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Mora-Barreto, L. ., & Suárez-Obando, F. . (2017). Aproximación diagnóstica de los errores innatos del metabolismo en la unidad de cuidado intensivo neonatal: acidosis metabólica, hiperamonemia e hipoglicemia. Biosalud, 16(2), 83–95. https://doi.org/10.17151/biosa.2017.16.2.8
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Los errores innatos del metabolismo del neonato son enfermedades que requieren una intervención temprana, dado que el manejo oportuno permite la prevención de secuelas severas o desenlaces fatales. Sin embargo, su diagnóstico se dificulta debido a las múltiples manifestaciones clínicas inespecíficas que lo acompañan y a las diversas alteraciones metabólicas que afectan la lectura de los estudios paraclínicos de rutina; sin embargo, una aproximación sistemática que tenga en cuenta las variaciones del metabolismo intermedio, interpretadas a través de pruebas básicas de laboratorio, permite alcanzar en la mayoría de los casos, un diagnóstico certero. La aproximación aquí propuesta se basa en la interpretación de tres estados metabólicos: acidosis metabólica, hiperamonemia e hipoglicemia, y su relación con los resultados de tests de laboratorio que están a la mano en la mayoría de unidades de neonatología. Se plantean diversas recomendaciones en relación a valores normales, flujogramas diagnósticos y recomendaciones sobre toma y conservación de muestras.
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1. Burgio GR. “Inborn errors of metabolism” and “chemical individuality”, two ideas of Sir Archibald Garrod briefly revisited 50 years after his death. European Journal of Pediatrics 1986; 145(1-2): 2-5.
2. Garrod AE. The incidence of alkaptonuria: a study in chemical individuality. 1902 [classical article]. The Yale Journal of Biology and Medicine 2002; 75(4): 221-31.
3. Garrod AE. The Lancet. The incidence of alkaptonuria: a study in chemical individuality. NutritionReviews 1975; 33(3): 81-3.
4. Meng M, Zhang YP. Impact of inborn errors of metabolism on admission in a neonatal intensive care unit: a 4-year report. Journal of Pediatric Endocrinology & Metabolism: JPEM 2013; 26(7
-8): 689-93.
5. Boneh A. Signal transduction in inherited metabolic disorders: a model for a possible pathogenetic mechanism. J Inherit Metab Dis 2015; 38(4): 729-40.
6. Chanprasert S, Scaglia F. Adult liver disorders caused by inborn errors of metabolism: review and update. Mol Genet Metab 2015; 114(1): 1-10.
7. Chaturvedi S et al. Human Metabolic Enzymes Deficiency: A Genetic Mutation Based Approach. Scientifica (Cairo), 2016; 2016: 9828672.
8. Taybert J. Procreation in families with inborn error of metabolism--new challenges for medical care. Developmental Period Medicine 2015; 19(4): 519-22.
9. Endo F et al. Clinical manifestations of inborn errors of the urea cycle and related metabolic disorders during childhood. J Nutr 2004; 134(6 Suppl): p. 1605S-1609S.
10. Al Bu Ali WH et al. Risk factors and birth prevalence of birth defects and inborn errors of metabolism in Al Ahsa, Saudi Arabia. Pan Afr Med J 2011: 8: 14.
11. Meyer BF. Strategies for the prevention of hereditary diseases in a highly consanguineous population. Ann Hum Biol, 2005; 32(2): 174-9.
12. El-Hattab AW. Inborn errors of metabolism. Clin Perinatol 2015; 42(2): 413-39.
13. Campistol J. Inborn errors of metabolism with neurological manifestations in the neonatal period. Medicina (B Aires), 2007; 67(6 Pt 1): 561-8.
14. Campistol J et al. Inborn errors of metabolism with neurological symptomathology in the neonatal period. Rev Neurol 2005; 40(6): 321-6.
15. Padhi TR et al. Macular cherry-red spot helps diagnose rare storage disorder in an infant with repeated respiratory tract infections: case report. Semin Ophthalmol 2015; 30(3): 224-6.
