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Phenotypic spectrum of 7 patients and 4 novel MTFMT mutations
920
Abstracts
panel test clinically available for it. Thus DES is the sole possible clinical approach to pin down the causative mutations in this family. The molecular diagnosis made through DES enables more efficient targeted therapy for mitochondrial disorders. For example, supplementation of high-dose CoQ10 and riboflavin may benefit the patients with coenzyme Q10 deficiency caused by ADCK3 mutations and riboflavin transporter dysfunction due to SLC52A2 defects, respectively. In summary, our experience demonstrates the clinical utility of DES as an efficient and comprehensive scheme for the diagnosis of mitochondrial disorders caused by nuclear gene mutations. Exome sequencing is unparalleled in searching for the underlying genetic defects in many cases and may guide personalized medical care. doi:10.1016/j.mito.2013.07.057
63 Phenotypic spectrum of 7 patients and 4 novel MTFMT mutations Presenter: Peter Freisinger P. Freisingera,1, T. Haackb,1, J. Mayrc,1, B. Pleckod, U. Ahtingb,1, B. Rolinskie,1, E. Willichowskif, Sperlc,1, H. Prokischb,1 a Department of Paediatrics, Klinikum Reutlingen, Germany b Institute of Human Genetics, Techn. Universität and Helmholtz Zentrum Munich, Germany c Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria d Childrens Hospital, University Zürich, Switzerland e Elblab GmbH Riesa, Germany f Childrens Hospital University, Göttingen, Germany 1 Mitocenter München-Salzburg, Austria. Introduction: Mitochondrial disorders are caused by mutations in structural proteins, assembly factors, cofactors, etc. Recently mutations in genes involved in mitochondrial protein synthesis have been identified. The clinical picture of this group of disorders is rather heterogeneous. One gene, MTFMT is involved in the formylation of MettRNAMet, which is crucial for initiation of mitochondrial translation. Only three patients with mutations in MTFMT have been described so far. We identified with whole exome screening pathogenic mutations in MTFMT in 7 patients from 5 families. Aims: identification of a typical phenotype in MTFMT-disease Method: clinical, radiological, biochemical and genetic comparison. Results: Clinic: the onset of disease was between 1 month and 3 years. The oldest patient is 24 years old. The neurologic symptoms are similar with variable expression: all patients show muscular hypotonia, movement disorder and mental retardation. 5/7 showed ataxia, 4/7 are microcephalic, and 1/7 had seizures. There was no involvement of visceral organs. One patient had a large VSD and suffered from dilated cardiomyopathy. MRI: All patients had symmetrical basal ganglia lesions, 5/7 showed white matter involvement of varying degree reaching from small lesions to extensive leukoencephalopathy. Biochemistry: 7/7 had mild to moderate lactate elevation in plasma. Analysis of respiratory chain function showed reduced activity of complex I in 7/7 patient, in 2/7 combined with complex IV deficiency. Genetics: remarkably all patients carried the mutation c.626CNT either homozygous or compound heterozygous. The other mutations were missense mutations and a deletion. Conclusions: In mitochondrial disorders with mild lactic acidosis, neurologic symptoms without visceral involvement and isolated or combined complex I deficiency mutations in MTFMT should be considered. All patients published so far up carry a mutation c.626 CNT homozygous or compound heterozygous. This might permit initial screening for this mutation (supported by mitoNet Germany). doi:10.1016/j.mito.2013.07.058
64 Exome sequencing as an approach to identify disease causing mutations in pediatric patients with mitochondrial diseases Presenter: Peter Freisinger T. Haacka,1, T. Stroma, P. Freisingerb,1, U. Ahtinga,1, B. Rolinskic,1, J. Mayrd,1, W. Sperld,1, T. Meitingerb,1, H. Prokischb,1 a Institute of Human Genetics, Technische Universität and Helmholtz Zentrum Munich, Germany b Department of Paediatrics, Klinikum Reutlingen, Germany c Elblab GmbH Riesa, Germany d Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg, Austria, 1 Mitocenter München-Salzburg, Austria. Mitochondrial disorders present as a genetically and clinically extremely heterogeneous disease. Up to now 250 mitochondrial genes have been identified, whereas more than 1000 genes are predicted to encode for mitochondrial proteins. To identify disease causing mutations, we applied exome sequencing in combination with stepwise filtering of gene variants and functional complementation for 120 unrelated individuals with childhood and juvenile-onset mitochondrial disorders without pathogenic variants in the mtDNA. We were able to detect mutations in known disease genes in 40% of cases, whereas in 10% novel disease causing genes were identified. The list of such newly identified genes increases steadily: most recently MGME1 was found to be the first exonuclease involved in mitochondrial replication (Kornblum et al., Nat. Genet. 