Author Archives: Angela Waits

迪伦Ĵ

迪伦Ĵ | 丙酸血症 | Age 2 1/2

迪伦结果表明：J出生在10月 12日, 2013 在沃科尼亚, 明尼苏达, 在称重 8 英镑, 2 ounces. 后迪伦诞生, 医生发现他有一个低于平均体温, 所以他们把他带回幼儿园温暖他，. 他被带回美国, 并从那里出来两天, 我们经历了一个正常, 健康的小男孩, 或者我们是这么认为.

在十月的清晨 15日, 只要 15 因为我们时间已经出院作为一个家庭的 3, 迪伦在演戏那样的陌生. 他很困, 似乎寒冷的触感. 我的老公, 亚当, 我把他的温度，他是在 95 度. 明知是不正常的, 我叫我的妹妹- 在- 法, 谁是NICU护士在这里的城市, 她告诉我们要尝试做皮肤上的皮肤温暖他，, 如果没有工作, 到大概拨打值班儿科医生. 但令我们失望, 一个小时过去了，他没有回暖所有, 即使一切后，我们曾尝试. 我叫值班的儿科医生，他告诉我们，看他在接下来的几个小时, 如果他仍然寒冷，还是很昏昏欲睡，不想吃, 我们可以等到把他带到儿科医生办公室那天早上在上午8点开, 或者我们可以带他到急诊室. 约一小时后, 我的丈夫拿起迪伦高达带到我这里来尝试和饲料, 而他的手臂无力地跌他的身体背后. 这是烙在我的脑海里的图像. 我们知道在那一刻，什么是错, 所以我们收拾他，在他的汽车座椅和开车把他送到急诊室. 一旦出现, 他们打量了他一下, 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, 但他们认为，他需要在明尼阿波利斯市中心被转移到一家儿童医院, 把他上呼吸机, 因为他正从工作，所以难以呼吸过于疲惫. 他离开房间, 我失去了它, 呼吸机, 我的小宝贝? 什么问题? 后来，医生回来说, 他居然相信他们也许可以只是尝试氧气, 所以他们在楼上他转移, 他们的新生儿重症监护病房, 看看我们可以得到它的控制之下.

就在那时, 该等待比赛开始. 他们做了多次验血, 在一个点来得出结论，他只是脱水. 他的血糖非常低, 而且他们认为他只是没吃饱. 时间过去了, 我们都在等待这并围绕多个郊区医院巡视的新生儿, 到达并期待在迪伦. 大约午饭时间, 医生走了进来，看着他，并告诉我们他认为迪伦仍然需要被转移到儿童医院的呼吸机被投入，因为氧气本身没有削减它. 当他告诉我们这, 一名护士走进来, 递给他一张纸, 到他看着, 回答说：“噢，我的天哪”, 离开房间. 我们被吓坏了, 但没想到的太多了吧. 几分钟后，他回来了，并告诉我们，迪伦的氨水平 900. 他看着我们很迷茫的脸，并告诉我们，这是非常, 很严重, 该正常范围是 10-35, 而迪伦可能不能使它. 我记得麻木, 的想法，我的品牌新的婴儿可能会死, 当一个小时前，我们刚刚还以为他是脱水. 医生离开了设立救护车把迪伦, 还没到儿童医院了, 但是到了明尼苏达大学儿童医院, 因为他需要特殊处理, 只适用于大学. 他需要放在透析.

我在迪伦救护车骑, 而这些都是最长 45 我的生活分钟. 我记得当时我想他会在救护车死, ，有什么我可以做, 我只是在前排座位坐起来祈祷. 当我们赶到医院, 它像一个场景动画的, 所有这些医生一拥而上我们, 告诉我，他们会一直在等待, 解释是怎么回事, 需要我签同意书，开始透析. 告诉我，在做透析 3 天大的婴儿是非常危险的, 但什么其他选择，确实我们有? 当我们来到他的氨已攀升至医院 1200. My husband and I, 和我们的家庭, 被领进我们等着听迪伦上的字家庭候车室. 就在这个时候，我们被介绍给我们的代谢医生. 她来了，遇见了我们，并描述了她相信Dylan有. 一种罕见的遗传疾病, 在那里，他不能正确分解蛋白质, 而不是将它分解, 他只会分解到某一个点，然后坏事 (丙酸和氨), 将备份在他的系统. 同在一处高，因为它是, 它被毒害他的器官. 他们告诉我们，他们认为他的大脑肿胀，什么脑损伤他从高氨氮收到他们不能肯定, 他们将采取超声波和核磁共振检查, 这两者出来相当不错的, 但真正的时间会告诉.

许多小时后, 透析开始, 和一名护士进来, 并且说的话, 我永远不会忘记“我知道这一直是你生命中最糟糕的一天, 但我想给你一些好消息, 迪伦的氨是90“! 一样快，他生病了, 他得到了更好的一样快. 他们能够赶迪伦的新生儿筛查结果和证实了他丙酸血症诊断. 医生现在有一个诊断，并能对他进行治疗. 随着日子一天天的过去了ICU, 他氨稳定, 他们能够开始他Propimex和母乳的低蛋白饮食, 他居然真的很好. 我们能够刚过回家 7 在ICU天.

