Genetic diseases mitochondrial

Although DNA mutations in nuclear DNA may cause mitochondrial dysfunction, the majority of genetically defined mitochondrial diseases are caused by mutations in mtDNA (M15, PI, S4). Point mutations and deletions of mtDNA have been reported to be associated with or responsible for mitochondrial myopathies and/or encephalomyopathies (M15, PI, S4). Patients with such diseases usually manifest major clinical symptoms early in life and at a later stage may develop additional multisystem disorders such as encephalopathy and/or peripheral neuropathy. Most of the mitochondrial myopathies occur sporadically and are often caused by large-scale mtDNA deletions (PI). However, there are several reports on maternally inherited mitochondrial myopathy and familial mitochondrial myopathy. These patients usually harbor a specific mtDNA mutation and often exhibit defects in NADH-CoQ reductase and/or cytochrome c oxidase. 

BD occurs in 1% of the population and affects an individual s emotional response, with symptoms cycling between depression and mania. It is a complex genetic disease thought to require additional environmental factors for onset. Gene expression studies in BD have identified many changes in common with SZ, including oligodendrocyte abnormalities [140] and mitochondrial dysfunction [141]. 

Jacobs HT, Turnbull DM. Nuclear genes and mitochondrial translation a new class of genetic disease. Trends Genet. 2005 21 312— 314. 

Mutations in Mitochondrial DNA Cause Several Genetic Diseases in Humans... 

In this chapter and the next, we will study some of the important biochemical reactions that occur in the mitochondria. A better understanding of the function of healthy mitochondria win eventually allow us to help those suffering from LHON and other mitochondrial genetic diseases. 

Mitochondial diseases. Mitochondria contain DNA and can reproduce by replicating their DNA and then dividing in half. Although nuclear DNA encodes most of the enzymes found in mitochondria, mitochondrial DNA encodes some of the subunits of the electron transport chain proteins and ATP synthase. Mutations in mitochondrial DNA result in a number of genetic diseases that affect skeletal muscle, neuronal, and renal tissues. They are implicated in aging. 

The inherited diseases of muscle in adults are highly variable. They may be X-linked, autosomal dominant, or autosomal recessive. They may result from germline mosaicism, from a genetically determined predisposition, or from an abnormality in mitochondrial DNA. As a result, these diseases are also variable in age of onset, in the severity of expression of disease, and in the management of the disease. 

Wallace DC (1992) Mitochondrial genetics a paradigm for aging and degenerative diseases. Science 256 628-632. 

PD affects approximately one million Americans (1% of people over 60 years of age). The average age of onset is 60 years of age, and PD is fairly uncommon in those under age 40. The etiology of PD is unknown, but genetic predisposition, environmental factors, or combinations of these have been proposed to explain why nerve cells in the substantia nigra deteriorate. About 15% of patients with PD have a first-degree relative with the disease. The pathogenesis of cell death (neuron degeneration) may be due to oxidative stress, mitochondrial... 

Puccio, H. and Koenig, M. Friedreich ataxia a paradigm for mitochondrial diseases. Curr. Opin. Genet. Dev. 12 272-277, 2002. 

The genetic classification of mitochondrial diseases divides them into three groups 707... 

Carnitine palmitoyltransferase deficiency is an autosomal recessive myopathy caused by a genetic defect of the mitochondrial enzyme CPT (Fig. 42-2). The disease is prevalent in men (male female ratio, 5.5 1) and appears to be the most common cause of recurrent myoglobinuria in adults [4]. 

Mitochondrial DNA is inherited maternally. What makes mitochondrial diseases particularly interesting from a genetic point of view is that the mitochondrion has its own DNA (mtDNA) and its own transcription and translation processes. The mtDNA encodes only 13 polypeptides nuclear DNA (nDNA) controls the synthesis of 90-95% of all mitochondrial proteins. All known mito-chondrially encoded polypeptides are located in the inner mitochondrial membrane as subunits of the respiratory chain complexes (Fig. 42-3), including seven subunits of complex I the apoprotein of cytochrome b the three larger subunits of cytochrome c oxidase, also termed complex IV and two subunits of ATPase, also termed complex V. 

It is important to emphasise that only the head of the sperm enters, so that it is only the nuclear genetic material that enters the ovum, that is, the genetic material in the mitochondria of the sperm does not enter the ovum and hence it does not appear in the zygote. Consequently, mitochondrial genes are inherited only from the mother. This has implications for some mitochondrial diseases (Chapter 9). 

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