Prevalence of nuclear and mtDNA mutations related to adult mitochondrial disease (original) (raw)
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Journal of Neurology, 2001
Mitochondrial disorders are human genetic diseases with extremely variable clinical and genetic features. To better define them, we made a genotype-phenotype correlation in a series of 207 affected patients, and we examined most of them with six laboratory examinations (serum CK and basal lactate levels, EMG, cardiac and EEG studies, neuroradiology). We found that, depending on the genetic abnormality, hyperckemia occurs most often with either chronic progressive external ophthalmoplegia (CPEO) and ptosis or with limb weakness. Myopathic EMGs are more common than limb weakness, except in patients with A8344G mutations. Peripheral neuropathy, when present, is always axonal. About 80 % of patients with A3243G and A8344G mutations have high basal lactate levels, whereas pure CPEO is never associated with increased lactate levels. Cardiac abnormalities mostly consist of conduction defectsAbnormalities on CT or MRI of the brain are relatively common in A3243G mutations independently of the clinical phenotype. Patients with multiple mtDNA deletions are somehow “protected” against the development of abnormalities with any of the tests. We conclude that, despite the phenotypic heterogeneity of mitochondrial disorders, correlation of clinical features and laboratory findings may give the clinician important clues to the genetic defect, allowing earlier diagnosis and counselling.
BMJ, 2021
ObjectiveTo determine whether whole genome sequencing can be used to define the molecular basis of suspected mitochondrial disease.DesignCohort study.SettingNational Health Service, England, including secondary and tertiary care.Participants345 patients with suspected mitochondrial disorders recruited to the 100 000 Genomes Project in England between 2015 and 2018.InterventionShort read whole genome sequencing was performed. Nuclear variants were prioritised on the basis of gene panels chosen according to phenotypes, ClinVar pathogenic/likely pathogenic variants, and the top 10 prioritised variants from Exomiser. Mitochondrial DNA variants were called using an in-house pipeline and compared with a list of pathogenic variants. Copy number variants and short tandem repeats for 13 neurological disorders were also analysed. American College of Medical Genetics guidelines were followed for classification of variants.Main outcome measureDefinite or probable genetic diagnosis.ResultsA defi...
Neurologic Disorders Due to Mitochondrial DNA Mutations
Seminars in Pediatric Neurology, 2012
The mitochondrial DNA (mtDNA) is a compact genome inherited through the maternal lineage. Mutations in mtDNA lead to many of the earliest identified syndromic mitochondrial diseases and display a diverse range of age of onset, symptoms, and outcomes-from isolated childhood onset vision or hearing loss to a multisystemic neurodegenerative disorder with strokes, neuropathy, ophthalmoparesis, and epilepsy beginning at any age. As a heterogeneous group, mitochondrial diseases represent one of the most common metabolic disorders in children and adults, frequently seen by both pediatric and adult specialists. Although the myriad of diseases can make diagnosis seems daunting, the need for extensive supportive care and treatment (the latter for at least a select few mitochondrial disorders) and a rapid and accurate recognition of these disorders is necessary. Here, we provide a review of the most common mitochondrial disease syndromes due to mtDNA mutations.
Clinical and bi-genomic DNA findings of patients suspected to have mitochondrial diseases
Frontiers in Genetics
Background: Mitochondrial diseases are the most common group of inherited metabolic disorders, causing difficulties in definite diagnosis due to clinical and genetic heterogeneity. Clinical components are predominantly associated with pathogenic variants shown in nuclear or mitochondrial genomes that affect vital respiratory chain function. The development of high-throughput sequencing technologies has accelerated the elucidation of the genetic etiology of many genetic diseases that previously remained undiagnosed.Methods: Thirty affected patients from 24 unrelated families with clinical, radiological, biochemical, and histopathological evaluations considered for mitochondrial diseases were investigated. DNA isolated from the peripheral blood samples of probands was sequenced for nuclear exome and mitochondrial DNA (mtDNA) analyses. MtDNA sequencing was also performed from the muscle biopsy material in one patient. For segregation, Sanger sequencing is performed for pathogenic alter...
Mitochondrial DNA mutations in human disease
Biochimica Et Biophysica Acta-bioenergetics, 2001
The small, maternally inherited mitochondrial DNA (mtDNA) has turned out to be a Pandora's box of pathogenic mutations: 13 years into the era of “molecular mitochondrial medicine,” more than 100 pathogenic point mutations and innumerable rearrangements have been associated with a striking variety of multisystemic as well as tissue-specific human diseases. After reviewing the principles of mitochondrial genetics, we consider disorders due to mutations in genes affecting mitochondrial protein synthesis and disorders due to mutations in protein-coding genes. In contrast to the remarkable progress in our understanding of etiology, pathogenesis is only partially explained by the rules of mitochondrial genetics and remains largely unclear. We review recent progress in prenatal diagnosis, epidemiology, and in the development of animal models harboring mtDNA mutations. © 2001 Wiley-Liss, Inc.