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Propionic acidemia(PROP)

MedGen UID:
75694
Concept ID:
C0268579
Disease or Syndrome
Synonyms: Glycinemia, ketotic; Hyperglycinemia with ketoacidosis and leukopenia; Ketotic hyperglycinemia; PROP
SNOMED CT: Propionic acidemia (69080001); Propionyl-CoA carboxylase deficiency (69080001); PCC - Propionyl-CoA carboxylase deficiency (69080001); Propionic aciduria (69080001); Hyperglycinemia with ketosis and leukopenia (69080001); Ketotic glycinemia (69080001); Ketotic hyperglycinemia (69080001)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Genes (locations): PCCA (13q32.3); PCCB (3q22.3)
 
HPO: HP:0003571
Monarch Initiative: MONDO:0011628
OMIM®: 606054
Orphanet: ORPHA35

Disease characteristics

Excerpted from the GeneReview: Propionic Acidemia
The spectrum of propionic acidemia (PA) ranges from neonatal-onset to late-onset disease. Neonatal-onset PA, the most common form, is characterized by a healthy newborn with poor feeding and decreased arousal in the first few days of life, followed by progressive encephalopathy of unexplained origin. Without prompt diagnosis and management, this is followed by progressive encephalopathy manifesting as lethargy, seizures, or coma that can result in death. It is frequently accompanied by metabolic acidosis with anion gap, lactic acidosis, ketonuria, hypoglycemia, hyperammonemia, and cytopenias. Individuals with late-onset PA may remain asymptomatic and suffer a metabolic crisis under catabolic stress (e.g., illness, surgery, fasting) or may experience a more insidious onset with the development of multiorgan complications including vomiting, protein intolerance, failure to thrive, hypotonia, developmental delays or regression, movement disorders, or cardiomyopathy. Isolated cardiomyopathy can be observed on rare occasion in the absence of clinical metabolic decompensation or neurocognitive deficits. Manifestations of neonatal and late-onset PA over time can include growth impairment, intellectual disability, seizures, basal ganglia lesions, pancreatitis, and cardiomyopathy. Other rarely reported complications include optic atrophy, hearing loss, premature ovarian insufficiency, and chronic renal failure. [from GeneReviews]
Authors:
Oleg A Shchelochkov  |  Nuria Carrillo  |  Charles Venditti   view full author information

