Skip to main content
SpringerLink
Log in

The Investigation of Inherited Metabolic Disease After Death

  • Chapter
Essentials of Autopsy Practice

Abstract

The term “inborn errors of metabolism” was first used by Garrod in 1909 to define a spectrum of genetically inherited disorders characterised by blocks in the metabolic pathway due to deficient activity of an enzyme in each pathway1. Initially, he described just four disorders — alkaptonuria, albinism, cystinuria and pentosuria. As our knowledge of the human genome has expanded, there has been a vast increase in the number of diseases defined and which may now be diagnosed. It is beyond the scope of this chapter to deal with each of these disorders individually; instead, we hope to raise awareness of the possibility of an underlying metabolic disease and to provide a framework for appropriate investigation.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 16.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Garrod AE. Inborn errors of metabolism. Oxford: Oxford University Press, 1909.

    Google Scholar 

  2. Bennett MJ, Rinaldo P. The metabolic autopsy comes of age. Clin Chem 2001; 47(7):1145–6.

    PubMed  CAS  Google Scholar 

  3. Chace DH, DiPerna JC, Mitchell BL, Sgroi B, Hofman LF, Naylor EW. Electrospray tandem mass spectrometry for acylcarnitines in dried post-mortem blood specimens collected at autopsy from infants with unexplained cause of death. Clin Chem 2001;47(7):1166–82.

    PubMed  CAS  Google Scholar 

  4. Roe CR, Ding J. Mitochondrial fatty acid oxidation disorders. In: Scriver CR, Beaudet al, Sly WS, Valle D, editors. The metabolic and molecular basis of inherited disease, 8th Ed. New York: McGraw-Hill, 2000;2297–326.

    Google Scholar 

  5. Bennett MJ, Allison FA, Pollitt RJ, Variend S. Fatty acid oxidation defects as cause of sudden death in infancy. Prog Clin Biol Res 1990;321:349–64.

    PubMed  CAS  Google Scholar 

  6. Ruitenbeek W, Poelis PJ, Turnbull DM, Garavaglia B, Chalmers RA, Taylor RW, et al. Rhabdomyolysis and acute encephalopathy in late-onset medium-chain acyl-CoA dehydrogenase deficiency. J Neurol Neurosurg Psychiatry 1995;58(2):209–14.

    Article  PubMed  CAS  Google Scholar 

  7. Rinaldo P, Raymond K, Barnes CA. Medium-chain acyl-CoA dehydrogenase deficiency: Sudden and unexpected death of a 45-year-old woman. J Inher Metab Dis 1999;22:104.

    Google Scholar 

  8. Gregersen N, Blakemore A, Winter V, Andresen BS, Kolvraa S, Bolund L, et al. Specific diagnosis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in dried blood spots by a polymerase chain reaction (PCR) assay detecting a point mutation (G985) in the MCAD gene. Clin Chim Acta 1991;203:23–34.

    Article  PubMed  CAS  Google Scholar 

  9. Brivet M, Boutron A, Slama A, Costa C, Thuillier L, Demaugre F, et al. Defects in activation and transport of fatty acids. J Inher Metab Dis 1999; 22:428–41.

    Article  PubMed  CAS  Google Scholar 

  10. Wanders RJA, Vreken P, Den Boer MEJ, Wijburg FA, Van Gennip AH, Ijlst L. Disorders of mitochondrial fatty acid acyl-CoA (-oxidation. J Inher Metab Dis 1999;22:442–87.

    Article  PubMed  CAS  Google Scholar 

  11. Chalmers RA, Stanley CA, English N, Wigglesworth JS. Mitochondrial carnitine acylcarnitine translocase deficiency presenting as sudden neonatal death. J Pediatr 1997; 131:220–5.

    Article  PubMed  CAS  Google Scholar 

  12. Olpin SE, Allen JC, Bonham JR, Clark S, Clayton PT, Calvin J, et al. Features of CPTI deficiency. J Inher Metab Dis 2001;24:35–42.

    Article  PubMed  CAS  Google Scholar 

  13. Pollitt RJ, Olpin SE, Bonham JR, Cahalane SF, Naughten E. Late-presenting carnitine transport defect. Enzyme and Protein 1993;3:175.

