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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
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, 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 homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
not inherited
MedGen UID:
832438
Concept ID:
CN227390
Intellectual Product
Source: Orphanet
Describes a disorder that is not inherited.
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
not inherited (Orphanet)
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)
 
Gene (location): PC (11q13.2)
OMIM®: 266150
Orphanet: ORPHA3008

Definition

Pyruvate carboxylase (PC) deficiency is characterized in most affected individuals by failure to thrive, developmental delay, recurrent seizures, and metabolic acidosis. Three clinical types are recognized: type A (infantile form), in which most affected children die in infancy or early childhood; type B (severe neonatal form), in which affected infants have hepatomegaly, pyramidal tract signs, and abnormal movement and die within the first three months of life; and type C (intermittent/benign form), in which affected individuals have normal or mildly delayed neurologic development and episodic metabolic acidosis. [from GTR]

Additional descriptions

From GeneReviews
Pyruvate carboxylase (PC) deficiency is characterized in most affected individuals by failure to thrive, developmental delay, recurrent seizures, and metabolic acidosis. Three clinical types are recognized: type A (infantile form), in which most affected children die in infancy or early childhood; type B (severe neonatal form), in which affected infants have hepatomegaly, pyramidal tract signs, and abnormal movement and die within the first three months of life; and type C (intermittent/benign form), in which affected individuals have normal or mildly delayed neurologic development and episodic metabolic acidosis.  https://www.ncbi.nlm.nih.gov/books/NBK6852
From GHR
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://ghr.nlm.nih.gov/condition/pyruvate-carboxylase-deficiency

Clinical features

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.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormal enlargement of the liver.
Clonus
MedGen UID:
40341
Concept ID:
C0009024
Sign or Symptom
A form of involuntary muscular movement characterized by alternating contractions and relaxation in rapid succession. In the context of reflex testing, the ability to elicit clonus indicates injury to the nerve tracts above the point at which the reflex was initiated.
Seizure Disorders
MedGen UID:
4506
Concept ID:
C0014544
Disease or Syndrome
A brain disorder characterized by episodes of abnormally increased neuronal discharge resulting in transient episodes of sensory or motor neurological dysfunction, or psychic dysfunction. These episodes may or may not be associated with loss of consciousness or convulsions.
Periventricular leukomalacia
MedGen UID:
6072
Concept ID:
C0023529
Disease or Syndrome
Degeneration of white matter adjacent to the CEREBRAL VENTRICLES following cerebral hypoxia or BRAIN ISCHEMIA in neonates. The condition primarily affects white matter in the perfusion zone between superficial and deep branches of the MIDDLE CEREBRAL ARTERY. Clinical manifestations include VISION DISORDERS; CEREBRAL PALSY; PARAPLEGIA; SEIZURES; and cognitive disorders. (From Adams et al., Principles of Neurology, 6th ed, p1021; Joynt, Clinical Neurology, 1997, Ch4, pp30-1)
Neuronal loss in the cerebral cortex
MedGen UID:
340336
Concept ID:
C1849485
Finding
Cognitive delay
MedGen UID:
351243
Concept ID:
C1864897
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.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70.
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.
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
A condition of decreased tone of the skeletal muscles and diminished resistance to passive stretching.
Lactic acidosis
MedGen UID:
1717
Concept ID:
C0001125
Disease or Syndrome
Acidosis caused by accumulation of lactic acid more rapidly than it can be metabolized. It may occur spontaneously or in association with diseases such as DIABETES MELLITUS; LEUKEMIA; or LIVER FAILURE.
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.
Increased serum lactate
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.
Increased blood alanine
MedGen UID:
374219
Concept ID:
C1839424
Finding
An increased concentration of alanine in the blood.
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.

Recent clinical studies

Etiology

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
Ahmad A, Kahler SG, Kishnani PS, Artigas-Lopez M, Pappu AS, Steiner R, Millington DS, Van Hove JL
Am J Med Genet 1999 Dec 3;87(4):331-8. PMID: 10588840
Higgins JJ, Glasgow AM, Lusk M, Kerr DS
J Child Neurol 1994 Oct;9(4):436-9. doi: 10.1177/088307389400900421. PMID: 7822739
Ullrich K, Schmidt H, van Teeffelen-Heithoff A
Acta Paediatr Scand 1988 Jul;77(4):531-6. PMID: 3134793
Robinson BH, Toone JR, Benedict RP, Dimmick JE, Oei J, Applegarth DA
Prenat Diagn 1985 Jan-Feb;5(1):67-71. PMID: 3919380

Diagnosis

Ortez C, Jou C, Cortès-Saladelafont E, Moreno J, Pérez A, Ormazábal A, Pérez-Cerdá C, Pérez B, Artuch R, Cusi V, García-Cazorla A
Gene 2013 Dec 15;532(2):302-6. Epub 2013 Aug 23 doi: 10.1016/j.gene.2013.08.036. PMID: 23973720
Monnot S, Serre V, Chadefaux-Vekemans B, Aupetit J, Romano S, De Lonlay P, Rival JM, Munnich A, Steffann J, Bonnefont JP
Hum Mutat 2009 May;30(5):734-40. doi: 10.1002/humu.20908. PMID: 19306334
Schiff M, Levrat V, Acquaviva C, Vianey-Saban C, Rolland MO, Guffon N
Mol Genet Metab 2006 Feb;87(2):175-7. Epub 2005 Dec 1 doi: 10.1016/j.ymgme.2005.10.007. PMID: 16325442
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
Mochel F, DeLonlay P, Touati G, Brunengraber H, Kinman RP, Rabier D, Roe CR, Saudubray JM
Mol Genet Metab 2005 Apr;84(4):305-12. doi: 10.1016/j.ymgme.2004.09.007. PMID: 15781190

Therapy

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
Mochel F, DeLonlay P, Touati G, Brunengraber H, Kinman RP, Rabier D, Roe CR, Saudubray JM
Mol Genet Metab 2005 Apr;84(4):305-12. doi: 10.1016/j.ymgme.2004.09.007. PMID: 15781190
Nyhan WL, Khanna A, Barshop BA, Naviaux RK, Precht AF, Lavine JE, Hart MA, Hainline BE, Wappner RS, Nichols S, Haas RH
Mol Genet Metab 2002 Sep-Oct;77(1-2):143-9. PMID: 12359142
Ahmad A, Kahler SG, Kishnani PS, Artigas-Lopez M, Pappu AS, Steiner R, Millington DS, Van Hove JL
Am J Med Genet 1999 Dec 3;87(4):331-8. PMID: 10588840
Higgins JJ, Glasgow AM, Lusk M, Kerr DS
J Child Neurol 1994 Oct;9(4):436-9. doi: 10.1177/088307389400900421. PMID: 7822739

Prognosis

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
Ortez C, Jou C, Cortès-Saladelafont E, Moreno J, Pérez A, Ormazábal A, Pérez-Cerdá C, Pérez B, Artuch R, Cusi V, García-Cazorla A
Gene 2013 Dec 15;532(2):302-6. Epub 2013 Aug 23 doi: 10.1016/j.gene.2013.08.036. PMID: 23973720
Monnot S, Serre V, Chadefaux-Vekemans B, Aupetit J, Romano S, De Lonlay P, Rival JM, Munnich A, Steffann J, Bonnefont JP
Hum Mutat 2009 May;30(5):734-40. doi: 10.1002/humu.20908. PMID: 19306334
Carbone MA, Applegarth DA, Robinson BH
Hum Mutat 2002 Jul;20(1):48-56. doi: 10.1002/humu.10093. PMID: 12112657
Ahmad A, Kahler SG, Kishnani PS, Artigas-Lopez M, Pappu AS, Steiner R, Millington DS, Van Hove JL
Am J Med Genet 1999 Dec 3;87(4):331-8. PMID: 10588840

Clinical prediction guides

Monnot S, Serre V, Chadefaux-Vekemans B, Aupetit J, Romano S, De Lonlay P, Rival JM, Munnich A, Steffann J, Bonnefont JP
Hum Mutat 2009 May;30(5):734-40. doi: 10.1002/humu.20908. PMID: 19306334
Wang D, Yang H, De Braganca KC, Lu J, Yu Shih L, Briones P, Lang T, De Vivo DC
Mol Genet Metab 2008 Sep-Oct;95(1-2):31-8. Epub 2008 Aug 3 doi: 10.1016/j.ymgme.2008.06.006. PMID: 18676167Free PMC Article
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
Mochel F, DeLonlay P, Touati G, Brunengraber H, Kinman RP, Rabier D, Roe CR, Saudubray JM
Mol Genet Metab 2005 Apr;84(4):305-12. doi: 10.1016/j.ymgme.2004.09.007. PMID: 15781190
Carbone MA, Applegarth DA, Robinson BH
Hum Mutat 2002 Jul;20(1):48-56. doi: 10.1002/humu.10093. PMID: 12112657

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