AUTHOR INFORMATION

Section 1 of 12

Authored by Richard E Frye, MD, PhD, Assistant Professor, Departments of Pediatrics and Neurology, University of Texas Health Science Center at Houston

Coauthored by Paul J Benke, MD, PhD, Director of Clinical Genetics, Associate Professor, Department of Pediatrics, University of Miami

Richard E Frye, MD, PhD, is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, Child Neurology Society, and International Neuropsychological Society

Edited by Ian Krantz, MD, Assistant Professor, Department of Pediatrics, University of Pennsylvania and Children's Hospital of Philadelphia; Robert Konop, PharmD, Director, Clinical Account Management, Ancillary Care Management, Inc; Robert Anthony Saul, MD, Senior Clinical Geneticist, Greenwood Genetic Center; Clinical Professor, Department of Pediatrics, University of South Carolina; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Richard E Frye, MD, PhD
Editor's Email:	Ian Krantz, MD

eMedicine Journal, April 29 2005, VOLUME 6, Number 4

INTRODUCTION

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Background: Pyruvate carboxylase deficiency (PCD) is a rare disorder that causes developmental delay and failure to thrive starting in the neonatal or early infantile period. PCD results in malfunction of the citric acid cycle and gluconeogenesis, thereby depriving the body of energy; the former biochemical process derives energy from carbohydrates, while the latter produces carbohydrate fuel for the body when carbohydrate intake is low.

Metabolic acidosis caused by an abnormal lactate production is associated with nonspecific symptoms such as severe lethargy, poor feeding, vomiting, and seizures, especially during periods of illness and metabolic stress. Progressive neurologic symptoms, starting in the neonatal or early infantile period, include developmental delay, poor muscle tone, abnormal eye movements, or seizures. Therapies can ameliorate the biochemical abnormalities but cannot undo the progressive neurologic damage.

Pathophysiology: Pyruvate carboxylase (PC) is a biotin-dependent mitochondrial enzyme that converts pyruvate to oxaloacetate. Oxaloacetate is one of two essential substrates needed to produce citrate, the first substrate in gluconeogenesis (Image 1). This deficit in oxaloacetate affects metabolism in 4 major ways.

• The production of citrate, the first substrate in the citric acid cycle, is limited, thus preventing the citric acid cycle from proceeding.

• The precursor of oxaloacetate, pyruvate, is shunted towards alternate metabolic pathways, leading to an increase in lactic acid, alanine, and acetylcoenzyme A (acetyl-CoA). Acetyl-CoA cannot produce citrate without oxaloacetate and is shunted to produce ketone bodies.

• Gluconeogenesis cannot proceed without oxaloacetate, resulting in hypoglycemia during times of prolonged fasting. Tissues that are solely dependent on glucose for fuel, such as the brain, are severely compromised during fasting states. Because cells cannot use the citric acid cycle to produce energy, energy is extracted from glucose exclusively through glycolysis. The highly inefficient process of glycolysis causes glucose to be degraded at a very high rate, resulting in a glucose deficit, thereby compounding the problem.

• Aspartic acid, which is derived from oxaloacetate, is required for the urea cycle. A decrease in aspartic acid production reduces ammonia disposal and leads to increased serum ammonia levels.

Frequency:

• In the US: PCD is a rare disorder, with an approximate incidence of 1 in 250,000 births. Infantile-onset PCD is more common in the United States. An increased incidence has been documented among certain populations, most notably native North American Indians who speak the Algonquin dialect. A founder effect has been postulated.

• Internationally: Neonatal onset PCD has a greater incidence in France.

Mortality/Morbidity:

• Most patients die within the first 6 months of life.

• PCD is a progressive disorder that manifests in the neonatal or infantile period. Some therapies may reduce the biochemical dysfunction. However, progressive neurologic deterioration results in significant morbidity. Most patients die within the first 6 months of life.

