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Pyruvate carboxylase deficiency

MedGen UID:
18801
Concept ID:
C0034341
Disease or Syndrome
Synonyms: Ataxia with lactic acidosis 2; ATAXIA WITH LACTIC ACIDOSIS II; Leigh necrotizing encephalopathy due to pyruvate carboxylase deficiency; Leigh syndrome due to pyruvate carboxylase deficiency; PC deficiency; Pyruvate Carboxylase Deficiency Disease
SNOMED CT: PC - Pyruvate carboxylase deficiency (87694001); Pyruvate carboxylase deficiency (87694001); PC deficiency (87694001); Ataxia with lactic acidosis II (87694001); Deficiency of pyruvic carboxylase (87694001); Deficiency of pyruvate carboxylase (87694001)
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).
Not genetically inherited
MedGen UID:
988794
Concept ID:
CN307044
Finding
Source: Orphanet
clinical entity without genetic inheritance.
 
Gene (location): PC (11q13.2)
 
Monarch Initiative: MONDO:0009949
OMIM®: 266150
Orphanet: ORPHA3008

Disease characteristics

Excerpted from the GeneReview: Pyruvate Carboxylase Deficiency
Pyruvate carboxylase (PC) deficiency is characterized in most affected individuals by failure to gain weight and/or linear growth failure, developmental delay, epilepsy, and metabolic acidosis. Three clinical phenotypes are recognized. Type A (infantile form) is characterized by infantile onset of metabolic and lactic acidosis, delayed motor development, intellectual disability, poor linear growth and/or weight gain, and neurologic findings (apathy, hypotonia, pyramidal and extrapyramidal signs, ataxia, and seizures). Brain anomalies can be noted. Most affected children die in infancy or early childhood. Type B (severe neonatal form) is characterized by neonatal or infantile onset of hypothermia, respiratory distress/failure, vomiting, severe lactic acidosis, hyperammonemia, and often hypoglycemia. Neurologic findings include brain abnormalities, lethargy, hypotonia, and pyramidal and extrapyramidal signs. Death typically occurs by age eight months. Type C (intermittent/attenuated form) is characterized by relatively normal or mildly delayed neurologic development, motor and/or gait abnormalities, (rarely) seizures, episodic movement disorders, and metabolic acidosis. Life span is unknown but survival into adulthood has been reported. [from GeneReviews]
Authors:
Maria Laura Duque Lasio  |  April N Lehman  |  Ayesha Ahmad, et. al.   view full author information

Additional description

From MedlinePlus Genetics
Pyruvate carboxylase deficiency is an inherited disorder that causes lactic acid and other potentially toxic compounds to accumulate in the blood. High levels of these substances can damage the body's organs and tissues, particularly in the nervous system.

Researchers have identified at least three types of pyruvate carboxylase deficiency, which are distinguished by the severity of their signs and symptoms. Type A, which has been identified mostly in people from North America, has severe symptoms that begin in infancy. Characteristic features include developmental delay and a buildup of lactic acid in the blood (lactic acidosis). Increased acidity in the blood can lead to vomiting, abdominal pain, extreme tiredness (fatigue), muscle weakness, and difficulty breathing. In some cases, episodes of lactic acidosis are triggered by an illness or periods without food (fasting). Children with pyruvate carboxylase deficiency type A typically survive only into infancy or early childhood.

Pyruvate carboxylase deficiency type B has life-threatening signs and symptoms that become apparent shortly after birth. This form of the condition has been reported mostly in Europe, particularly France. Affected infants have severe lactic acidosis, a buildup of ammonia in the blood (hyperammonemia), and liver failure. They experience neurological problems including weak muscle tone (hypotonia), abnormal movements, seizures, and coma. Infants with this form of the condition usually survive for less than 3 months after birth.

A milder form of pyruvate carboxylase deficiency, sometimes called type C, has also been described. This type is characterized by slightly increased levels of lactic acid in the blood and minimal signs and symptoms affecting the nervous system.  https://medlineplus.gov/genetics/condition/pyruvate-carboxylase-deficiency

