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NAMDC Patient Registry and Biorepository

ABSTRACT:

Mitochondrial diseases are caused by dysfunction of the mitochondria, which are specialized compartments that are present in every cell of the body except red blood cells. Mitochondria generate more than 90% of the energy that the body needs to sustain life and support growth. When they fail, less and less energy is generated within the cell. This injures the cell and can cause its death. If this process is repeated throughout the body, whole organ systems begin to fail, and the life of the person in whom this is happening is severely compromised. Mitochondrial diseases primarily affect children, but adult onset is becoming more and more common.

Mitochondrial diseases are probably the most diverse human disorders at every level: clinical, biochemical, and genetic. Some affect only the nervous system but most affect many body systems, including the brain, heart, liver, skeletal muscles, kidney, and the endocrine and respiratory systems. Although mitochondrial disorders vary in severity, they are usually progressive, and often crippling. They can cause paralysis, seizures, mental retardation, dementia, hearing loss, blindness, weakness and premature death.

Because of the range of symptoms and the frequent involvement of multiple body systems, mitochondrial diseases can be a great challenge to diagnose. Even when accurately diagnosed, they pose an even more formidable challenge to treat, as there are very few therapies and most are only partially effective.

About this Study

The first objective of this study is to establish a clinical registry of patients with suspected or confirmed mitochondrial diseases. We are collecting medical and family history, diagnostic test results, and prospective medical information for these patients and, using agreed procedures developed by the leading research clinicians in the field, providing, for the first time, standardized diagnoses of these complex disorders for the patients. The clinical information we collect from the participants will be used to learn about the spectrum of mitochondrial disorders and their prevalence. We will also develop studies which allow us to better understand how these diseases progress, which we do not understand well enough. When we begin clinical trials for mitochondrial diseases, patients enrolled in the registry who are identified as potentially eligible will be offered enrollment. Patients will only be included in studies if they give their consent in advance.

The second objective of this study is to establish a biorepository for specimens and DNA from patients with mitochondrial diseases, in order to make materials easily available to consortium researchers.

PROVIDER: phs001538 | dbGaP |

REPOSITORIES: dbGaP

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			Action	DRS
	GapExchange_phs001538.v1.p1.xml	Xml
	dbGaPEx2.1.5.xsd	Other
	phs001538.v1-Documents.zip	Other
	Study_Report.phs001538.NAMDC_7401.v1.p1.MULTI.pdf	Pdf
	manifest_phs001538.NAMDC_7401.v1.p1.c1.GRU-IRB-PUB.pdf	Pdf

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Project description:This model is from the article: A metabolic model of the mitochondrion and its use in modelling diseases of the tricarboxylic acid cycle. Smith AC, Robinson AJ. BMC Syst Biol. 2011 Jun 29;5(1):102. 21714867 , Abstract: BACKGROUND:Mitochondria are a vital component of eukaryotic cells and their dysfunction is implicated in a large number of metabolic, degenerative and age-related human diseases. The mechanism or these disorders can be difficult to elucidate due to the inherent complexity of mitochondrial metabolism. To understand how mitochondrial metabolic dysfunction contributes to these diseases, a metabolic model of a human heart mitochondrion was created. RESULTS: A new model of mitochondrial metabolism was built on the principle of metabolite availability using MitoMiner, a mitochondrial proteomics database, to evaluate the subcellular localisation of reactions that have evidence for mitochondrial localisation. Extensive curation and manual refinement was used to create a model called iAS253, containing 253 reactions, 245 metabolites and 89 transport steps across the inner mitochondrial membrane. To demonstrate the predictive abilities of the model, flux balance analysis was used to calculate metabolite fluxes under normal conditions and to simulate three metabolic disorders that affect the TCA cycle: fumarase deficiency, succinate dehydrogenase deficiency and alpha-ketoglutarate dehydrogenase deficiency. CONCLUSION: The results of simulations using the new model corresponded closely with phenotypic data under normal conditions and provided insight into the complicated and unintuitive phenotypes of the three disorders, including the effect of interventions that may be of therapeutic benefit, such as low glucose diets or amino acid supplements. The model offers the ability to investigate other mitochondrial disorders and can provide the framework for the integration of experimental data in future studies. Created by Anthony C. Smith (Mon Mar 14 11:03:11 2011) MRC - Mitochondrial Biology Unit, Cambridge, UK. acs@mrc-mbu.cam.ac.uk This metabolic network is a stocihiometric model of a human heart mitochondrion. Identifiers are KEGG Ids. This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

Project description:Background. Many age-associated disorders (including diabetes, cancer, and neurodegenerative diseases) have been linked to mitochondrial dysfunction, which leads to impaired cellular bioenegetics (decreased ATP production) and increased oxidative stress. However, it is not known what genetic and molecular pathways underlie differential vulnerability to mitochondrial dysfunction observed among different cell types. Methodology/Principal Findings. Starting with CRI-G1 insulinoma cells as a model of a neuronal/endocrine cell type, we isolated a novel (CRI-G1-RS) cell line that was more susceptible to cell death induced by mitochondrial respiratory chain inhibitors or direct oxidants than the parental CRI-G1 cell line (for clarity renamed CRI-G1-RR). In contrast, RS cells were equally vulnerable to mitochondrial uncoupling and less vulnerable to protein kinase inhibition than RR cells, suggesting that differences in vulnerability to mitochondrial toxins among the two cell types did not stem from differences in ATP production/utilization or in downstream apoptotic machinery. Genome-wide gene expression analysis and follow-up biochemical studies revealed that, in this experimental system, increased vulnerability to mitochondrial and oxidative stress was associated with (1) inhibition of ARE/Nrf2/Keap1 antioxidant pathway; (2) decreased expression of antioxidant and phase I/II conjugation enzymes, most of which are Nrf2 transcriptional targets; (3) increased expression of molecular chaperones, many of which are also considered Nrf2 transcriptional targets; and (4) increased expression of β cell-specific genes and transcription factors that specify/maintain β cell fate. Conclusions/Significance. The molecular profile presented here will enable identification of individual genes and/or gene clusters that shape vulnerability to mitochondrial dysfunction and thus represent potential therapeutic targets for diabetes and neurodegenerative diseases. In addition, the newly identified CRI-G1-RS cell line represents a new experimental model for investigating how endogenous antioxidants affect glucose sensing and insulin release by pancreatic β cells. Six biological replicates for each of two cell types (12 samples total)

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NAMDC Patient Registry and Biorepository

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