• The severe energy deficit in the central nervous system causes neurologic symptoms and congenital brain malformation due to a lack of energy during neurogenesis. In neonates with apparently normal brains, progressive neurologic deterioration is variable. Hypomyelination, cystic lesions, and gliosis of the cortex or cerebellum with gray matter degeneration or necrotizing encephalopathy occur in some infants. Others develop Leigh syndrome, which is a gliosis of the brainstem and basal ganglia with capillary proliferation and characteristic changes on CT and MRI scanning.

Age:

• Age of presentation varies from the prenatal period to early infancy.

• Severe disease has prenatal onset with congenital brain abnormalities.

• Less severe cases manifest in early infancy.

CLINICAL

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History:

• Birth: Low Apgar scores and small size for gestational age are nonspecific symptoms of metabolic disturbance during gestation.



• General: The development of poor feeding, vomiting, and lethargy are nonspecific but common symptoms of metabolic illnesses. If these symptoms are instigated by a mild viral illness and are more severe than would be expected, a metabolic disturbance should be considered, especially after a bacterial infection has been ruled out.



• Development: Mental, psychomotor, and/or growth retardation are nonspecific symptoms of metabolic disease.



• Neurologic: Poor acquisition or loss of motor milestones, new-onset seizures, episodic incoordination, abnormal eye movements, and poor response to visual stimuli are signs of poor neurologic development or degenerative disease.



• Respiratory: A history of apnea, dyspnea, or respiratory depression is consistent with neurologic disease or severe lactic acidosis.

Physical:

• Neurologic


• • Hypotonia, ataxia, tremors, and choreoathetosis are consistent with PCD.
  
  
  
  • Progressive motor pathway degeneration results in a present Babinski sign and spastic diplegia or quadriplegia.
  
  
  
  • Ophthalmologic examination may reveal poor visual tracking, grossly dysconjugate eye movements, poor pupillary response, and blindness.
  
  
  
  • Prenatal microcephaly or postnatal microcephaly also may be evident on physical examination.
  
  
  
• Respiratory: Intermittent hyperpnea at rest, apnea, dyspnea, Cheyne-Stokes respiration, and respiratory failure are nonspecific signs of metabolic and neurologic disease or severe acidosis.

Causes:

• The gene that encodes PC has been localized to bands 11q13.4-q13.5.



• An autosomal recessive inheritance pattern is characteristic.



• Neonatal PCD is associated with complete absence of messenger ribonucleic acid (mRNA) and the PC enzyme protein.



• Infantile-onset PCD is associated with a residual enzyme activity less than 2% of normal levels.

DIFFERENTIALS

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Biotinidase Deficiency
Holocarboxylase Synthetase Deficiency
MELAS Syndrome
Pyruvate Dehydrogenase Complex Deficiency

Other Problems to be Considered:

Gluconeogenesis abnormalities
Fatty acid beta-oxidation deficiencies
Leigh encephalopathy
Pyruvate dehydrogenase complex deficiency
Phosphoenolpyruvate carboxykinase deficiency
2-Ketoglutarate dehydrogenase deficiency
Dihydrolipoamide dehydrogenase deficiency
Fumarase deficiency

WORKUP

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Lab Studies:

• Lactate and pyruvate levels


• • High blood lactate and pyruvate with or without a lactic aciduria suggests an inborn error of energy metabolism.
  
  
  
  • An increased lactate-to-pyruvate ratio is characteristic of citric acid cycle disorders.
  
  
  
• This ratio may be particularly elevated during periods of crisis, such as illness or metabolic stress.



• Hypoglycemia


• • Hypoglycemia during fasting results from greatly reduced gluconeogenesis.
  
  
  
  • Period of fasting required to produce symptoms is much shorter in PCD than other disorders.
  
  
  
• Amino acid levels


• • Measurement of serum amino acids reveals hyperalaninemia, hypercitrullinemia, hyperlysinemia, and low aspartic acid levels.
  
  
  
  • Hyperalaninemia is due to the pyruvate shunting.
  
