Metabolic Autopsy and Molecular Autopsy in Sudden Unexpected Death in Infancy

  • Takuma YamamotoEmail author
  • Hajime Nishio
Part of the Current Human Cell Research and Applications book series (CHCRA)


Metabolic diseases are one of the main causes of sudden infant death, but definitive postmortem diagnosis is difficult, because metabolic diseases are functional and have fewer morphological abnormalities. Metabolic autopsy is a procedure that focuses on metabolic diseases, which includes the analysis of metabolic products or genetic analysis. However, it is not routinely performed, and only a small number of cases of sudden death with metabolic diseases have been reported in Japan. Furthermore conventional genetic analysis is “one gene, one exon at a time” and is therefore time-consuming and effort-intensive. Recently, next-generation sequencing methods have become available and can comprehensively screen numerous genes, making the technique practical for sudden death in the field of forensic science. In this chapter, we describe the basis of metabolic disease and discuss several case reports. Furthermore, we introduce a recent study into sudden unexpected death in infancy from the perspective of “functional autopsy.” Some causes of sudden infant death are inherited diseases, and accurate diagnosis, even postmortem, can prevent further tragedies among the remaining family.


Metabolic autopsy Sudden infant death Inherited disease Functional autopsy Preventable death 


  1. 1.
    Iino M, O’Donnell C. Postmortem computed tomography findings of upper airway obstruction by food. J Forensic Sci. 2010;55:1251–8.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Yamamoto T, Hayashi T, Murakami T, Hayashi H, Murase T, Abe Y, et al. Postmortem imaging identified pneumomediastinum in two cases of diabetic ketoacidosis. J Forensic Radiol Imaging. 2017;10:5–8.CrossRefGoogle Scholar
  3. 3.
    Bennett MJ, Rinaldo P. The metabolic autopsy comes of age. Clin Chem. 2001;47:1145–6.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Reye RD, Morgan G, Baral J. Encephalopathy and fatty degeneration of the viscera. A disease entity in childhood. Lancet. 1963;2:749–52.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Pugliese A, Beltramo T, Torre D. Reye’s and Reye’s-like syndromes. Cell Biochem Funct. 2008;26:741–6.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Howat AJ, Bennett MJ, Variend S, Shaw L. Deficiency of medium chain fatty acylcoenzyme A dehydrogenase presenting as the sudden infant death syndrome. Br Med J (Clin Res Ed). 1984;288:976.PubMedCentralCrossRefGoogle Scholar
  7. 7.
    Howat AJ, Bennett MJ, Variend S, Shaw L, Engel PC. Defects of metabolism of fatty acids in the sudden infant death syndrome. Br Med J (Clin Res Ed). 1985;290:1771–3.CrossRefGoogle Scholar
  8. 8.
    Bennett MJ, Powell S. Metabolic disease and sudden, unexpected death in infancy. Hum Pathol. 1994;25:742–6.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Cote A, Russo P, Michaud J. Sudden unexpected deaths in infancy: what are the causes? J Pediatr. 1999;135:437–43.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Loughrey CM, Preece MA, Green A. Sudden unexpected death in infancy (SUDI). J Clin Pathol. 2005;58:20–1.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Nagao M. Frequency of 985A-to-G mutation in medium-chain acyl-CoA dehydrogenase gene among patients with sudden infant death syndrome, Reye syndrome, severe motor and intellectual disabilities and healthy newborns in Japan. Acta Paediatr Jpn. 1996;38:304–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Sawaguchi T, Nishida H. Fatty liver in sudden infant death autopsies. Am J Forensic Med Pathol. 1998;19:294.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Ohashi Y, Hasegawa Y, Murayama K, Ogawa M, Hasegawa T, Kawai M, et al. A new diagnostic test for VLCAD deficiency using immunohistochemistry. Neurology. 2004;62:2209–13.PubMedCrossRefGoogle Scholar
  14. 14.