    Google Scholar 

  14. De Vivo DC, Tein I. Primary and secondary disorders of carnitine metabolism. Internat Paediatr 1990;5:134–41.

    Google Scholar 

  15. Manning NJ, Olpin SE, Pollitt RJ, Webley J. A comparison of [9,10-3H]myristic and [9,10-3H]palmitic acids for the detection of fatty acid oxidation in intact cultured fibroblasts. J Inher Metab Dis 1990;13:58–68.

    Article  PubMed  CAS  Google Scholar 

  16. Olpin SE, Manning NJ, Pollitt RJ, Bonham JR, Downing M, Clark S. The use of [9,10-3H]myristate, [9,10-3H]palmitate and [9,10-3H]oleate for the detection and diagnosis of medium- and long-chain fatty acid oxidation disorders in intact cultured fibroblasts. In: Quant PA, Eaton S, editors. Current views of fatty acid oxidation and ketogenesis (Proceedings of the 4th International Symposium on Fatty Acid Oxidation) New York: Plenum Press. 1999.

    Google Scholar 

  17. Olpin SE, Manning NJ, Pollitt RJ, Bonham JR, Downing M, Clark S. Adv Exp Med Biol 1999;466:321–5.

    Article  PubMed  CAS  Google Scholar 

  18. Nada MA, Rhead WJ, Sprecher H, Schulz H, Roe CR Evidence for intermediate channelling in mitochondrial beta-oxidation. J Biol Chem 1995;270:530–5.

    Article  PubMed  CAS  Google Scholar 

  19. Roe CR, Roe DS. Recent developments in the investigation of inherited metabolic disorders using cultured human cells. Mol Genet Metab 1999;68(2):243–57.

    Article  PubMed  CAS  Google Scholar 

  20. Ijlst L, Ruiter JP, Hoovers JM, Jakobs ME, Wanders RJ. Common mis-sense mutation G1528C in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Characterisation and expression of the mutant protein, mutation analysis on genomic DNA and chromosomal localization of the mitochondrial trifunctional protein alpha subunit gene. J Clin Invest 1996;98:1028–33.

    Article  PubMed  CAS  Google Scholar 

  21. Munnich A, Rotig A, Cormier-Daire V, Rustin P. Clinical presentation of respiratory chain deficiency. In: Scriver CR, Beaudet al, Sly WS, Valle D, editors. The metabolic and molecular basis of inherited disease, 8th ed. New York: McGraw-Hill, 2000;2261–74.

    Google Scholar 

  22. Soussi B, Idstrom J, Schersten T, Bylund-Fellenius A. Cytochrome c oxidase and cardiolipin alterations in response to skeletal muscle ischaemia and reperfusion. Acta Physiol Scand 1990;138:481–7.

    Article  Google Scholar 

  23. Pitkanen S, Feigenbaum A, Laframboise R, Robinson BH. NADH-coenzyme Q reductase (complex I) deficiency: heterogeneity in phenotype and biochemical findings. J Inher Metab Dis 1996;19:675–86.

    Article  PubMed  CAS  Google Scholar 

  24. Robinson BH, Ward J, Goodyer P, Baudet A. Respiratory chain defects in the mitochondria of cultured fibroblasts from three patients with lacticacidaemia. J Clin Invest 1986;77:1422–7.

    Article  PubMed  CAS  Google Scholar 

  25. Robinson BH, De Meirlier L, Glerum P, Sherwood G, Becker L. Clinical presentation of mitochondrial respiratory chain defects in NADH-coenzyme Q reductase and cytochrome oxidase. Clues to pathogenesis of Leigh disease. J Pediatr 1987;110:216–22.

    Article  PubMed  CAS  Google Scholar 

  26. Robinson BH, Glerum DM, Chow W, Petrova-Benedict R, Lightowlers R, Capaldi R. The use of skin fibroblast cultures in the detection of respiratory chain defects in patients with lactic acidaemia. Pediatr Res 1990;28:549–55.

    Article  PubMed  CAS  Google Scholar 

  27. Van Erven PM, Ruiten W, Gabreels FM, Renier WO. Mitochondrial encephalopathy: association with an NADH dehydrogenase deficiency. Arch Neurol 1987;44:775–8.

