The Mitochondrial and
Metabolic Disease Center

University of California San Diego

Specializing in Mitochondrial Disease Treatment and Research

Associated with UCSD Biochemical Genetics

Background

In 1994, Dr. Richard H. Haas established the Leigh's Center at the University of Califomia San Diego (UCSD). This facility has provided state-of-the-art diagnosis and treatment for children around the world who suffered with Leigh's syndrome, a neurodegenerative disorder caused by defects in mitochondrial metabolism. Over the first two years of operation, nearly 150 children and adults with mitochondrial disorders were seen and evaluated. The diagnosis of Leigh's syndrome was confirmed in 14 children. More than 9 out of 10 children seen at the UCSD Leigh's Center did not have Leigh's syndrome. Nonetheless, all of the children had serious mitochondrial and metabolic disease that required the specialized facilities of the Center and the UCSD Biochemical Genetics laboratories, directed by Dr. William Nyhan and Dr. Bruce Barshop, for proper diagnosis and treatment.

In 1996, Dr. Robert K. Naviaux designed the Mitochondrial and Metabolic Disease Center at UCSD to meet the growing need for treatment, diagnosis, and research in the emerging field of mitochondrial medicine. This Center will bring together the talents of seven physicians and scientists with special training in human genetics and metabolism. It will embrace and extend the present capabilities and mission of the Leigh's Center. The new Center is a direct outgrowth of the ground-breaking efforts of Dr. William L. Nyhan, who established the Division of Biochemical Genetics and Metabolism at UCSD in 1969. Dr. Nyhan's continuing efforts have made UC San Diego a world leader in the diagnosis and treatment of childhood metabolic disease. He is one of the founding fathers of the field.

What is Mitochondrial Disease?

If a child is stricken with a catastrophic disease affecting three or more organ systems, or if a child has been afflicted with a relapsing disease that affects two or more organ systems and leads to slow but measurable deterioration, he or she may have a mitochondrial disease. At times, mitochondrial diseases can cause isolated symptoms. These may include unexplained seizures, low blood counts, dystonia (abnormal muscle tone or spasms), blindness, deafness, dementia, ataxia (stumbling or tremors), cerebral palsy, heart failure, or progressive muscle weakness. More often, however, several organ systems are affected in sequence, one faltering or failing after another. Good periods are frequently punctuated by abrupt deteriorations that are caused by simple infections. For children with mitochondrial disease these infections can be life threatening, and leave them with deficits that cannot be recovered.

What Do Mitochondria Do?

Air and food are metabolized by mitochondria. Every nucleated cell in the body contains from 5 to 2000 mitochondria. They are the size and shape of long, thread-like bacteria woven through our cells. Mitochondria consume over 80 percent of the oxygen we breathe and make over 90 percent of the energy our cells need to function. They use the oxygen in the air we breathe to release energy from food. This process transforms food calories into chemical energy, water, and carbon dioxide. The released chemical energy is then stored in the form of adenosine triphosphate (ATP). ATP is the universal currency of energy used by all life on earth. It is like an electrical power source that drives the engines of the cell. This process of burning food to make ATP is called oxidative phosphorylation. Only mitochondria can do it. Without it, muscles could not contract and neurons could not fire. Mitochondria literally make it possible for us to move and think.

Recent popular and scientific publications have focused on the "powerplant" functions of mitochondria. While it is true that energy production is one function of mitochondria, this is only a small part of what they do. Mitochondria in different tissues differ dramatically in their ability to consume oxygen and make ATP. For example, liver mitochondria consume just 2% of the oxygen that heart mitochondria do. Liver mitochondria are specialized for other duties. They contain, for examples, enzymes that allow them to detoxify ammonia, a waste product of protein metabolism. These enzymes are not made in the heart. Mitochondria also differ in the fuels they can bum. For example, mitochondria in the heart cannot use sugar for energy. They are entirely dependent on the metabolism of fats to meet their energy needs. In contrast, mitochondria in the liver can use both fats and sugars. The specialized functions of mitochondria help each tissue to perform its role in the day-to-day operation of the body. Children with mitochondrial disease have inherited specific mutations in either mitochondrial or nuclear genes (DNA). Their symptoms are a reflection of the tissues that need the function of that gene or genes most.

