Author Archives: Angela Waits

Dylan J

Dylan J |  Propionic Acidemia  |  Age 2 1/2

Dylan  J was born on October 12th, 2013 in Waconia, Minnesota, weighing in at 8 pounds, 2 ounces.  After Dylan was born, the doctors noticed that he had a lower than average body temperature, so they brought him back to the nursery to warm him up.  He was brought back to us, and from there on out for two days, we experienced a normal, healthy little boy, or so we thought.

In the early morning hours on October 15th, only 15 hours since we had been discharged from the hospital as a family of 3, Dylan was acting kind of strange.  He was very sleepy, and seemed cold to the touch.  My husband, Adam, and I took his temperature and he was at 95 degrees.  Knowing that wasn’t normal, I called my sister- in- law, who is a NICU nurse here in the cities, and she told us to try doing skin-on-skin to warm him up, and if that didn’t work, to probably call the on-call pediatrician.  Much to our dismay, an hour passed and he hadn’t warmed up at all, even after everything we had tried.  I called the on-call pediatrician and he told us to watch him over the next several hours, if he was still cold and was still very lethargic and didn’t want to eat, we could wait to bring him to the pediatrician office that opened at 8am that morning, or we could bring him to the emergency room.  About an hour later, my husband picked Dylan up to bring him to me to try and feed, and his arms fell limply behind his body.  It’s an image that is burned into my mind.  We knew at that moment something was wrong, so we packed him up in his car seat and drove him to the emergency room.  Once there, they looked him over, and told us that since babies can’t tell us what’s wrong, they would need to do many blood tests and a spinal tap to narrow down what was going on.  I remember the ER doctor telling us it was hard to watch little babies get pricked so he told us to go wait in another room (little did I know I would witness far more worse that these pokes in Dylan’s life to come).  Dylan’s breathing also started to become extremely  labored, he was really trying hard to get each breath in and out.  I don’t remember how long we were in the room, but I do remember the doctor coming and telling my husband and I, they didn’t have any results back yet, but they believed he needed to be transferred to a Children’s hospital in downtown Minneapolis, to put him on a ventilator, because he was getting too exhausted from working so hard to breathe.  He left the room, and I lost it, a ventilator, for my little baby?  What was wrong?  Later the doctor came back and said, he actually believed they might be able to just try oxygen, so they were transferring him upstairs, to their NICU, to see if we could get it under control.

It was then, that the waiting game began.  They did multiple blood tests, at one point coming to the conclusion that he was just dehydrated.  His blood sugar was very low, and they believed he just hadn’t eaten enough.  Hours passed by, and we were waiting for the neonatologist that did his rounds around the more suburban hospitals, to arrive and look at Dylan.  Around lunch time, the doctor came in and looked at him and told us he believed Dylan still needed to be transferred to the Children’s hospital to be put on a ventilator because the oxygen itself was not cutting it.  As he was telling us this, a nurse walked in, handed him a piece of paper, to which he looked at, replied “oh my gosh”, and left the room.  We were freaked out, but didn’t think too much of it.  Minutes later he came back in and told us that Dylan’s ammonia level was 900.  He looked at our very confused faces and told us that this was very, very serious, that the normal range was 10-35, and that Dylan may not make it.  I remember being numb, to the idea that my brand new baby could die, when an hour earlier we had just thought he was dehydrated.  The doctor left to set up an ambulance to take Dylan, not to the Children’s hospital anymore, but to the University of Minnesota Children’s hospital, because he needed special treatment, only available at the University.  He needed to be placed on Dialysis.

I rode in the ambulance with Dylan, and those were the longest 45 minutes of my life.  I remember thinking he was going to die in the ambulance, that there was nothing I could do, I just had to sit up in the front seat and pray.  Once we arrived at the hospital, it was like a scene out of a movie, all these doctors swarmed us, telling me they’d been waiting, explaining what was going on, needing me to sign consent forms to start dialysis.  Telling me that doing dialysis on a 3 day old baby was very risky, but what other choice did we have?  By the time we arrived at the hospital his ammonia had climbed to 1200.  My husband and I, and our families, were ushered into the family waiting room where we waited to hear word on Dylan.  It was at this time we were introduced to our metabolic doctor.  She came and met with us and described what she believed Dylan had.  A rare genetic disorder, where he could not break down protein correctly, and instead of breaking it down, he would only break down to a certain point and then the bad things (propionic acid and ammonia), would back up in his system.  With it being as high as it was, it was poisoning his organs.  They told us they believed his brain was swollen and they couldn’t be sure what brain damage he had received from the high ammonia, they would take ultrasounds and an MRI, which both came out fairly good, but really time would tell.

