Glutaric aciduria type I (GA-1) is a rare autosomal-recessive disorder of the degradation of the ... more Glutaric aciduria type I (GA-1) is a rare autosomal-recessive disorder of the degradation of the amino acids lysine and tryptophan caused by mutations of the GCDH gene encoding glutaryl-CoA-dehydrogenase. Newborn screening (NBS) for this condition is based on elevated levels of glutarylcarnitine (C5DC) in dried blood spots (DBS). Here we report four cases from three families in whom a correctly performed NBS did not detect the condition. Glutarylcarnitine concentrations were either normal (slightly below) or slightly above the cut-off. Ratios to other acylcarnitines were also not persistently elevated. Therefore, three cases were defined as screen negative, and one case was defined as normal, after a normal control DBS sample. One patient was diagnosed after an acute encephalopathic crisis, and the other three patients had an insidious onset of the disease. GA-1 was genetically confirmed in all cases. Despite extensive efforts to increase sensitivity and specificity of NBS for GA-1,...
Zusammenfassung Nach jahrelangen Vorarbeiten wurde nach Erstellung eines Rehabilitationsplans für... more Zusammenfassung Nach jahrelangen Vorarbeiten wurde nach Erstellung eines Rehabilitationsplans für Kinder und Jugendliche, der Betten- und Indikationszuordnungen zu die jeweiligen Gesundheitsregionen und auch der Klärung der Finanzierung der Tagessätze nun die Errichtung von Kinder- und Jugendlichenrehabilitationszentren in Österreich durchgeführt. Der Start ist gelungen, engagierte MitarbeiterInnen konnten in allen Berufsbereichen für eine kinder- und jugendlichensspezifische Rehabilitation gewonnen werden. Kritische Punkte sind die Mitaufnahme von Begleitpersonen bzw. anderer Familienangehöriger, wobei eine Z-Diagnose für Begleitpersonen analog der familienorientierten Rehabilitation hämatoonkologischer Kinder für alle Indikationen wichtig wäre, um die entsprechende Freistellung vom Arbeitgeber zu bekommen. Ein wesentlicher Punkt ist auch die fallweise Ausweitung der familienorientierten Rehabilitation über die Hämatoonkologie hinaus. Die Transition sollte ebenfalls geregelt werden...
Isolated complex I deficiency is a common biochemical phenotype observed in pediatric mitochondri... more Isolated complex I deficiency is a common biochemical phenotype observed in pediatric mitochondrial disease and often arises as a consequence of pathogenic variants affecting one of the ∼65 genes encoding the complex I structural subunits or assembly factors. Such genetic heterogeneity means that application of next-generation sequencing technologies to undiagnosed cohorts has been a catalyst for genetic diagnosis and gene-disease associations. We describe the clinical and molecular genetic investigations of four unrelated children who presented with neuroradiological findings and/or elevated lactate levels, highly suggestive of an underlying mitochondrial diagnosis. Next-generation sequencing identified bi-allelic variants in NDUFA6, encoding a 15 kDa LYR-motif-containing complex I subunit that forms part of the Q-module. Functional investigations using subjects' fibroblast cell lines demonstrated complex I assembly defects, which were characterized in detail by mass-spectromet...
The Warburg theory of cancer postulates that an important driver of tumorigenesis is insufficient... more The Warburg theory of cancer postulates that an important driver of tumorigenesis is insufficient respiration due to mitochondrial defects, and concomitant enhancement of lactate production due to increased aerobic glycolysis. We analysed 48 melanoma samples by immunohistochemistry and found that 38% of melanomas are characterized by areas of isolated or combined deficiencies of complexes of the oxidative phosphorylation (OXPHOS) system, whereby the incidence of OXPHOS-deficient areas is associated with an increased Breslow index; 62% of melanomas showed high expression of all OXPHOS complexes. Expression of carbonic anhydrase IX was low, indicating that melanomas generally are well-oxygenated. Expression of HIF-1α and MCT4 was high, which might be a consequence of increased lactate dehydrogenase A levels in melanomas. Our data indicate that there are two types of melanomas: one that features a classic Warburg effect, whereas the other one, despite being glycolytic, maintains a high...