    PubMed  Google Scholar 

  28. Robinson BH, Oei J, Sherwood WG, Applegarth D, Wong L, Haworth J, et al.. The molecular basis for the two different clinical presentations of classical pyruvate carboxylase deficiency. Am J Hum Genet 1984;36:283–94.

    PubMed  CAS  Google Scholar 

  29. Wanders RJA, Ruiter JPN, Wijburg GA. Studies on mitochondrial oxidative phosphorylation in permeabilised skin fibroblasts: application to mitochondrial encephalomyopathies. Biochim Biophys Acta 1993;181:219–22.

    Google Scholar 

  30. Fischer JC, Ruitenbeek W, Stadhouders AM, Trijbels JM, Sengers RC, Janssen AJ, et al. Investigations of mitochondrial metabolism in small human skeletal muscle biopsy specimens. Improvement of preparation procedure. Clin Chim Acta 1985;145:89–94.

    Article  PubMed  CAS  Google Scholar 

  31. Glerum M, Yanamura W, Capaldi R, Robinson BH. Characterisation of cytochrome oxidase mutations in human fibroblasts. FEBS Lett 1988;236:100–104.

    Article  PubMed  CAS  Google Scholar 

  32. Moreadith RW, Batshaw ML, Ohinishi T, Kerr D, Knox B, Jackson D, et al. Deficiency of ironsulphur clusters of mitochondrial reduced nicotinamide-adenine dineucleotide-ubiquinone oxidoreductase (complex I) in an infant with congenital lactic acidosis. J Clin Invest 1984;74:685–97.

    Article  PubMed  CAS  Google Scholar 

  33. Rustin P, Chretien D, Bourgeron T, Gerard B, Rotig A, Saudubray JM, et al. Biochemical and molecular investigations in respiratory chain deficiencies. Clin Chim Acta 1994;228:35–51.

    Article  PubMed  CAS  Google Scholar 

  34. Besley GT, Wraith JE. Lysosomal disorders Mini-symposium: Metabolic disease. Curr Paediatr 1997;7:128–34.

    Article  Google Scholar 

  35. Van Maldergem L, Jauniaux E, Fourneau C, Gillerot Y. Genetic causes of hydrops fetalis. Paediatrics 1992;89:81–6.

    Google Scholar 

  36. Poggi-Travert F, Fournier B, Poll-The BT, Saudubray J-M. Clinical approach to inherited peroxisomal disorders. In: Roels F, De Bie S, Schutgens RB, Besley GT, Eds. Diagnosis of human peroxisomal disorders — a handbook. 1995.

    Google Scholar 

  37. Poggi-Travert F, Fournier B, Poll-The BT, Saudubray J-M. J Inher Metab Dis 1995;18:1–18

    Article  PubMed  Google Scholar 

  38. Espeel M, Van Limbergen G. Immunocytochemical localisation of peroxisomal proteins in human liver and kidney. J Inher Metab Dis 1995;18:135–54.

    Article  PubMed  CAS  Google Scholar 

  39. Kerckaert I, De Craemer D, Van Limbergen G. Practical guide to morphometry of human per-oxisomes on electron micrographs. J Inher Metab Dis 1995;18:172–80.

    Article  PubMed  Google Scholar 

  40. Olpin SE, Manning NJ, Pollitt RJ, Clarke S. [9,10-3H]Oleic acid - for the improved detection of long-chain fatty acid oxidation defects in intact cells. J Inher Metab Dis 1997;20: 415–19.

    Article  PubMed  CAS  Google Scholar 

  41. Leonard JV, Morris AAM. Inborn errors of metabolism around the time of birth. Lancet 2000;356:583–7

    Article  PubMed  CAS  Google Scholar 

  42. Beckwith JB. Observations on the pathological anatomy of the sudden infant death syndrome. In: Bergman AB, Beckwith JB, Ray CG, editors. Sudden Infant Death Syndrome. Seattle: University of Washington Press, 1970:83–102.

    Google Scholar 

  43. Sinclair-Smith C, Dinsdale F, Emery J. Evidence of duration and type of illness in children found unexpectedly dead. Arch Dis Child 1976;51:424–8.

    Article  PubMed  CAS  Google Scholar 

  44. Saudubray J-M, Charpentier C. Clinical Phenotypes: Diagnosis/Algorithms. In: Scriver CR, Beaudet al, Sly WS, Valle D, editors. The metabolic and molecular basis of inherited disease, 8th ed. New York: McGraw-Hill, 2000; 1327–403.