    Yamamoto T, Tanaka H, Kobayashi H, Okamura K, Tanaka T, Emoto Y, et al. Retrospective review of Japanese sudden unexpected death in infancy: the importance of metabolic autopsy and expanded newborn screening. Mol Genet Metab. 2011;102:399–406.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Yamamoto T, Emoto Y, Murayama K, Tanaka H, Kuriu Y, Ohtake A, et al. Metabolic autopsy with postmortem cultured fibroblasts in sudden unexpected death in infancy: diagnosis of mitochondrial respiratory chain disorders. Mol Genet Metab. 2012;106:474–7.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Yamamoto T, Tanaka H, Emoto Y, Umehara T, Fukahori Y, Kuriu Y, et al. Carnitine palmitoyltransferase 2 gene polymorphism is a genetic risk factor for sudden unexpected death in infancy. Brain Dev. 2014;36:479–83.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Yamamoto T, Mishima H, Mizukami H, Fukahori Y, Umehara T, Murase T, et al. Metabolic autopsy with next generation sequencing in sudden unexpected death in infancy: postmortem diagnosis of fatty acid oxidation disorders. Mol Genet Metab Rep. 2015;5:26–32.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Takahashi T, Yamada K, Kobayashi H, Hasegawa Y, Taketani T, Fukuda S, et al. Metabolic disease in 10 patients with sudden unexpected death in infancy or acute life-threatening events. Pediatr Int. 2015;57:348–53.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Takahashi T, Hasegawa Y, Yamada K, Bo R, Kobayashi H, Taketani T, et al. Metabolic survey of hidden inherited metabolic diseases in children with apparent life-threatening event (ALTE) or sudden unexpected death in infancy (SUDI) by analyses of organic acids and acylcarnitines using mass spectrometries. Shimane J Med Sci. 2016;32:61–8.Google Scholar
  20. 20.
    Oshima Y, Yamamoto T, Ishikawa T, Mishima H, Matsusue A, Umehara T, et al. Postmortem genetic analysis of sudden unexpected death in infancy: neonatal genetic screening may enable the prevention of sudden infant death. J Hum Genet. 2017;62:989–95.PubMedCrossRefGoogle Scholar
  21. 21.
    Semba S, Yasujima H, Takano T, Yokozaki H. Autopsy case of the neonatal form of carnitine palmitoyltransferase-II deficiency triggered by a novel disease-causing mutation del1737C. Pathol Int. 2008;58:436–41.PubMedCrossRefGoogle Scholar
  22. 22.
    Takahashi Y, Sano R, Nakajima T, Kominato Y, Kubo R, Takahashi K, et al. Combination of postmortem mass spectrometry imaging and genetic analysis reveals very long-chain acyl-CoA dehydrogenase deficiency in a case of infant death with liver steatosis. Forensic Sci Int. 2014;244:e34–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Takahashi Y, Sano R, Kominato Y, Kubo R, Takahashi K, Nakajima T, et al. A case of sudden unexpected infant death involving a homozygotic twin with the thermolabile CPT2 variant, accompanied by rotavirus infection and treatment with an antibiotic containing pivalic acid. Leg Med (Tokyo). 2016;22:13–7.CrossRefGoogle Scholar
  24. 24.
    Sinclair-Smith C, Dinsdale F, Emery J. Evidence of duration and type of illness in children found unexpectedly dead. Arch Dis Child. 1976;51:424–9.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Boles RG, Buck EA, Blitzer MG, Platt MS, Cowan TM, Martin SK, et al. Retrospective biochemical screening of fatty acid oxidation disorders in postmortem livers of 418 cases of sudden death in the first year of life. J Pediatr. 1998;132:924–33.PubMedCrossRefGoogle Scholar
  26. 26.
    Rinaldo P, Yoon HR, Yu C, Raymond K, Tiozzo C, Giordano G. Sudden and unexpected neonatal death: a protocol for the postmortem diagnosis of fatty acid oxidation disorders. Semin Perinatol. 1999;23:204–10.PubMedCrossRefGoogle Scholar
  27. 27.
    Yang Z, Lantz PE, Ibdah JA. Post-mortem analysis for two prevalent beta-oxidation mutations in sudden infant death. Pediatr Int. 2007;49:883–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Uchida K, Unuma K, Uemura K. A fatality in a child with severe fatty liver due to n-butane and isopentane poisoning resulting from long-term inhalation of an antiperspirant aerosol. Forensic Sci Med Pathol. 2015;11:631–2.PubMedCrossRefGoogle Scholar
  29. 29.
    Woolf AD, Wynshaw-Boris A, Rinaldo P, Levy HL. Intentional infantile ethylene glycol poisoning presenting as an inherited metabolic disorder. J Pediatr. 1992;120:421–4.PubMedCrossRefGoogle Scholar
  30. 30.