  
  
  • Hypercitrullinuria and hyperlysinemia results from a metabolic block in the urea cycle due to a low aspartic acid.
  
  
  
  • Low aspartic acid is due to the deficiency in the oxaloacetate precursor.
  
  
  
  • Amino acid levels vary with the general metabolic state of the patient. If the patient is in a catabolic state, proteins are degraded, resulting in the elevation of many amino acids and a nonspecific amino acid profile.
  
  
  
• Other studies


• • Hyperammonemia results from poor ammonia disposal and decreased urea cycle function.
  
  
  
  • Abnormal enzyme function can be detected by functional assays performed on leukocytes, fibroblasts, or properly preserved tissue samples.
  
  
  
  • The severe form of PCD can be diagnosed by demonstrating the absence of PC mRNA or specific cross-reacting material.
  
  
  
  • Cerebrospinal fluid shows an elevation of lactate and pyruvate.
  
  
  
  • Cerebrospinal fluid glutamine is markedly reduced, while glutamic acid and proline levels are elevated.
  
  
  

Imaging Studies:

• MRI


• • MRI in the neonatal period may show ventricular dilation, cerebrocortical and white matter atrophy, or periventricular white matter cysts.
  
  
  
  • MRI in infants with progressive neurologic symptoms may show symmetric cystic lesions and gliosis in the cortex, basal ganglia, brainstem, or cerebellum and/or generalized hypomyelination.
  
  
  
• Magnetic resonance spectroscopy (MRS): Brain MRS shows high lactate levels, as well as levels of N-acetylaspartate and choline consistent with hypomyelination.

Central nervous system neuropathology may include poor myelination, paucity of cerebral cortex neurons, gliosis, and proliferation of astrocytes.

TREATMENT

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Medical Care:

• Treatments are aimed at stimulating the pyruvate dehydrogenase complex (PDC) and providing alternative fuels. Correction of the biochemical abnormality can reverse some symptoms, but central nervous system damage progresses regardless of treatment.



• The PDC can provide an alternative pathway for pyruvate metabolism PDC activity can be optimized by cofactor supplementation with thiamine and lipoic acid and administration of dichloroacetate. Increased pyruvate metabolism through this pathway can help reduce the pyruvate and lactate levels.



• Biotin supplementation is given to help optimize the residual enzyme activity but is usually of little use.



• Citrate supplementation reduces the acidosis and provides the needed substrate in the citric acid cycle.



• Aspartic acid supplementation allows the urea cycle to proceed and reduces the ammonia level.



• One patient reportedly was successfully treated with a continuous nocturnal gastric drip feeding of uncooked cornstarch.

• Triheptanoin has reportedly reversed hepatic failure and biochemical abnormalities in one case by presumably providing a source of acetyl-CoA and anaplerotic propionyl-CoA. However, life expectancy was not prolonged.

• Orthotopic liver transplantation has reversed the biochemical abnormalities in one patient.

Consultations:

• Evaluation by an expert in metabolic and genetic disorders is necessary to confirm the diagnosis, guide the appropriate treatment, and determine the prognosis.



• Genetic counseling for the parents is important in order to determine the risk of recurrence in future pregnancies.

Diet:

• Diet has a small effect on outcome.



• A high-carbohydrate, high-protein diet may help to maintain an anabolic state and prevent activation of gluconeogenesis.

MEDICATION

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Drug Category: Enzyme activator -- Dichloroacetate (DCA) sodium is the only drug found to activate the enzyme complex.

