Current Research Articles on Propionic Acidemia

Major Breakthrough on Propionic Acidemia Research

PaVe-GT: Paving the Way for Rare Disease Gene Therapies

Adeno-associated virus serotype 8 (AAV8) Gene Transfer Rescues a Neonatal Lethal Murine Model of Propionic Acidemia

New Drug Relieves TCA Cycle Block In Patients With PA And MMA

GeneReviews: Propionic Acidemia


Prenatal Diagnosis


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
The re-occurrence of cardiomyopathy in propionic acidemia after liver transplantation Propionate-Induced changes in cardiac metabolism, notably CoA trapping, are not altered by L-Carnitine Prolonged QTc intervals and decreased left ventricular contractility in patients with propionic acidemia.
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
Cardiac Arrest Secondary to Long QT(C )in a Child with Propionic Acidemia.
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.

Gut Mobility         The importance of gut motility in the metabolic control of propionic
        J Pediatr. 2004 Apr;144(4):532-5.

Liver Transplantation​​ Methylmalonic acidemia/propionic acidemia – the biochemical presentation and comparing the outcome between liver transplantation versus non-liver transplantation groups (2019) Auxiliary liver transplantation for propionic acidemia: a 10-year follow-up.
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.

Mitochondrial Dysfunction Secondary mitochondrial dysfunction in propionic aciduria: a pathogenic role for endogenous mitochondrial toxins.
Biochem J. 2006 Aug 15;398(1):107-12.

Mouse Model of PA / Gene Therapy Fatal propionic acidemia in mice lacking propionyl-CoA carboxylase and its rescueby postnatal, liver-specific supplementation via a transgene 
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.

Pancreatitis            J Pediatr Gastroenterol Nutr. 2008 Sep;47(3):370-1.
         (Contact OAA if interested in receiving a copy of this article).

PCC Enzyme Characterization of four variant forms of human propionyl-CoA carboxylase expressed in Escherichia coli.
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.
Hum Mol Genet. 1996 Mar;5(3):331-7.  

PCCA , PCCB Mutation Analysis Propionic and Methylmalonic Acidemia: Antisense Therapeutics for Intronic ariations Causing Aberrantly Spliced Messenger RNA.
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. Structure of the PCCA gene and distribution of mutations causing propionic acidemia.
Mol Genet Metab. 2001 Sep-Oct;74(1-2):238-47. Overview of mutations in the PCCA and PCCB genes causing propionic acidemia.
Hum Mutat. 1999;14(4):275-82. 

Metabolomics Metabolomics identifies perturbations in human disorders of propionate metabolism.
Clin Chem. 2007 Dec;53(12):2169-76. Epub 2007 Oct 19.

Dietary Modifications

Improved growth and nutrition status in children with methylmalonic or propionic acidemia fed an elemental medical food.
Mol Genet Metab. 2003 Sep-Oct;80(1-2):181-8.

Hyperammoneamia Metabolic changes associated with hyperammonemia in patients with propionic acidemia.
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.

Neurology Propionate increases neuronal histone acetylation, but is metabolized oxidatively by glia. Relevance for propionic acidemia.
J Neurochem. 2007 May;101(3):806-14.

Dermatology Propionic acidemia manifesting with low isoleucine generalized exfoliative dermatosis.
Pediatr Dermatol. 2007 Sep-Oct;24(5):508-10.

Ophthalmology Optic nerve atrophy in propionic acidemia.
Ophthalmology. 2003 Sep;110(9):1850-4.



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

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