Why are Mitochondria so Specialized?

Mitochondria are stuffed with about 3000 proteins, and an average of 5 copies of their own ring-shaped, DNA. Mitochondrial DNA is the only DNA that we inherit exclusively from our mothers. Some scientists have called it our 24th chromosome. It codes for just 13 mitochondrial proteins. All the other proteins in mitochondria (>99%) come from genes in the nucleus, and are therefor expressed and tailored to meet the specialized needs of each cell. Iin fact, since a cell makes only about 10,000 to 15,000 proteins, mitochondria contain 20 to 30% of all the proteins in the cell. Since the 13 proteins that are made by mitochondrial DNA are involved in electron transport and are used to make ATP, mutations in mitochondrial DNA lead to problems with the powerplant function of the organelles. Mutations in nuclear genes, on the other hand, can lead to disturbances in both the powerplant functions and the many other, more specialized functions of mitochondrial metabolism. Only systematic clinical observation, coupled with state-of-the-art laboratory study and basic research will help to ensure an accurate diagnosis, and permit the development of effective treatment.

All of this depends on research into both the normal and disease biology of mitochondria. At present, the diagnosis of mitochondrial disease is often missed because scientists do not fully understand the normal function of mitochondria in specialized cells. Even when properly diagnosed, mitochondrial diseases are not easily treated because present treatments are not yet able to target these specialized functions.

How Common is Childhood Mitochondrial Disease?

There are more than 50 inherited diseases of metabolism that are known to affect mitochondria. Taken together, more than 1 in 4,000 children born in the United States each year will develop a mitochondrial disease by 10 year of age. Four million children are born in the US each year. This means that 1000 to 4000 children will be born each year with mitochondrial disease. By comparison, about 8000 new cases of childhood cancer are reported each year. Both mitochondrial disease and childhood cancer range in mortality from 1O to 50 percent per year, depending on the specific disease. Leigh's syndrome, for example, is one of the more lethal mitochondrial diseases. It has a mortality of about 50 percent per year after diagnosis.

How Common is Adult Mitochondrial Disease?

Defects in mitochondrial function have now been I inked to many of the most common diseases of aging. These include Type II Diabetes Mellitus, Parkinson Disease, Atherosclerotic Heart Disease, Stroke, Alzheimer Dementia, and Cancer. Over 50 million people in the US suffer from these chronic degenerative disorders. While it cannot yet be said that mitochondria cause these problems, it is clear that mitochondria are involved because their function is measurably disturbed. Even autoimmune diseases such as Multiple Sclerosis, Systemic Lupus Erythematosus, and Rheumatoid Arthritis appear to have mitochondrial components.

In 1995, the entire program of the 25th annual meeting of the American Aging Association and the American College of Clinical Gerontologv was devoted to the role of mitochondria in the chronic diseases of aging. Even so, most physicians in America are not yet aware of the connection between chronic diseases and abnormalities in mitochondrial function. Fortunately, this is changing through education. But real change in medicine requires two elements- education and the availability of effective treatment. Progress will be slow until effective treatments for mitochondrial diseases are developed.

Why Should Adults be Concerned About Mitochondrial Diseases of Children?

The diseases of aging outnumber mitochondrial diseases in children about 5000 to 1. But from a scientific point of view, the chronic diseases of aging are very complex, so complex they are hard to study. They take 20 to 50 years to develop. During that long period of time, every adult has been exposed to many environmental agents that may increase his risk for disease. The task of sorting out the causal factors from the incidental is very complicated, and sometimes impossible. The founders of the Mitochondria Center at UCSD have cared for many adults and children over the years. They were struck by the great similarity between some of the childhood disorders of mitochondrial metabolism, and many of the much more common diseases of aging described above. This clinical similarity suggested a common cause.

