Propionic acidemia

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Propionic acidemia
Other namesHyperglycinemia with ketoacidosis and leukopenia
Propionic acid structure.svg
Propionic acid
Specialty Endocrinology   OOjs UI icon edit-ltr-progressive.svg
Symptoms Poor muscle tone, lethargy, vomiting
Diagnostic method Genetic testing; high levels of propionic acid in the urine
TreatmentLow-protein diet
Prognosis Development may be normal, or patients may have lifelong learning disabilities

Propionic acidemia, also known as propionic aciduria or propionyl-CoA carboxylase deficiency (PCC deficiency), [1] is a rare autosomal recessive metabolic disorder, classified as a branched-chain organic acidemia. [2] [3]

Contents

The disorder presents in the early neonatal period with poor feeding, vomiting, lethargy, and lack of muscle tone. [4] Without treatment, death can occur quickly, due to secondary hyperammonemia, infection, cardiomyopathy, or brain damage. [5]

Symptoms and signs

Propionic acidemia can vary in severity. [6] Severe propionic acidemia lead to symptoms already seen in newborns. [7] Symptoms include poor feeding, vomiting, dehydration, acidosis, low muscle tone (hypotonia), seizures, and lethargy. The effects of propionic acidemia quickly become life-threatening.[ citation needed ]

Long-term complications can include intellectual disability, autism, [8] chronic kidney disease, [9] cardiomyopathy, and prolonged QTc interval. [10]

Pathophysiology

Propionic acidemia is caused by a defect in enzyme called propionyl-CoA carboxylase. Odd-chain FA oxydation.png
Propionic acidemia is caused by a defect in enzyme called propionyl-CoA carboxylase.
Propionic acidemia has an autosomal recessive pattern of inheritance. Autorecessive.svg
Propionic acidemia has an autosomal recessive pattern of inheritance.

In healthy individuals, enzyme propionyl-CoA carboxylase converts propionyl-CoA to methylmalonyl-CoA. This is one of many steps in the process of converting certain amino acids and fats into energy. Individuals with propionic acidemia cannot perform this conversion because the enzyme propionyl-CoA carboxylase is nonfunctional. The essential amino acids valine, methionine, isoleucine, and threonine can not be converted and this leads 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.[ citation needed ]

In many cases, propionic acidemia can damage the brain, heart, kidney, liver, cause seizures and delays to normal development such as walking or talking. The accumulation of propionic acid is known to induce differential responses in different organs. The heart and liver are specific targets of the complication. The patient may need to be hospitalized to prevent breakdown of proteins within the body. Dietary needs must be closely managed.[ citation needed ]

Mutations in both copies of the PCCA or PCCB genes cause propionic acidemia. [11] These genes contain instructions to form alpha- and beta-subunits of PCC, the enzyme called propionyl-CoA carboxylase.[ citation needed ]

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. Hyperammonemia develops due to the inhibitory effects of propionyl-CoA on N-acetylglutamate synthase, indirectly resulting in slowing of the urea cycle. [12]

Diagnosis

Elevated metabolites of propionic acid (for example, 3-hydroxypropionate, 2-methylcitrate, tiglylglycine, propionylglycine) found in blood and urine along with normal activity of biotinidase and normal levels of methylmalonic acid. [10]

Management

Patients with propionic acidemia should be started as early as possible on a low protein diet. In addition to a protein mixture that is devoid of methionine, threonine, valine, and isoleucine, the patient should also receive L-carnitine treatment and should be given antibiotics 10 days per month in order to remove the intestinal propiogenic flora. The patient should have diet protocols prepared for them with a "well day diet" with low protein content, a "half emergency diet" containing half of the protein requirements, and an "emergency diet" with no protein content. These patients are under the risk of severe hyperammonemia during infections that can lead to comatose states. [13]

Liver transplant is gaining a role in the management of these patients, with small series showing improved quality of life.[ citation needed ]

Epidemiology

Propionic acidemia is inherited in an autosomal recessive pattern and is found in about 1 in 35,000 [11] live births in the United States. The condition appears to be more common in Saudi Arabia, [14] with a frequency of about 1 in 3,000. [11] The condition also appears to be common in Amish, Mennonite and other populations with higher frequency of consanguinity. [15]