Clinical features

From HPO
Hyperglycinuria
MedGen UID:
107456
Concept ID:
C0543541
Disease or Syndrome
The imino acids, proline and hydroxyproline, share a renal tubular reabsorptive mechanism with glycine. Iminoglycinuria (IG; 242600), a benign inborn error of amino acid transport, is also a normal finding in neonates and infants under 6 months of age (Chesney, 2001). Early studies of families with iminoglycinuria suggested genetic complexity, with homozygotes developing IG and heterozygotes manifesting only hyperglycinuria (HG) (summary by Broer et al., 2008). A phenotype of combined glucosuria and glycinuria has been described (see 138070).
Increased level of hippuric acid in urine
MedGen UID:
1640306
Concept ID:
C4703632
Finding
An increase in the level of hippuric acid in the urine.
Limb hypertonia
MedGen UID:
333083
Concept ID:
C1838391
Finding
Cerebellar hemorrhage
MedGen UID:
488779
Concept ID:
C0149854
Pathologic Function
Hemorrhage into the parenchyma of the cerebellum.
Cardiomyopathy
MedGen UID:
209232
Concept ID:
C0878544
Disease or Syndrome
A myocardial disorder in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Constipation
MedGen UID:
1101
Concept ID:
C0009806
Sign or Symptom
Infrequent or difficult evacuation of feces.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Poor appetite
MedGen UID:
68562
Concept ID:
C0232462
Sign or Symptom
A reduced desire to eat.
Feeding difficulties in infancy
MedGen UID:
436211
Concept ID:
C2674608
Finding
Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.
Coma
MedGen UID:
1054
Concept ID:
C0009421
Disease or Syndrome
Complete absence of wakefulness and content of conscience, which manifests itself as a lack of response to any kind of external stimuli.
Dystonic disorder
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Lethargy
MedGen UID:
7310
Concept ID:
C0023380
Sign or Symptom
A state of disinterestedness, listlessness, and indifference, resulting in difficulty performing simple tasks or concentrating.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Acute encephalopathy
MedGen UID:
224930
Concept ID:
C1306587
Disease or Syndrome
A life-threatening disorder characterized by delirium, seizures, and neuromuscular changes.
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
Pancytopenia
MedGen UID:
18281
Concept ID:
C0030312
Disease or Syndrome
An abnormal reduction in numbers of all blood cell types (red blood cells, white blood cells, and platelets).
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
Osteoporosis
MedGen UID:
14535
Concept ID:
C0029456
Disease or Syndrome
Osteoporosis is a systemic skeletal disease characterized by low bone density and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility. According to the WHO criteria, osteoporosis is defined as a BMD that lies 2.5 standard deviations or more below the average value for young healthy adults (a T-score below -2.5 SD).
Axial hypotonia
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.
Apnea
MedGen UID:
2009
Concept ID:
C0003578
Sign or Symptom
Lack of breathing with no movement of the respiratory muscles and no exchange of air in the lungs. This term refers to a disposition to have recurrent episodes of apnea rather than to a single event.
Tachypnea
MedGen UID:
66669
Concept ID:
C0231835
Finding
Very rapid breathing.
Eczema
MedGen UID:
3968
Concept ID:
C0013595
Disease or Syndrome
Eczema is a form of dermatitis. The term eczema is broadly applied to a range of persistent skin conditions and can be related to a number of underlying conditions. Manifestations of eczema can include dryness and recurring skin rashes with redness, skin edema, itching and dryness, crusting, flaking, blistering, cracking, oozing, or bleeding.
Pancreatitis
MedGen UID:
14586
Concept ID:
C0030305
Disease or Syndrome
The presence of inflammation in the pancreas.
Neutropenia
MedGen UID:
163121
Concept ID:
C0853697
Finding
An abnormally low number of neutrophils in the peripheral blood.
Lactic acidosis
MedGen UID:
1717
Concept ID:
C0001125
Disease or Syndrome
An abnormal buildup of lactic acid in the body, leading to acidification of the blood and other bodily fluids.
Dehydration
MedGen UID:
8273
Concept ID:
C0011175
Disease or Syndrome
A condition resulting from the excessive loss of water from the body. It is usually caused by severe diarrhea, vomiting or diaphoresis.
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
A decreased concentration of glucose in the blood.
Metabolic acidosis
MedGen UID:
65117
Concept ID:
C0220981
Pathologic Function
Metabolic acidosis (MA) is characterized by a fall in blood pH due to a reduction of serum bicarbonate concentration. This can occur as a result of either the accumulation of acids (high anion gap MA) or the loss of bicarbonate from the gastrointestinal tract or the kidney (hyperchloremic MA). By definition, MA is not due to a respirary cause.
Hyperammonemia
MedGen UID:
113136
Concept ID:
C0220994
Disease or Syndrome
An increased concentration of ammonia in the blood.
Hyperglycinemia
MedGen UID:
82817
Concept ID:
C0268559
Disease or Syndrome
An elevated concentration of glycine in the blood.
Propionyl-CoA carboxylase deficiency
MedGen UID:
1638582
Concept ID:
C4551877
Finding
Propionic acidemia is an autosomal recessive metabolic disorder caused by defective functioning in the mitochondrial enzyme propionyl CoA carboxylase (PCC), resulting in the accumulation of propionic acid metabolites, and dysfunction in the respiratory chain and urea cycle pathways. The disorder is clinically heterogeneous. A neonatal-onset form is characterized by poor feeding, vomiting, and fatigue in the first days of life in a previously healthy infant, and if untreated, may be followed by lethargy, seizures, coma, and death. The neonatal form is frequently accompanied by metabolic acidosis with anion gap, ketonuria, hypoglycemia, hyperammonemia, and cytopenia. A late-onset form in older children and adults has a milder phenotype, is less common, and may present with developmental regression, chronic vomiting, protein intolerance, failure to thrive, hypotonia, and occasionally basal ganglia infarction, which may result in dystonia and choreoathetosis, and cardiomyopathy. Metabolically unstable individuals can have an acute decompensation that resembles the neonatal presentation, often precipitated by a catabolic stress such as infection, injury, or surgery, or an excessive intake of intact (i.e., complete, dietary, or natural) protein. Long-term manifestations of neonatal and late onset of propionic acidemia can include growth impairment, intellectual disability, seizures, basal ganglia lesions, pancreatitis, and cardiomyopathy. Other less common manifestations include optic atrophy, hearing loss, premature ovarian insufficiency, and chronic renal failure (summary by Jurecki et al., 2019).