    Hoffman M. Scientific sleuths solve a murder mystery. Science. 1991;254:931.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Shoemaker JD, Lynch RE, Hoffmann JW, Sly WS. Misidentification of propionic acid as ethylene glycol in a patient with methylmalonic acidemia. J Pediatr. 1992;120:417–21.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    DiMauro S, DiMauro PM. Muscle carnitine palmityltransferase deficiency and myoglobinuria. Science. 1973;182:929–31.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Moczulski D, Majak I, Mamczur D. An overview of beta-oxidation disorders. Postepy Hig Med Dosw (Online). 2009;63:266–77.Google Scholar
  34. 34.
    Rinaldo P, Matern D, Bennett MJ. Fatty acid oxidation disorders. Annu Rev Physiol. 2002;64:477–502.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Tamaoki Y, Kimura M, Hasegawa Y, Iga M, Inoue M, Yamaguchi S. A survey of Japanese patients with mitochondrial fatty acid beta-oxidation and related disorders as detected from 1985 to 2000. Brain Dev. 2002;24:675–80.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Fukao T, Mitchell G, Sass JO, Hori T, Orii K, Aoyama Y. Ketone body metabolism and its defects. J Inherit Metab Dis. 2014;37:541–51.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Koizumi A, Nozaki J, Ohura T, Kayo T, Wada Y, Nezu J, et al. Genetic epidemiology of the carnitine transporter OCTN2 gene in a Japanese population and phenotypic characterization in Japanese pedigrees with primary systemic carnitine deficiency. Hum Mol Genet. 1999;8:2247–54.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Flanagan JL, Simmons PA, Vehige J, Willcox MD, Garrett Q. Role of carnitine in disease. Nutr Metab (Lond). 2010;7:30.CrossRefGoogle Scholar
  39. 39.
    Treem WR, Stanley CA, Finegold DN, Hale DE, Coates PM. Primary carnitine deficiency due to a failure of carnitine transport in kidney, muscle, and fibroblasts. N Engl J Med. 1988;319:1331–6.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Stanley CA. Carnitine deficiency disorders in children. Ann N Y Acad Sci. 2004;1033:42–51.PubMedCrossRefGoogle Scholar
  41. 41.
    Longo N, Amat di San Filippo C, Pasquali M. Disorders of carnitine transport and the carnitine cycle. Am J Med Genet C Semin Med Genet. 2006;142C:77–85.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Bougneres PF, Saudubray JM, Marsac C, Bernard O, Odievre M, Girard J. Fasting hypoglycemia resulting from hepatic carnitine palmitoyl transferase deficiency. J Pediatr. 1981;98:742–6.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Bonnefont JP, Djouadi F, Prip-Buus C, Gobin S, Munnich A, Bastin J. Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects. Mol Asp Med. 2004;25:495–520.CrossRefGoogle Scholar
  44. 44.
    Hug G, Soukup S, Berry H, Bove K. Carnitine palmityl transferase (CPT): deficiency of CPT II but not of CPT I with reduced total and free carnitine but increased acylcarnitine. Pediatr Res. 1989;25:115A.CrossRefGoogle Scholar
  45. 45.
    Hug G, Bove KE, Soukup S. Lethal neonatal multiorgan deficiency of carnitine palmitoyltransferase II. N Engl J Med. 1991;325:1862–4.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Zinn AB, Zurcher VL, Kraus F, Strohl C, Walsh-Sukys MC, Hoppel CL. Carnitine palmitoyltransferase B (CPT B) deficiency: a heritable cause of neonatal cardiomyopathy and dysgenesis of the kidney. Pediatr Res. 1991;29:73A.Google Scholar
  47. 47.