The papillary thyroid carcinoma (PTC) is the most common malignant tumor of the thyroid gland, wi... more The papillary thyroid carcinoma (PTC) is the most common malignant tumor of the thyroid gland, with disruptive mutations in mitochondrial complex I subunits reported at very low frequency. Furthermore, metabolic diversity of PTC has been postulated owing to variable messenger RNA (mRNA) expression of genes encoding subunits of the oxidative phosphorylation (OXHPOS) complexes. The aim of the present study was to evaluate the metabolic diversity of the OXPHOS system at the protein level by using immunohistochemical staining. Analysis of 18 human PTCs revealed elevated mitochondrial biogenesis but significantly lower levels of OXPHOS complex I in the tumor tissue ( < 0.0001) compared to the adjacent normal tissue. In contrast, OXPHOS complexes II⁻V were increased in the majority of PTCs. In three PTCs, we found pathologic mutations within mitochondrially encoded complex I subunits. Our data indicate that PTCs are characterized by an oncocytic metabolic signature that is in low compl...
Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mit... more Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy. We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), ...
Biogenesis of the mitochondrial oxidative phosphorylation system, which produces the bulk of ATP ... more Biogenesis of the mitochondrial oxidative phosphorylation system, which produces the bulk of ATP for almost all eukaryotic cells, depends on the translation of 13 mtDNA-encoded polypeptides by mitochondria-specific ribosomes in the mitochondrial matrix. These mitoribosomes are dual-origin ribonucleoprotein complexes, which contain mtDNA-encoded rRNAs and tRNAs and ∼80 nucleus-encoded proteins. An increasing number of gene mutations that impair mitoribosomal function and result in multiple OXPHOS deficiencies are being linked to human mitochondrial diseases. Using exome sequencing in two unrelated subjects presenting with sensorineural hearing impairment, mild developmental delay, hypoglycemia, and a combined OXPHOS deficiency, we identified mutations in the gene encoding the mitochondrial ribosomal protein S2, which has not previously been implicated in disease. Characterization of subjects' fibroblasts revealed a decrease in the steady-state amounts of mutant MRPS2, and this de...
Respiratory chain complex I deficiency is the most frequently identified biochemical defect in ch... more Respiratory chain complex I deficiency is the most frequently identified biochemical defect in childhood mitochondrial diseases. Clinical symptoms range from fatal infantile lactic acidosis to Leigh syndrome and other encephalomyopathies or cardiomyopathies. To date, disease-causing variants in genes coding for 27 complex I subunits, including 7 mitochondrial DNA genes, and in 11 genes encoding complex I assembly factors have been reported. Here, we describe rare biallelic variants in NDUFB8 encoding a complex I accessory subunit revealed by whole-exome sequencing in two individuals from two families. Both presented with a progressive course of disease with encephalo(cardio)myopathic features including muscular hypotonia, cardiac hypertrophy, respiratory failure, failure to thrive, and developmental delay. Blood lactate was elevated. Neuroimaging disclosed progressive changes in the basal ganglia and either brain stem or internal capsule. Biochemical analyses showed an isolated decr...
Folates enable the activation and transfer of one-carbon units for the biosynthesis of purines, t... more Folates enable the activation and transfer of one-carbon units for the biosynthesis of purines, thymidine and methionine. Antifolates are important immunosuppressive and anticancer agents. In proliferating lymphocytes and human cancers, mitochondrial folate enzymes are particularly strongly upregulated. This in part reflects the need for mitochondria to generate one-carbon units and export them to the cytosol for anabolic metabolism. The full range of uses of folate-bound one-carbon units in the mitochondrial compartment itself, however, has not been thoroughly explored. Here we show that loss of the catalytic activity of the mitochondrial folate enzyme serine hydroxymethyltransferase 2 (SHMT2), but not of other folate enzymes, leads to defective oxidative phosphorylation in human cells due to impaired mitochondrial translation. We find that SHMT2, presumably by generating mitochondrial 5,10-methylenetetrahydrofolate, provides methyl donors to produce the taurinomethyluridine base a...
3-Methylglutaconic aciduria, dystonia-deafness, hepatopathy, encephalopathy, Leigh-like syndrome ... more 3-Methylglutaconic aciduria, dystonia-deafness, hepatopathy, encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1. This multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported. Sixty-seven individuals (39 previously unreported) from 59 families were included (age range = 5 days-33.4 years, median age = 9 years). A total of 41 different SERAC1 variants were identified, including 20 that have not been reported before. With the exception of 2 families with a milder phenotype, all affected individuals showed a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia were seen in >40% of all cases. Starting at a median age of 6 months, muscular hypotonia (91%) was seen, followed by progressive spasticity (82%, median onset = 15 months) and dystonia (82%, 18 months). The majority of affected individuals neve...