Professional guidelines

PubMed

Van Calcar SC, Sowa M, Rohr F, Beazer J, Setlock T, Weihe TU, Pendyal S, Wallace LS, Hansen JG, Stembridge A, Splett P, Singh RH
Mol Genet Metab 2020 Sep-Oct;131(1-2):23-37. Epub 2020 Oct 6 doi: 10.1016/j.ymgme.2020.10.001. PMID: 33093005
Fraser JL, Venditti CP
Curr Opin Pediatr 2016 Dec;28(6):682-693. doi: 10.1097/MOP.0000000000000422. PMID: 27653704Free PMC Article
Baumgartner MR, Hörster F, Dionisi-Vici C, Haliloglu G, Karall D, Chapman KA, Huemer M, Hochuli M, Assoun M, Ballhausen D, Burlina A, Fowler B, Grünert SC, Grünewald S, Honzik T, Merinero B, Pérez-Cerdá C, Scholl-Bürgi S, Skovby F, Wijburg F, MacDonald A, Martinelli D, Sass JO, Valayannopoulos V, Chakrapani A
Orphanet J Rare Dis 2014 Sep 2;9:130. doi: 10.1186/s13023-014-0130-8. PMID: 25205257Free PMC Article

Curated

American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated C3 Acylcarnitine, Propionic Acidemia (PA) and Methylmalonic Acidemia (MMA), 2022

American College of Medical Genetics and Genomics, Algorithm, Propionic and Methylmalonic Acidemia: C3 Elevated, 2022

PROP Nutrition Management Guidelines

Recent clinical studies

Etiology

Zhang Y, Peng C, Wang L, Chen S, Wang J, Tian Z, Wang C, Chen X, Zhu S, Zhang GF, Wang Y
Orphanet J Rare Dis 2023 Sep 9;18(1):281. doi: 10.1186/s13023-023-02898-w. PMID: 37689673Free PMC Article
Vockley J, Burton B, Jurecka A, Ganju J, Leiro B, Zori R, Longo N
Mol Genet Metab 2023 Jul;139(3):107612. Epub 2023 May 21 doi: 10.1016/j.ymgme.2023.107612. PMID: 37245378
Alfadhel M, Nashabat M, Saleh M, Elamin M, Alfares A, Al Othaim A, Umair M, Ahmed H, Ababneh F, Al Mutairi F, Eyaid W, Alswaid A, Alohali L, Faqeih E, Almannai M, Aljeraisy M, Albdah B, Hussein MA, Rahbeeni Z, Alasmari A
Orphanet J Rare Dis 2021 Oct 11;16(1):422. doi: 10.1186/s13023-021-02032-8. PMID: 34635114Free PMC Article
Van Calcar SC, Sowa M, Rohr F, Beazer J, Setlock T, Weihe TU, Pendyal S, Wallace LS, Hansen JG, Stembridge A, Splett P, Singh RH
Mol Genet Metab 2020 Sep-Oct;131(1-2):23-37. Epub 2020 Oct 6 doi: 10.1016/j.ymgme.2020.10.001. PMID: 33093005
Pillai NR, Stroup BM, Poliner A, Rossetti L, Rawls B, Shayota BJ, Soler-Alfonso C, Tunuguntala HP, Goss J, Craigen W, Scaglia F, Sutton VR, Himes RW, Burrage LC
Mol Genet Metab 2019 Dec;128(4):431-443. Epub 2019 Nov 7 doi: 10.1016/j.ymgme.2019.11.001. PMID: 31757659Free PMC Article