16. Janzen N et al. Early cataract formation due to galactokinase deficiency: impact of newborn screening. Arch Med Res 2011; 42(7): 608-12.
17. Rajappa M, Goyal A, Kaur J. Inherited metabolic disorders involving the eye: a clinico-biochemical perspective. Eye (Lond), 2010; 24(4): 507-18.
18. Burton BK. Inborn errors of metabolism in infancy: a guide to diagnosis. Pediatrics 1998; 102(6): E69.
19. Haberle J et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis 2012; 7: 32.
20. Kolker S et al. The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation. J Inherit Metab Dis 2015; 38(6): 1041-57.
21. Berisavac I et al. How to recognize and treat metabolic encephalopathy in Neurology intensive care unit. Neurol India 2017; 65(1): 123-128.
22. Hartung B et al. Ornithine transcarbamylase deficiency of a male newborn with fatal outcome. Int J Legal Med 2016; 130(3): 783-5.
23. Santamaria F et al. Respiratory manifestations in patients with inherited metabolic diseases. Eur Respir Rev 2013; 22(130): 437-53.
24. Barshes NR et al. Evaluation and management of patients with propionic acidemia undergoing liver transplantation: a comprehensive review. Pediatr Transplant 2006; 10(7): 773-81.
25. Bonnet D et al. Arrhythmias and Conduction Defects as Presenting Symptoms of Fatty Acid Oxidation Disorders in Children. Circulation 1999; 100(22): 2248-2253.
26. Byers SL Ficicioglu C. Infant with cardiomyopathy: When to suspect inborn errors of metabolism? World J Cardiol 2014; 6(11): 1149-55.
27. De Las Heras J et al. An update on the use of benzoate, phenylacetate and phenylbutyrate ammonia scavengers for interrogating and modifying liver nitrogen metabolism and its implications in urea cycle disorders and liver disease. Expert Opin Drug Metab Toxicol 2016: 1-10.
28. Maisels MJ. Managing the jaundiced newborn: a persistent challenge. CMAJ 2015; 187(5): 335-43.
29. Del Orbe Barreto R et al. Severe neonatal jaundice due to a de novo glucose-6-phosphate dehydrogenase deficient mutation. Int J Lab Hematol, 2016. 38(2): p. e27-9.
30. Minucci A et al. Co-inheritance of G6PD and PK deficiencies in a neonate carrying a Novel UGT1A1 genotype associated to Crigler-Najjar type II syndrome. Pediatr Blood Cancer 2015; 62
(9): 1680-1.
31. Atik SU et al. Clinical, molecular, and genetic evaluation of galactosemia in Turkish children. Turk Pediatri Ars 2016; 51(4): 204-209.
32. Gotti G et al. Neonatal Jaundice with Splenomegaly: Not a Common Pick. Fetal Pediatr Pathol 2016; 35(2): 108-11.
33. Fraile PQ et al. Niemann-Pick type C disease: From neonatal cholestasis to neurological degeneration. Different phenotypes. An Pediatr (Barc), 2010; 73(5): 257-63.
34. Durand P. Management of metabolic acidosis in children, inherited metabolic disorders excluded. Arch Pediatr 2010; 17(6): 678-9.
35. Raghuveer TS, Garg U, Graf WD. Inborn errors of metabolism in infancy and early childhood: an update. Am Fam Physician 2006; 73(11): 1981-90.
36. Lim S. Metabolic acidosis. Acta Med Indones 2007; 39(3): 145-50.
37. Swenson ER. Metabolic acidosis. Respir Care 2001; 46(4): 342-53.
38. Andrade OV, Ihara FOE, Troster J. Metabolic acidosis in childhood: why, when and how to treat. J Pediatr (Rio J), 2007; 83(2 Suppl): S11-21.
39. Morris CG, Low J. Metabolic acidosis in the critically ill: part 2. Causes and treatment. Anaesthesia 2008; 63(4): 396-411.
40. Mandell I. Serum anion gap in metabolic acidosis. Neonatal Netw 2009; 28(4): 252-4.
41. Forni LG. et al. Circulating anions usually associated with the Krebs cycle in patients with metabolic acidosis. Crit Care 2005; 9(5): R591-5.
