Clinical Mitochondrial Disease

Mitochondrial diseases affect patients of all ages. In many ways this makes sense – the more severe the mitochondrial defect the earlier the onset is likely to be. The disease 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 with major disability and often leads to early death (certainly in those patients who present in childhood with severe symptoms).

This Clinical Mitochondrial Disease theme aims to:

• Determine the nature, mechanisms and potential therapies for patients with mitochondrial DNA disease

The main areas of Clinical mitochondrial Disease Research are: 

Clinical Research

The Wellcome 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.

Our research programmes are focussed on addressing specific questions around the neurological involvement in mitochondrial disease.

Clinical research at the Wellcome Centre for Mitochondrial Research has been facilitated by the development of a large clinical cohort of patients with mitochondrial disease sponsored by the MRC.

Neuropathology

One of the major research themes of the Centre is to understand the neurological features in patients with mitochondrial disease. These are extremely variable and importantly some mildly affected patients may have no neurological problems. In children a common presentation of mitochondrial disease is a selective and progressive disturbance of the brainstem and basal ganglia– this is called Leigh’s disease. This may be due to the presence of several different mitochondrial genetic defects and usually results in death in childhood. Another disease we see in childhood is a severe progressive condition called Alpers’ syndrome. This condition usually starts very early in childhood and leads to severe neurodegeneration with seizures. It is unusual because there is marked involvement of the visual cortex for reasons we do not understand. The underlying genetic defects in the majority of patients with Alpers’ syndrome are mutations in polymerase gamma gene (POLG); this is the only mitochondrial DNA polymerase.

As patients get older we see a lot of other neurological symptoms. Patients may develop stroke-like episodes associated with a major neurological deficit and seizures. These episodes are stroke-like because they do not follow the major vascular territories. Whilst a range of different genetic defects may cause stroke-like episodes, the majority of patients have a specific mitochondrial DNA mutation (m.3243A>G). The m.3243A>G mutation is the commonest pathogenic mitochondrial DNA mutation however less than 10% of patients carrying this mutation develop the stroke-like episodes and so identifying those patient most at risk is challenging. Another mitochondrial DNA mutation rarely causes stroke-like episodes but frequently leads to a specific form of seizures called -myoclonic epilepsy. This mutation (m.8344A>G) 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 people require cochlear implants, severe blindness due to involvement of the optic nerve, peripheral neuropathy and severe muscle weakness.

The challenges we face arise because there are few effective treatments for patients with mitochondrial disease. Trying to correct the biochemical defect due the defect in oxidative metabolism is not possible at the moment but we believe early intervention for problems such as epilepsy maybe very beneficial. Certainly active treatment of symptoms is crucial. One way to better treatment is to understand some of the mechanisms involved in the development of symptoms. This work presents several challenges including that there are no good animal models of mitochondrial DNA disease.

Treatments

There is currently no cure for patients with Mitochondrial Disease and so a major theme of the Wellcome Centre is to develop treatments for Mitochondrial disease . The research theme aims to identify novel drugs that can improve mitochondrial function using our unique collection of patient samples that make up the Mitochondrial Biobank. This exceptional bioresource, which include tissues and cell lines from patients obtained for research or excess to diagnostic procedures, allows our preclinical research to be performed to the highest standard using the most relevant models of Mitochondrial Disease.

Drug development within the Centre is currently done using two different approaches. We are collaborating with a number of pharmaceutical companies to test large numbers of different compounds and identify those that can affect the mitochondria and how they function. We are also working with smaller, specialised companies to test compounds that have already been shown to affect mitochondrial function using cell-based models of Mitochondrial Disease.

By utilising both approaches to drug development, it is hoped that these preclinical studies will lead to potential drug trials for our patients. The Mitochondrial Patient Cohort will allow us to identify eligible patients from all over the UK to take part in such clinical trials in the future. We believe that we are closer than ever to finding effective treatments for Mitochondrial Disease and as such, improving the lives of our patients.