Drug Name	Sodium dichloroacetate -- Used to treat lactic acidosis. This is a compound that is believed to activate the PDC by inhibiting the inactivating kinase, resulting in decreased lactate production and promotion of pyruvate oxidation.
Adult Dose	30-100 mg/kg/d IV divided bid
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Reduces urate clearance and may counteract the effect of uricosuric drugs
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Sedation is common; stimulates myocardial contractility; may elevate serum transaminases; polyneuropathy has been reported with long-term administration of DCA; urinary oxalate crystal formation has been reported and is a dose-related phenomenon; DCA is currently an investigational agent and is not commercially available; it is only available through an investigational protocol at this time

Drug Category: Alkalinizing agents -- Sodium bicarbonate is used as a gastric, systemic, and urinary alkalinizer and has been used in the treatment of acidosis resulting from metabolic and respiratory causes, including diabetic coma, diarrhea, kidney disturbances, and shock. Sodium bicarbonate also increases renal clearance of acidic drugs.

Drug Name	Bicarbonate sodium -- Bicarbonate can be used to correct the acidosis in chronic and acute settings.
Adult Dose	Acidosis during acute attacks: 1-2 mEq/kg IV over 20 min; infusion can be repeated up to q30min prn in an emergency setting but careful monitoring of blood pH must be obtained Chronic acidosis: 1-3 mEq/kg/d PO qid
Pediatric Dose	Acidosis during acute attacks: Administer as in adults Chronic acidosis: 2-5 mEq/kg/d PO qid
Contraindications	Alkalosis; hypernatremia; severe pulmonary edema; hypocalcemia; unknown abdominal pain
Interactions	Sodium bicarbonate inactivates catecholamines, calcium salts, and atropine when mixed together; shown to decrease therapeutic levels of methotrexate, tetracyclines, and salicylates due to urinary alkalinization
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	May precipitate hypernatremia, circulatory overload, and hypocalcemia; may cause a metabolic alkalosis; avoid extravasation; carefully monitor arterial or venous blood pH with IV infusion; response to bicarbonate should be checked 10-20 min after infusion; guide repeat treatment with bicarbonate by clinical change in the patient's condition along with laboratory values; take particular care when using with neonates because of increased risk of intraventricular hemorrhage

Drug Name	Citrate solutions (Bicitra, Polycitra) -- Several solutions containing citrate with sodium or potassium or both are available as alkalinizing agents. With normal hepatic function, 1 mEq of citrate is converted to 1 mEq of bicarbonate.
Adult Dose	Chronic acidosis: 1-3 mEq/kg/d PO divided tid/qid
Pediatric Dose	Chronic acidosis: 2-5 mEq/kg/d PO divided tid/qid
Contraindications	Severe renal impairment; acute dehydration
Interactions	Urine alkalinization may decrease serum levels of lithium, chlorpropamide, methenamine, methotrexate, salicylates, or tetracyclines; urine alkalinization may increase serum levels of flecainide, quinidine, or sympathomimetics
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	May cause hypokalemia, hypernatremia, and/or hyperkalemia depending on the formulation used; formulation should be individually based with consideration of other supplementation and the ability of the patient to tolerate sodium or potassium loads

FOLLOW-UP

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Further Inpatient Care:

• Acute decompensation during illness requires admission and management of the acidosis with hydration and intravenous bicarbonate. The patient must be supplied with adequate carbohydrates.

Further Outpatient Care:

• Lactate levels should be monitored closely.



• A dietary log should be completed to help evaluate dietary manipulations and to ensure compliance.



• An informational statement that describes the child's disorder and the appropriate medical treatment for the disorder in an emergency setting should be carried by the parents at all times.

Prognosis:

• Although diet manipulation and supplementation of substrates and cofactors can reverse some of the biochemical abnormalities, neurologic abnormalities typically progress, and demise within the first 6 months of life is the rule.



• Enzyme activity of cultured chorionic villus cells can be determined in time to allow for early prenatal diagnosis.

Patient Education:

• The patient and the parents should be well educated on the factors that elicit a crisis and the early signs of decompensation.



• For excellent patient education resources, please refer to eMedicinehealth.

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Several other metabolic encephalopathies can manifest with the same signs and symptoms as PCD. Exclude other disorders of the citric acid cycle, such as PDC deficiency and other mitochondropathies. Biotinidase deficiency is also important to exclude because it is potentially treatable.



