Editing Propionic acidemia

{{short description|Rare autosomal recessive metabolic disorder, classified as a branched-chain organic acidemia}}
{{Infobox medical condition (new)
| synonyms        = Hyperglycinemia with ketoacidosis and leukopenia
| image           = Propionic acid structure.svg
| caption         = [[Propionic acid]]
| symptoms        = Poor muscle tone, lethargy, vomiting
| complications   =
| onset           =
| duration        =
| types           =
| causes          =
| risks           =
| diagnosis       = Genetic testing; high levels of propionic acid in the urine
| differential    =
| prevention      =
| treatment       = Low-protein diet
| medication      =
| prognosis       = Development may be normal, or patients may have lifelong learning disabilities
| frequency       =
| deaths          =
}}

'''Propionic acidemia''', also known as '''propionic aciduria''' or '''[[propionyl-CoA carboxylase]] deficiency''' ('''PCC deficiency'''),<ref>{{OMIM|606054}}</ref> is a rare [[Dominance (genetics)|autosomal recessive]] [[metabolic disorder]], classified as a [[branched-chain amino acid|branched-chain]] [[organic acidemia]].<ref>{{cite journal |pmid=10820128 |date=July 2000 |author1=Ravn K |author2=Chloupkova M |author3= Christensen E |author4=Brandt NJ |author5=Simonsen H |author6=Kraus JP |author7=Nielsen IM |author8=Skovby F |author9=Schwartz M |title=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 |volume=67 |issue=1 |pages=203–206 |pmc=1287078 |doi=10.1086/302971 |journal=American Journal of Human Genetics}}</ref><ref name="oad">{{cite journal |vauthors =Deodato F, Boenzi S, Santorelli FM, Dionisi-Vici C |title=Methylmalonic and propionic aciduria |journal=[[Am J Med Genet C Semin Med Genet]] |volume=142 |issue=2 |pages=104–112 |year=2006 |pmid=16602092 |doi=10.1002/ajmg.c.30090 |s2cid=21114631 }}</ref>

The disorder presents in the early [[neonatal]] period with poor feeding, vomiting, lethargy, and lack of muscle tone.<ref name=NCATS>{{cite news|title=Propionic acidemia |url=https://rarediseases.info.nih.gov/diseases/467/propionic-acidemia |date=2 Dec 2015 |access-date=6 June 2018 |publisher=[[National Center for Advancing Translational Sciences]]}}</ref> Without treatment, death can occur quickly, due to secondary [[hyperammonemia]], infection, cardiomyopathy, or brain damage.<ref name="pbg">{{cite journal |vauthors =Hamilton RL, Haas RH, Nyhan WC, Powell HC, Grafe MR |title=Neuropathology of propionic acidemia: a report of two patients with basal ganglia lesions |journal=Journal of Child Neurology |volume=10 |issue=1 |pages=25–30 |year=1995 |pmid=7769173 |doi=10.1177/088307389501000107 |s2cid=12674920 }}</ref>

==Symptoms and signs==
Propionic acidemia can vary in severity.<ref>{{Cite journal |last1=Shchelochkov |first1=Oleg A. |last2=Manoli |first2=Irini |last3=Juneau |first3=Paul |last4=Sloan |first4=Jennifer L. |last5=Ferry |first5=Susan |last6=Myles |first6=Jennifer |last7=Schoenfeld |first7=Megan |last8=Pass |first8=Alexandra |last9=McCoy |first9=Samantha |last10=Van Ryzin |first10=Carol |last11=Wenger |first11=Olivia |last12=Levin |first12=Mark |last13=Zein |first13=Wadih |last14=Huryn |first14=Laryssa |last15=Snow |first15=Joseph |date=August 2021 |title=Severity modeling of propionic acidemia using clinical and laboratory biomarkers |journal=Genetics in Medicine |language=en |volume=23 |issue=8 |pages=1534–1542 |doi=10.1038/s41436-021-01173-2 |pmid=34007002 |pmc=8354856 |s2cid=234779025 |issn=1530-0366|doi-access=free }}</ref> Severe propionic acidemia lead to symptoms already seen in newborns.<ref>{{Citation |last1=Shchelochkov |first1=Oleg A. |title=Propionic Acidemia |date=1993 |url=http://www.ncbi.nlm.nih.gov/books/NBK92946/ |work=GeneReviews® |editor-last=Adam |editor-first=Margaret P. |place=Seattle (WA) |publisher=University of Washington, Seattle |pmid=22593918 |access-date=2022-11-26 |last2=Carrillo |first2=Nuria |last3=Venditti |first3=Charles |editor2-last=Everman |editor2-first=David B. |editor3-last=Mirzaa |editor3-first=Ghayda M. |editor4-last=Pagon |editor4-first=Roberta A.}}</ref> Symptoms include poor feeding, [[vomiting]], [[dehydration]], [[acidosis]], low [[muscle]] tone ([[hypotonia]]), seizures, and [[lethargy]]. The effects of propionic acidemia quickly become life-threatening.{{cn|date=October 2024}}