Clinical features

From HPO
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Athetosis
MedGen UID:
2115
Concept ID:
C0004158
Disease or Syndrome
A slow, continuous, involuntary writhing movement that prevents maintenance of a stable posture. Athetosis involves continuous smooth movements that appear random and are not composed of recognizable sub-movements or movement fragments. In contrast to chorea, in athetosis, the same regions of the body are repeatedly involved. Athetosis may worsen with attempts at movement of posture, but athetosis can also occur at rest.
Clonus
MedGen UID:
40341
Concept ID:
C0009024
Sign or Symptom
A series of rhythmic and involuntary muscle contractions (at a frequency of about 5 to 7 Hz) that occur in response to an abruptly applied and sustained stretch.
Leukodystrophy
MedGen UID:
6070
Concept ID:
C0023520
Disease or Syndrome
Leukodystrophy refers to deterioration of white matter of the brain resulting from degeneration of myelin sheaths in the CNS. Their basic defect is directly related to the synthesis and maintenance of myelin membranes. Symmetric white matter involvement at MRI is a typical finding in patients with leukodystrophies.
Periventricular leukomalacia
MedGen UID:
6072
Concept ID:
C0023529
Disease or Syndrome
Periventricular leukomalacia is characterized by diffuse injury of deep cerebral white matter, accompanied in its most severe form by focal necrosis. The neuropathologic hallmarks of PVL are microglial activation and focal and diffuse periventricular depletion of premyelinating oligodendroglia.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
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.
Neuronal loss in the cerebral cortex
MedGen UID:
340336
Concept ID:
C1849485
Finding
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
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.
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
A decreased concentration of glucose in the blood.
Proximal renal tubular acidosis
MedGen UID:
82804
Concept ID:
C0268435
Disease or Syndrome
A type of renal tubular acidosis characterized by a failure of the proximal tubular cells to reabsorb bicarbonate, leading to urinary bicarbonate wasting and subsequent acidemia.
Hyper-beta-alaninemia
MedGen UID:
75702
Concept ID:
C0268630
Disease or Syndrome
An increased concentration of alanine in the blood.
Increased circulating lactate concentration
MedGen UID:
332209
Concept ID:
C1836440
Finding
Abnormally increased level of blood lactate (2-hydroxypropanoic acid). Lactate is produced from pyruvate by lactate dehydrogenase during normal metabolism. The terms lactate and lactic acid are often used interchangeably but lactate (the component measured in blood) is strictly a weak base whereas lactic acid is the corresponding acid. Lactic acidosis is often used clinically to describe elevated lactate but should be reserved for cases where there is a corresponding acidosis (pH below 7.35).
Increased serum pyruvate
MedGen UID:
376596
Concept ID:
C1849488
Finding
An increased concentration of pyruvate in the blood.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
Follow this link to review classifications for Pyruvate carboxylase deficiency in Orphanet.

Professional guidelines

PubMed

Coci EG, Gapsys V, Shur N, Shin-Podskarbi Y, de Groot BL, Miller K, Vockley J, Sondheimer N, Ganetzky R, Freisinger P
Hum Mutat 2019 Jun;40(6):816-827. Epub 2019 Apr 13 doi: 10.1002/humu.23742. PMID: 30870574
Wang HS, Lin KL
Biomed J 2013 Jan-Feb;36(1):16-7. doi: 10.4103/2319-4170.107155. PMID: 23515149
Marsac C, Augereau C, Feldman G, Wolf B, Hansen TL, Berger R
Clin Chim Acta 1982 Feb 26;119(1-2):121-7. doi: 10.1016/0009-8981(82)90412-0. PMID: 6800673

Curated

American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, [Elevated Citrulline], Amino Acidemia/Urea Cycle Disorder, 2022

American College of Medical Genetics and Genomics, Elevated Citrulline: Amino Acidemia Algorithm, 2022

Recent clinical studies

Etiology

Robinson BH, MacKay N, Chun K, Ling M
J Inherit Metab Dis 1996;19(4):452-62. doi: 10.1007/BF01799106. PMID: 8884569
Krause KH, Bonjour JP, Berlit P, Kochen W
Ann N Y Acad Sci 1985;447:297-313. doi: 10.1111/j.1749-6632.1985.tb18447.x. PMID: 3925859
Robinson BH, Sherwood WG
J Inherit Metab Dis 1984;7 Suppl 1:69-73. doi: 10.1007/BF03047378. PMID: 6434848
Bartlett K
Adv Clin Chem 1983;23:141-98. doi: 10.1016/s0065-2423(08)60400-x. PMID: 6152513
Packman S, Cowan MJ, Golbus MS, Caswell NM, Sweetman L, Burri BJ, Nyhan WL, Baker H
Lancet 1982 Jun 26;1(8287):1435-8. doi: 10.1016/s0140-6736(82)92452-7. PMID: 6123722

