Dr. Miyazaki

Dr. Toru Miyazaki, M.D.,Ph.D.                                              

The University of Texas Southwestern Medical Center  Dallas, Texas

Prior to becoming a 501(c)3, the PAF established a Propionic Acidemia Fund at UT Southwestern Medical Center in Dallas, Texas to promote the studies of Dr. Toru Miyazaki. With PAF’s help, this fund raised over $90,000. Dr. Miyazaki has succeeded in constructing a mutant mouse model of PA. The construction of this mouse model is significant because scientists now have a valuable tool to observe PA gene manipulation in an animal with propionic acidemia. This allows researchers to evaluate the function of genes transferred into the animal and to see how the body responds. Experiments in mice must precede human clinical trials involving gene therapy, so it is extremely important for this research to be performed.

Two genes, PCCA and PCCB are necessary for the production of propionyl-CoA carboxylase (PCC) an enzyme involved in the metabolism of the amino acids methionine, threonine, isoleucine and valine. Dr. Miyazaki’s mouse model contains a mutation in PCCA and these mice are unable to make PCC. PA mutant mice exhibit symptoms of propionic acidemia similar to human PA patients including poor feeding, dehydration and accelerated ketosis progressing towards death.

Dr. Miyazaki has confirmed that supplementation of 15-20% PCC (propionyl-CoA carboxylase) enzyme activity via a transgene to PA mice resulted in abolishment of most PA symptoms. Treated mice were able to consume a normal diet containing a high level of protein. Additionally they grew and developed like normal mice, procreated and lived a normal lifespan.

There is currently no research being done at UT Southwestern on Propionic Acidemia.   Those interested in reading more about Dr. Miyazaki’s studies may visit the sites below.

Dr. Barry August 2006 Progress Update

Michael A. Barry

August 2006 Progress Update from PAF Newsletter

The Barry Laboratory at the Mayo Clinic is working on a project to test if gene therapy can be used to treat propionic acidemia.  To test this, PA mice from Dr. Miyazaki are being used as subjects for delivery of the PCCA gene to their livers.  Sean Hofherr, a graduate student in Dr. Barry’s laboratory is pursuing this project for his Ph.D. thesis.  To date, Sean has generated a series of gene therapy vectors expressing either the human or the mouse PCCA gene for testing in the PA mice.  Preliminary experiments in the mice indicate that the vectors can be used to deliver PCCA gene to the liver to express amplified amounts of the protein.  Work is underway to determine how this modifies the blood levels of propionate metabolites and to what degree this rescues the whole body and neurological symptoms of the disease in the mice.   In the process of this work, Dr. Barry’s group generated antibodies against different parts of the PCCA protein to help in tracking where, when, and how much of the PCCA protein was being produced by their gene therapy vectors.  With these tools in hand, as a side project, their group has also used them to probe some of the basic biology of the PCCA protein.  While much is known about the genetics and disease symptoms of PA, little data can be found in the literature regarding the distribution of PCCA protein in different tissues.  For example, the level of protein expression in different tissues may explain (in part) some of the tissue damage and symptoms due to loss of PCCA.  Likewise, knowing where PCCA is and is not expressed might better guide how transplantation and gene therapies need to be applied and how this might differ between a mouse model and humans.  For example, one might predict that the liver expresses the highest level of PCCA given its role in metabolizing excess amino acids and fatty acids.  Conversely, one might predict that the brain or the basal ganglion might express lower amounts of PCCA, since many of the symptoms of the disease are manifested in these sites, particularly if these are due to effects within individual cells rather than due to metabolite overload.   Given these issues, Dr. Barry’s group used these new antibodies to screen for PCCA protein production in mouse and human tissue panels.  While they expected PCCA to be either ubiquitously expressed or expressed at highest levels in the liver, to their surprise, they observed a marked variation in amount of PCCA in different tissues.  In both mouse and human tissues, the kidney appeared to have the highest levels of PCCA protein, in fact higher than in the liver per unit protein.  In contrast, in the brain, PCCA was undetected in mouse (but not necessarily zero), and was detectable, but at low levels in the human brain samples.   These data suggest PCCA is not ubiquitously expressed at high levels in all tissues and that the kidney may play a significant role in elimination of propionic metabolites.  While the kidney had higher levels of PCCA when equalized for protein in the different tissues, it should be noted that the liver is still substantially larger in size and so likely  “handles” substantially more metabolites.  However, better knowledge of the locations of PCCA and cross-talk between organs may assist in optimizing therapeutics and to avoid mis-steps when translating between mouse models and PA patients.  Work is underway to screen more specific regions of the brain for PCCA expression and to track how the protein’s expression may change over time in the PCCA mutant mice.