    Demaugre F, Bonnefont JP, Colonna M, Cepanec C, Leroux JP, Saudubray JM. Infantile form of carnitine palmitoyltransferase II deficiency with hepatomuscular symptoms and sudden death. Physiopathological approach to carnitine palmitoyltransferase II deficiencies. J Clin Invest. 1991;87:859–64.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Bonnefont JP, Demaugre F, Prip-Buus C, Saudubray JM, Brivet M, Abadi N, et al. Carnitine palmitoyltransferase deficiencies. Mol Genet Metab. 1999;68:424–40.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Sigauke E, Rakheja D, Kitson K, Bennett MJ. Carnitine palmitoyltransferase II deficiency: a clinical, biochemical, and molecular review. Lab Investig. 2003;83:1543–54.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Stanley CA, Hale DE, Berry GT, Deleeuw S, Boxer J, Bonnefont JP. Brief report: a deficiency of carnitine-acylcarnitine translocase in the inner mitochondrial membrane. N Engl J Med. 1992;327:19–23.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Rubio-Gozalbo ME, Bakker JA, Waterham HR, Wanders RJ. Carnitine-acylcarnitine translocase deficiency, clinical, biochemical and genetic aspects. Mol Asp Med. 2004;25:521–32.CrossRefGoogle Scholar
  52. 52.
    Aoyama T, Uchida Y, Kelley RI, Marble M, Hofman K, Tonsgard JH, et al. A novel disease with deficiency of mitochondrial very-long-chain acyl-CoA dehydrogenase. Biochem Biophys Res Commun. 1993;191:1369–72.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Bertrand C, Largilliere C, Zabot MT, Mathieu M, Vianey-Saban C. Very long chain acyl-CoA dehydrogenase deficiency: identification of a new inborn error of mitochondrial fatty acid oxidation in fibroblasts. Biochim Biophys Acta. 1993;1180:327–9.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Yamaguchi S, Indo Y, Coates PM, Hashimoto T, Tanaka K. Identification of very-long-chain acyl-CoA dehydrogenase deficiency in three patients previously diagnosed with long-chain acyl-CoA dehydrogenase deficiency. Pediatr Res. 1993;34:111–3.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Andresen BS, Olpin S, Poorthuis BJ, Scholte HR, Vianey-Saban C, Wanders R, et al. Clear correlation of genotype with disease phenotype in very-long-chain acyl-CoA dehydrogenase deficiency. Am J Hum Genet. 1999;64:479–94.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Carpenter K, Pollitt RJ, Middleton B. Human liver long-chain 3-hydroxyacyl-coenzyme A dehydrogenase is a multifunctional membrane-bound beta-oxidation enzyme of mitochondria. Biochem Biophys Res Commun. 1992;183:443–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Uchida Y, Izai K, Orii T, Hashimoto T. Novel fatty acid beta-oxidation enzymes in rat liver mitochondria. II. Purification and properties of enoyl-coenzyme A (CoA) hydratase/3-hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase trifunctional protein. J Biol Chem. 1992;267:1034–41.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Ushikubo S, Aoyama T, Kamijo T, Wanders RJ, Rinaldo P, Vockley J, et al. Molecular characterization of mitochondrial trifunctional protein deficiency: formation of the enzyme complex is important for stabilization of both alpha- and beta-subunits. Am J Hum Genet. 1996;58:979–88.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Orii KE, Aoyama T, Wakui K, Fukushima Y, Miyajima H, Yamaguchi S, et al. Genomic and mutational analysis of the mitochondrial trifunctional protein beta-subunit (HADHB) gene in patients with trifunctional protein deficiency. Hum Mol Genet. 1997;6:1215–24.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Tyni T, Pihko H. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Acta Paediatr. 1999;88:237–45.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Wanders RJ, Duran M, Ijlst L, de Jager JP, van Gennip AH, Jakobs C, et al. Sudden infant death and long-chain 3-hydroxyacyl-CoA dehydrogenase. Lancet. 1989;2:52–3.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Wanders RJ, IJlst L, van Gennip AH, Jakobs C, de Jager JP, Dorland L, et al. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of a new inborn error of mitochondrial fatty acid beta-oxidation. J Inherit Metab Dis. 1990;13:311–4.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Wanders RJ, IJlst L, Poggi F, Bonnefont JP, Munnich A, Brivet M, et al. Human trifunctional protein deficiency: a new disorder of mitochondrial fatty acid beta-oxidation. Biochem Biophys Res Commun. 1992;188:1139–45.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Jackson S, Kler RS, Bartlett K, Briggs H, Bindoff LA, Pourfarzam M, et al. Combined enzyme defect of mitochondrial fatty acid oxidation. J Clin Invest. 1992;90:1219–25.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Das AM, Illsinger S, Lucke T, Hartmann H, Ruiter JP, Steuerwald U, et al. Isolated mitochondrial long-chain ketoacyl-CoA thiolase deficiency resulting from mutations in the HADHB gene. Clin Chem. 2006;52:530–4.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    den Boer ME, Wanders RJ, Morris AA, IJlst L, Heymans HS, Wijburg FA. Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: clinical presentation and follow-up of 50 patients. Pediatrics. 2002;109:99–104.CrossRefGoogle Scholar
  67. 67.
