this same chromosomal region, and advocated in literature as a highly probable candidate gene for the Syndrome on both functional and positional grounds. We carried out sequence and quantitative expression analyses to detect potential disease-associated mutations in the ABCB6 gene. No mutations in the coding region of ABCB6 were found, and the expression level of ABCB6 in patient fibroblasts was found to be comparable to controls. Haplotype analysis of the critical DNA region provided evidence for positional exclusion also. Based on these data, ABCB6 is not the causative gene for GRACILE Syndrome.
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antenatal diagnosis of hereditary fetal growth retardation with aminoaciduria cholestasis iron overload and lactic acidosis in the newborn infant
Acta Obstetricia et Gynecologica Scandinavica, 2002Co-Authors: Vineta Fellman, Ilona Visapaa, Mihailo Vujic, Ullabritt Wennerholm, Leena PeltonenAbstract:OBJECTIVE: A prenatal diagnosis of the fetus for a mother of two previously deceased infants who died from the recently described autosomal recessive disease (OMIM 603358). The infants presented with intrauterine growth retardation, aminoaciduria, cholestasis, iron overload, severe lactic acidosis, and early death (GRACILE Syndrome). STUDY DESIGN: DNA was extracted from the fibroblasts and tissue samples of the deceased infants, parental leukocytes, and from a chorion villus biopsy in the next pregnancy. Haplotypes were determined using the relevant markers flanking the disease-associated region of chromosome 2. RESULTS: Both deceased infants were homozygous for the four critical markers. The fetal haploptypes were identical to those of the siblings and the pregnancy was terminated. The iron content of the fetal liver was increased (5000 microg/g) compared with the controls, with a marked iron accumulation in the Kupffer cells. CONCLUSIONS: Antenatal diagnosis can be performed based on linkage analysis in families with at least one affected child because the disease locus has been assigned to a restricted chromosomal region. Typical histological abnormalities may be present in early fetal life.
Kotarsky Heike - One of the best experts on this subject based on the ideXlab platform.
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Fasting reveals largely intact systemic lipid mobilization mechanisms in respiratory chain complex III deficient mice
'Elsevier BV', 2020Co-Authors: Tomašić Nikica, Kotarsky Heike, De Oliveira Figueiredo Rejane, Hansson Eva, Mörgelin Matthias, Tomašić Ivan, Kallijärvi Jukka, Elmér Eskil, Jauhiainen Matti, Eklund, Erik A.Abstract:Mice homozygous for the human GRACILE Syndrome mutation (Bcs1lc.A232G) display decreased respiratory chain complex III activity, liver dysfunction, hypoglycemia, rapid loss of white adipose tissue and early death. To assess the underlying mechanism of the lipodystrophy in homozygous mice (Bcs1lp.S78G), these and wild-type control mice were subjected to a short 4-hour fast. The homozygotes had low baseline blood glucose values, but a similar decrease in response to fasting as in wild-type mice, resulting in hypoglycemia in the majority. Despite the already depleted glycogen and increased triacylglycerol content in the mutant livers, the mice responded to fasting by further depletion and increase, respectively. Increased plasma free fatty acids (FAs) upon fasting suggested normal capacity for mobilization of lipids from white adipose tissue into circulation. Strikingly, however, serum glycerol concentration was not increased concomitantly with free FAs, suggesting its rapid uptake into the liver and utilization for fuel or gluconeogenesis in the mutants. The mutant hepatocyte mitochondria were capable of responding to fasting by appropriate morphological changes, as analyzed by electron microscopy, and by increasing respiration. Mutants showed increased hepatic gene expression of major metabolic controllers typically associated with fasting response (Ppargc1a, Fgf21, Cd36) already in the fed state, suggesting a chronic starvation-like metabolic condition. Despite this, the mutant mice responded largely normally to fasting by increasing hepatic respiration and switching to FA utilization, indicating that the mechanisms driving these adaptations are not compromised by the CIII dysfunction. Summary statement: Bcs1l mutant mice with severe CIII deficiency, energy deprivation and post-weaning lipolysis respond to fasting similarly to wild-type mice, suggesting largely normal systemic lipid mobilization and utilization mechanisms
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Fasting reveals largely intact systemic lipid mobilization mechanisms in respiratory chain complex III deficient mice
'Elsevier BV', 2020Co-Authors: Tomašić Nikica, Kotarsky Heike, Hansson Eva, Mörgelin Matthias, Kallijärvi Jukka, Elmér Eskil, Jauhiainen Matti, Figueiredo, Rejane De Oliveira, Tomasic Ivan, Eklund, Erik A.Abstract:Mice homozygous for the human GRACILE Syndrome mutation (Bcs1l (c.A232G)) display decreased respiratory chain complex III activity, liver dysfunction, hypoglycemia, rapid loss of white adipose tissue and early death. To assess the underlying mechanism of the lipodystrophy in homozygous mice (Bcs1l(p.S)(78G)), these and wild-type control mice were subjected to a short 4-hour fast. The homozygotes had low baseline blood glucose values, but a similar decrease in response to fasting as in wild-type mice, resulting in hypoglycemia in the majority. Despite the already depleted glycogen and increased triacylglycerol content in the mutant livers, the mice responded to fasting by further depletion and increase, respectively. Increased plasma free fatty acids (FAs) upon fasting suggested normal capacity for mobilization of lipids from white adipose tissue into