Diagnosis

Marchuk H, Wang Y, Ladd ZA, Chen X, Zhang GF
Pharmacol Ther 2023 Sep;249:108501. Epub 2023 Jul 22 doi: 10.1016/j.pharmthera.2023.108501. PMID: 37482098
Forny P, Hörster F, Ballhausen D, Chakrapani A, Chapman KA, Dionisi-Vici C, Dixon M, Grünert SC, Grunewald S, Haliloglu G, Hochuli M, Honzik T, Karall D, Martinelli D, Molema F, Sass JO, Scholl-Bürgi S, Tal G, Williams M, Huemer M, Baumgartner MR
J Inherit Metab Dis 2021 May;44(3):566-592. Epub 2021 Mar 9 doi: 10.1002/jimd.12370. PMID: 33595124Free PMC Article
Pillai NR, Stroup BM, Poliner A, Rossetti L, Rawls B, Shayota BJ, Soler-Alfonso C, Tunuguntala HP, Goss J, Craigen W, Scaglia F, Sutton VR, Himes RW, Burrage LC
Mol Genet Metab 2019 Dec;128(4):431-443. Epub 2019 Nov 7 doi: 10.1016/j.ymgme.2019.11.001. PMID: 31757659Free PMC Article
Fraser JL, Venditti CP
Curr Opin Pediatr 2016 Dec;28(6):682-693. doi: 10.1097/MOP.0000000000000422. PMID: 27653704Free PMC Article
Baumgartner MR, Hörster F, Dionisi-Vici C, Haliloglu G, Karall D, Chapman KA, Huemer M, Hochuli M, Assoun M, Ballhausen D, Burlina A, Fowler B, Grünert SC, Grünewald S, Honzik T, Merinero B, Pérez-Cerdá C, Scholl-Bürgi S, Skovby F, Wijburg F, MacDonald A, Martinelli D, Sass JO, Valayannopoulos V, Chakrapani A
Orphanet J Rare Dis 2014 Sep 2;9:130. doi: 10.1186/s13023-014-0130-8. PMID: 25205257Free PMC Article

Therapy

Vockley J, Burton B, Jurecka A, Ganju J, Leiro B, Zori R, Longo N
Mol Genet Metab 2023 Jul;139(3):107612. Epub 2023 May 21 doi: 10.1016/j.ymgme.2023.107612. PMID: 37245378
Alfadhel M, Nashabat M, Saleh M, Elamin M, Alfares A, Al Othaim A, Umair M, Ahmed H, Ababneh F, Al Mutairi F, Eyaid W, Alswaid A, Alohali L, Faqeih E, Almannai M, Aljeraisy M, Albdah B, Hussein MA, Rahbeeni Z, Alasmari A
Orphanet J Rare Dis 2021 Oct 11;16(1):422. doi: 10.1186/s13023-021-02032-8. PMID: 34635114Free PMC Article
Pillai NR, Stroup BM, Poliner A, Rossetti L, Rawls B, Shayota BJ, Soler-Alfonso C, Tunuguntala HP, Goss J, Craigen W, Scaglia F, Sutton VR, Himes RW, Burrage LC
Mol Genet Metab 2019 Dec;128(4):431-443. Epub 2019 Nov 7 doi: 10.1016/j.ymgme.2019.11.001. PMID: 31757659Free PMC Article
Haijes HA, van Hasselt PM, Jans JJM, Verhoeven-Duif NM
J Inherit Metab Dis 2019 Sep;42(5):745-761. Epub 2019 Jul 9 doi: 10.1002/jimd.12128. PMID: 31119742
Longo N, Price LB, Gappmaier E, Cantor NL, Ernst SL, Bailey C, Pasquali M
Mol Genet Metab 2017 Sep;122(1-2):51-59. Epub 2017 Jul 12 doi: 10.1016/j.ymgme.2017.07.003. PMID: 28712602Free PMC Article