Jan Kraus Update from 8 2006 Newsletter

Jan Kraus

Progress Update as seen in the August 2006 PAF Newsletter

The strength of our research lies in the finding that some forms of mutant PCC are very responsive to an addition of small chemicals called chemical chaperones. These altered forms of the enzyme are not deficient in their ability to carry out the enzymatic reaction but rather in their ability to form the proper structure and assume the correct shape. The chaperone helps them to fold with a large increase in activity. We have carried out the initial experiments on normal and three mutant forms of PCC in a bacterial system in which the human enzyme can be manufactured. Later, we have used the chaperones in skin cell cultures derived from controls and propionic acidemia patients. Again, in some cases we saw large increases in PCC activity. We will continue to screen different chemicals and different mutations for their ability to yield more active PCC. The hope is that this approach can be introduced in clinical practice and help some patients to overcome their metabolic disease. The real promise is that some of the drugs, which gave us the best results, are already in use in clinical practice to treat other disorders.

PCC Website:   http://www.uchsc.edu/cbs/pcc/about_pcc.htm


Dr. Kraus Research studies in PA

Research Studies in Propionic Acidemia
Dr. Jan Kraus’ laboratory, Dept. of Pediatrics, University of Colorado School of Medicine – Update 11/2011


Propionic acidemia (PA) is a serious life threatening inherited disorder of metabolism. The disease is caused by deficiency of an enzyme called Propionyl CoA Carboxylase or PCC for short. PCC is a large enzyme consisting of six alpha and six beta subunits. The enzyme deficiency in turn is caused by mutations in either the PCCA or PCCB gene. My laboratory is currently supported by PAF for two projects associated with this disease.

The first project deals with the determination of the mutations or inherited changes in the DNA of propionic acidemia patients from USA whose DNA samples have been submitted to the Corriell Institute. Most of these patients are members of the PA foundation. Knowing the mutations will lead to better understanding of the disease and lead to improved treatment for the affected patients. We will also determine which of the two mutations in each patient came from which parent. This determination, in turn, will enable diagnoses of mutation carrier status in both parents’ families. The second project is entitled Enzyme Replacement Therapy for Propionic Acidemia. The main objective of this research proposal is to develop a therapeutic treatment of propionic acidemia (PA) by enzyme replacement therapy. Hurdles with enzyme replacement therapy include the delivery of the active enzyme into the patient cells as well as directing it to the correct location within the cell.  In the case of PCC it needs to be delivered to the mitochondria.  The mitochondria are separate membrane enclosed organelles within the cell that mainly supply the energy for cells.  One promising way to deliver the PCC subunits across both the cell and mitochondrial membrane is the use of what is known as the TAT peptide.  This peptide can cross cellular membranes and will also take along anything that is attached to it.  Thus we propose to use the TAT peptide and a mitochondrial targeting sequence as a way to deliver the functioning PCC subunits to cells. The peptide and the targeting sequence will then be removed from PCC by another enzyme already present in mitochondria.

None of this work would have been possible without generous support from the Propionic Acidemia Foundation. Please give money to the foundation to support these and other studies on this devastating disease.