42. Sass JO. Inborn errors of ketogenesis and ketone body utilization. J Inherit Metab Dis 2012; 35(1): 23-8.
43. Fukao T et al. Ketone body metabolism and its defects. J Inherit Metab Dis 2014; 37(4): 541-51.
44. Hori T et al. Inborn errors of ketone body utilization. Pediatr Int 2015; 57(1): 41-8.
45. Christopher R, Sankaran BP. An insight into the biochemistry of inborn errors of metabolism for a clinical neurologist. Ann Indian Acad Neurol 2008; 11(2): 68-81.
46. Ellaway CJ, Wilcken B, Christodoulou J. Clinical approach to inborn errors of metabolism presenting in the newborn period. J Paediatr Child Health, 2002; 38(5): 511-7.
47. van Karnebeek CD et al. The metabolic evaluation of the child with an intellectual developmental disorder: diagnostic algorithm for identification of treatable causes and new digital resource. Mol Genet Metab 2014; 111(4): 428-38.
48. Debray FG et al. Diagnostic accuracy of blood lactate-to-pyruvate molar ratio in the differential diagnosis of congenital lactic acidosis. Clin Chem 2007; 53(5): 916-21.
49. Shchelochkov OA, Carrillo N, Venditti, C. Propionic Acidemia. In: GeneReviews (R), R.A. Pagon, et al., Editors. 1993: Seattle (WA).
50. Haas RH, et al. The in-depth evaluation of suspected mitochondrial disease. Mol Genet Metab 2008; 94(1): 16-37.
51. Danhauser K et al. Fatal neonatal encephalopathy and lactic acidosis caused by a homozygous lossof-function variant in COQ9. Eur J Hum Genet 2016; 24(3): 450-4.
52. Palermo RA et al. Masquerading acidosis after cardiopulmonary bypass: a case of propionic acidemia and congenital heart disease. World J Pediatr Congenit Heart Surg 2015; 6(2): 291-4.
53. Simalti AK et al. An unusual cause of persisting hyperlactatemia in a neonate undergoing open heart surgery. World J Pediatr Congenit Heart Surg 2015; 6(1): 130-4.
54. Enns G, Cowan T. Hyperammonemia. In: Signs and Symptoms of Genetic Conditions, L. Hudgins, et al., Editors. 2015, Oxford University Press: New York.
55. Takanashi J et al. Brain MR imaging in neonatal hyperammonemic encephalopathy resulting from proximal urea cycle disorders. AJNR Am J Neuroradiol 2003; 24(6): 1184-7.
56. Stojanovic VD et al. A case of transient hyperammonemia in the newborn transient neonatal hyperammonemia. J Matern Fetal Neonatal Med 2010; 23(4): 347-50.
57. Waterham HR Ferdinandusse S, Wanders RJ. Human disorders of peroxisome metabolism and biogenesis. Biochim Biophys Acta 2016; 1863(5): 922-33.
58. Baruteau J et al. Clinical and biological features at diagnosis in mitochondrial fatty acid beta-oxidation defects: a French pediatric study of 187 patients. J Inherit Metab Dis 2013;
36(5): 795-803.
59. Lichter-Konecki U et al. Ornithine Transcarbamylase Deficiency. In: GeneReviews (R), R.A. Pagon, et al., Editors. 1993: Seattle (WA).
60. Caldovic L. et al. Genotype-Phenotype Correlations in Ornithine Transcarbamylase Deficiency: A Mutation Update. J Genet Genomics 2015. 42(5): 181-94.
61. Vatas D, Packman S. Hypoglycemia. In: Signs and Symptoms of Genetic Conditions, L. Hudgins, et al., Editors. 2015, Oxford University Press: New York.
62. Ghosh A, Banerjee I, Morris AA. Recognition, assessment and management of hypoglycaemia in childhood. Arch Dis Child 2016; 101(6): 575-80.
63. Adeva-Andany MM et al. Glycogen metabolism in humans. BBA Clin 2016; 5: 85-100.
64. Donner MG, Erhardt A, Haussinger D. Metabolic disorders of the liver. Part 2: glycogen storage diseases, hereditary fructose intolerance, galactosemia and hepatic porphyrias. Dtsch Med Wochenschr 2010; 135(50): 2540-7.