Therapie schwer behandelbarer Epilepsien bei Kindern und Jugendlichen Zusammenfassung Bei Vorlieg... more Therapie schwer behandelbarer Epilepsien bei Kindern und Jugendlichen Zusammenfassung Bei Vorliegen einer schwer behandelbaren Epilepsie gilt es nach Überprüfung der Syndromdiagnose die individuell aussichtsreichste Behandlung zu wählen. Die Epilepsiechirurgie stellt mit postoperativen Anfallsfreiheitsraten von 50-70% die Therapie der Wahl dar, falls ein solcher Eingriff bei einem individuellen Patienten möglich ist. Eine derartige Operation kommt für etwa 10-15% der Kinder mit schwer behandelbaren Epilepsien in Frage. Die Anwendung weiterer Antiepileptika erfordert eine große Erfahrung und Kenntnis um Wirksamkeitsspektren und Nebenwirkungspotenzial der Medikamente. Im Fall einer Kombinationsbehandlung müssen potenzielle Wechselwirkungen berücksichtigt werden. Als alternative Behandlungsformen kommen Vagusnervstimulation und ketogene Diät in Frage. Das Vorliegen einer schwer behandelbaren Epilepsie erfordert ein interdisziplinäres Behandlungskonzept unter besonderer Berücksichtigung psychosozialer Aspekte.
3-Methyl-Glutaconic aciduria, Dystonia-Deafness, Hepatopathy, Encephalopathy, Leigh-like syndrome... more 3-Methyl-Glutaconic aciduria, Dystonia-Deafness, Hepatopathy, Encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1. Multi centre study concerning the course of disease for each organ system, together with metabolic, neuroradiological and genetic findings. 67 individuals (39 previously unreported) from 59 families were included (age range 5 days - 33.4 years, median age 9 years). A total of 41 different SERAC1 variants were identified, including 20 that have not been reported before. With exception of two families with a milder phenotype, all affected individuals show a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia was seen in more than 40% of all cases. Starting at a median age of six months muscular hypotonia (91%) was seen, followed by progressive spasticity (82%, median onset 15 months) and dystonia (82%, 18 months). The majority of affected individuals never learnt to w...
LYRM7 is involved in the last steps of mitochondrial complex III assembly where it acts as a chap... more LYRM7 is involved in the last steps of mitochondrial complex III assembly where it acts as a chaperone for the Rieske iron‑sulfur (Fe-S) protein in the mitochondrial matrix. Using exome sequencing, we identified homozygosity for a splice site destroying 4 base pair deletion in LYRM7 in a child with recurrent lactic acidotic crises and distinct early-onset leukencephalopathy. Sanger sequencing showed variant segregation in similarly affected family members. Functional analyses revealed a reduced amount of the Rieske Fe-S protein, which was restored after re-expression of LYRM7. Our data provide further evidence for the importance of LYRM7 for mitochondrial function and emphasize the importance of whole exome sequencing in the diagnosis of rare mitochondrial diseases.
Switching of cellular energy production from oxidative phosphorylation (OXPHOS) by mitochondria t... more Switching of cellular energy production from oxidative phosphorylation (OXPHOS) by mitochondria to aerobic glycolysis occurs in many types of tumors. However, the significance of this switching for the development of gastric carcinoma and what connection it may have to Helicobacter pylori infection of the gut, a primary cause of gastric cancer, are poorly understood. Therefore, we investigated the expression of OXPHOS complexes in two types of human gastric carcinomas (“intestinal” and “diffuse”), bacterial gastritis with and without metaplasia, and chemically induced gastritis by using immunohistochemistry. Furthermore, we analyzed the effect of HP infection on several key mitochondrial proteins. Complex I expression was significantly reduced in intestinal type (but not diffuse) gastric carcinomas compared to adjacent control tissue, and the reduction was independent of HP infection. Significantly, higher complex I and complex II expression was present in large tumors. Furthermore,...