    Gregersen N, Lauritzen R, Rasmussen K. Suberylglycine excretion in the urine from a patient with dicarboxylic aciduria. Clin Chim Acta. 1976;70:417–25.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Gregersen N, Wintzensen H, Christensen SK, Christensen MF, Brandt NJ, Rasmussen K. C6-C10-dicarboxylic aciduria: investigations of a patient with riboflavin responsive multiple acyl-CoA dehydrogenation defects. Pediatr Res. 1982;16:861–8.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Grosse SD, Khoury MJ, Greene CL, Crider KS, Pollitt RJ. The epidemiology of medium chain acyl-CoA dehydrogenase deficiency: an update. Genet Med. 2006;8:205–12.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Przyrembel H, Wendel U, Becker K, Bremer HJ, Bruinvis L, Ketting D, et al. Glutaric aciduria type II: report on a previously undescribed metabolic disorder. Clin Chim Acta. 1976;66:227–39.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Olsen RK, Andresen BS, Christensen E, Bross P, Skovby F, Gregersen N. Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency. Hum Mutat. 2003;22:12–23.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Yotsumoto Y, Hasegawa Y, Fukuda S, Kobayashi H, Endo M, Fukao T, et al. Clinical and molecular investigations of Japanese cases of glutaric acidemia type 2. Mol Genet Metab. 2008;94:61–7.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Angle B, Burton BK. Risk of sudden death and acute life-threatening events in patients with glutaric acidemia type II. Mol Genet Metab. 2008;93:36–9.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Faull K, Bolton P, Halpern B, Hammond J, Danks DM, Hahnel R, et al. Letter: patient with defect in leucine metabolism. N Engl J Med. 1976;294:1013.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Faull KF, Bolton PD, Halpern B, Hammond J, Danks DM. The urinary organic acid profile associated with 3-hydroxy-3-methylglutaric aciduria. Clin Chim Acta. 1976;73:553–9.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Pie J, Lopez-Vinas E, Puisac B, Menao S, Pie A, Casale C, et al. Molecular genetics of HMG-CoA lyase deficiency. Mol Genet Metab. 2007;92:198–209.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Daum RS, Lamm PH, Mamer OA, Scriver CR. A “new” disorder of isoleucine catabolism. Lancet. 1971;2:1289–90.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Fukao T, Scriver CR, Kondo N. The clinical phenotype and outcome of mitochondrial acetoacetyl-CoA thiolase deficiency (beta-ketothiolase or T2 deficiency) in 26 enzymatically proved and mutation-defined patients. Mol Genet Metab. 2001;72:109–14.PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Shigematsu Y, Hata I, Kikawa Y, Mayumi M, Tanaka Y, Sudo M, et al. Modifications in electrospray tandem mass spectrometry for a neonatal-screening pilot study in Japan. J Chromatogr B Biomed Sci Appl. 1999;731:97–103.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Sarafoglou K, Matern D, Redlinger-Grosse K, Bentler K, Gaviglio A, Harding CO, et al. Siblings with mitochondrial acetoacetyl-CoA thiolase deficiency not identified by newborn screening. Pediatrics. 2011;128:e246–50.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Edmondson AC, Salant J, Ierardi-Curto LA, Ficicioglu C. Missed newborn screening case of carnitine Palmitoyltransferase-II deficiency. JIMD Rep. 2017;33:93–7.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Yasuno T, Kaneoka H, Tokuyasu T, Aoki J, Yoshida S, Takayanagi M, et al. Mutations of carnitine palmitoyltransferase II (CPT II) in Japanese patients with CPT II deficiency. Clin Genet. 2008;73:496–501.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Ackerman MJ, Siu BL, Sturner WQ, Tester DJ, Valdivia CR, Makielski JC, et al. Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome. JAMA. 2001;286:2264–9.PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Kijima K, Sasaki A, Niki T, Umetsu K, Osawa M, Matoba R, et al. Sudden infant death syndrome is not associated with the mutation of PHOX2B gene, a major causative gene of congenital central hypoventilation syndrome. Tohoku J Exp Med. 2004;203:65–8.