Children give us the opportunity to see the causes and consequences of mitochondrial disease with a clarity that is not possible in adults. Because children have not yet lived long lives, the list of factors that must be considered in discovering the precise cause of their disease is much shorter than the list of factors for a similar disease in adults. Clarity in science leads to new insights. For these reasons, many of the freshest new insights into the diseases of aging will come from the study of the young. Moreover, the physicians and scientists of the Mitochondrial and Metabolic Disease Center feel that when effective therapies are developed for children, these therapies will also be shown to be effective in treating similar disorders in adults.

Goals of the Mitochondrial and Metabolic Disease Center

Patient care is at the heart, and research is at the foundation of the Mitochondrial and Metabolic Disease Center at UCSD. This Center unites the three essential elements of medical progress- diagnosis, treatment, and research. In most other medical centers around the world, these three elements are isolated because the individual physicians and scientists are all working toward separate goals. The physicians and scientists of the Center at UCSD are all working toward a common goal- to understand and develop more effective treatments for mitochondrial and metabolic disease. This is accomplished through a unified program of patient care. basic science. and clinical research.

When a child is stricken with a catastrophic disease, it can take weeks, months, or even years before the diagnosis of mitochondrial disease is reached. Many children die before the correct diagnosis is made. A second child in the family is sometimes tragically affected before the possibility of a metabolic disease is considered. While most physicians can easily recognize cancer when they see it, very few physicians are yet able to recognize mitochondrial disease. Moreover, very few medical centers are equipped to offer the specialized diagnostic, treatment, and research facilities required for the comprehensive management of children with mitochondrial disease. The Mitochondrial and Metabolic Disease Center at UCSD was designed to fill this need.

How Can I Help?

The Mitochondrial and Metabolic Disease Center at UCSD has the goal of raising a substantial amount of money over the next two years to expand its clinical services and support research. Our mission is to create a comprehensive center of excellence for research, diagnosis, and treatment of children and young adults with mitochondrial disease. Your contributions will help make this a reality. By contributing $100 or more, you will become a sponsor of the Center and will receive our semiannual newsletter. The newsletter will include highlights of research results and treatment advances important for children and adults with mitochondrial disease. It will also give you an update on our continuing care and services for children with mitochondrial and metabolic disease, and a report on the progress we have made toward

Many companies have matching plans that allow employees to donate a day or more of vacation pay to a charity of their choosing. Whether you are an employer or an employee, this is a simple way you can help make a difference in our fight against mitochondrial and metabolic disease.


A Word About Our Founders

Dr. Richard H. Haas is a board certified pediatric neurologist and pediatrician. He is nationally known for his basic and clinical work in neurometabolic disease, and has carried out both clinical and bench research on the mitochondrial and metabolic diseases of children for over 20 years. He received his undergraduate and master's degrees from Cambridge University, England, and studied clinical medicine at University College Hospital in London. He was trained in both intemal medicine in Southampton, and pediatrics at the Hammersmith and Great Ormond Street Hospitals in London, and is a member of the Royal College of Physicians. He completed his advanced clinical training in pediatric neurology at the University of Colorado, Denver, where he also conducted basic research in mitochondrial biology in the laboratory of Dr. David Stumpf as a National Institutes of Health Fellow in the biochemistry of mental retardation. He is a professor at the University of Califomia, San Diego, with joint appointments in the departments of Neurosciences and Pediatrics. Dr. Haas has been a practicing physician since 1972.

Dr. Robert K. Naviaux is board certified in intemal medicine and a specialist in biochemical genetics and metabolism. His research experience spans 20 years and embraces the fields of virology, genetics, cancer, and metabolism. He received his undergraduate degree from the University of California at Davis. He was an undergraduate research intern in tumor immunology at the National Institutes of Health (NIH) in Bethesda, Maryland, and studied biochemistry at the GeorgAugust University in Gottingen, Germany. He was trained as a medical scientist at the Indiana University School of Medicine, where he received both M.D. and Ph.D. degrees, graduating with highest distinction. In 1990, he was named one of ten National Medical Residents of the Year for clinical excellence by the NIH. He completed his advanced training in virology and molecular biology at the Salk Institute in La Jolla, Califomia, where he conducted research in cancer gene therapy and basic retrovirus biology in the laboratory of Dr. Inder M. Verma. Dr. Naviaux has been a practicing physician since 1986.


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