The following work is licensed under a Creative Commons: Attribution-NonCommercial-NoDerivatives ... more The following work is licensed under a Creative Commons: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) License.
Mitochondrial diseases are highly heterogeneous on the clinical, biochemical, and genetic level. ... more Mitochondrial diseases are highly heterogeneous on the clinical, biochemical, and genetic level. In the traditional diagnostic approach (“biopsy first”) the evaluation of the affected individual and his body fluids, combined with the analysis of the respiratory chain enzymes in muscle based the subsequent Sanger sequencing of single candidate genes (“from function to gene”). Within the past few years, next-generation sequencing techniques of leucocyte-derived DNA (e.g., exome sequencing), with a diagnostic yield of more than 40%, have become the first line routine technology. This implicates that the invasive muscle biopsy is performed less often, especially in children. Furthermore, in this “genetics-first” approach the detection of new candidate genes precedes functional evaluations (“from gene to function”) leading to reverse phenotyping of affected individuals. Here, we line out the value of muscle and other tissue biopsies in this “genetics-first” era. We describe when and why ...
Complement component 1 Q subcomponent-binding protein (C1QBP; also known as p32) is a multi-compa... more Complement component 1 Q subcomponent-binding protein (C1QBP; also known as p32) is a multi-compartmental protein whose precise function remains unknown. It is an evolutionary conserved multifunctional protein localized primarily in the mitochondrial matrix and has roles in inflammation and infection processes, mitochondrial ribosome biogenesis, and regulation of apoptosis and nuclear transcription. It has an N-terminal mitochondrial targeting peptide that is proteolytically processed after import into the mitochondrial matrix, where it forms a homotrimeric complex organized in a doughnut-shaped structure. Although C1QBP has been reported to exert pleiotropic effects on many cellular processes, we report here four individuals from unrelated families where biallelic mutations in C1QBP cause a defect in mitochondrial energy metabolism. Infants presented with cardiomyopathy accompanied by multisystemic involvement (liver, kidney, and brain), and children and adults presented with myopathy and progressive external ophthalmoplegia. Multiple mitochondrial respiratory-chain defects, associated with the accumulation of multiple deletions of mitochondrial DNA in the later-onset myopathic cases, were identified in all affected individuals. Steady-state C1QBP levels were decreased in all individuals' samples, leading to combined respiratory-chain enzyme deficiency of complexes I, III, and IV. C1qbp-/mouse embryonic fibroblasts (MEFs) resembled the human disease phenotype by showing multiple defects in oxidative phosphorylation (OXPHOS). Complementation with wild-type, but not mutagenized, C1qbp restored OXPHOS protein levels and mitochondrial enzyme activities in C1qbp-/-MEFs. C1QBP deficiency represents an important mitochondrial disorder associated with a clinical spectrum ranging from infantile lactic acidosis to childhood (cardio)myopathy and late-onset progressive external ophthalmoplegia.
F-box and leucine-rich repeat protein 4 (FBXL4) is a mitochondrial protein whose exact function i... more F-box and leucine-rich repeat protein 4 (FBXL4) is a mitochondrial protein whose exact function is not yet known. However, cellular studies have suggested that it plays significant roles in mitochondrial bioenergetics, mitochondrial DNA (mtDNA) maintenance, and mitochondrial dynamics. Biallelic pathogenic variants in FBXL4 are associated with an encephalopathic mtDNA maintenance defect syndrome that is a multisystem disease characterized by lactic acidemia, developmental delay, and hypotonia. Other features are feeding difficulties, growth failure, microcephaly, hyperammonemia, seizures, hypertrophic cardiomyopathy, elevated liver transaminases, recurrent infections, variable distinctive facial features, white matter abnormalities and cerebral atrophy found in neuroimaging, combined deficiencies of multiple electron transport complexes, and mtDNA depletion. Since its initial description in 2013, 36 different pathogenic variants in FBXL4 were reported in 50 affected individuals. In this report, we present 37 additional affected individuals and 11 previously unreported pathogenic variants. We summarize the clinical features of all 87 individuals with FBXL4-related mtDNA maintenance defect, review FBXL4 structure and function, map the 47 pathogenic variants onto the gene structure to assess the variants distribution, and investigate the genotype-phenotype correlation. Finally, we provide future directions to understand the disease mechanism and identify treatment strategies. This article is protected by copyright. All rights reserved.