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Nishio H, Iwata M, Suzuki K. Postmortem molecular screening for cardiac ryanodine receptor type 2 mutations in sudden unexplained death: R420W mutated case with characteristics of status thymico-lymphatics. Circ J. 2006;70:1402–6.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Ameno K, Ameno S, Kinoshita H, Jamal M, Wang W, Kumihashi M, et al. Autopsy and postmortem examination case study on genetic risk factors for cardiac death: polymorphisms of endothelial nitric oxide synthase gene Glu298Asp variant and T-786C mutation, human paraoxonase 1 (PON1) gene and alpha2beta-adrenergic receptor gene. Vojnosanit Pregl. 2006;63:357–61. discussion 362.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Otagiri T, Kijima K, Osawa M, Ishii K, Makita N, Matoba R, et al. Cardiac ion channel gene mutations in sudden infant death syndrome. Pediatr Res. 2008;64:482–7.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Nishio H, Iwata M, Tamura A, Miyazaki T, Tsuboi K, Suzuki K. Identification of a novel mutation V2321M of the cardiac ryanodine receptor gene of sudden unexplained death and a phenotypic study of the gene mutations. Leg Med (Tokyo). 2008;10:196–200.CrossRefGoogle Scholar
  89. 89.
    Nakatome M, Yamamoto T, Isobe I, Matoba R. Diplotype analysis of the human cardiac sodium channel regulatory region in Japanese cases of sudden death by unknown causes. Leg Med (Tokyo). 2009;11:298–301.CrossRefGoogle Scholar
  90. 90.
    Nishio H, Kuwahara M, Tsubone H, Koda Y, Sato T, Fukunishi S, et al. Identification of an ethnic-specific variant (V207M) of the KCNQ1 cardiac potassium channel gene in sudden unexplained death and implications from a knock-in mouse model. Int J Legal Med. 2009;123:253–7.PubMedCrossRefGoogle Scholar
  91. 91.
    Osawa M, Kimura R, Hasegawa I, Mukasa N, Satoh F. SNP association and sequence analysis of the NOS1AP gene in SIDS. Leg Med (Tokyo). 2009;11:S307–8.CrossRefGoogle Scholar
  92. 92.
    Murakami C, Nakamura S, Kobayashi M, Maeda K, Irie W, Wada B, et al. Analysis of the sarcomere protein gene mutation on cardiomyopathy—mutations in the cardiac troponin I gene. Leg Med (Tokyo). 2010;12:280–3.CrossRefGoogle Scholar
  93. 93.
    Sato T, Nishio H, Suzuki K. Sudden death during exercise in a juvenile with arrhythmogenic right ventricular cardiomyopathy and desmoglein-2 gene substitution: a case report. Leg Med (Tokyo). 2011;13:298–300.CrossRefGoogle Scholar
  94. 94.
    Matsusue A, Kashiwagi M, Hara K, Waters B, Sugimura T, Kubo S. An autopsy case of sudden unexpected nocturnal death syndrome with R1193Q polymorphism in the SCN5A gene. Leg Med (Tokyo). 2012;14:317–9.CrossRefGoogle Scholar
  95. 95.
    Kamei S, Sato N, Harayama Y, Nunotani M, Takatsu K, Shiozaki T, et al. Molecular analysis of potassium ion channel genes in sudden death cases among patients administered psychotropic drug therapy: are polymorphisms in LQT genes a potential risk factor? J Hum Genet. 2014;59:95–9.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Hata Y, Mori H, Tanaka A, Fujita Y, Shimomura T, Tabata T, et al. Identification and characterization of a novel genetic mutation with prolonged QT syndrome in an unexplained postoperative death. Int J Legal Med. 2014;128:105–15.PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Sato T, Nishio H, Suzuki K. Identification of arrhythmogenic right ventricular cardiomyopathy-causing gene mutations in young sudden unexpected death autopsy cases. J Forensic Sci. 2015;60:457–61.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Loporcaro CG, Tester DJ, Maleszewski JJ, Kruisselbrink T, Ackerman MJ. Confirmation of cause and manner of death via a comprehensive cardiac autopsy including whole exome next-generation sequencing. Arch Pathol Lab Med. 2014;138:1083–9.PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Bagnall RD, Das KJ, Duflou J, Semsarian C. Exome analysis-based molecular autopsy in cases of sudden unexplained death in the young. Heart Rhythm. 2014;11:655–62.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Narula N, Tester DJ, Paulmichl A, Maleszewski JJ, Ackerman MJ. Post-mortem whole exome sequencing with gene-specific analysis for autopsy-negative sudden unexplained death in the young: a case series. Pediatr Cardiol. 2015;36:768–78.PubMedCrossRefGoogle Scholar
  101. 101.