2013). Most notably, it is also possible to detect mutations in genes which are not predicted candidates for being a mitochondrial protein but which cause a clear mitochondriopathy phenotype e.g. mutations in the riboflavin transporter encoding gene SLC52A2. The challenge now is, apart from improving sequencing technology, to annotate variants in non-coding regions, to identify indels and copy number variants, as well as considering how to tackle diseases caused by di- or oligogenic mutations exerting a synergistic effect. Till then, each gene newly identified by exome sequencing holds the promise for new treatment options, as for example riboflavin supplementation in the case of mutations in the riboflavin transporter SLC52A2, and helps to shed more light on mitochondrial physiology (supported by mitoNet Germany). doi:10.1016/j.mito.2013.07.059
65 Bezafibrate as treatment option in patients with mitochondrial complex I deficiency Presenter: Peter Freisinger P. Freisingera,1, B. Haberbergerb,1, V. Streckerc, M. Stegerc, K. Heimc, U. Ahtingb,1, B. Rolinskic,1, J. Mayrd,1, A. Rötige, W. Sperld,1, M. Zevianif, I. Wittigc, T. Meitingerb,1, H. Prokischb,1 a Department of Paediatrics, Klinikum Reutlingen, Germany b Institute of Human Genetics, Technische Universität and Helmholtz Zentrum Munich, Germany c Molekulare Bioenergetik, Goethe-Universität Frankfurt, Frankfurt, Germany d Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg, Austria e Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France f Unit of Child Neurology, Neurological Institute ‘Carlo Besta’-IRCCS Foundation, Milan, Italy 1 Mitocenter München-Salzburg, Austria. Mitochondriopathies are an important cause of metabolic disorders. Rapid progress has been made in identifying the molecular cause, however curative therapeutic options are barely available. Bastin et al.
Abstracts
panel test clinically available for it. Thus DES is the sole possible clinical approach to pin down the causative mutations in this family. The molecular diagnosis made through DES enables more efficient targeted therapy for mitochondrial disorders. For example, supplementation of high-dose CoQ10 and riboflavin may benefit the patients with coenzyme Q10 deficiency caused by ADCK3 mutations and riboflavin transporter dysfunction due to SLC52A2 defects, respectively. In summary, our experience demonstrates the clinical utility of DES as an efficient and comprehensive scheme for the diagnosis of mitochondrial disorders caused by nuclear gene mutations. Exome sequencing is unparalleled in searching for the underlying genetic defects in many cases and may guide personalized medical care. doi:10.1016/j.mito.2013.07.057
63 Phenotypic spectrum of 7 patients and 4 novel MTFMT mutations Presenter: Peter Freisinger P. Freisingera,1, T. Haackb,1, J. Mayrc,1, B. Pleckod, U. Ahtingb,1, B. Rolinskie,1, E. Willichowskif, Sperlc,1, H. Prokischb,1 a Department of Paediatrics, Klinikum Reutlingen, Germany b Institute of Human Genetics, Techn. Universität and Helmholtz Zentrum Munich, Germany c Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria d Childrens Hospital, University Zürich, Switzerland e Elblab GmbH Riesa, Germany f Childrens Hospital University, Göttingen, Germany 1 Mitocenter München-Salzburg, Austria. Introduction: Mitochondrial disorders are caused by mutations in structural proteins, assembly factors, cofactors, etc. Recently mutations in genes involved in mitochondrial protein synthesis have been identified. The clinical picture of this group of disorders is rather heterogeneous. One gene, MTFMT is involved in the formylation of MettRNAMet, which is crucial for initiation of mitochondrial translation. Only three patients with mutations in MTFMT have been described so far. We identified with whole exome screening pathogenic mutations in MTFMT in 7 patients from 5 families. Aims: identification of a typical phenotype in MTFMT-disease Method: clinical, radiological, biochemical and genetic comparison. Results: Clinic: the onset of disease was between 1 month and 3 years. The oldest patient is 24 years old. The neurologic symptoms are similar with variable expression: all patients show muscular hypotonia, movement disorder and mental retardation. 