Glutaric aciduria type I (GA-1) is a rare autosomal-recessive disorder of the degradation of the ... more Glutaric aciduria type I (GA-1) is a rare autosomal-recessive disorder of the degradation of the amino acids lysine and tryptophan caused by mutations of the GCDH gene encoding glutaryl-CoA-dehydrogenase. Newborn screening (NBS) for this condition is based on elevated levels of glutarylcarnitine (C5DC) in dried blood spots (DBS). Here we report four cases from three families in whom a correctly performed NBS did not detect the condition. Glutarylcarnitine concentrations were either normal (slightly below) or slightly above the cut-off. Ratios to other acylcarnitines were also not persistently elevated. Therefore, three cases were defined as screen negative, and one case was defined as normal, after a normal control DBS sample. One patient was diagnosed after an acute encephalopathic crisis, and the other three patients had an insidious onset of the disease. GA-1 was genetically confirmed in all cases. Despite extensive efforts to increase sensitivity and specificity of NBS for GA-1,...
Zusammenfassung Nach jahrelangen Vorarbeiten wurde nach Erstellung eines Rehabilitationsplans für... more Zusammenfassung Nach jahrelangen Vorarbeiten wurde nach Erstellung eines Rehabilitationsplans für Kinder und Jugendliche, der Betten- und Indikationszuordnungen zu die jeweiligen Gesundheitsregionen und auch der Klärung der Finanzierung der Tagessätze nun die Errichtung von Kinder- und Jugendlichenrehabilitationszentren in Österreich durchgeführt. Der Start ist gelungen, engagierte MitarbeiterInnen konnten in allen Berufsbereichen für eine kinder- und jugendlichensspezifische Rehabilitation gewonnen werden. Kritische Punkte sind die Mitaufnahme von Begleitpersonen bzw. anderer Familienangehöriger, wobei eine Z-Diagnose für Begleitpersonen analog der familienorientierten Rehabilitation hämatoonkologischer Kinder für alle Indikationen wichtig wäre, um die entsprechende Freistellung vom Arbeitgeber zu bekommen. Ein wesentlicher Punkt ist auch die fallweise Ausweitung der familienorientierten Rehabilitation über die Hämatoonkologie hinaus. Die Transition sollte ebenfalls geregelt werden...
Isolated complex I deficiency is a common biochemical phenotype observed in pediatric mitochondri... more Isolated complex I deficiency is a common biochemical phenotype observed in pediatric mitochondrial disease and often arises as a consequence of pathogenic variants affecting one of the ∼65 genes encoding the complex I structural subunits or assembly factors. Such genetic heterogeneity means that application of next-generation sequencing technologies to undiagnosed cohorts has been a catalyst for genetic diagnosis and gene-disease associations. We describe the clinical and molecular genetic investigations of four unrelated children who presented with neuroradiological findings and/or elevated lactate levels, highly suggestive of an underlying mitochondrial diagnosis. Next-generation sequencing identified bi-allelic variants in NDUFA6, encoding a 15 kDa LYR-motif-containing complex I subunit that forms part of the Q-module. Functional investigations using subjects' fibroblast cell lines demonstrated complex I assembly defects, which were characterized in detail by mass-spectromet...
The Warburg theory of cancer postulates that an important driver of tumorigenesis is insufficient... more The Warburg theory of cancer postulates that an important driver of tumorigenesis is insufficient respiration due to mitochondrial defects, and concomitant enhancement of lactate production due to increased aerobic glycolysis. We analysed 48 melanoma samples by immunohistochemistry and found that 38% of melanomas are characterized by areas of isolated or combined deficiencies of complexes of the oxidative phosphorylation (OXPHOS) system, whereby the incidence of OXPHOS-deficient areas is associated with an increased Breslow index; 62% of melanomas showed high expression of all OXPHOS complexes. Expression of carbonic anhydrase IX was low, indicating that melanomas generally are well-oxygenated. Expression of HIF-1α and MCT4 was high, which might be a consequence of increased lactate dehydrogenase A levels in melanomas. Our data indicate that there are two types of melanomas: one that features a classic Warburg effect, whereas the other one, despite being glycolytic, maintains a high...