Many hours later, dialysis began, and a nurse came in, and said the words, I will never forget “I know this has been the worst day of your life, but I wanted to give you some good news, Dylan’s ammonia is 90”!  As fast as he got sick, he got better just as quickly.  They were able to rush Dylan’s newborn screening results and that confirmed his diagnosis of Propionic Acidemia.  The doctors now had a diagnosis and were able to treat him.  As the days passed in the ICU, his ammonia stabilized, they were able to start him on a low protein diet of Propimex and breast milk, and he did really well.  We were able to go home after just 7 days in the ICU.

Life with Dylan after that seemed to go very well, and to us was “normal”.  He was a good eater, always ate the amount of protein and calories he needed to get in a day and was developing normally.  I would check his ketones in his urine daily (our doctors thought I was a little crazy for checking so much, but it was my indicator something was off), and they were always negative until he was about 5 months old.  Dylan started getting trace to small ketones in his urine almost daily.  We would try to push more fluids, but they would still go back up.  He was eating all of his bottles very well still and acting completely normal.  However, once we saw ketones, we would bring him in to the emergency room and his ammonia would be high, in the 100’s.  The scariest part was, he never acted different, never showed signs his ammonia was high, except for the ketones.

After being in and out of the hospital for weeks at a time between February and May, our metabolic doctors decided to start him on Carbaglu, to help keep his ammonia in check.  When we were discharged from the hospital in late April after starting Carbaglu, we met for a follow up appointment with our metabolic doctors.  It was at this appointment that Dylan’s doctor sat us down and told us she believed Dylan needed a liver transplant.  You see, they were never able to tell us for certain if Dylan had a more severe case of PA or not, because after genetic testing was done, it came back that both of his mutations had never been seen before.  So we kind of had to wait and see how he did.  We were shocked, never had we thought liver transplant would be something we would be discussing for Dylan.  My husband and I went home and for a few weeks thought about it, prayed about it, cried about it, researched it, got stories from other parents that had gone through this, and ultimately decided that we didn’t want to wait until another crisis happened to Dylan and he had brain damage or worse, we wanted Dylan to remain Dylan.  So on May 8th of this year, when Dylan was 7 months old, we placed Dylan on the transplant list to get a new liver.

On July 24th, we got the call that they had a new liver for Dylan.  We dropped what we were doing and raced to the hospital where they did all the pre-surgery prep work, prepared us, and waited for word as to when the organ would be in Minnesota and when surgery would start.  On July 26th, the surgery happened.  My husband and I walked Dylan down to the pre-op room and handed him over to the transplant team.  We were guided to the family waiting room where we waited with our families for 8 very long hours.  When the surgeon came out, with a smile on his face, and told us it had gone very well, it was such a relief.  We were taken up to the PICU where we were able to see Dylan, and as scared as I was to see him, when we did, he looked so good.  Yes, he was hooked up to so many tubes and lines, and he was swollen, but he looked just like our boy.  We stayed in the hospital for 18 days as Dylan recovered.  His body accepted the new liver very well, and one of the best moments of our lives, was when our metabolic doctor came in and told us that the organic acid tests they had taken on Dylan after surgery had shown he had no propionic acid in his body!  What a miracle.

It’s been almost 2 years since Dylan has had his transplant and he is doing fantastic.  He’s had a few complications since but he’s gotten through them with flying colors.   Dylan will be on anti-rejection medications his whole life.  There’s the fear that he may go into rejection at any time, but if caught early enough, it is very treatable.  And here in Minnesota, with our doctors, they will keep a very close eye on him.  We also don’t have much research on if this liver will last his whole life, or if he would need a new one eventually, but at the same time, we don’t have a ton of data on what PA does to the body long term.  Our metabolic doctors are being very cautious with him, they kept him on his metabolic formula just until this last October when we tried to see what his labs did if he went off it and so far he has remained stable.  He is still on a restricted protein diet, right now he gets 30-35g a day.  The change in him since transplant has been tenfold.  Before he had low tone and now his tone is so much better, he runs and climbs just like every other 2 ½ year old when we’re playing at the park!  Although it was the toughest decision my husband and I have ever made, this was the right decision for us, we wanted Dylan to lead the best life he could, and even though there were so many risks, and we don’t know 100% what the future will hold, it was worth it, because he is such a happy and very healthy 2 ½ year old little boy!

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

Molecular Biology/Biochemistry