circulation. Strikingly, however, serum glycerol concentration was not increased concomitantly with free FM, suggesting its rapid uptake into the liver and utilization for fuel or gluconeogenesis in the mutants. The mutant hepatocyte mitochondria were capable of responding to fasting by appropriate morphological changes, as analyzed by electron microscopy, and by increasing respiration. Mutants showed increased hepatic gene expression of major metabolic controllers typically associated with fasting response (Ppargc1a, Fgf21, Cd36) already in the fed state, suggesting a chronic starvation-like metabolic condition. Despite this, the mutant mice responded largely normally to fasting by increasing hepatic respiration and switching to FA utilization, indicating that the mechanisms driving these adaptations are not compromised by the CIII dysfunction. Summary statement: Bcs1l mutant mice with severe CIII deficiency, energy deprivation and post-weaning lipolysis respond to fasting similarly to wild-type mice, suggesting largely normal systemic lipid mobilization and utilization mechanisms.Peer reviewe
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A Turkish Bcs1L Mutation Causes GRACILE-Like Disorder
'The Turkish Journal of Pediatrics', 2016Co-Authors: Serdaroğlu Esra, Kotarsky Heike, Takcı Şahin, Çil Onur, Utine Eda, Yiğit Sule, Fellman VinetaAbstract:A full-term growth-restricted female newborn (1790 g), presented with lactic acidosis (12.5 mmol/L) after birth. She had renal tubulopathy, cholestasis and elevated serum ferritin concentration (2819 ng/ml). Two similarly affected sisters had died before 3 months of age. Mitochondrial disorder was suspected since the disease resembled the Finnish GRACILE Syndrome, caused by a homozygous mutation (c.232A>G) in BCS1L. Thus, we sequenced the BCS1L gene, encoding the assembly factor for respiratory chain complex III. The patient had a homozygous mutation (c. 296C>T; p.P99L), for which both parents were heterozygous. In four previously published patients of Turkish origin, the same homozygous mutation resulted in complex III deficiency, tubulopathy, encephalopathy, and liver failure. The p.P99L mutation seems to be specific to Turkish population and leads to GRACILE-like or Leigh-like condition. Assembly defects in complex III should be investigated in the affected tissues, since fibroblasts may not exhibit the deficiency.WoSScopu
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Effect of High-Carbohydrate Diet on Plasma Metabolome in Mice with Mitochondrial Respiratory Chain Complex III Deficiency
'MDPI AG', 2016Co-Authors: Rajendran Jayasimman, Tomašić Nikica, Kotarsky Heike, Hansson Eva, Kallijärvi Jukka, Velagapudi Vidya, Fellman VinetaAbstract:Mitochondrial disorders cause energy failure and metabolic derangements. Metabolome profiling in patients and animal models may identify affected metabolic pathways and reveal new biomarkers of disease progression. Using liver metabolomics we have shown a starvation-like condition in a knock-in (Bcs1l(c.232A>G)) mouse model of GRACILE Syndrome, a neonatal lethal respiratory chain complex III dysfunction with hepatopathy. Here, we hypothesized that a high-carbohydrate diet (HCD, 60% dextrose) will alleviate the hypoglycemia and promote survival of the sick mice. However, when fed HCD the homozygotes had shorter survival (mean +/- SD, 29 +/- 2.5 days, n = 21) than those on standard diet (33 +/- 3.8 days, n = 30), and no improvement in hypoglycemia or liver glycogen depletion. We investigated the plasma metabolome of the HCD- and control diet-fed mice and found that several amino acids and urea cycle intermediates were increased, and arginine, carnitines, succinate, and purine catabolites decreased in the homozygotes. Despite reduced survival the increase in aromatic amino acids, an indicator of liver mitochondrial dysfunction, was normalized on HCD. Quantitative enrichment analysis revealed that glycine, serine and threonine metabolism, phenylalanine and tyrosine metabolism, and urea cycle were also partly normalized on HCD. This dietary intervention revealed an unexpected adverse effect of high-glucose diet in complex III deficiency, and suggests that plasma metabolomics is a valuable tool in evaluation of therapies in mitochondrial disorders.Peer reviewe
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Metabolite Profiles Reveal Energy Failure and Impaired Beta-Oxidation in Liver of Mice with Complex III Deficiency Due to a BCS1L Mutation
Public Library of Science, 2012Co-Authors: Kotarsky Heike, Davoudi Mina, Keller Matthias, Levéen Per, Karikoski Riitta, Enot David P., Fellman VinetaAbstract:, the causative mutation for GRACILE Syndrome. The homozygous mice develop mitochondrial hepatopathy with steatosis and fibrosis after weaning. Our aim was to assess cellular mechanisms for disease onset and progression using metabolomics. production and expression of antioxidants.Homozygotes had a similar metabolic profile at 14 days of age as controls, with the exception of slightly decreased AMP. At 24 days, when hepatocytes display first histopathological signs, increases in succinate, fumarate and AMP were found associated with impaired glucose turnover and beta-oxidation. At end stage disease after 30 days, these changes were pronounced with decreased carbohydrates, high levels of acylcarnitines and amino acids, and elevated biogenic amines, especially putrescine. Signs of oxidative stress were present in end-stage disease.The findings suggest an early Krebs cycle defect with increases of its intermediates, which might play a role in disease onset. During disease progression, carbohydrate and fatty acid metabolism deteriorate leading to a starvation-like condition. The mouse model is valuable for further investigations on mechanisms in mitochondrial hepatopathy and for interventions