    Hata Y, Kinoshita K, Mizumaki K, Yamaguchi Y, Hirono K, Ichida F, et al. Postmortem genetic analysis of sudden unexplained death syndrome under 50 years of age: a next-generation sequencing study. Heart Rhythm. 2016;13:1544–51.PubMedCrossRefGoogle Scholar
  102. 102.
    Hata Y, Yoshida K, Kinoshita K, Nishida N. Epilepsy-related sudden unexpected death: targeted molecular analysis of inherited heart disease genes using next-generation DNA sequencing. Brain Pathol. 2017;27:292–304.PubMedCrossRefGoogle Scholar
  103. 103.
    Hata Y, Kinoshita K, Nishida N. An autopsy case of sudden unexpected death of a young adult in a hot bath: molecular analysis using next-generation DNA sequencing. Clin Med Insights Case Rep. 2017;10:1179547617702884.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Schwartz PJ, Stramba-Badiale M, Crotti L, Pedrazzini M, Besana A, Bosi G, et al. Prevalence of the congenital long-QT syndrome. Circulation. 2009;120:1761–7.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Yoshinaga M, Ushinohama H, Sato S, Tauchi N, Horigome H, Takahashi H, et al. Electrocardiographic screening of 1-month-old infants for identifying prolonged QT intervals. Circ Arrhythm Electrophysiol. 2013;6:932–8.PubMedCrossRefGoogle Scholar
  106. 106.
    Narita N, Narita M, Takashima S, Nakayama M, Nagai T, Okado N. Serotonin transporter gene variation is a risk factor for sudden infant death syndrome in the Japanese population. Pediatrics. 2001;107:690–2.PubMedCrossRefGoogle Scholar
  107. 107.
    Moon RY, Horne RS, Hauck FR. Sudden infant death syndrome. Lancet. 2007;370:1578–87.PubMedCrossRefGoogle Scholar
  108. 108.
    Guntheroth WG, Spiers PS. The triple risk hypotheses in sudden infant death syndrome. Pediatrics. 2002;110:e64.PubMedCrossRefGoogle Scholar
  109. 109.
    Van Norstrand DW, Ackerman MJ. Genomic risk factors in sudden infant death syndrome. Genome Med. 2010;2:86.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Brown NF, Mullur RS, Subramanian I, Esser V, Bennett MJ, Saudubray JM, et al. Molecular characterization of L-CPT I deficiency in six patients: insights into function of the native enzyme. J Lipid Res. 2001;42:1134–42.PubMedPubMedCentralGoogle Scholar
  111. 111.
