Abstract
The inherent complex and pleiotropic phenotype of mitochondrial diseases poses a significant diagnostic challenge for clinicians as well as an analytical barrier for scientists. To overcome these obstacles we compiled a novel database, www.mitodb.com, containing the clinical features of primary mitochondrial diseases. Based on this we developed a number of qualitative and quantitative measures, enabling us to determine whether a disorder can be characterized as mitochondrial. These included a clustering algorithm, a disease network, a mitochondrial barcode and two scoring algorithms. Using these tools we detected mitochondrial involvement in a number of diseases not previously recorded as mitochondrial. As a proof of principle Cockayne syndrome, ataxia with oculomotor apraxia 1 (AOA1), spinocerebellar ataxia with axonal neuropathy 1 (SCAN1) and ataxia-telangiectasia have recently been shown to have mitochondrial dysfunction and those diseases showed strong association with mitochondrial disorders. We next evaluated mitochondrial involvement in aging and detected two distinct categories of accelerated aging disorders, one of them being associated with mitochondrial dysfunction. Normal aging seemed to associate stronger with the mitochondrial diseases than the non-mitochondrial partially supporting a mitochondrial theory of aging.
Highlights
Bona fide mitochondrial diseases represent a heterogeneous group of genetic syndromes with a combined incidence of around 1:5000 [1]
Using various sources such as the United Mitochondrial Disease Foundation webpage, Pubmed and the Online Mendelian Inheritance in Man database we identified 31 monogenic diseases that all have been characterized as mitochondrial describing a total of 1,265 patients (Supplementary table 1)
Out of 117 clinical parameters seen in mitochondrial diseases, lactate accumulation, hypotonia, muscle weakness, developmental delay and seizures are among the most common
Summary
Bona fide mitochondrial diseases represent a heterogeneous group of genetic syndromes with a combined incidence of around 1:5000 [1]. The complete pathogenesis remains unknown, energy deficiency in affected tissues is believed to be the causative agent in most of these disorders [2] Besides their cardinal role in ATP metabolism mitochondria are the main producers of endogenous oxidative radicals. We compiled a database of the clinical parameters seen in mitochondrial diseases, www.mitodb.com Based on this database we developed extensive bioinformatics tools to dissect whether a disease could be characterized as mitochondrial or not. Normal aging seemed to associate closer with the mitochondrial group in the clustering algorithm but showed mixed mitochondrial and non-mitochondrial values in the support vector machine and mitoscore Taken together these findings indicate at least two separate causes of aging, one of them possibly being mitochondrial
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