Prognosis

Zhang Y, Peng C, Wang L, Chen S, Wang J, Tian Z, Wang C, Chen X, Zhu S, Zhang GF, Wang Y
Orphanet J Rare Dis 2023 Sep 9;18(1):281. doi: 10.1186/s13023-023-02898-w. PMID: 37689673Free PMC Article
Zhao C, Wang Y, Yang H, Wang S, Tang MC, Cyr D, Parente F, Allard P, Waters P, Furtos A, Yang G, Mitchell GA
Mol Genet Metab 2022 Jan;135(1):47-55. Epub 2021 Nov 27 doi: 10.1016/j.ymgme.2021.11.011. PMID: 34896004
Pillai NR, Stroup BM, Poliner A, Rossetti L, Rawls B, Shayota BJ, Soler-Alfonso C, Tunuguntala HP, Goss J, Craigen W, Scaglia F, Sutton VR, Himes RW, Burrage LC
Mol Genet Metab 2019 Dec;128(4):431-443. Epub 2019 Nov 7 doi: 10.1016/j.ymgme.2019.11.001. PMID: 31757659Free PMC Article
Grünert SC, Müllerleile S, De Silva L, Barth M, Walter M, Walter K, Meissner T, Lindner M, Ensenauer R, Santer R, Bodamer OA, Baumgartner MR, Brunner-Krainz M, Karall D, Haase C, Knerr I, Marquardt T, Hennermann JB, Steinfeld R, Beblo S, Koch HG, Konstantopoulou V, Scholl-Bürgi S, van Teeffelen-Heithoff A, Suormala T, Sperl W, Kraus JP, Superti-Furga A, Schwab KO, Sass JO
Orphanet J Rare Dis 2013 Jan 10;8:6. doi: 10.1186/1750-1172-8-6. PMID: 23305374Free PMC Article
Deodato F, Boenzi S, Santorelli FM, Dionisi-Vici C
Am J Med Genet C Semin Med Genet 2006 May 15;142C(2):104-12. doi: 10.1002/ajmg.c.30090. PMID: 16602092

Clinical prediction guides

Head PE, Meier JL, Venditti CP
J Inherit Metab Dis 2023 May;46(3):436-449. doi: 10.1002/jimd.12617. PMID: 37078237
Alfadhel M, Nashabat M, Saleh M, Elamin M, Alfares A, Al Othaim A, Umair M, Ahmed H, Ababneh F, Al Mutairi F, Eyaid W, Alswaid A, Alohali L, Faqeih E, Almannai M, Aljeraisy M, Albdah B, Hussein MA, Rahbeeni Z, Alasmari A
Orphanet J Rare Dis 2021 Oct 11;16(1):422. doi: 10.1186/s13023-021-02032-8. PMID: 34635114Free PMC Article
Jiang YZ, Shi Y, Shi Y, Gan LX, Kong YY, Zhu ZJ, Wang HB, Sun LY
Orphanet J Rare Dis 2019 Dec 16;14(1):292. doi: 10.1186/s13023-019-1268-1. PMID: 31842933Free PMC Article
Martinez Alvarez L, Jameson E, Parry NR, Lloyd C, Ashworth JL
Br J Ophthalmol 2016 Jan;100(1):98-104. Epub 2015 Jul 24 doi: 10.1136/bjophthalmol-2015-306798. PMID: 26209586
Zayed H
Gene 2015 Jun 15;564(2):119-24. Epub 2015 Apr 9 doi: 10.1016/j.gene.2015.04.019. PMID: 25865301

Recent systematic reviews

Zhou GP, Jiang YZ, Wu SS, Kong YY, Sun LY, Zhu ZJ
Transplantation 2021 Oct 1;105(10):2272-2282. doi: 10.1097/TP.0000000000003501. PMID: 33093405
Almási T, Guey LT, Lukacs C, Csetneki K, Vokó Z, Zelei T
Orphanet J Rare Dis 2019 Feb 13;14(1):40. doi: 10.1186/s13023-018-0987-z. PMID: 30760309Free PMC Article
Sutton VR, Chapman KA, Gropman AL, MacLeod E, Stagni K, Summar ML, Ueda K, Ah Mew N, Franks J, Island E, Matern D, Peña L, Smith B, Urv T, Venditti C, Chakarapani A
Mol Genet Metab 2012 Jan;105(1):26-33. Epub 2011 Sep 10 doi: 10.1016/j.ymgme.2011.08.034. PMID: 21963082

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.
    • Bookshelf
      See practice and clinical guidelines in NCBI Bookshelf. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG ACT, 2022
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated C3 Acylcarnitine, Propionic Acidemia (PA) and Methylmalonic Acidemia (MMA), 2022
    • ACMG Algorithm, 2022
      American College of Medical Genetics and Genomics, Algorithm, Propionic and Methylmalonic Acidemia: C3 Elevated, 2022
    • GMDI/SERN, 2017
      PROP Nutrition Management Guidelines

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