• MRI brain abnormalities can be essential to the diagnosis of an energy deficiency syndrome such as PCD but may not develop early in the disease course. Thus, repeat MRI scans at regular intervals in children who display signs and symptoms consistent with an energy deficiency syndrome.



• Urine organic acids may be nonspecific or may only demonstrate abnormalities during times of stress. Thus, this test may need to be repeated several times for a meaningful result.

TEST QUESTIONS

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CME Question 1: Parents of a child with pyruvate carboxylase deficiency have a 2- and 3-year-old boy and girl, respectively. They are wondering if they should have any more children. Which of the following is the most appropriate response?

A: Because they have had a child with this disorder, they are unlikely to have another child with this disorder.
B: There is a 50% chance that their next child may have this disorder.
C: During the next pregnancy, an amniocentesis should be performed to obtain genetic material for testing.
D: A functional assay should be performed from cells obtained by chorionic villus sampling during the next pregnancy.
E: A surrogate gamete donor should be considered to ensure the next child is not born with this disorder.

The correct answer is D: Pyruvate carboxylase deficiency is a very rare disorder, occurring once in 250,000 births. The disorder is transmitted in an autosomal recessive manner, and both parents must have 1 abnormal gene. The chances of this couple having another child with this disorder are 1 in 4. Once this couple is found to be at risk, the fetus can be tested by a functional assay from cells obtained by chorionic villus sampling during the next pregnancy. Of course, the results will guide further management of the pregnancy, and termination of the pregnancy may be considered if the functional assay demonstrates the abnormal phenotype. The options for testing and therapy must be discussed with the parents before the next pregnancy so they are prepared to make the appropriate decision. If the parents have moral or religious objections to pregnancy termination, then other options, such as surrogate gamete donation or adoption might be considered.

CME Question 2: Parents of a child with pyruvate carboxylase deficiency have a 2-year-old boy and 3-year-old girl. They wish to know if their children will have children with this disorder. Which of the following is the most appropriate response?

A: Their grandchildren will definitely not manifest this disorder.
B: Although their children most likely carry a defective gene, the frequency of this gene in the population is low and their grandchildren will most likely not manifest the disorder.
C: Their children probably are not carriers of the defective gene, and the grandchildren will probably not manifest this disorder.
D: Their grandchildren have a 25% chance of being affected.
E: Only the child with the disorder can transmit the defective gene.

The correct answer is B: Only 1 in every 250 people carries the gene defect for pyruvate carboxylase deficiency. Sixty-six percent of unaffected children born to carrier parents are themselves carriers of this gene defect, and the defect is transmitted in an autosomal recessive manner, so the chance of this couple`s carrier children having a child with the disorder can be calculated to be 1 in 1000, assuming reproduction is with a nonconsanguineous partner with a negative family history. Their children can have chorionic villus sampling during pregnancy.

Pearl Question 1 (T/F): In pyruvate carboxylase deficiency, hyperammonemia can be resolved by the supplementing aspartic acid.

The correct answer is True: Aspartic acid supplementation allows the urea cycle to proceed and reduces the ammonia level.

Pearl Question 2 (T/F): Citrulline, lysine, and aspartic acid levels are abnormal in pyruvate carboxylase deficiency but not in pyruvate dehydrogenase deficiency.

The correct answer is True: In pyruvate carboxylase deficiency, measurement of serum amino acids reveals hyperalaninemia, hypercitrullinemia, hyperlysinemia, and low aspartic acid levels. Hyperalaninemia is due to the shunting of pyruvate toward an alanine production pathway. A metabolic block in the urea cycle due to a deficiency in aspartic acid results in hypercitrullinemia and hyperlysinemia. Low aspartic acid levels are due to the deficiency in the oxaloacetate precursor. Amino acid levels vary with the general metabolic state of the patient. If the patient is in a catabolic state, proteins are degraded, resulting in the elevation of many amino acids and a nonspecific amino acid profile.

