The term "mitochondrial disorders" has been applied to clinical syndromes associated with abnormalities of the common final pathway of mitochondrial energy metabolism. Neurodegeneration and neuronal dysfunction underlie the most prominent and disabling features of mitochondrial diseases. They can manifest with variable clinical presentation ranging from a focal deficit, such as optic neuropathy, to necrotic lesions of the basal ganglia and brain stem nuclei and even to more global processes such as progressive dementia and ataxia. We reviewed our cohort of pediatric patients (n=22, age of onset between 2 months and 7 years old) affected by mitochondrial disorders, collected in our Center in the last years. An in-depth clinical assessment was performed. Biochemical and histological studies on muscle biopsy were performed on almost patients. Molecular studies included: mitochondrial DNA investigations (Southern blot, qPCR, direct sequencing) and sequence analysis of several nuclear genes related to mitochondrial disorders. Main clinical symptoms shared by our patients included: mental retardation, developmental delay, hypotonia and hypotrophy, ptosis. Epileptic seizures, revealed by EEG investigations were often observed (8 of 22 cases). RMN or CT scans showed necrotic lesions in several brain regions in 14 patients. Isolated respiratory chain complex I and IV defects were observed in five and four patients, respectively. Multiple complex deficit was observed in 12 patients, mainly affected (n=7) by mitochondrial DNA depletion syndrome. Molecular diagnosis was achieved in 16 patients (72.7% of the sample). In particular, pathogenic mutations in mitochondrial DNA were disclosed in a third of subjects in genes encoding respiratory chain structural subunits, namely complex I (ND3, -5, -6) and complex IV (MT-COII) or mitochondrial tRNAs (MT-TL1, MT-TH). Pathways leading to pathogenesis due to nuclear DNA mutations included respiratory chain assembly (SURF1), mtDNA homeostasis (TK2) or mitochondrial import (GFER). The in-depth clinical evaluation and the knowledge acquired in the last 20 years contributed to the high mutation rate found in our relatively small sample of highly selected pediatric cases Clinical involvement of CNS is observed in all the patients of our cohort. Biochemical and molecular features leading to mitochondrial encephalopathy will be discussed. Elucidating the genetic bases of mitochondrial diseases is essential for genetic diagnosis of patients, for fundamental knowledge of these disorders and for the development of rational therapy.
CNS involvement in a cohort of pediatric patients affected with mitochondrial disorders caused by heterogeneous biochemical and genetic defects / D. Ronchi, S. Orcesi, V. Spartà, A. Cosi, A. Bordoni, V. Lucchini, F. Fortunato, E. Fassone, D. Tonduti, G. Rulfi, M. Ranieri, M. Rizzuti, M. Ripolone, M. Sciacco, M. Moggio, S. Corti, S. Savata, A. Berardinelli, P. Veggiotti, G.P. Comi. ((Intervento presentato al convegno SFN tenutosi a Washington nel 2011.
CNS involvement in a cohort of pediatric patients affected with mitochondrial disorders caused by heterogeneous biochemical and genetic defects
D. RonchiPrimo
;A. Cosi;A. Bordoni;V. Lucchini;F. Fortunato;E. Fassone;D. Tonduti;M. Ranieri;M. Ripolone;S. Corti;P. Veggiotti;G.P. Comi
2011
Abstract
The term "mitochondrial disorders" has been applied to clinical syndromes associated with abnormalities of the common final pathway of mitochondrial energy metabolism. Neurodegeneration and neuronal dysfunction underlie the most prominent and disabling features of mitochondrial diseases. They can manifest with variable clinical presentation ranging from a focal deficit, such as optic neuropathy, to necrotic lesions of the basal ganglia and brain stem nuclei and even to more global processes such as progressive dementia and ataxia. We reviewed our cohort of pediatric patients (n=22, age of onset between 2 months and 7 years old) affected by mitochondrial disorders, collected in our Center in the last years. An in-depth clinical assessment was performed. Biochemical and histological studies on muscle biopsy were performed on almost patients. Molecular studies included: mitochondrial DNA investigations (Southern blot, qPCR, direct sequencing) and sequence analysis of several nuclear genes related to mitochondrial disorders. Main clinical symptoms shared by our patients included: mental retardation, developmental delay, hypotonia and hypotrophy, ptosis. Epileptic seizures, revealed by EEG investigations were often observed (8 of 22 cases). RMN or CT scans showed necrotic lesions in several brain regions in 14 patients. Isolated respiratory chain complex I and IV defects were observed in five and four patients, respectively. Multiple complex deficit was observed in 12 patients, mainly affected (n=7) by mitochondrial DNA depletion syndrome. Molecular diagnosis was achieved in 16 patients (72.7% of the sample). In particular, pathogenic mutations in mitochondrial DNA were disclosed in a third of subjects in genes encoding respiratory chain structural subunits, namely complex I (ND3, -5, -6) and complex IV (MT-COII) or mitochondrial tRNAs (MT-TL1, MT-TH). Pathways leading to pathogenesis due to nuclear DNA mutations included respiratory chain assembly (SURF1), mtDNA homeostasis (TK2) or mitochondrial import (GFER). The in-depth clinical evaluation and the knowledge acquired in the last 20 years contributed to the high mutation rate found in our relatively small sample of highly selected pediatric cases Clinical involvement of CNS is observed in all the patients of our cohort. Biochemical and molecular features leading to mitochondrial encephalopathy will be discussed. Elucidating the genetic bases of mitochondrial diseases is essential for genetic diagnosis of patients, for fundamental knowledge of these disorders and for the development of rational therapy.Pubblicazioni consigliate
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