Long-term complications can include intellectual disability, autism,<ref>{{Cite journal |last=Shchelochkov |first=Oleg A. |last2=Farmer |first2=Cristan A. |last3=Chlebowski |first3=Colby |last4=Adedipe |first4=Dee |last5=Ferry |first5=Susan |last6=Manoli |first6=Irini |last7=Pass |first7=Alexandra |last8=McCoy |first8=Samantha |last9=Van Ryzin |first9=Carol |last10=Sloan |first10=Jennifer |last11=Thurm |first11=Audrey |last12=Venditti |first12=Charles P. |date=2024-01-11 |title=Intellectual disability and autism in propionic acidemia: a biomarker-behavioral investigation implicating dysregulated mitochondrial biology |url=https://www.nature.com/articles/s41380-023-02385-5 |journal=Molecular Psychiatry |language=en |pages=1–8 |doi=10.1038/s41380-023-02385-5 |issn=1476-5578|doi-access=free |pmc=11176071 }}</ref> chronic kidney disease,<ref>{{Cite journal|last1=Shchelochkov|first1=Oleg A.|last2=Manoli|first2=Irini|last3=Sloan|first3=Jennifer L.|last4=Ferry|first4=Susan|last5=Pass|first5=Alexandra|last6=Van Ryzin|first6=Carol|last7=Myles|first7=Jennifer|last8=Schoenfeld|first8=Megan|last9=McGuire|first9=Peter|last10=Rosing|first10=Douglas R.|last11=Levin|first11=Mark D.|date=2019-06-28|title=Chronic kidney disease in propionic acidemia|journal=Genetics in Medicine |volume=21|issue=12|pages=2830–2835|doi=10.1038/s41436-019-0593-z|issn=1530-0366|pmid=31249402|pmc=7045176}}</ref> cardiomyopathy, and prolonged QTc interval.<ref name="Propionic Acidemia">{{Citation|last1=Shchelochkov|first1=Oleg A.|title=Propionic Acidemia|date=1993|url=http://www.ncbi.nlm.nih.gov/books/NBK92946/|work=GeneReviews®|editor-last=Adam|editor-first=Margaret P.|publisher=University of Washington, Seattle|pmid=22593918|access-date=2019-09-29|last2=Carrillo|first2=Nuria|last3=Venditti|first3=Charles|editor2-last=Ardinger|editor2-first=Holly H.|editor3-last=Pagon|editor3-first=Roberta A.|editor4-last=Wallace|editor4-first=Stephanie E.}}</ref>

==Pathophysiology==
[[File:Odd-chain FA oxydation.png|thumb|right|Propionic acidemia is caused by a defect in enzyme called propionyl-CoA carboxylase.]]
[[Image:autorecessive.svg|thumb|left|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|date=June 2020}}

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|date=October 2021}}

Mutations in both copies of the ''[[Propionyl-CoA carboxylase|PCCA]]'' or ''[[PCCB]]'' [[gene]]s cause propionic acidemia.<ref name="pamr">[http://mayoresearch.mayo.edu/mayo/research/barry_lab/ropionic-Aciademia.cfm http://mayoresearch.mayo.edu/mayo/research/barry_lab/ropionic-Aciademia.cfm] {{webarchive|url=https://web.archive.org/web/20080829225331/http://mayoresearch.mayo.edu/mayo/research/barry_lab/ropionic-Aciademia.cfm |date=2008-08-29 }}<br />Barry Lab - Vector and Virus Engineering. ''Gene therapy for Propionic Acidemia''</ref> These genes contain instructions to form alpha- and beta-subunits of PCC, the [[enzyme]] called propionyl-CoA carboxylase.{{cn|date=October 2024}}