Pearl Question 3 (T/F): Biotinidase deficiency is a major inborn error of metabolism that can manifest similarly to pyruvate carboxylase deficiency and can be treated easily with supplementation.

The correct answer is True: Pyruvate carboxylase is a biotin-dependent mitochondrial enzyme that converts pyruvate to oxaloacetate. Oxaloacetate is one of two essential substrates needed to produce citrate and the first substrate in gluconeogenesis.

Pearl Question 4 (T/F): Leigh syndrome is a neurodegenerative syndrome that can be caused by pyruvate carboxylase deficiency and is characterized by gliosis of the brainstem and basal ganglia with capillary proliferation.

The correct answer is True: The severe energy deficit in the central nervous system causes neurologic symptoms and congenital brain malformation due to a lack of energy during neurogenesis. In neonates with apparently normal brains, progressive neurologic deterioration is variable. Hypomyelination, cystic lesions, and gliosis of the cortex or cerebellum with gray matter degeneration or necrotizing encephalopathy occur in some infants. Others develop Leigh syndrome, which is a gliosis of the brainstem and basal ganglia with capillary proliferation and characteristic changes on CT scan and MRI.

PICTURES

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Caption: Picture 1. This is a diagrammatic representation of the citric acid cycle and the abnormalities found in pyruvate carboxylase deficiency. The dotted line represents absent pathways. Pyruvate cannot produce oxaloacetate and is shunted to alternative pathways that produce lactic acid and alanine. The lack of oxaloacetate prevents gluconeogenesis and urea cycle function.
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BIBLIOGRAPHY

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• Al-Essa MA, Ozand PT: Manual of Metabolic Disease. King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia 1998; 1st Edition.
• Augereau C, Pham Dinh D, Moncion A: Pyruvate carboxylase deficiencies: complementation studies between "French" and "American" phenotypes in cultured fibroblasts. J Inherit Metab Dis 1985; 8(2): 59-62[Medline].
• Bartlett K, Ghneim HK, Stirk JH: Pyruvate carboxylase deficiency. J Inherit Metab Dis 1984; 7 Suppl 1: 74-8[Medline].
• De Meirleir L: Defects of pyruvate metabolism and the Krebs cycle. J Child Neurol 2002 Dec; 17 Suppl 3: 3S26-33; discussion 3S33-4[Medline].
• Higgins JJ, Glasgow AM, Lusk M: MRI, clinical, and biochemical features of partial pyruvate carboxylase deficiency. J Child Neurol 1994 Oct; 9(4): 436-9[Medline].
• Mochel F, Delonlay P, Touati G: Pyruvate carboxylase deficiency: clinical and biochemical response to anaplerotic diet therapy. Mol Genet Metab 2005 Apr; 84(4): 305-12[Medline].
• Nyhan WL, Khanna A, Barshop BA: Pyruvate carboxylase deficiency--insights from liver transplantation. Mol Genet Metab 2002 Sep-Oct; 77(1-2): 143-9[Medline].
• Perry TL, Haworth JC, Robinson BH: Brain amino acid abnormalities in pyruvate carboxylase deficiency. J Inherit Metab Dis 1985; 8(2): 63-6[Medline].
• Stacpoole PW, Barnes CL, Hurbanis MD: Treatment of congenital lactic acidosis with dichloroacetate [see comments]. Arch Dis Child 1997 Dec; 77(6): 535-41[Medline].
• Ullrich K, Schmidt H, van Teeffelen-Heithoff A: Glycogen storage disease type I and III and pyruvate carboxylase deficiency: results of long-term treatment with uncooked cornstarch. Acta Paediatr Scand 1988 Jul; 77(4): 531-6[Medline].
• Van Coster RN, Janssens S, Misson JP: Prenatal diagnosis of pyruvate carboxylase deficiency by direct measurement of catalytic activity on chorionic villi samples. Prenat Diagn 1998 Oct; 18(10): 1041-4[Medline].

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