    Gessner BD, Gillingham MB, Birch S, Wood T, Koeller DM. Evidence for an association between infant mortality and a carnitine palmitoyltransferase 1A genetic variant. Pediatrics. 2010;126:945–51.PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Sinclair GB, Collins S, Popescu O, McFadden D, Arbour L, Vallance HD. Carnitine palmitoyltransferase I and sudden unexpected infant death in British Columbia First Nations. Pediatrics. 2012;130:e1162–9.PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Collins SA, Surmala P, Osborne G, Greenberg C, Bathory LW, Edmunds-Potvin S, et al. Causes and risk factors for infant mortality in Nunavut, Canada 1999-2011. BMC Pediatr. 2012;12:190.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Chen Y, Mizuguchi H, Yao D, Ide M, Kuroda Y, Shigematsu Y, et al. Thermolabile phenotype of carnitine palmitoyltransferase II variations as a predisposing factor for influenza-associated encephalopathy. FEBS Lett. 2005;579:2040–4.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Yao D, Mizuguchi H, Yamaguchi M, Yamada H, Chida J, Shikata K, et al. Thermal instability of compound variants of carnitine palmitoyltransferase II and impaired mitochondrial fuel utilization in influenza-associated encephalopathy. Hum Mutat. 2008;29:718–27.PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Kubota M, Chida J, Hoshino H, Ozawa H, Koide A, Kashii H, et al. Thermolabile CPT II variants and low blood ATP levels are closely related to severity of acute encephalopathy in Japanese children. Brain Dev. 2012;34:20–7.PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Shinohara M, Saitoh M, Takanashi J, Yamanouchi H, Kubota M, Goto T, et al. Carnitine palmitoyl transferase II polymorphism is associated with multiple syndromes of acute encephalopathy with various infectious diseases. Brain Dev. 2011;33:512–7.PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Plant LD, Bowers PN, Liu Q, Morgan T, Zhang T, State MW, et al. A common cardiac sodium channel variant associated with sudden infant death in African Americans, SCN5A S1103Y. J Clin Invest. 2006;116:430–5.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Van Norstrand DW, Tester DJ, Ackerman MJ. Overrepresentation of the proarrhythmic, sudden death predisposing sodium channel polymorphism S1103Y in a population-based cohort of African-American sudden infant death syndrome. Heart Rhythm. 2008;5:712–5.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Kubota T, Horie M, Takano M, Yoshida H, Takenaka K, Watanabe E, et al. Evidence for a single nucleotide polymorphism in the KCNQ1 potassium channel that underlies susceptibility to life-threatening arrhythmias. J Cardiovasc Electrophysiol. 2001;12:1223–9.PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Yamaguchi Y, Nishide K, Kato M, Hata Y, Mizumaki K, Kinoshita K, et al. Glycine/serine polymorphism at position 38 influences KCNE1 subunit’s modulatory actions on rapid and slow delayed rectifier K+ currents. Circ J. 2014;78:610–8.PubMedCrossRefPubMedCentralGoogle Scholar
  122. 122.
    Akyol M, Jalilzadeh S, Sinner MF, Perz S, Beckmann BM, Gieger C, et al. The common non-synonymous variant G38S of the KCNE1-(minK)-gene is not associated to QT interval in Central European Caucasians: results from the KORA study. Eur Heart J. 2007;28:305–9.PubMedCrossRefPubMedCentralGoogle Scholar
  123. 123.
    Ozawa T, Ito M, Tamaki S, Yao T, Ashihara T, Kita Y, et al. Gender and age effects on ventricular repolarization abnormality in Japanese general carriers of a G643S common single nucleotide polymorphism for the KCNQ1 gene. Circ J. 2006;70:645–50.PubMedCrossRefPubMedCentralGoogle Scholar
  124. 124.
    Laitinen P, Fodstad H, Piippo K, Swan H, Toivonen L, Viitasalo M, et al. Survey of the coding region of the HERG gene in long QT syndrome reveals six novel mutations and an amino acid polymorphism with possible phenotypic effects. Hum Mutat. 2000;15:580–1.PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Scherer CR, Lerche C, Decher N, Dennis AT, Maier P, Ficker E, et al. The antihistamine fexofenadine does not affect I(Kr) currents in a case report of drug-induced cardiac arrhythmia. Br J Pharmacol. 2002;137:892–900.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Crotti L, Lundquist AL, Insolia R, Pedrazzini M, Ferrandi C, De Ferrari GM, et al. KCNH2-K897T is a genetic modifier of latent congenital long-QT syndrome. Circulation. 2005;112:1251–8.PubMedCrossRefPubMedCentralGoogle Scholar
  127. 127.
    Nof E, Cordeiro JM, Perez GJ, Scornik FS, Calloe K, Love B, et al. A common single nucleotide polymorphism can exacerbate long-QT type 2 syndrome leading to sudden infant death. Circ Cardiovasc Genet. 2010;3:199–206.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Wang Q, Chen S, Chen Q, Wan X, Shen J, Hoeltge GA, et al. The common SCN5A mutation R1193Q causes LQTS-type electrophysiological alterations of the cardiac sodium channel. J Med Genet. 2004;41:e66.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Yamamoto T, Matsusue A, Umehara T, Kubo S, Ikematsu K, et al. No association between cardiac ion channel variants and sudden infant death. Pediatr Int. 2018;60(5):483–4.PubMedCrossRefPubMedCentralGoogle Scholar

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© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Department of Legal MedicineHyogo College of MedicineNishinomiyaJapan

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