- By oaanews
- September 5, 2022
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Current Research Articles on Propionic Acidemia
Major Breakthrough on Propionic Acidemia Research
PaVe-GT: Paving the Way for Rare Disease Gene Therapies
New Drug Relieves TCA Cycle Block In Patients With PA And MMA
GeneReviews: Propionic Acidemia
- Severity modeling of propionic acidemia using clinical and laboratory biomarkers
- A novel small molecule approach for the treatment of propionic and methylmalonic acidemias
- Severe anemia in patients with Propionic acidemia is associated with branched-chain amino acid imbalance
- Propionic Acidemia Consensus Conference Summary
- Natural History of Propionic Acidemia
- Neurologic Considerations in Propionic Acidemia
- Acute Management of Propionic Acidemia
- Chronic Management and Health Supervision of Individuals with Propionic Acidemia
- Sass JO, Hofmann M, Skladal D, Mayatepek E, Schwahn B, Sperl W. Propionic acidemia revisited: a workshop report. Clin Pediatr (Phila). 2004 Nov-Dec;43(9):837-43.
- Bustamante-Aragones A, Pérez-Cerdá C, Pérez B, Rodriguez de Alba M, Ugarte M, Ramos C. Prenatal diagnosis in maternal plasma of a fetal mutation causing propionic acidemia. Mol Genet Metab. 2008 Jul 1. [Epub ahead of print]
- Inoue Y, Ohse M, Shinka T, Kuhara T. Prenatal diagnosis of propionic acidemia by measuring methylcitric acid in dried amniotic fluid on filter paper using GC/MS J Chromatogr B Analyt Technol Biomed Life Sci. 2008 Jul 15;870(2):160-3. Epub 2008 Mar 4.
Successful reversal of propionic acidaemia associated cardiomyopathy: Evidence for low myocardial coenzyme Q10 status and secondarymitochondrial dysfunction as an underlying pathophysiological mechanism
- J. Baruteau a,⁎, I. Hargreaves b, S. Krywawychc, A. Chalasani b, J.M. Land b, J.E. Davison a, M.K. Kwoka,
G. Christov d, A. Karimova d, M. Ashworthe, G. Andersone, H. Pruntyc, S. Rahman a,f, S. Grünewald a,f
J Pediatr. 2007 Feb;150(2):192-7, 197.e1. Coincidence of Long QT Syndrome and Propionic Acidemia
- B. Kakavand, V.A. Schroeder, T.G. Di Sessa
Pediatr Cardiol. 2007 Dec 5; Coincidence of long QT syndrome and propionic acidemia.propionate-induced_changes_in_cardiac_metabolism_notably_coa_trapping_are_not_altered_by_l-carnitine.pdf
Pediatr Cardiol. 2006 Jan-Feb;27(1):160-1. Clinical, pathological, and biochemical studies in a patient with propionic acidemia and fatal cardiomyopathy.
Mol Genet Metab. 2005 Aug;85(4):286-90.
acidemia.
J Pediatr. 2004 Apr;144(4):532-5.
- Liver Transplantation in Children With Propionic Acidemia: Medium-Term Outcomes
- Tzu-Hung Chu1,13, Yin-Hsiu Chien2 , Hsiang-Yu Lin3,4, Hsuan-Chieh Liao5 , Huey-Jane Ho6 , Chih-Jou Lai7 , Chuan-Chi Chiang5 , Niang-Cheng Lin8 , Chia-Feng Yang1,9, Wuh-Liang Hwu2 , Ni-Chung Lee2 , Shuan-Pei Lin3 , Chin-Su Liu8 , Rey-Heng Hu10, Ming-Chih Ho10 and Dau-Ming Niu1,11
Am J Transplant. 2007 Sep;7(9):2200-3. Evaluation and management of patients with propionic acidemia undergoing liver transplantation: a comprehensive review.
Pediatr Transplant. 2006 Nov;10(7):773-81. Liver transplantation for inborn errors of metabolism.
Transplantation. 2005 Sep 27;80(1 Suppl):S135-7. Review. Long-term survival after liver transplantation in children with metabolic disorders.
Pediatr Transplant. 2002 Aug;6(4):295-300.
Biochem J. 2006 Aug 15;398(1):107-12.
J Biol Chem. 2001 Sep 21;276(38):35995-9. Epub 2001 Jul 18. Polyethylene glycol modification of adenovirus reduces platelet activation, endothelial cell activation, and thrombocytopenia.
Hum Gene Ther. 2007 Sep;18(9):837-48.
- Bultron G, Seashore MR, Pashankar DS, Husain SZ.ecurrent Acute Pancreatitis in Propionic Acidemia.
(Contact OAA if interested in receiving a copy of this article).
J Biol Chem. 2005 Jul 29;280(30):27719-27. Kinetic characterization of mutations found in propionic acidemia and methylcrotonylglycinuria: evidence for cooperativity in biotin carboxylase.
J Biol Chem. 2004 Apr 16;279(16):15772-8. Propionic acidemia: analysis of mutant propionyl-CoA carboxylase enzymes expressed in Escherichia coli. Hum Mutat. 2002 Jun;19(6):629-40. Chaperonin-mediated assembly of wild-type and utant subunits of human propionyl-CoA carboxylase expressed in Escherichia coli.
