Propionic acidemia pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
Overview
Propionic acidemia, also known as propionic aciduria, propionyl-CoA carboxylase deficiency and ketotic glycinemia,[1] is an autosomal recessive[2] metabolic disorder, classified as a branched-chain organic acidemia.[3]
The disorder presents in the early neonatal period with progressive encephalopathy. Death can occur quickly, due to secondary hyperammonemia, infection, cardiomyopathy, or basal ganglial stroke.[4]
Propionic acidemia is a rare disorder that is inherited from both parents. Being autosomal recessive, neither parent shows symptoms, but both carry a defective gene responsible for this disease. It takes two faulty genes to cause PA, so there is a 1 in 4 chance for these parents to have a child with PA.
Pathophysiology
In healthy individuals, the enzyme propionyl CoA carboxylase converts propionyl CoA to methylmalonyl CoA. This is one step in the process of converting certain amino acids and fats into sugar for energy. Individuals with PA cannot perform this conversion because the enzyme propionyl CoA carboxylase is nonfunctional. The essential amino acids isoleucine, valine, threonine, and methionine, as well as odd-chain fatty acids, are simply converted to propionyl CoA, before the process stops, leading to a buildup of propionyl CoA. Instead of being converted to methylmalonyl CoA, propionyl CoA is then converted into propionic acid, which builds up in the bloodstream. This in turn causes an accumulation of dangerous acids and toxins, which can cause damage to the organs.
In many cases, PA can damage the brain, heart, and liver, cause seizures, and delays to normal development like walking and talking. During times of illness the affected person may need to be hospitalized to prevent breakdown of proteins within the body. Each meal presents a challenge to those with PA. If not constantly monitored, the effects would be devastating. Dietary needs must be closely managed by a metabolic geneticist or metabolic dietician.
Mutations in both copies of the PCCA or PCCB genes cause propionic acidemia.[5] These genes are responsible for the formation of the enzyme propionyl-CoA carboxylase (EC 6.4.1.3), referred to as PCC.
PCC is required for the normal breakdown of the essential amino acids valine, isoleucine, threonine, and methionine, as well as certain odd-chained fatty-acids. Mutations in the PCCA or PCCB genes disrupt the function of the enzyme, preventing these acids from being metabolized. As a result, propionyl-CoA, propionic acid, ketones, ammonia, and other toxic compounds accumulate in the blood, causing the signs and symptoms of propionic acidemia.
References
- ↑ Online Mendelian Inheritance in Man (OMIM) 606054
- ↑ Ravn K; Chloupkova M; Christensen E; Brandt NJ; Simonsen H; Kraus JP; Nielsen IM; Skovby F; Schwartz M (July 2000). "High incidence of propionic acidemia in greenland is due to a prevalent mutation, 1540insCCC, in the gene for the beta-subunit of propionyl CoA carboxylase". American Journal of Human Genetics. 67 (1): 203–206. doi:10.1086/302971. PMC 1287078. PMID 10820128.
- ↑ Deodato F, Boenzi S, Santorelli FM, Dionisi-Vici C (2006). "Methylmalonic and propionic aciduria". Am J Med Genet C Semin Med Genet. 142 (2): 104–112. doi:10.1002/ajmg.c.30090. PMID 16602092.
- ↑ Hamilton RL, Haas RH, Nyhan WC, Powell HC, Grafe MR (1995). "Neuropathology of propionic acidemia: a report of two patients with basal ganglia lesions". Journal of Child Neurology. 10 (1): 25–30. doi:10.1177/088307389501000107. PMID 7769173.
- ↑ http://mayoresearch.mayo.edu/mayo/research/barry_lab/ropionic-Aciademia.cfm
Barry Lab - Vector and Virus Engineering. Gene therapy for Propionic Acidemia