生活之后迪伦似乎去非常好, 和对我们是“正常”的. 他是一个很好吃, 总是吃蛋白，他需要在一天获得热量的量和被正常显影. 我每天会检查他酮在他的尿 (我们的医生认为我是检查与其说是一个有点疯狂, 但它是我的指标是事关), 而且他们总是消极的，直到他正要 5 months old. 迪伦几乎每天开始获取跟踪小酮在他的尿. 我们将努力推动更多的流体, 但他们仍然会涨回去. 他正在吃他所有的瓶子非常好动，演戏完全正常. 但, 一旦我们看到酮, 我们将带来他在急诊室，他的氨会很高, 在100的. 最可怕的是, 他从来没有演过不同, 从未表现出他的招牌氨高, 除了酮.

在二月至五月间的暂时进出医院周后, 我们的代谢医生决定开始他Carbaglu, 以帮助保持他的氨检查. 当我们从医院在四月下旬开始Carbaglu后出院, 我们遇到了与我们的代谢医生跟进预约. 正是在这个约会迪伦的医生坐在我们失望，并告诉我们，她认为迪伦需要肝脏移植. 你看, 他们从来没有能够告诉我们某些如果Dylan有PA与否的一个更严重的情况下，, 因为基因检测已完成后，, 它回来了，无论他的突变从未见过. 所以，我们种不得不等待，看看他怎么做. 我们被震惊了, 从未有过，我们认为肝移植手术会是这样，我们将讨论对迪伦. 我和我丈夫回家了几个星期想过这个问题, 祈祷吧, 哭一下吧, 它研究, 其他家长有故事，已通过了这, 并最终决定，我们不想等到另一场危机发生的迪伦和他有脑损伤或更糟, 我们希望迪伦保持迪伦. 所以在五月 8日 今年, 当迪伦 7 months old, 我们放置在移植名单迪伦获得一个新的肝脏.

On July 24日, 我们得到了他们有一个新的肝脏迪伦通话. 我们丢弃我们在做什么，并跑到了医院，他们做了所有的手术前的准备工作, 我们准备, 又等了字何时机关将在明尼苏达州和手术时将开始. On July 26日, 手术发生. 我丈夫和我走迪伦到运前的房间，把他交给移植小组. 我们被引导到我们与家人等待着家庭候车室 8 时间很长. 当外科医生走了出来, 在他的脸上露出了笑容, 并告诉我们，它已经非常顺利, 它是这样一种解脱. 我们被带到了我们能够看到迪伦PICU, 和害怕，因为我是看他, 当我们做, 他看起来那么好. Yes, 他迷上了这么多管和线, 他被肿, 但他看起来就像我们的孩子. 我们住在医院 18 天视迪伦恢复. 他的身体接受了新的肝脏非常好, 和我们生命中最美好的时刻之一, 是当我们的新陈代谢医生进来告诉我们，他们对迪伦采取手术已经显示后有机酸测试，他在他的身体没有任何丙酸! 这真是一个奇迹.

这是近 2 因为迪伦年有他的移植，他是做奇妙. 他曾因为并发症少，但他通过他们得到出色. 迪伦将在抗排斥药物，他的一生. 有说他可能进入拒绝在任何时候恐惧, 但如果发现及时, 这是非常可治疗. 在这里，在明尼苏达州, 与我们的医生, 他们将保持非常密切关注他. 我们还没有关于如果肝脏会持续一生大量的研究, 或者，如果他需要一个新的最终, 但在同一时间, 我们没有对什么PA确实给体长期一吨的数据. 我们的代谢医生正在非常谨慎与他, 他们让他在他的代谢公式只是直到去年10月，我们想看看他有什么实验室做了，如果他走了它，到目前为止，他一直保持稳定. 他仍然在限制蛋白饮食, 现在他得到30-35克，每天. 因为移植在他的变化一直十倍. 之前，他曾语气低沉而现在他的语气是如此美好, 他运行，并爬上就像所有其他 2 ½当我们打岁在公园! 虽然这是最艰难的决定，我的丈夫和我都做过, 这是一个正确的决定对我们, 我们希望迪伦带领他可以最好的生活, 而且，即使有这么多风险, 我们不知道 100% 什么样的未来将举行, 这是值得的, 因为他是如此开心，也很健康 2 ½岁的小男孩!

博士. 宫崎

博士. 彻宫崎, M.D.,Ph.D.

The University of Texas Southwestern Medical Center Dallas, 得克萨斯州

Prior to becoming a 501(Ç)3, the PAF established a Propionic Acidemia Fund at UT Southwestern Medical Center in Dallas, Texas to promote the studies of Dr. 彻宫崎. With PAF’s help, this fund raised over $90,000. 博士. 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. 博士. 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.

博士. 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.

博士. Barry August 2006 Progress Update

Michael A. Barry

八月 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. 肖恩Hofherr, a graduate student in Dr. Barry’s laboratory is pursuing this project for his Ph.D. thesis. 到目前为止，, 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, 博士. 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. 例如, 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. 例如, one might predict that the liver expresses the highest level of PCCA given its role in metabolizing excess amino acids and fatty acids. 反过来, 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. 鉴于这些问题，, 博士. 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. 但, 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 通讯

一月克劳斯

Progress Update as seen in the August 2006 PAF通讯
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

 

博士. Kraus Research studies in PA

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

 

丙酸血症 (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.

 

更新 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. 例如, 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, 博士, CGC

Study Coordinator

电话 (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. 但, 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

分子生物学/生物化学