The papillary thyroid carcinoma (PTC) is the most common malignant tumor of the thyroid gland, wi... more The papillary thyroid carcinoma (PTC) is the most common malignant tumor of the thyroid gland, with disruptive mutations in mitochondrial complex I subunits reported at very low frequency. Furthermore, metabolic diversity of PTC has been postulated owing to variable messenger RNA (mRNA) expression of genes encoding subunits of the oxidative phosphorylation (OXHPOS) complexes. The aim of the present study was to evaluate the metabolic diversity of the OXPHOS system at the protein level by using immunohistochemical staining. Analysis of 18 human PTCs revealed elevated mitochondrial biogenesis but significantly lower levels of OXPHOS complex I in the tumor tissue ( < 0.0001) compared to the adjacent normal tissue. In contrast, OXPHOS complexes II⁻V were increased in the majority of PTCs. In three PTCs, we found pathologic mutations within mitochondrially encoded complex I subunits. Our data indicate that PTCs are characterized by an oncocytic metabolic signature that is in low compl...
Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mit... more Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy. We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), ...
Biogenesis of the mitochondrial oxidative phosphorylation system, which produces the bulk of ATP ... more Biogenesis of the mitochondrial oxidative phosphorylation system, which produces the bulk of ATP for almost all eukaryotic cells, depends on the translation of 13 mtDNA-encoded polypeptides by mitochondria-specific ribosomes in the mitochondrial matrix. These mitoribosomes are dual-origin ribonucleoprotein complexes, which contain mtDNA-encoded rRNAs and tRNAs and ∼80 nucleus-encoded proteins. An increasing number of gene mutations that impair mitoribosomal function and result in multiple OXPHOS deficiencies are being linked to human mitochondrial diseases. Using exome sequencing in two unrelated subjects presenting with sensorineural hearing impairment, mild developmental delay, hypoglycemia, and a combined OXPHOS deficiency, we identified mutations in the gene encoding the mitochondrial ribosomal protein S2, which has not previously been implicated in disease. Characterization of subjects' fibroblasts revealed a decrease in the steady-state amounts of mutant MRPS2, and this de...
Respiratory chain complex I deficiency is the most frequently identified biochemical defect in ch... more Respiratory chain complex I deficiency is the most frequently identified biochemical defect in childhood mitochondrial diseases. Clinical symptoms range from fatal infantile lactic acidosis to Leigh syndrome and other encephalomyopathies or cardiomyopathies. To date, disease-causing variants in genes coding for 27 complex I subunits, including 7 mitochondrial DNA genes, and in 11 genes encoding complex I assembly factors have been reported. Here, we describe rare biallelic variants in NDUFB8 encoding a complex I accessory subunit revealed by whole-exome sequencing in two individuals from two families. Both presented with a progressive course of disease with encephalo(cardio)myopathic features including muscular hypotonia, cardiac hypertrophy, respiratory failure, failure to thrive, and developmental delay. Blood lactate was elevated. Neuroimaging disclosed progressive changes in the basal ganglia and either brain stem or internal capsule. Biochemical analyses showed an isolated decr...
Folates enable the activation and transfer of one-carbon units for the biosynthesis of purines, t... more Folates enable the activation and transfer of one-carbon units for the biosynthesis of purines, thymidine and methionine. Antifolates are important immunosuppressive and anticancer agents. In proliferating lymphocytes and human cancers, mitochondrial folate enzymes are particularly strongly upregulated. This in part reflects the need for mitochondria to generate one-carbon units and export them to the cytosol for anabolic metabolism. The full range of uses of folate-bound one-carbon units in the mitochondrial compartment itself, however, has not been thoroughly explored. Here we show that loss of the catalytic activity of the mitochondrial folate enzyme serine hydroxymethyltransferase 2 (SHMT2), but not of other folate enzymes, leads to defective oxidative phosphorylation in human cells due to impaired mitochondrial translation. We find that SHMT2, presumably by generating mitochondrial 5,10-methylenetetrahydrofolate, provides methyl donors to produce the taurinomethyluridine base a...
3-Methylglutaconic aciduria, dystonia-deafness, hepatopathy, encephalopathy, Leigh-like syndrome ... more 3-Methylglutaconic aciduria, dystonia-deafness, hepatopathy, encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1. This multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported. Sixty-seven individuals (39 previously unreported) from 59 families were included (age range = 5 days-33.4 years, median age = 9 years). A total of 41 different SERAC1 variants were identified, including 20 that have not been reported before. With the exception of 2 families with a milder phenotype, all affected individuals showed a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia were seen in >40% of all cases. Starting at a median age of 6 months, muscular hypotonia (91%) was seen, followed by progressive spasticity (82%, median onset = 15 months) and dystonia (82%, 18 months). The majority of affected individuals neve...
