Epilepsia partialis continua associated with NADH-coenzyme Q reductase deficiency
Carlo AntozziSilvana FranceschettiGraziella FilippiniBruno BarbiroliM. SavoiardoF. FiacchinoMarco RimoldiRaffaele LodiP. ZaniolMassimo Zeviani
25
Citation
31
Reference
10
Related Paper
Citation Trend
Keywords:
Epilepsia partialis continua
Mitochondrial respiratory chain
Mitochondrial disease
Bioenergetics
Mitochondrial respiratory chain
Muscle weakness
Cite
Citations (33)
Mitochondrial disorders have the highest incidence among congenital metabolic diseases, and are thought to occur at a rate of 1 in 5000 births. About 25% of the diseases diagnosed as mitochondrial disorders in the field of pediatrics have mitochondrial DNA abnormalities, while the rest occur due to defects in genes encoded in the nucleus. The most important function of the mitochondria is biosynthesis of ATP. Mitochondrial disorders are nearly synonymous with mitochondrial respiratory chain disorder, as respiratory chain complexes serve a central role in ATP biosynthesis. By next-generation sequencing of the exome, we analyzed 104 patients with mitochondrial respiratory chain disorders. The results of analysis to date were 18 patients with novel variants in genes previously reported to be disease-causing, and 27 patients with mutations in genes suggested to be associated in some way with mitochondria, and it is likely that they are new disease-causing genes in mitochondrial disorders. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.
Mitochondrial disease
Mitochondrial respiratory chain
Human mitochondrial genetics
Exome
Cite
Citations (55)
Epilepsia partialis continua
Mitochondrial respiratory chain
Cite
Citations (11)
Mitochondrial disorders, once thought to be relatively rare, are now thought to be the most prevalent metabolic disease. They represent a challenge to clinicians, especially in children, in whom clinical presentation and course show enormous variation. We report a respiratory chain enzyme activity disorder (complex I, III and IV) in a girl, with a severe presentation since the perinatal period. An older female sibling had died at the age of 11 months from an encephalopathy, with a similar clinical presentation. Enzyme activity disorders could not been disclosed. This association has been described only rarely. Mitochondrial disorders associated with defects in the respiratory chain can be attributable to mutations in the mitochondrial genome (mitochondrial DNA) or the nuclear genome (nuclear DNA). The diagnosis is based on the presence of clusters of abnormal mitochondria in muscle cells and a biochemically defined defect in the respiratory chain enzymes or, more recently, also on mutations in the mitochondrial DNA. In our case muscular biopsy to assess enzymatic activity of the respiratory chain complexes disclosed defects in respiratory chain complexes I, III and IV (cytochrome c oxidase). The patients, as our case, usually present early in life and are more severely affected than patients with isolated complex deficiencies. Therapy remains largely ineffective.
Mitochondrial disease
Mitochondrial respiratory chain
Cite
Citations (0)
Mitochondrial respiratory chain
Mitochondrial disease
Abnormality
Myoclonic epilepsy
Cite
Citations (68)
Genetic defects of the mitochondrial respiratory chain show marked phenotypic variability. Laboratory diagnosis is complicated and includes biochemical screening tests, tissue histopathology, functional enzyme studies, and molecular tests where available. Normal respiratory chain function necessitates the co-ordinated expression of over 100 different gene loci, and the interaction of two genetic systems, the nuclear and mitochondrial genomes. Thus genetic counselling for the mitochondrial disorders is extremely challenging. In this review, the classes of mitochondrial and nuclear defects that give rise to functional abnormalities of the mitochondrial respiratory chain are discussed, with specific instructive examples described in some detail.
Mitochondrial disease
Mitochondrial respiratory chain
Nuclear gene
Cite
Citations (36)
A 23-year-old woman and a 13-year-old boy were diagnosed with mitochondrial respiratory chain disease. The woman had muscle pain, fatigue and bilateral ophthalmoplegia--symptoms consistent with Kearns-Sayre syndrome. The boy had aspecific symptoms; eventually, reduced activity of complex 1 was found to be the cause of the mitochondrial respiratory chain disease in the boy and his mother, who had suffered from unexplained fatigue and muscle pain for 15 years. Mitochondrial diseases often involve several organ systems. Diagnosis can be difficult, because laboratory tests such as serum and urinary lactate and creatine kinase have low sensitivity and specificity. Biochemical assessment of muscle biopsy can reveal reduced oxidation ATP synthesis and sometimes specific abnormalities in individual protein complexes. DNA analysis may be helpful in demonstrating mitochondrial or nuclear mutations or deletions. The goal of treatment is to increase mitochondrial ATP production, improve clinical symptoms and enhance stamina. Replacement of the following substances (also referred to as cofactors) may be attempted: co-enzyme Q10, antioxidants (lipoic acid, vitamins C and E), riboflavin, thiamine, creatine and carnitine. Evidence regarding the optimal treatment approach is lacking; one usually has to rely on observing effects in the individual patient.
Mitochondrial disease
Coenzyme Q10
Kearns–Sayre syndrome
Mitochondrial respiratory chain
Creatine kinase
MELAS syndrome
Creatine
Cite
Citations (0)
Mitochondrial disease
Mitochondrial respiratory chain
Cite
Citations (24)
Abstract Two homoplasmic variants in tRNA Glu (m.14674T>C/G) are associated with reversible infantile respiratory chain deficiency. This study sought to further characterize the expression of the individual mitochondrial respiratory chain complexes and to describe the natural history of the disease. Seven patients from four families with mitochondrial myopathy associated with the homoplasmic m.14674T>C variant were investigated. All patients underwent skeletal muscle biopsy and mtDNA sequencing. Whole‐genome sequencing was performed in one family. Western blot and immunohistochemical analyses were used to characterize the expression of the individual respiratory chain complexes. Patients presented with hypotonia and feeding difficulties within the first weeks or months of life, except for one patient who first showed symptoms at 4 years of age. Histopathological findings in muscle included lipid accumulation, numerous COX‐deficient fibers, and mitochondrial proliferation. Ultrastructural abnormalities included enlarged mitochondria with concentric cristae and dense mitochondrial matrix. The m.14674T>C variant in MT ‐ TE was identified in all patients. Immunohistochemistry and immunoblotting demonstrated pronounced deficiency of the complex I subunit NDUFB8. The expression of MTCO1, a complex IV subunit, was also decreased, but not to the same extent as NDUFB8. Longitudinal follow‐up data demonstrated that not all features of the disorder are entirely transient, that the disease may be progressive, and that signs and symptoms of myopathy may develop during childhood. This study sheds new light on the involvement of complex I in reversible infantile respiratory chain deficiency, it shows that the disorder may be progressive, and that myopathy can develop without an infantile episode.
Mitochondrial respiratory chain
Mitochondrial disease
Mitochondrial matrix
Congenital myopathy
Cite
Citations (5)