As all child neurologists know, “mitochondrial disorder” is frequently on the differential diagnosis for many children with neurological disease. However, determining whether a patient actually has a mitochondrial disorder is virtually always problematic. Tests of serum and CSF lactate levels are neither sensitive nor specific. Tissue biopsies are invasive and expensive. Genetic tests often yield a genetic variant that has not been previously reported and whose clinical meaning is unclear. Desperately needed is a simple and reliable test of mitochondrial activity.
Dr. Melissa Walker, MD, PhD, an Instructor in Neurology at the Massachusetts General Hospital, is aiming to develop a rapid, facile blood test for mitochondrial activity that can be performed from a single blood draw. Because mitochondrial disorders manifest most strongly in post-mitotic cells, she is planning to use peripheral blood mononuclear cells (PMBC), which are a nondividing cellular component of blood, as the substrate for her test. She is testing a variety of ways of “stressing” the PBMC in their biochemical environment in such a way that cells with mitochondrial dysfunction react differently than those with normal mitochondrial function.
Dr. Walker is testing a variety of ways of “stressing” the PBMC in their biochemical environment in such a way that cells with mitochondrial dysfunction react differently than those with normal mitochondrial function.
Dr. Walker first became interested in mitochondrial disorders as an intern in pediatrics, when she rotated through a mitochondrial disorders clinic. She found the patients fascinating and their stories compelling, and she noted the difficulties facing the physicians trying to diagnose them. The seeds were sewn, even at that very early stage of her career, for her determination to improve the diagnostic approach to mitochondrial disorders.
Dr. Walker’s educational background provided her with the perfect framework for her later research. With an undergraduate degree in biochemistry and an MD-PhD in biophysics, Dr. Walker is well prepared for the challenges of studying mitochondrial disorders.
Dr. Walker is also in an excellent intellectual environment in which to pursue development of a test for mitochondrial dysfunction. As a physician, she spends most of her clinical time in a mitochondrial disorders clinic. As a scientist, she is working in the laboratory of Dr. Vamsi Mootha, one of the world’s foremost mitochondrial biologists. Dr. Mootha, a Professor of Systems Biology and Medicine at Harvard Medical School, has made major contributions in mitochondrial biology, including identification of numerous mitochondrial disease genes and discovery of the machinery of the mitochondrial calcium uniporter.
If Drs. Walker and Mootha can identify a stressor and a read-out that distinguishes cells with abnormal mitochondria from normal ones, then this could revolutionize testing for mitochondrial disturbances. Gone would be the days when physicians wonder if a patient is afflicted with a mitochondrial disturbance, but have no good way of determining the answer.