Therapie schwer behandelbarer Epilepsien bei Kindern und Jugendlichen Zusammenfassung Bei Vorlieg... more Therapie schwer behandelbarer Epilepsien bei Kindern und Jugendlichen Zusammenfassung Bei Vorliegen einer schwer behandelbaren Epilepsie gilt es nach Überprüfung der Syndromdiagnose die individuell aussichtsreichste Behandlung zu wählen. Die Epilepsiechirurgie stellt mit postoperativen Anfallsfreiheitsraten von 50-70% die Therapie der Wahl dar, falls ein solcher Eingriff bei einem individuellen Patienten möglich ist. Eine derartige Operation kommt für etwa 10-15% der Kinder mit schwer behandelbaren Epilepsien in Frage. Die Anwendung weiterer Antiepileptika erfordert eine große Erfahrung und Kenntnis um Wirksamkeitsspektren und Nebenwirkungspotenzial der Medikamente. Im Fall einer Kombinationsbehandlung müssen potenzielle Wechselwirkungen berücksichtigt werden. Als alternative Behandlungsformen kommen Vagusnervstimulation und ketogene Diät in Frage. Das Vorliegen einer schwer behandelbaren Epilepsie erfordert ein interdisziplinäres Behandlungskonzept unter besonderer Berücksichtigung psychosozialer Aspekte.
3-Methyl-Glutaconic aciduria, Dystonia-Deafness, Hepatopathy, Encephalopathy, Leigh-like syndrome... more 3-Methyl-Glutaconic aciduria, Dystonia-Deafness, Hepatopathy, Encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1. Multi centre study concerning the course of disease for each organ system, together with metabolic, neuroradiological and genetic findings. 67 individuals (39 previously unreported) from 59 families were included (age range 5 days - 33.4 years, median age 9 years). A total of 41 different SERAC1 variants were identified, including 20 that have not been reported before. With exception of two families with a milder phenotype, all affected individuals show a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia was seen in more than 40% of all cases. Starting at a median age of six months muscular hypotonia (91%) was seen, followed by progressive spasticity (82%, median onset 15 months) and dystonia (82%, 18 months). The majority of affected individuals never learnt to w...
LYRM7 is involved in the last steps of mitochondrial complex III assembly where it acts as a chap... more LYRM7 is involved in the last steps of mitochondrial complex III assembly where it acts as a chaperone for the Rieske iron‑sulfur (Fe-S) protein in the mitochondrial matrix. Using exome sequencing, we identified homozygosity for a splice site destroying 4 base pair deletion in LYRM7 in a child with recurrent lactic acidotic crises and distinct early-onset leukencephalopathy. Sanger sequencing showed variant segregation in similarly affected family members. Functional analyses revealed a reduced amount of the Rieske Fe-S protein, which was restored after re-expression of LYRM7. Our data provide further evidence for the importance of LYRM7 for mitochondrial function and emphasize the importance of whole exome sequencing in the diagnosis of rare mitochondrial diseases.
Switching of cellular energy production from oxidative phosphorylation (OXPHOS) by mitochondria t... more Switching of cellular energy production from oxidative phosphorylation (OXPHOS) by mitochondria to aerobic glycolysis occurs in many types of tumors. However, the significance of this switching for the development of gastric carcinoma and what connection it may have to Helicobacter pylori infection of the gut, a primary cause of gastric cancer, are poorly understood. Therefore, we investigated the expression of OXPHOS complexes in two types of human gastric carcinomas (“intestinal” and “diffuse”), bacterial gastritis with and without metaplasia, and chemically induced gastritis by using immunohistochemistry. Furthermore, we analyzed the effect of HP infection on several key mitochondrial proteins. Complex I expression was significantly reduced in intestinal type (but not diffuse) gastric carcinomas compared to adjacent control tissue, and the reduction was independent of HP infection. Significantly, higher complex I and complex II expression was present in large tumors. Furthermore,...