History

In 1957, a male child was born with poor mental development, repeated attacks of acidosis, and high levels of ketones and glycine in the blood. Upon dietary testing, Dr. Barton Childs discovered that his symptoms worsened when given the amino acids leucine, isoleucine, valine, methionine, and threonine. In 1961, the medical team at Johns Hopkins Hospital in Baltimore, Maryland published the case, calling the disorder ketotic hyperglycinemia. In 1969, using data from the original patient's sister, scientists established that propionic acidemia was a recessive disorder, and that propionic acidemia and methylmalonic acidemia are caused by deficiencies in the same enzyme pathway. [16]

See also

Related Research Articles

<span class="mw-page-title-main">Methionine</span> Sulfur-containing amino acid

Methionine is an essential amino acid in humans.

<span class="mw-page-title-main">Isoleucine</span> Chemical compound

Isoleucine (symbol Ile or I) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH+3 form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −COO− form under biological conditions), and a hydrocarbon side chain with a branch (a central carbon atom bound to three other carbon atoms). It is classified as a non-polar, uncharged (at physiological pH), branched-chain, aliphatic amino acid. It is essential in humans, meaning the body cannot synthesize it. Essential amino acids are necessary in the human diet. In plants isoleucine can be synthesized from threonine and methionine. In plants and bacteria, isoleucine is synthesized from pyruvate employing leucine biosynthesis enzymes. It is encoded by the codons AUU, AUC, and AUA.

<span class="mw-page-title-main">Threonine</span> Amino acid

Threonine is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group, a carboxyl group, and a side chain containing a hydroxyl group, making it a polar, uncharged amino acid. It is essential in humans, meaning the body cannot synthesize it: it must be obtained from the diet. Threonine is synthesized from aspartate in bacteria such as E. coli. It is encoded by all the codons starting AC.

Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −COO− form under biological conditions), and a side chain isopropyl group, making it a non-polar aliphatic amino acid. Valine is essential in humans, meaning the body cannot synthesize it; it must be obtained from dietary sources which are foods that contain proteins, such as meats, dairy products, soy products, beans and legumes. It is encoded by all codons starting with GU (GUU, GUC, GUA, and GUG).

<span class="mw-page-title-main">Methylmalonic acidemias</span> Medical condition

Methylmalonic acidemias, also called methylmalonic acidurias, are a group of inherited metabolic disorders, that prevent the body from properly breaking down proteins and fats. This leads to a buildup of a toxic level of methylmalonic acid in body liquids and tissues. Due to the disturbed branched-chain amino acids (BCAA) metabolism, they are among the classical organic acidemias.

<span class="mw-page-title-main">Isovaleric acidemia</span> Medical condition disrupting normal metabolism

Isovaleric acidemia is a rare autosomal recessive metabolic disorder which disrupts or prevents normal metabolism of the branched-chain amino acid leucine. It is a classical type of organic acidemia.

<span class="mw-page-title-main">Maple syrup urine disease</span> Autosomal recessive metabolic disorder

Maple syrup urine disease (MSUD) is a rare, inherited metabolic disorder that affects the body's ability to metabolize amino acids due to a deficiency in the activity of the branched-chain alpha-ketoacid dehydrogenase (BCKAD) complex. It particularly affects the metabolism of amino acids—leucine, isoleucine, and valine. With MSUD, the body is not able to properly break down these amino acids, therefore leading to the amino acids to build up in urine and become toxic. The condition gets its name from the distinctive sweet odor of affected infants' urine and earwax due to the buildup of these amino acids.

<span class="mw-page-title-main">Malonic aciduria</span> Medical condition

Malonic aciduria or malonyl-CoA decarboxylase deficiency (MCD) is an autosomal-recessive metabolic disorder caused by a genetic mutation that disrupts the activity of Malonyl-CoA decarboxylase. This enzyme breaks down Malonyl-CoA into acetyl-CoA and carbon dioxide.

<span class="mw-page-title-main">Methylmalonyl-CoA mutase deficiency</span> Medical condition

Methylmalonyl-CoA mutase is a mitochondrial homodimer apoenzyme that focuses on the catalysis of methylmalonyl CoA to succinyl CoA. The enzyme is bound to adenosylcobalamin, a hormonal derivative of vitamin B12 in order to function. Methylmalonyl-CoA mutase deficiency is caused by genetic defect in the MUT gene responsible for encoding the enzyme. Deficiency in this enzyme accounts for 60% of the cases of methylmalonic acidemia.