Diagnosis

Olivera-Bravo S, Isasi E, Fernández A, Casanova G, Rosillo JC, Barbeito L
Adv Exp Med Biol 2016;949:227-243. doi: 10.1007/978-3-319-40764-7_11. PMID: 27714692
Robinson BH
Mol Genet Metab 2006 Sep-Oct;89(1-2):3-13. Epub 2006 Jul 18 doi: 10.1016/j.ymgme.2006.05.015. PMID: 16854608
Tibrewala VN, Ambani LM, Shah SB, Apte BN
Indian Pediatr 1990 Sep;27(9):974-6. PMID: 2286443
Wolf B, Heard GS, McVoy JR, Grier RE
Ann N Y Acad Sci 1985;447:252-62. doi: 10.1111/j.1749-6632.1985.tb18443.x. PMID: 3925856
Stumpf DA
Neurol Clin 1985 Feb;3(1):47-57. PMID: 3921817

Therapy

Olivera-Bravo S, Isasi E, Fernández A, Casanova G, Rosillo JC, Barbeito L
Adv Exp Med Biol 2016;949:227-243. doi: 10.1007/978-3-319-40764-7_11. PMID: 27714692
Tibrewala VN, Ambani LM, Shah SB, Apte BN
Indian Pediatr 1990 Sep;27(9):974-6. PMID: 2286443
Bartlett K, Ghneim HK, Stirk HJ, Wastell H
J Inherit Metab Dis 1985;8 Suppl 1:46-52. doi: 10.1007/BF01800659. PMID: 2864473
Wolf B, Feldman GL
Am J Hum Genet 1982 Sep;34(5):699-716. PMID: 6127031Free PMC Article
Roth KS
Am J Clin Nutr 1981 Sep;34(9):1967-74. doi: 10.1093/ajcn/34.9.1967. PMID: 6116428

Prognosis

Maryami F, Rismani E, Davoudi-Dehaghani E, Khalesi N, Talebi S, Mahdian R, Zeinali S
Iran Biomed J 2023 Sep 1;27(5):307-19. Epub 2023 Jun 19 doi: 10.61186/ibj.27.5.307. PMID: 37873728Free PMC Article
Xue M
Front Endocrinol (Lausanne) 2023;14:1199590. Epub 2023 Jul 7 doi: 10.3389/fendo.2023.1199590. PMID: 37484962Free PMC Article
Coci EG, Gapsys V, Shur N, Shin-Podskarbi Y, de Groot BL, Miller K, Vockley J, Sondheimer N, Ganetzky R, Freisinger P
Hum Mutat 2019 Jun;40(6):816-827. Epub 2019 Apr 13 doi: 10.1002/humu.23742. PMID: 30870574
Breen C, White FJ, Scott CA, Heptinstall L, Walter JH, Jones SA, Morris AA
Eur J Pediatr 2014 Mar;173(3):361-6. Epub 2013 Oct 10 doi: 10.1007/s00431-013-2166-5. PMID: 24114256
Packman S, Cowan MJ, Golbus MS, Caswell NM, Sweetman L, Burri BJ, Nyhan WL, Baker H
Lancet 1982 Jun 26;1(8287):1435-8. doi: 10.1016/s0140-6736(82)92452-7. PMID: 6123722

Clinical prediction guides

Lasio MLD, Leshinski AC, Ducich NH, Flore LA, Lehman A, Shur N, Jayakar PB, Hainline BE, Basinger AA, Wilson WG, Diaz GA, Erbe RW, Koeberl DD, Vockley J, Bedoyan JK
Mol Genet Metab 2023 Jun;139(2):107605. Epub 2023 May 9 doi: 10.1016/j.ymgme.2023.107605. PMID: 37207470Free PMC Article
Coci EG, Gapsys V, Shur N, Shin-Podskarbi Y, de Groot BL, Miller K, Vockley J, Sondheimer N, Ganetzky R, Freisinger P
Hum Mutat 2019 Jun;40(6):816-827. Epub 2019 Apr 13 doi: 10.1002/humu.23742. PMID: 30870574
Roe CR, Mochel F
J Inherit Metab Dis 2006 Apr-Jun;29(2-3):332-40. doi: 10.1007/s10545-006-0290-3. PMID: 16763896
García-Cazorla A, Rabier D, Touati G, Chadefaux-Vekemans B, Marsac C, de Lonlay P, Saudubray JM
Ann Neurol 2006 Jan;59(1):121-7. doi: 10.1002/ana.20709. PMID: 16278852
Chalmers RA
J Inherit Metab Dis 1984;7 Suppl 1:79-89. doi: 10.1007/BF03047380. PMID: 6434850

Supplemental Content

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    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 Sheet, 2022
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, [Elevated Citrulline], Amino Acidemia/Urea Cycle Disorder, 2022
    • ACMG Algorithm, 2022
      American College of Medical Genetics and Genomics, Elevated Citrulline: Amino Acidemia Algorithm, 2022

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