65. Goel H, Lusher A, Boneh A. Pediatric mortality due to inborn errors of metabolism in Victoria, Australia: a population-based study. JAMA 2010; 304(10): 1070-2.
66. Emery JL et al. Investigation of inborn errors of metabolism in unexpected infant deaths. Lancet 1988; 2(8601): 29-31.
67. Taybert J. Procreation in families with inborn error of metabolism--new challenges for medical care. Dev Period Med 2015; 19(4): 519-22.
68. Olpin SE. The metabolic investigation of sudden infant death. Ann Clin Biochem 2004; 41(Pt 4): 282-93.
2. Garrod AE. The incidence of alkaptonuria: a study in chemical individuality. 1902 [classical article]. The Yale Journal of Biology and Medicine 2002; 75(4): 221-31.
3. Garrod AE. The Lancet. The incidence of alkaptonuria: a study in chemical individuality. NutritionReviews 1975; 33(3): 81-3.
4. Meng M, Zhang YP. Impact of inborn errors of metabolism on admission in a neonatal intensive care unit: a 4-year report. Journal of Pediatric Endocrinology & Metabolism: JPEM 2013; 26(7
-8): 689-93.
5. Boneh A. Signal transduction in inherited metabolic disorders: a model for a possible pathogenetic mechanism. J Inherit Metab Dis 2015; 38(4): 729-40.
6. Chanprasert S, Scaglia F. Adult liver disorders caused by inborn errors of metabolism: review and update. Mol Genet Metab 2015; 114(1): 1-10.
7. Chaturvedi S et al. Human Metabolic Enzymes Deficiency: A Genetic Mutation Based Approach. Scientifica (Cairo), 2016; 2016: 9828672.
8. Taybert J. Procreation in families with inborn error of metabolism--new challenges for medical care. Developmental Period Medicine 2015; 19(4): 519-22.
9. Endo F et al. Clinical manifestations of inborn errors of the urea cycle and related metabolic disorders during childhood. J Nutr 2004; 134(6 Suppl): p. 1605S-1609S.
10. Al Bu Ali WH et al. Risk factors and birth prevalence of birth defects and inborn errors of metabolism in Al Ahsa, Saudi Arabia. Pan Afr Med J 2011: 8: 14.
11. Meyer BF. Strategies for the prevention of hereditary diseases in a highly consanguineous population. Ann Hum Biol, 2005; 32(2): 174-9.
12. El-Hattab AW. Inborn errors of metabolism. Clin Perinatol 2015; 42(2): 413-39.
13. Campistol J. Inborn errors of metabolism with neurological manifestations in the neonatal period. Medicina (B Aires), 2007; 67(6 Pt 1): 561-8.
14. Campistol J et al. Inborn errors of metabolism with neurological symptomathology in the neonatal period. Rev Neurol 2005; 40(6): 321-6.
15. Padhi TR et al. Macular cherry-red spot helps diagnose rare storage disorder in an infant with repeated respiratory tract infections: case report. Semin Ophthalmol 2015; 30(3): 224-6.
16. Janzen N et al. Early cataract formation due to galactokinase deficiency: impact of newborn screening. Arch Med Res 2011; 42(7): 608-12.
17. Rajappa M, Goyal A, Kaur J. Inherited metabolic disorders involving the eye: a clinico-biochemical perspective. Eye (Lond), 2010; 24(4): 507-18.
18. Burton BK. Inborn errors of metabolism in infancy: a guide to diagnosis. Pediatrics 1998; 102(6): E69.
19. Haberle J et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis 2012; 7: 32.
20. Kolker S et al. The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation. J Inherit Metab Dis 2015; 38(6): 1041-57.
21. Berisavac I et al. How to recognize and treat metabolic encephalopathy in Neurology intensive care unit. Neurol India 2017; 65(1): 123-128.
22. Hartung B et al. Ornithine transcarbamylase deficiency of a male newborn with fatal outcome. Int J Legal Med 2016; 130(3): 783-5.