The following work is licensed under a Creative Commons: Attribution-NonCommercial-NoDerivatives ... more The following work is licensed under a Creative Commons: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) License.
Mitochondrial diseases are highly heterogeneous on the clinical, biochemical, and genetic level. ... more Mitochondrial diseases are highly heterogeneous on the clinical, biochemical, and genetic level. In the traditional diagnostic approach (“biopsy first”) the evaluation of the affected individual and his body fluids, combined with the analysis of the respiratory chain enzymes in muscle based the subsequent Sanger sequencing of single candidate genes (“from function to gene”). Within the past few years, next-generation sequencing techniques of leucocyte-derived DNA (e.g., exome sequencing), with a diagnostic yield of more than 40%, have become the first line routine technology. This implicates that the invasive muscle biopsy is performed less often, especially in children. Furthermore, in this “genetics-first” approach the detection of new candidate genes precedes functional evaluations (“from gene to function”) leading to reverse phenotyping of affected individuals. Here, we line out the value of muscle and other tissue biopsies in this “genetics-first” era. We describe when and why ...
Complement component 1 Q subcomponent-binding protein (C1QBP; also known as p32) is a multi-compa... more Complement component 1 Q subcomponent-binding protein (C1QBP; also known as p32) is a multi-compartmental protein whose precise function remains unknown. It is an evolutionary conserved multifunctional protein localized primarily in the mitochondrial matrix and has roles in inflammation and infection processes, mitochondrial ribosome biogenesis, and regulation of apoptosis and nuclear transcription. It has an N-terminal mitochondrial targeting peptide that is proteolytically processed after import into the mitochondrial matrix, where it forms a homotrimeric complex organized in a doughnut-shaped structure. Although C1QBP has been reported to exert pleiotropic effects on many cellular processes, we report here four individuals from unrelated families where biallelic mutations in C1QBP cause a defect in mitochondrial energy metabolism. Infants presented with cardiomyopathy accompanied by multisystemic involvement (liver, kidney, and brain), and children and adults presented with myopathy and progressive external ophthalmoplegia. Multiple mitochondrial respiratory-chain defects, associated with the accumulation of multiple deletions of mitochondrial DNA in the later-onset myopathic cases, were identified in all affected individuals. Steady-state C1QBP levels were decreased in all individuals' samples, leading to combined respiratory-chain enzyme deficiency of complexes I, III, and IV. C1qbp-/mouse embryonic fibroblasts (MEFs) resembled the human disease phenotype by showing multiple defects in oxidative phosphorylation (OXPHOS). Complementation with wild-type, but not mutagenized, C1qbp restored OXPHOS protein levels and mitochondrial enzyme activities in C1qbp-/-MEFs. C1QBP deficiency represents an important mitochondrial disorder associated with a clinical spectrum ranging from infantile lactic acidosis to childhood (cardio)myopathy and late-onset progressive external ophthalmoplegia.
F-box and leucine-rich repeat protein 4 (FBXL4) is a mitochondrial protein whose exact function i... more F-box and leucine-rich repeat protein 4 (FBXL4) is a mitochondrial protein whose exact function is not yet known. However, cellular studies have suggested that it plays significant roles in mitochondrial bioenergetics, mitochondrial DNA (mtDNA) maintenance, and mitochondrial dynamics. Biallelic pathogenic variants in FBXL4 are associated with an encephalopathic mtDNA maintenance defect syndrome that is a multisystem disease characterized by lactic acidemia, developmental delay, and hypotonia. Other features are feeding difficulties, growth failure, microcephaly, hyperammonemia, seizures, hypertrophic cardiomyopathy, elevated liver transaminases, recurrent infections, variable distinctive facial features, white matter abnormalities and cerebral atrophy found in neuroimaging, combined deficiencies of multiple electron transport complexes, and mtDNA depletion. Since its initial description in 2013, 36 different pathogenic variants in FBXL4 were reported in 50 affected individuals. In this report, we present 37 additional affected individuals and 11 previously unreported pathogenic variants. We summarize the clinical features of all 87 individuals with FBXL4-related mtDNA maintenance defect, review FBXL4 structure and function, map the 47 pathogenic variants onto the gene structure to assess the variants distribution, and investigate the genotype-phenotype correlation. Finally, we provide future directions to understand the disease mechanism and identify treatment strategies. This article is protected by copyright. All rights reserved.
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