Update 10/2010

“This project deals with the determination of the mutations or inherited changes in the DNA of Propionic Acidmia patients from USA whose DNA samples have been submitted to the Coriell Institute.  Most of thse patients are members of the PA Foundation.  Knowing mutations will lead to better understanding of the disease and lead to improved treatment for the affected patients.  We will also determine which of the two mutations in each patient came from which parent.  This determination, in turn will enable diagnoses of mutation carrier status in both parents’ families.”

Duke Biomarkers

A prospective study of biochemical parameters reflective of metabolic control in propionic acidemia

Individuals of any age with propionic acidemia who have not had a liver transplant may be eligible to take part in a research study on biomarkers

being done by Dr. Loren Pena at Duke University Medical Center.


  • All information and samples (blood and urine) for the research study will be taken during regular visits to a geneticist/metabolic physician and during times of hospital admission. No extra visits to a doctor are needed.
  • Information and samples will be sent from the geneticist/metabolic physician to the research staff at Duke.
  • The cost of sending samples to Duke will be covered by the study. You will not be paid for taking part in the study.


Study goals

Biomarkers are compounds that can be measured by laboratory tests in body fluids such as blood and urine and are helpful in predicting disease states. For example, cholesterol level is a biomarker for heart disease. For patients with some metabolic disorders, biomarkers can be helpful in guiding treatments (such as the amount of protein a person can eat) and can predict whether a person is at risk to develop a health problem associated with that metabolic disorder. Currently, there is no standard set of laboratory tests recommended to help guide treatment for people with propionic acidemia. This is because little is understood about which biomarkers are most helpful. The goals of this study are:


  • To better understand how different biomarkers can be used to guide treatment in people with propionic acidemia
  • To investigate whether a specific disease process called oxidative stress is involved in propionic acidemia
  • To look at specific risk factors for pancreatitis in people with propionic acidemia.



For more information, please contact:

Jennifer Goldstein, PhD, CGC

Study Coordinator

Phone (919) 684-0626

[email protected]


Duke University

Update on “Laboratory parameters reflective of metabolic control in individuals with propionic acidemia” at Duke University
Understanding how the results of laboratory tests relate to a person’s current health, treatment options, and future health risks can be invaluable. However, this is an area on which little information for people with propionic acidemia (PA) is available. To address this question, we are measuring and comparing levels of plasma and urine metabolites in people with PA when they are well and during illness. By doing so, we hope to identify laboratory tests that can help healthcare providers decide on the best available treatments, and identify patients most at risk for developing health issues such as pancreatitis.

Since the research study began in April 2013, we have received samples from 11 participants. Participants provide urine and blood samples for the research study during regular visits to their metabolic specialist and if they are hospitalized while ill. We are also including information from samples previously processed at Duke, and reviewing medical records and laboratory test results from the participant’s treating physician.

We have already seen some promising results that warrant further investigation.

This includes:

* Differences between the values of specific amino acids found by comparison of amino acid levels in approximately 110 samples from well individuals with those in 20 samples obtained during illness. We will continue to focus on these amino acids during analysis of future samples.

* Results from our analysis of urine organic acids suggest dysfunction of the tricarboxylic acid (Krebs) cycle, a series of biochemical reactions that produce ATP, the energy currency of the cell. These results confirm previous findings. Continued investigation may help to determine whether treatment with metabolites in the TCA cycle could be helpful.

* As part of the study, fatty acids (components of fat molecules) were measured in blood samples in a small number of participants. Our exploratory data warrants further investigation of odd chain fatty acids as long-term markers of metabolic control.

We still have a wealth of data to analyze and will continue to enroll new participants and collect samples now that the study has entered its third year.

We greatly appreciate the support of this study and would like to thank all of the families who have contacted us.

For questions about the study, please contact the study coordinator, Jennifer Goldstein, at phone number (919) 684-0626 or email [email protected]


Molecular Biology/Biochemistry