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Am J Hum Genet. 2007 Oct 26;81(6) Qualitative and quantitative analysis of the effect of splicing mutations in propionic acidemia underlying non-severe phenotypes.
Hum Genet. 2004 Aug;115(3):239-47. Propionic acidemia: identification of twenty-four novel mutations in Europe and North America. Mol Genet Metab. 2003 Jan;78(1):59-67. Functional analysis of PCCB mutations causing propionic acidemia based on expression studies in deficient human skin fibroblasts.
Biochim Biophys Acta. 2003 May 20;1638(1):43-9.
- Clavero S, Martínez MA, Pérez B, Pérez-Cerdá C, Ugarte M, Desviat LR. Functional characterization of PCCA mutations causing propionic acidemia.
Biochim Biophys Acta. 2002 Nov 20;1588(2):119-25. - Campeau E, Desviat LR, Leclerc D, Wu X, Pérez B, Ugarte M, Gravel RA.
Mol Genet Metab. 2001 Sep-Oct;74(1-2):238-47. Overview of mutations in the PCCA and PCCB genes causing propionic acidemia.
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Clin Chem. 2007 Dec;53(12):2169-76. Epub 2007 Oct 19.
- Long term follow-up of the dietary intake in propionic acidemia
- Yannicelli S, Acosta PB, Velazquez A, Bock HG, Marriage B, Kurczynski TW, Miller M, Korson M, Steiner RD, Rutledge L, Bernstein L, Chinsky J, Galvin-Parton P, Arnold GL.
Mol Genet Metab. 2003 Sep-Oct;80(1-2):181-8.
Mol Genet Metab. 2006 Jun;88(2):123-30. N-carbamylglutamate markedly enhances ureagenesis in N-acetylglutamate deficiency and propionic acidemia as measured by isotopic incorporation and blood biomarkers.
Pediatr Res. 2008 Apr 9.
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For many years, there has been speculation that propionic acidemia (PA) would be a good disorder to treat using gene therapy. However, when researchers created mice with PA (aka “knock-out” mice), the very real challenge of manipulating these animals became apparent. PA knock-out mice show a similar phenotype to the most severely affected humans and unfortunately, always die within 24-48 hours after birth. At this stage of life, the mice weigh around one gram and are the size of a tootsie-roll. Their small size, fragile medical condition and very short life-span make all experiments with the PA mice technically difficult.
Recently, we have had great success in the treatment of methylmalonic acidemia (MMA) mice with viral gene delivery (Reference 1). The MMA mice are very similar to the PA mice in that they also are severely affected and always die from their metabolic disorder in the first few days of life. We reasoned that an identical viral gene delivery approach should be effective in the PA mouse model because the metabolic defects that cause both PA and MMA lie in the same general biochemical pathway.
Viral gene delivery takes advantage of the natural life cycle of a virus, in which the virus normally infects cells, and then delivers its own genes. By using genetic engineering, it is possible to redesign viruses to deliver human genes. In our experiments, an adeno-associated virus (AAV) was designed to carry the propionyl-CoA carboxylase alpha subunit (PCCA) gene, which is defective in the mouse model of PA. Adeno-associated virus (AAV) is a small virus that naturally infects humans and some other primate species. AAV can infect both dividing and non-dividing cells, and express genes for long periods of time. The combination of efficient gene expression, ability to target tissues and direct sustained gene expression make AAV a very attractive candidate for use in gene therapy. Perhaps most importantly, AAV is not currently known to cause disease; it is not a human pathogen.
The AAV expressing the PCCA gene was then injected directly into the liver of newborn mice, and the animals were followed to determine if the gene therapy prevented death and lowered metabolite levels. The results we have observed are very encouraging: following AAV gene delivery of the PCCA gene, the propionic acidemia mice have survived for at least six months with a single treatment, and without treatment these mice uniformly perish within the first 48 hours after birth. The treated mice exhibited PCCA expression in the liver and had decreased levels of methylcitrate in the blood, which like propionic acid, is elevated in propionic acidemia. The decrease in methylcitrate levels indicates that a significant increase in propionyl-CoA carboxylase activity followed gene delivery. The full details of these experiments have been published (Reference 2) and provide the first demonstration that gene therapy may be an effective treatment for PA in mice, and by extension, perhaps someday, in patients with propionic acidemia.
AAV has already shown promise in the treatment of other genetic diseases and has been safely used in numerous clinical trials. The results of the AAV treatment in the mouse model of propionic acidemia, the success of this approach in other genetic disease, and a historic safety record after AAV administration in humans have generated a lot of excitement. However, cautious optimism should be used since the translation of therapeutic success in animal models are sometimes difficult to replicate in humans. Extensive safety testing and FDA approval need to occur before any gene delivery clinical trial can occur.
Reference 1. Chandler R.J. and Venditti C.P. (2010) Long-term rescue of a lethal murine model of methylmalonic acidemia using adeno-associated viral gene therapy. Mol Ther 18(1): 11-16. PMID: 19861951
Reference 2. Chandler R.J., Chandrasekaran S., Carrillo-Carrasco N., Senac J.S., Hoferr S.E., Barry M.A., and Venditti C.P. (2010) Adeno-associated virus serotype 8 (AAV8) Gene Transfer Rescues a Neonatal Lethal Murine Model of Propionic Acidemia, Human Gene Therapy, [Epub ahead of print], Oct 15, PMID 20950151