23. Santamaria F et al. Respiratory manifestations in patients with inherited metabolic diseases. Eur Respir Rev 2013; 22(130): 437-53.
24. Barshes NR et al. Evaluation and management of patients with propionic acidemia undergoing liver transplantation: a comprehensive review. Pediatr Transplant 2006; 10(7): 773-81.
25. Bonnet D et al. Arrhythmias and Conduction Defects as Presenting Symptoms of Fatty Acid Oxidation Disorders in Children. Circulation 1999; 100(22): 2248-2253.
26. Byers SL Ficicioglu C. Infant with cardiomyopathy: When to suspect inborn errors of metabolism? World J Cardiol 2014; 6(11): 1149-55.
27. De Las Heras J et al. An update on the use of benzoate, phenylacetate and phenylbutyrate ammonia scavengers for interrogating and modifying liver nitrogen metabolism and its implications in urea cycle disorders and liver disease. Expert Opin Drug Metab Toxicol 2016: 1-10.
28. Maisels MJ. Managing the jaundiced newborn: a persistent challenge. CMAJ 2015; 187(5): 335-43.
29. Del Orbe Barreto R et al. Severe neonatal jaundice due to a de novo glucose-6-phosphate dehydrogenase deficient mutation. Int J Lab Hematol, 2016. 38(2): p. e27-9.
30. Minucci A et al. Co-inheritance of G6PD and PK deficiencies in a neonate carrying a Novel UGT1A1 genotype associated to Crigler-Najjar type II syndrome. Pediatr Blood Cancer 2015; 62
(9): 1680-1.
31. Atik SU et al. Clinical, molecular, and genetic evaluation of galactosemia in Turkish children. Turk Pediatri Ars 2016; 51(4): 204-209.
32. Gotti G et al. Neonatal Jaundice with Splenomegaly: Not a Common Pick. Fetal Pediatr Pathol 2016; 35(2): 108-11.
33. Fraile PQ et al. Niemann-Pick type C disease: From neonatal cholestasis to neurological degeneration. Different phenotypes. An Pediatr (Barc), 2010; 73(5): 257-63.
34. Durand P. Management of metabolic acidosis in children, inherited metabolic disorders excluded. Arch Pediatr 2010; 17(6): 678-9.
35. Raghuveer TS, Garg U, Graf WD. Inborn errors of metabolism in infancy and early childhood: an update. Am Fam Physician 2006; 73(11): 1981-90.
36. Lim S. Metabolic acidosis. Acta Med Indones 2007; 39(3): 145-50.
37. Swenson ER. Metabolic acidosis. Respir Care 2001; 46(4): 342-53.
38. Andrade OV, Ihara FOE, Troster J. Metabolic acidosis in childhood: why, when and how to treat. J Pediatr (Rio J), 2007; 83(2 Suppl): S11-21.
39. Morris CG, Low J. Metabolic acidosis in the critically ill: part 2. Causes and treatment. Anaesthesia 2008; 63(4): 396-411.
40. Mandell I. Serum anion gap in metabolic acidosis. Neonatal Netw 2009; 28(4): 252-4.
41. Forni LG. et al. Circulating anions usually associated with the Krebs cycle in patients with metabolic acidosis. Crit Care 2005; 9(5): R591-5.
42. Sass JO. Inborn errors of ketogenesis and ketone body utilization. J Inherit Metab Dis 2012; 35(1): 23-8.
43. Fukao T et al. Ketone body metabolism and its defects. J Inherit Metab Dis 2014; 37(4): 541-51.
44. Hori T et al. Inborn errors of ketone body utilization. Pediatr Int 2015; 57(1): 41-8.
45. Christopher R, Sankaran BP. An insight into the biochemistry of inborn errors of metabolism for a clinical neurologist. Ann Indian Acad Neurol 2008; 11(2): 68-81.
46. Ellaway CJ, Wilcken B, Christodoulou J. Clinical approach to inborn errors of metabolism presenting in the newborn period. J Paediatr Child Health, 2002; 38(5): 511-7.