    Google Scholar 

  45. Hoffman GF, Athanassopoulos S, Burlina AB, et al. Clinical course early diagnosis, treatment, and prevention of disease in glutaryl-CoA dehydrogenase deficiency. Neuropaediatrics 1996;27:115–23.

    Article  Google Scholar 

  46. Wilkins B. Head injury ’ abuse or accident? Arch Dis Child 1997;76:393–7.

    Article  PubMed  CAS  Google Scholar 

  47. Tsubata S, Bowles KR, Vatta M, Zintz C, Titus J, Muhonen L. Mutations in human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy. J Clin Invest 2000;106(5):655–62.

    Article  PubMed  CAS  Google Scholar 

  48. Peters TJ, Wells G, Oakley CM, Brooksby IA, Jenkins BS, Webb-Peploe MM, et al. Enzymatic analysis of endomyocardial biopsy specimens from patients with cardiomyopathies. Br Heart J 1997;39:1333.

    Article  Google Scholar 

  49. von Kleist-Retzow JC, Cormier-Daire V, de Lonlay P, Parfait B, Chretien D, Rustin P. A high rate of parental consanguinity (20–30%) in cytochrome oxidase deficiency. Am J Hum Genet 1998;63:428.

    Article  Google Scholar 

  50. Marin-Garcia J, Ananthakrishnan R, Goldenthal MJ, Pierpoint ME. Biochemical and molecular basis for mitochondrial cardiomyopathy in neonates and children. J Inher Metab Dis 2000;23: 625–33.

    Article  PubMed  CAS  Google Scholar 

  51. Gibert-Barness E. Cardiovascular system, Part II. In: Gibert-Barness E, editor, Potter’s pathology of the fetus and infant. St. Louis: Mosby Year Book, 1997.

    Google Scholar 

  52. Lamhonwah A-M, Olpin SE, Pollitt RJ, Vianey-Saban C, Divry P, Guffon N, Besley GTN, Onizuka R, De Meirleir LJ, Cvitanovic-Sojat L, Baric I, Dionisi-Vici C, Fumic K, Maradin M, Tein I. Lack of Genotype-phenotype correlation in eleven individuals with novel OCTN2 mutations: Early carnitine therapy prevents cardiomyopathy. Am J Med Genet 2002;111(3):271–84.

    Article  PubMed  Google Scholar 

  53. Adams PC, Strand RD, Bresnan MJ, Lucky AW. Kinky hair syndrome: serial study of radiological findings with emphasis on the similarity to the battered child syndrome. Paediatr Radiol 1974;56:117–18.

    Google Scholar 

  54. Okun JG, Kolker S, Schulze A, Kohlmuller D, Olgemoller K, Linder M, Hoffmann GF, Wanders RJA, Mayatepek E. A method for quantitative acylcarnitine profiling in human skin fibroblasts using unlabelled palmitic acid: diagnosis of fatty acid oxidation disorders and differentiation between biochemical phenotypes of MCAD deficiency. Biochim Acta 2002;1584:91–8.

    CAS  Google Scholar 

Download references

Authors
  1. S. E. Olpin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M.-J. Evans
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Division of Forensic Pathology, University of Leicester, Leicester, UK

    Guy Nathan Rutty MD, MB, BS, FRCPath, DipRCPath(Forensic) (Professor of Forensic Pathology and Head of Division, Consultant Home Office Pathologist) (Professor of Forensic Pathology and Head of Division, Consultant Home Office Pathologist)

Rights and permissions

Reprints and permissions

Copyright information

© 2004 Springer-Verlag London Limited

About this chapter

Cite this chapter

Olpin, S.E., Evans, MJ. (2004). The Investigation of Inherited Metabolic Disease After Death. In: Rutty, G.N. (eds) Essentials of Autopsy Practice. Springer, London. https://doi.org/10.1007/978-1-4471-0637-1_2

Download citation

  • DOI: https://doi.org/10.1007/978-1-4471-0637-1_2

  • Publisher Name: Springer, London

  • Print ISBN: 978-1-4471-1168-9

  • Online ISBN: 978-1-4471-0637-1

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation