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Pyruvate Carboxylase Deficiency

Ataxia with Lactic Acidosis Type 2

Pyruvate carboxylase deficiency is an infrequent autosomal recessive disorder characterized by an insufficient activity of pyruvate carboxylase, a mitochondrial enzyme that turns bicarbonate and pyruvate to oxaloacetate. Decreased pyruvate carboxylase activity causes decreased glutamate production and lactic acid accumulation. Pyruvate carboxylase also plays an important role in lipogenesis and neurotransmitter biosynthesis, which explains neurologic signs.


Pyruvate carboxylase deficiency patients may be divided, depending on manifestations and underlying biochemical abnormalities into three groups [1] [2]: the North American phenotype (type A), the French phenotype (type B), and the benign phenotype (type C). Clinical abnormalities in patients belonging to the first two groups have early onset. Type A patients exhibit signs of disease during infancy and type B during the neonatal period. Children in the first group exhibit mental retardation and motor delay, but survive beyond the adolescence period (although deaths within the first 5 years of life have also been reported), whereas the second group has up to a 3 months lifespan. These children have low Apgar scores and are born small for gestational age. Type C patients have no neurologic abnormalities because lactate elevation is not persistent, but occurs in an episodic manner and is mild or moderate.

When symptomatic, pyruvate carboxylase deficiency causes accentuated lethargy, ataxia, tremor, choreoathetosis, seizures, abnormal eye movements, vomiting, hypotonia, mottled skin, and poor feeding. Progressive illness leads to spastic diplegia or quadriplegia and positive Babinski sign. Patients fail to thrive and to achieve developmental milestones, may have episodes of incoordination, and have a diminished response to visual stimuli [3]. Respiratory manifestations include dyspnea, tachypnea, apneic episodes, respiratory depression, as well as resting hyperpnea and Cheyne-Stokes respiration [4]. Hepatomegaly and splenomegaly could be present, while macrocephaly has also been reported [5]. On the other hand, some patients present with microcephaly, that can be diagnosed before or after birth.

  • Ethnic origin Danish Somalian Turkish Turkish Turkish Turkish Turkish Pregnancy and birth N.a.[ncbi.nlm.nih.gov]
  • The mutations found here are novel; it is noteworthy that four Turkish patients did not have any mutations in common, despite the rarity of PC deficiency. There is thus no evidence for recurrent mutations in the Turkish or other populations.[doi.org]
  • In the untreated state, profound biotinidase deficiency during infancy is usually characterized by neurologic and cutaneous findings that include seizures, hypotonia, and rash, often accompanied by hyperventilation, laryngeal stridor, and apnea.[ncbi.nlm.nih.gov]
Abdominal Pain
  • 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.[en.wikipedia.org]
  • 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).[ghr.nlm.nih.gov]
  • pain, vomiting, tiredness and muscle weakness.[rarediseases.org]
  • The signs and symptoms may include: Developmental delays and mental retardation Poor feeding, loss of appetite Lethargy and fatigue Seizures, neonatal fits Abdominal pain and vomiting Breathing difficulties Psychomotor retardation: Mental or emotional[dovemed.com]
Psychomotor Retardation
  • The most severe form (form B) is characterized by neonatal lethal lactic acidosis, whereas patients with form A suffer chronic lactic acidosis with psychomotor retardation.[ncbi.nlm.nih.gov]
  • Psychomotor retardation with seizures and spasticity are the major clinical manifestations.[merckmanuals.com]
  • The signs and symptoms may include: Developmental delays and mental retardation Poor feeding, loss of appetite Lethargy and fatigue Seizures, neonatal fits Abdominal pain and vomiting Breathing difficulties Psychomotor retardation: Mental or emotional[dovemed.com]
  • Some patients present with psychomotor retardation in the infantile period, an increase of plasma lactate with normal lactate to pyruvate ratio and survival up to 5 years (type A).[invitae.com]
  • We report a case of pyruvate-carboxylase deficiency (EC, McKusick 26615) with neonatal onset of lactic acidosis, hyperammonemia, and citrullinemia.[ncbi.nlm.nih.gov]
  • Type B: The French phenotype is characterized by neonatal onset, high lactate and ammonia levels, abnormal lactate-to-pyruvate ratio, and death within the first few months of life.[emedicine.com]
  • The neonatal onset type B pyruvate carboxylase deficiency has a greater incidence in France, although it has been described in Canada, Egypt, and Saudi Arabia.[emedicine.medscape.com]
Generalized Seizure
  • Her psychomotor development was retarded, her movements were dystonic and generalized seizures punctuated her course.[ncbi.nlm.nih.gov]


Blood workup should include lactate and pyruvate levels, which are high, as is a lactate-to-pyruvate ratio in most serious cases. These substances, as well as glutamic acid and proline, are also high in the cerebrospinal fluid. Glycemia is low, especially during fasting periods, while blood ammonia is high. More sophisticated assays, not widely available, include leukocytes, fibroblasts or chorionic villi enzyme testing. Postmortem studies of the brain demonstrated defective myelination and decreased neuron numbers. Affected regions include the cortex, cerebellum and basal ganglia. The hypotonia may be due to these neurological abnormalities or due to a form of myopathy, suggested by nemaline rods on muscle biopsy [6]. If amino acid level measurements are available, they will demonstrate high alanine, citrulline, and lysine levels, while aspartic acid levels would be low. Lactate levels are high in the brain, as demonstrated by magnetic resonance spectroscopy. Classical magnetic resonance imaging reveals brain atrophy, ventricular dilatation, gliosis, and white matter cysts.

Genetic analysis reveals several mutations which interfere with biotin metabolism [7]. Mutations are frameshift, intron retention, or splice site types [8] [9].

If ocular abnormalities are noticed, an ophthalmologic consultation should be in order. The ophthalmologist may describe disconjugate eye movements, decreased visual tracking and pupillary response, or frank blindness.

Alanine Increased
  • This condition is caused by mutations in the PC gene and inherited in an autosomal recessive pattern. 0001290 Global developmental delay 0001263 Hepatomegaly Enlarged liver 0002240 Hyperalaninemia Increased blood alanine Increased serum alanine This means[rarediseases.info.nih.gov]


  • When treatment with aspartic acid was temporarily discontinued, lactate and pyruvate concentrations increased so markedly that the drug was resumed.[ncbi.nlm.nih.gov]
  • Treatment [ edit ] Pyruvate carboxylase deficiency treatment typically consists of providing the body with alternate sources of energy (anaplerotic therapy), such as a diet rich in proteins and carbohydrates but not lipids.[en.wikipedia.org]
  • Direct in style but comprehensive in content, with ample tables and summaries, the Handbook of Epilepsy Treatment covers: Treatment of the different forms and causes of epilepsy Treatment in the different commonly encountered clinical situations Treatment[books.google.com]


  • This concept has been used in PCD. [ 8 ] Prognosis Despite all therapeutic interventions, the prognosis remains poor, with the majority of affected children dying before the age of six months.[patient.info]
  • (Outcomes/Resolutions) The prognosis of Pyruvate Carboxylase Deficiency is poor.[dovemed.com]
  • Consultations Evaluation of the patient by an expert in metabolic and genetic disease is necessary to confirm the diagnosis, guide appropriate treatment, and determine prognosis. Enzyme testing and DNA confirmation are available.[emedicine.medscape.com]


  • These results demonstrate heterogeneity in the etiology of pyruvate carboxylase deficiency.[ncbi.nlm.nih.gov]
  • Their etiology is not precisely century with the first clinical recognition of known, so we have included chapters that dis symptoms and patterns for diagnosis of car cuss many aspects of congenital cardiac mal diovascular diseases.[books.google.com]
  • (Etiology) Pyruvate carboxylase (PC) is an enzyme which plays a significant role in the process of converting pyruvate to oxaloacetate.[dovemed.com]
  • Etiology The gene that encodes pyruvate carboxylase (PC) has been localized to chromosome band 11q13.4-q13.5. PC deficiency is inherited from parents by an autosomal recessive inheritance pattern.[emedicine.medscape.com]


  • Epidemiology Three forms of this disorder have been described: A, B and C. [ 2 ] C is the least severe. Infantile form (type A) is most commonly seen in North America with an incidence of approximately 1 in 250,000.[patient.info]
  • Epidemiology Frequency United States Pyruvate carboxylase deficiency is a rare disorder, with an approximate incidence of 1 in 250,000 births. Infantile-onset pyruvate carboxylase deficiency (A type) is more common in the United States.[emedicine.com]
  • The investigators examined 9 novel mutations of the PC gene in 5 unrelated patients, 2 of whom had type A and 3 of whom had type B PC deficiency. [4, 5] Epidemiology Pyruvate carboxylase (PC) deficiency is a rare disorder, with an approximate incidence[emedicine.medscape.com]
  • […] acidosis,presenting as a severe neonatal form with hyperammonemia and abnormal redox state,a milder form with mental retardation,and developmental delay and a benign form Relevant External Links for PC Genetic Association Database (GAD) PC Human Genome Epidemiology[genecards.org]
Sex distribution
Age distribution


  • A better comprehension of that field would increase understanding of the pathophysiology of neurological symptoms and neurotransmitter plasticity.[ncbi.nlm.nih.gov]
  • Pathophysiology Pyruvate carboxylase (PC) is a biotin-dependent mitochondrial enzyme that plays an important role in energy production and anaplerotic pathways. [1, 2] PC catalyzes the conversion of pyruvate to oxaloacetate.[emedicine.com]
  • Pathophysiology Pyruvate carboxylase (PC) deficiency affects metabolism in several major ways.[emedicine.medscape.com]


  • The lack of oxaloacetate prevents gluconeogenesis and urea cycle function.[emedicine.com]
  • Provide a high-carbohydrate and high-protein diet with frequent feedings to help prevent dependence on gluconeogenesis. Prevention of Secondary Complications Individuals with PC deficiency are very brittle metabolically.[ncbi.nlm.nih.gov]
  • Currently, there are no specific methods or guidelines to prevent Pyruvate Carboxylase Deficiency, since it is a genetic condition Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus[dovemed.com]
  • The production of citrate, the first substrate in the citric acid cycle, is limited, thus preventing the citric acid cycle from functioning, shown in the figure below.[emedicine.medscape.com]



  1. Robinson B. Lactic acidemia and mitochondrial disease. Mol Genet Metab. 2006;89(1-2):3-13.
  2. Marin-Valencia I, Roe C, Pascual J. Pyruvate carboxylase deficiency: mechanisms, mimics and anaplerosis. Mol Genet Metab. 2010;101(1):9–17.
  3. Ortez C, Jou C, Cortes-Saladelafont E, et al. Infantile parkinsonism and GABAergic hypotransmission in a patient with pyruvate carboxylase deficiency. Gene. 2013;532(2):302-306.
  4. Schiff M, Levrat V, Acquaviva C, et al. A case of pyruvate carboxylase deficiency with atypical clinical and neuroradiological presentation. Molec Genet Metab. 2006;87:175-177.
  5. Brun N, Robitaille Y, Grignon A, et al. Pyruvate carboxylase deficiency: prenatal onset of ischemia-like brain lesions in two sibs with the acute neonatal form. Am. J. Med. Genet. 1999;84:94-101.
  6. Unal O, Orhan D, Ostergaard E, et al. A patient with pyruvate carboxylase deficiency and nemaline rods on muscle biopsy. J Child Neurol. 2013;28(11):1505-1508.
  7. Monnot S, Serre V, Chadefaux-Vekemans B, et al. Structural insights on pathogenic effects of novel mutations causing pyruvate carboxylase deficiency. Hum Mutat. 2009;30(5):734–740.
  8. Carbone M, Applegarth D, Robinson B. Intron retention and frameshift mutations result in severe pyruvate carboxylase deficiency in two male siblings. Hum Mutat. 2002;20(1):48–56.
  9. Wexler I, Kerr D, Du Y, et al. Molecular characterization of pyruvate carboxylase deficiency in two consanguineous families. Pediat Res. 1998;43:579–584.

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Last updated: 2019-07-11 20:09