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Researching brain power failure

February 20, 2013
An image of human brain cells

An image of human brain cells

ThInk columnist Professor Doug Turnbull is Director of the Wellcome Trust Centre for Mitochondrial Research. Here he describes some of the neurological symptoms which may result from mitochondrial disease and explains why research in this area is both vital, and awash with challenges.

The Wellcome Trust Centre for Mitochondrial Research at Newcastle University is the research arm of our initiative to help patients with mitochondrial disease. Four of the principal investigators of the new Centre have major clinical commitments looking after patients with mitochondrial disease and this link between the clinical studies and research within the Centre is crucial.

For both doctors and researchers the scarcity of effective treatments for patients with mitochondrial disease is a constant challenge. The main function of mitochondria is to generate energy by a complicated process called oxidative phosphorylation. In patients with mitochondrial disease there is a defect in this pathway and unfortunately there are no effective treatments to correct this abnormality.

One of the Centre’s major research themes is to understand the neurological features found in patients with mitochondrial disease, in order to inform the development of better treatments.

Symptoms of mitochondrial diseases are extremely variable and, importantly, some mildly affected patients may have no neurological problems.  The disease affects patients of all ages – the more severe the mitochondrial defect the earlier the onset is likely to be. It can start immediately after birth with severe muscle weakness, heart involvement, and impaired overall brain function. Unfortunately these children die in the first few days of life. More commonly, mitochondrial disease presents later in childhood, in adolescence, and in adulthood. In the vast majority of patients this is a progressive illness causing major disability and often leading to early death.

Neurological symptoms in childhood

In children a common presentation of mitochondrial disease is a progressive disturbance of the brainstem and basal ganglia [a part of the brain that controls movement] predominantly. This is called Leigh’s disease. Children with Leigh’s disease develop weakness, and difficulty breathing and swallowing. These symptoms often get worse at times of stress, such as when the patient has an additional infection. Leigh’s disease may be caused by several different mitochondrial genetic defects and it usually results in death in childhood.

Another disease we see in childhood is a severe progressive condition called Alper’s syndrome. This condition usually starts very early in childhood and leads to severe neurodegeneration with seizures. It is an unusual condition because it has a marked effect on the visual cortex, for reasons we do not understand. The underlying genetic defects in the majority of patients with Alper’s syndrome are mutations in polymerase gamma gene – the only mitochondrial DNA polymerase [an enzyme which mitochondrial DNA needs in order to replicate].

Neurological symptoms in older patients

As patients get older we see a lot of other neurological symptoms. Patients may get stroke like episodes and seizures. These episodes are stroke like rather than true strokes because, whereas true strokes are due to a blockage of a single blood vessel, these episodes cross the boundaries of several different blood vessels. Whilst a range of different genetic defects may cause these stroke-like episodes, the majority of patients have a specific mitochondrial DNA mutation (m.3243A>G). The m.3243A>G mutation is the most common pathogenic mitochondrial DNA mutation, but less than 10% of patients carrying this mutation develop the stroke like episodes and one challenge that we face is how to identify those patient most at risk.

Another mitochondrial DNA mutation (m.8344A>G) rarely causes stroke like episodes, but frequently causes a specific form of seizure called myoclonic epilepsy [small involuntary jerks rather than the large movements seen with most motor seizures]. This mutation also causes ataxia [marked disturbance of balance] and muscle weakness. Other neurological features include cognitive impairment, which can be progressive and severe in some patients, deafness so severe that people require cochlear implants, severe blindness due to involvement of the optic nerve, peripheral neuropathy, and severe muscle weakness.

Our research

Understanding some of the mechanisms involved in the development of symptoms is one way to improve treatment. But research in this area presents several challenges, including the fact that there are no good animal models of mitochondrial DNA disease.

One aspect of our own work is exploring the changes seen in the post-mortem brains and spinal cords of patients who have died with mitochondrial disease. These studies are very important because they are the only way we have of looking carefully at the changes that have occurred in the presence of the genetic defect in mitochondrial function. We do an extensive number of studies on post-mortem tissue and these are only possible because patients and their families have donated tissue for research.

These studies show extensive changes to the brains of patients with mitochondrial disease – both neurodegeneration and evidence of severe oxidative phosphorylation defects, which we believe is a forerunner to cell loss. Interestingly, specific areas of the brain seem to be more affected than others. One of the intriguing challenges of our work is to discover why this occurs. It may be, for example, that some neurons have a particularly high need for energy and are therefore more sensitive to the impairment of mitochondrial function.

Other studies include both work on animal models and cells in cultures to try and understand whether the predominant defect is found in the neurons themselves or the glia [the supporting cells for the neurons], as this could lead to different treatments. For example it may be possible to target specific drugs to glia which would not enter the neuron. Another possibility is that one of the major defects occurs in the connections between different brain regions, as these are highly dependent on energy. This could explain some of the problems patients have with their memories and other thought processes.

The challenges of understanding the neurological defect in patients with mitochondrial disease are considerable, and frustrating at times. However in the Wellcome Trust Centre we see just how important these problems are for our patients and this reminds us of the importance of this work.

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