5/7 showed ataxia, 4/7 are microcephalic, and 1/7 had seizures. There was no involvement of visceral organs. One patient had a large VSD and suffered from dilated cardiomyopathy. MRI: All patients had symmetrical basal ganglia lesions, 5/7 showed white matter involvement of varying degree reaching from small lesions to extensive leukoencephalopathy. Biochemistry: 7/7 had mild to moderate lactate elevation in plasma. Analysis of respiratory chain function showed reduced activity of complex I in 7/7 patient, in 2/7 combined with complex IV deficiency. Genetics: remarkably all patients carried the mutation c.626CNT either homozygous or compound heterozygous. The other mutations were missense mutations and a deletion. Conclusions: In mitochondrial disorders with mild lactic acidosis, neurologic symptoms without visceral involvement and isolated or combined complex I deficiency mutations in MTFMT should be considered. All patients published so far up carry a mutation c.626 CNT homozygous or compound heterozygous. This might permit initial screening for this mutation (supported by mitoNet Germany). doi:10.1016/j.mito.2013.07.058
64 Exome sequencing as an approach to identify disease causing mutations in pediatric patients with mitochondrial diseases Presenter: Peter Freisinger T. Haacka,1, T. Stroma, P. Freisingerb,1, U. Ahtinga,1, B. Rolinskic,1, J. Mayrd,1, W. Sperld,1, T. Meitingerb,1, H. Prokischb,1 a Institute of Human Genetics, Technische Universität and Helmholtz Zentrum Munich, Germany b Department of Paediatrics, Klinikum Reutlingen, Germany c Elblab GmbH Riesa, Germany d Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg, Austria, 1 Mitocenter München-Salzburg, Austria. Mitochondrial disorders present as a genetically and clinically extremely heterogeneous disease. Up to now 250 mitochondrial genes have been identified, whereas more than 1000 genes are predicted to encode for mitochondrial proteins. To identify disease causing mutations, we applied exome sequencing in combination with stepwise filtering of gene variants and functional complementation for 120 unrelated individuals with childhood and juvenile-onset mitochondrial disorders without pathogenic variants in the mtDNA. We were able to detect mutations in known disease genes in 40% of cases, whereas in 10% novel disease causing genes were identified. The list of such newly identified genes increases steadily: most recently MGME1 was found to be the first exonuclease involved in mitochondrial replication (Kornblum et al., Nat. Genet. 2013). Most notably, it is also possible to detect mutations in genes which are not predicted candidates for being a mitochondrial protein but which cause a clear mitochondriopathy phenotype e.g. mutations in the riboflavin transporter encoding gene SLC52A2. The challenge now is, apart from improving sequencing technology, to annotate variants in non-coding regions, to identify indels and copy number variants, as well as considering how to tackle diseases caused by di- or oligogenic mutations exerting a synergistic effect. Till then, each gene newly identified by exome sequencing holds the promise for new treatment options, as for example riboflavin supplementation in the case of mutations in the riboflavin transporter SLC52A2, and helps to shed more light on mitochondrial physiology (supported by mitoNet Germany). doi:10.1016/j.mito.2013.07.059
65 Bezafibrate as treatment option in patients with mitochondrial complex I deficiency Presenter: Peter Freisinger P. Freisingera,1, B. Haberbergerb,1, V. Streckerc, M. Stegerc, K. Heimc, U. Ahtingb,1, B. Rolinskic,1, J. Mayrd,1, A. Rötige, W. Sperld,1, M. Zevianif, I. Wittigc, T. Meitingerb,1, H. Prokischb,1 a Department of Paediatrics, Klinikum Reutlingen, Germany b Institute of Human Genetics, Technische Universität and Helmholtz Zentrum Munich, Germany c Molekulare Bioenergetik, Goethe-Universität Frankfurt, Frankfurt, Germany d Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg, Austria e Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France f Unit of Child Neurology, Neurological Institute ‘Carlo Besta’-IRCCS Foundation, Milan, Italy 1 Mitocenter München-Salzburg, Austria. Mitochondriopathies are an important cause of metabolic disorders. Rapid progress has been made in identifying the molecular cause, however curative therapeutic options are barely available. Bastin et al.