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|N-acetylglutamate synthase]], indirectly resulting in slowing of the [[urea cycle]].<ref>{{Cite journal|last1=Dercksen|first1=M.|last2=IJlst|first2=L.|last3=Duran|first3=M.|last4=Mienie|first4=L. J.|last5=van Cruchten|first5=A.|last6=van der Westhuizen|first6=F. H.|last7=Wanders|first7=R. J. A.|date=December 2014|title=Inhibition of N-acetylglutamate synthase by various monocarboxylic and dicarboxylic short-chain coenzyme A esters and the production of alternative glutamate esters|journal=Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease|volume=1842|issue=12 Pt A|pages=2510–2516|doi=10.1016/j.bbadis.2013.04.027|issn=0006-3002|pmid=23643712|doi-access=free}}</ref>

==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.<ref name="Propionic Acidemia"/>

==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|<small>L</small>-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.<ref>Saudubray JM, Van Der Bergh G, Walter J : Inborn Metabolic Diseases Diagnosis and Treatment (2012)</ref>

Liver transplant is gaining a role in the management of these patients, with small series showing improved quality of life.{{cn|date=October 2024}}

==Epidemiology==

Propionic acidemia is inherited in an [[autosomal]] [[recessive]] pattern and is found in about 1 in 35,000<ref name="pamr" /> live births in the [[United States]]. The condition appears to be more common in [[Saudi Arabia]],<ref name="pasa">{{cite journal |vauthors =Al-Odaib AN, Abu-Amaro KK, Ozand PT, Al-Hellani AM |title=A new era for preventive genetic programs in the Arabian Peninsula |journal=Saudi Medical Journal |volume=24 |issue=11 |pages=1168–1175 |year=2003 |pmid=14647548 }}</ref> with a frequency of about 1 in 3,000.<ref name="pamr" /> The condition also appears to be common in [[Amish]], [[Mennonite]] and other populations with higher frequency of consanguinity.<ref name="paam">{{cite journal |vauthors =Kidd JR, Wolf B, Hsia E, Kidd KK |title=Genetics of propionic acidemia in a Mennonite-Amish kindred |journal=Am J Hum Genet |volume=32 |issue=2 |pages=236–245 |year=1980 |pmid=7386459 |pmc=1686010 }}</ref>

==History==
In 1957, a male child was born with poor mental development, repeated attacks of acidosis, and high levels of [[ketone]]s 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.<ref>{{cite web|last=Hsia |first=T. |title=How Ketotic Hyperglycinemia Became Propionic Acidemia| publisher=Paresearch.org |date=2003 |access-date=7 June 2018 |url=http://www.paresearch.org/images/HistoryofPADrHsia.pdf}}</ref>

==See also==
* [[Methylmalonic acidemia]]
* [[Isovaleric acidemia]]
* [[Maple syrup urine disease]]

==References==
{{Reflist}}

== External links ==
* {{NLM|propionicacidemia}}
* {{RareDiseases|467|Propionic acidemia}}
* {{cite web |url=http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=EN&Expert=35 |title=Propionic acidemia |work=Orphanet }}
{{Medical resources
| ICD10           = {{ICD10|E|71|1|e|70}}
| ICD9            = {{ICD9|270.3}}
| ICDO            =
| OMIM            = 606054
| MedlinePlus     =
| eMedicineSubj   = ped
| eMedicineTopic  = 1906
| DiseasesDB      = 29673
| Orphanet        = 35
| ICD10CM         = {{ICD10CM|E71.121}}
}}
{{Amino acid metabolic pathology}}
{{Fatty-acid metabolism disorders}}

{{DEFAULTSORT:Propionic Acidemia}}
[[Category:Amino acid metabolism disorders]]
[[Category:Autosomal recessive disorders]]
[[Category:Rare diseases]]
[[Category:Fatty-acid metabolism disorders]]