47. van Karnebeek CD et al. The metabolic evaluation of the child with an intellectual developmental disorder: diagnostic algorithm for identification of treatable causes and new digital resource. Mol Genet Metab 2014; 111(4): 428-38.
48. Debray FG et al. Diagnostic accuracy of blood lactate-to-pyruvate molar ratio in the differential diagnosis of congenital lactic acidosis. Clin Chem 2007; 53(5): 916-21.
49. Shchelochkov OA, Carrillo N, Venditti, C. Propionic Acidemia. In: GeneReviews (R), R.A. Pagon, et al., Editors. 1993: Seattle (WA).
50. Haas RH, et al. The in-depth evaluation of suspected mitochondrial disease. Mol Genet Metab 2008; 94(1): 16-37.
51. Danhauser K et al. Fatal neonatal encephalopathy and lactic acidosis caused by a homozygous lossof-function variant in COQ9. Eur J Hum Genet 2016; 24(3): 450-4.
52. Palermo RA et al. Masquerading acidosis after cardiopulmonary bypass: a case of propionic acidemia and congenital heart disease. World J Pediatr Congenit Heart Surg 2015; 6(2): 291-4.
53. Simalti AK et al. An unusual cause of persisting hyperlactatemia in a neonate undergoing open heart surgery. World J Pediatr Congenit Heart Surg 2015; 6(1): 130-4.
54. Enns G, Cowan T. Hyperammonemia. In: Signs and Symptoms of Genetic Conditions, L. Hudgins, et al., Editors. 2015, Oxford University Press: New York.
55. Takanashi J et al. Brain MR imaging in neonatal hyperammonemic encephalopathy resulting from proximal urea cycle disorders. AJNR Am J Neuroradiol 2003; 24(6): 1184-7.
56. Stojanovic VD et al. A case of transient hyperammonemia in the newborn transient neonatal hyperammonemia. J Matern Fetal Neonatal Med 2010; 23(4): 347-50.
57. Waterham HR Ferdinandusse S, Wanders RJ. Human disorders of peroxisome metabolism and biogenesis. Biochim Biophys Acta 2016; 1863(5): 922-33.
58. Baruteau J et al. Clinical and biological features at diagnosis in mitochondrial fatty acid beta-oxidation defects: a French pediatric study of 187 patients. J Inherit Metab Dis 2013;
36(5): 795-803.
59. Lichter-Konecki U et al. Ornithine Transcarbamylase Deficiency. In: GeneReviews (R), R.A. Pagon, et al., Editors. 1993: Seattle (WA).
60. Caldovic L. et al. Genotype-Phenotype Correlations in Ornithine Transcarbamylase Deficiency: A Mutation Update. J Genet Genomics 2015. 42(5): 181-94.
61. Vatas D, Packman S. Hypoglycemia. In: Signs and Symptoms of Genetic Conditions, L. Hudgins, et al., Editors. 2015, Oxford University Press: New York.
62. Ghosh A, Banerjee I, Morris AA. Recognition, assessment and management of hypoglycaemia in childhood. Arch Dis Child 2016; 101(6): 575-80.
63. Adeva-Andany MM et al. Glycogen metabolism in humans. BBA Clin 2016; 5: 85-100.
64. Donner MG, Erhardt A, Haussinger D. Metabolic disorders of the liver. Part 2: glycogen storage diseases, hereditary fructose intolerance, galactosemia and hepatic porphyrias. Dtsch Med Wochenschr 2010; 135(50): 2540-7.
65. Goel H, Lusher A, Boneh A. Pediatric mortality due to inborn errors of metabolism in Victoria, Australia: a population-based study. JAMA 2010; 304(10): 1070-2.
66. Emery JL et al. Investigation of inborn errors of metabolism in unexpected infant deaths. Lancet 1988; 2(8601): 29-31.
67. Taybert J. Procreation in families with inborn error of metabolism--new challenges for medical care. Dev Period Med 2015; 19(4): 519-22.
68. Olpin SE. The metabolic investigation of sudden infant death. Ann Clin Biochem 2004; 41(Pt 4): 282-93.
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