<span class="mw-page-title-main">Methylmalonyl-CoA mutase</span> Mammalian protein found in Homo sapiens

Methylmalonyl-CoA mutase (EC 5.4.99.2, MCM), mitochondrial, also known as methylmalonyl-CoA isomerase, is a protein that in humans is encoded by the MUT gene. This vitamin B12-dependent enzyme catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA in humans. Mutations in MUT gene may lead to various types of methylmalonic aciduria.

<span class="mw-page-title-main">Amino acid synthesis</span> The set of biochemical processes by which amino acids are produced

Amino acid biosynthesis is the set of biochemical processes by which the amino acids are produced. The substrates for these processes are various compounds in the organism's diet or growth media. Not all organisms are able to synthesize all amino acids. For example, humans can synthesize 11 of the 20 standard amino acids. These 11 are called the non-essential amino acids.

Propionyl-CoA is a coenzyme A derivative of propionic acid. It is composed of a 24 total carbon chain and its production and metabolic fate depend on which organism it is present in. Several different pathways can lead to its production, such as through the catabolism of specific amino acids or the oxidation of odd-chain fatty acids. It later can be broken down by propionyl-CoA carboxylase or through the methylcitrate cycle. In different organisms, however, propionyl-CoA can be sequestered into controlled regions, to alleviate its potential toxicity through accumulation. Genetic deficiencies regarding the production and breakdown of propionyl-CoA also have great clinical and human significance.

<span class="mw-page-title-main">Propionyl-CoA carboxylase</span>

Propionyl-CoA carboxylase (EC 6.4.1.3, PCC) catalyses the carboxylation reaction of propionyl-CoA in the mitochondrial matrix. PCC has been classified both as a ligase and a lyase. The enzyme is biotin-dependent. The product of the reaction is (S)-methylmalonyl CoA.

<span class="mw-page-title-main">Methylmalonic acid</span> Chemical compound

Methylmalonic acid (MMA) is a chemical compound from the group of dicarboxylic acids. It consists of the basic structure of malonic acid and also carries a methyl group. The salts of methylmalonic acid are called methylmalonates.

<span class="mw-page-title-main">Methylmalonyl-CoA</span> Chemical compound

Methylmalonyl-CoA is the thioester consisting of coenzyme A linked to methylmalonic acid. It is an important intermediate in the biosynthesis of succinyl-CoA, which plays an essential role in the tricarboxylic acid cycle.

<span class="mw-page-title-main">Methylmalonyl CoA epimerase</span>

Methylmalonyl CoA epimerase is an enzyme involved in fatty acid catabolism that is encoded in human by the "MCEE" gene located on chromosome 2. It is routinely and incorrectly labeled as "methylmalonyl-CoA racemase". It is not a racemase because the CoA moiety has 5 other stereocenters.

Organic acidemia is a term used to classify a group of metabolic disorders which disrupt normal amino acid metabolism, particularly branched-chain amino acids, causing a buildup of acids which are usually not present.

<span class="mw-page-title-main">Aldehyde dehydrogenase 6 family, member A1</span> Protein-coding gene in the species Homo sapiens

Methylmalonate-semialdehyde dehydrogenase [acylating], mitochondrial (MMSDH) is an enzyme that in humans is encoded by the ALDH6A1 gene.

Combined malonic and methylmalonic aciduria (CMAMMA), also called combined malonic and methylmalonic acidemia is an inherited metabolic disease characterized by elevated levels of malonic acid and methylmalonic acid. However, the methylmalonic acid levels exceed those of malonic acid. CMAMMA is not only an organic aciduria but also a defect of mitochondrial fatty acid synthesis (mtFASII). Some researchers have hypothesized that CMAMMA might be one of the most common forms of methylmalonic acidemia, and possibly one of the most common inborn errors of metabolism. Due to being infrequently diagnosed, it most often goes undetected.

References

  1. ↑ Online Mendelian Inheritance in Man (OMIM): 606054
  2. ↑ 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.
  3. ↑ 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. S2CID   21114631.
  4. ↑ "Propionic acidemia". National Center for Advancing Translational Sciences. 2 Dec 2015. Retrieved 6 June 2018.
  5. ↑ 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. S2CID   12674920.
  6. ↑ Shchelochkov, Oleg A.; Manoli, Irini; Juneau, Paul; Sloan, Jennifer L.; Ferry, Susan; Myles, Jennifer; Schoenfeld, Megan; Pass, Alexandra; McCoy, Samantha; Van Ryzin, Carol; Wenger, Olivia; Levin, Mark; Zein, Wadih; Huryn, Laryssa; Snow, Joseph (August 2021). "Severity modeling of propionic acidemia using clinical and laboratory biomarkers". Genetics in Medicine. 23 (8): 1534–1542. doi: 10.1038/s41436-021-01173-2 . ISSN   1530-0366. PMC   8354856 . PMID   34007002. S2CID   234779025.
  7. ↑ Shchelochkov, Oleg A.; Carrillo, Nuria; Venditti, Charles (1993), Adam, Margaret P.; Everman, David B.; Mirzaa, Ghayda M.; Pagon, Roberta A. (eds.), "Propionic Acidemia", GeneReviews®, Seattle (WA): University of Washington, Seattle, PMID   22593918 , retrieved 2022-11-26
  8. ↑ Shchelochkov, Oleg A.; Farmer, Cristan A.; Chlebowski, Colby; Adedipe, Dee; Ferry, Susan; Manoli, Irini; Pass, Alexandra; McCoy, Samantha; Van Ryzin, Carol; Sloan, Jennifer; Thurm, Audrey; Venditti, Charles P. (2024-01-11). "Intellectual disability and autism in propionic acidemia: a biomarker-behavioral investigation implicating dysregulated mitochondrial biology". Molecular Psychiatry: 1–8. doi: 10.1038/s41380-023-02385-5 . ISSN   1476-5578. PMC   11176071 .
  9. ↑ Shchelochkov, Oleg A.; Manoli, Irini; Sloan, Jennifer L.; Ferry, Susan; Pass, Alexandra; Van Ryzin, Carol; Myles, Jennifer; Schoenfeld, Megan; McGuire, Peter; Rosing, Douglas R.; Levin, Mark D. (2019-06-28). "Chronic kidney disease in propionic acidemia". Genetics in Medicine. 21 (12): 2830–2835. doi:10.1038/s41436-019-0593-z. ISSN   1530-0366. PMC   7045176 . PMID   31249402.
  10. 1 2 Shchelochkov, Oleg A.; Carrillo, Nuria; Venditti, Charles (1993), Adam, Margaret P.; Ardinger, Holly H.; Pagon, Roberta A.; Wallace, Stephanie E. (eds.), "Propionic Acidemia", GeneReviews®, University of Washington, Seattle, PMID   22593918 , retrieved 2019-09-29
  11. 1 2 3 http://mayoresearch.mayo.edu/mayo/research/barry_lab/ropionic-Aciademia.cfm Archived 2008-08-29 at the Wayback Machine
    Barry Lab - Vector and Virus Engineering. Gene therapy for Propionic Acidemia
  12. ↑ Dercksen, M.; IJlst, L.; Duran, M.; Mienie, L. J.; van Cruchten, A.; van der Westhuizen, F. H.; Wanders, R. J. A. (December 2014). "Inhibition of N-acetylglutamate synthase by various monocarboxylic and dicarboxylic short-chain coenzyme A esters and the production of alternative glutamate esters". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1842 (12 Pt A): 2510–2516. doi: 10.1016/j.bbadis.2013.04.027 . ISSN   0006-3002. PMID   23643712.
  13. ↑ Saudubray JM, Van Der Bergh G, Walter J : Inborn Metabolic Diseases Diagnosis and Treatment (2012)
  14. ↑ Al-Odaib AN, Abu-Amaro KK, Ozand PT, Al-Hellani AM (2003). "A new era for preventive genetic programs in the Arabian Peninsula". Saudi Medical Journal. 24 (11): 1168–1175. PMID   14647548.
  15. ↑ Kidd JR, Wolf B, Hsia E, Kidd KK (1980). "Genetics of propionic acidemia in a Mennonite-Amish kindred". Am J Hum Genet. 32 (2): 236–245. PMC   1686010 . PMID   7386459.
  16. ↑ Hsia, T. (2003). "How Ketotic Hyperglycinemia Became Propionic Acidemia" (PDF). Paresearch.org. Retrieved 7 June 2018.
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