Journal of Inherited Metabolic Disease

, Volume 37, Issue 6, pp 889–898 | Cite as

Systematic review and meta-analysis to estimate the birth prevalence of five inherited metabolic diseases

  • Sowmiya MoorthieEmail author
  • Louise Cameron
  • Gurdeep S. Sagoo
  • Jim R. Bonham
  • Hilary Burton
Original Article


Many newborn screening programmes now use tandem mass spectrometry in order to screen for a variety of diseases. However, countries have embraced this technology with a differing pace of change and for different conditions. This has been facilitated by the ability of this diagnostic method to limit analysis to specific metabolites of interest, enabling targeted screening for particular conditions. MS/MS was introduced in 2009 in England to implement newborn bloodspot screening for medium chain acyl-CoA dehydrogenase deficiency (MCADD) raising the possibility of screening for other inherited metabolic disorders. Recently, a pilot screening programme was conducted in order to evaluate the health and economic consequences of screening for five additional inherited metabolic disorders in England. As part of this study we conducted a systematic review and meta-analysis to estimate the birth prevalence of these conditions: maple syrup urine disease, homocystinuria (pyridoxine unresponsive), glutaric aciduria type I, isovaleric acidaemia and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency including trifunctional protein deficiency. We identified a total of 99 studies that were able to provide information on the prevalence of one or more of the disorders. The vast majority of studies were of screening programmes with some reporting on clinically detected cases.


Newborn Screening Western Population Congenital Hypothyroidism Homocystinuria Maple Syrup Urine Disease 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Glutaric aciduria type 1




Health technology assessment


Inherited metabolic disease


Isovaleric acidaemia


Long chain 3-hydroxy acyl-CoA dehydrogenase deficiency


Medium chain acyl-CoA dehydrogenase deficiency


Tandem mass spectrometry


Maple syrup urine disease



The authors would like to acknowledge with thanks the laboratories who contributed data for this report.

Conflict of interest

Sowmiya Moorthie Louise Cameron, Gurdeep S Sagoo, Jim Bonham and Hilary Burton declare they have no conflict of interest.

This article does not contain any studies with human or animal subjects performed by any of the authors.


This review was funded by the National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care for South Yorkshire (NIHR CLAHRC SY).

Supplementary material

10545_2014_9729_MOESM1_ESM.docx (62 kb)
ESM 1 (DOCX 61.7 kb)


  1. Abdel-Hamid M, Tisocki K, Sharaf L, Ramadan D (2007) Development, validation and application of tandem mass spectrometry for screening of inborn metabolic disorders in Kuwaiti infants. Med Princ and Pract 16(3):215–221CrossRefGoogle Scholar
  2. Abdenur J, Chamoles N, Schenone A, Guinle A, Fusta M, Gagglioli D (2000) Supplemental newborn screening of amino acids (AA) and acylcarnitines (AC) by electrospray tandem mass spectrometry (ESI-MS/MS): experiences in Argentina. J Inherit Metab Dis 23(1):13Google Scholar
  3. Abdul-Rahman S, Mohd YZ, Yew SC, Omar A, Othman NA, Shaharudin AS (2007) Pilot project on neonatal screening of inborn errors of metabolism (IEM) using tandem mass spectrometry in Malaysia. J Inherit Metab Dis 30:4–4Google Scholar
  4. AECNE (2012) Programas de cribado neonatal en España (2001-2011) Retrieved from: (May 2013). Programas de cribado neonatal en España (2001–2011) Google Scholar
  5. Aoki K (2003) Long term follow-up of patients with inborn errors of metabolism detected by the newborn screening program in Japan. Southeast Asian J Trop Med Public Health 34(Suppl 3):19–23PubMedGoogle Scholar
  6. Applegarth DA, Toone JR, Lowry RB (2000) Incidence of inborn errors of metabolism in British Columbia, 1969–1996. Pediatrics 105(1):e10PubMedCrossRefGoogle Scholar
  7. Banta-Wright SA, Steiner RD (2004) Tandem mass spectrometry in newborn screening: a primer for neonatal and perinatal nurses. J Perinatal Neonatal Nurs 18(1):41–58, quiz 59–60CrossRefGoogle Scholar
  8. Chace DH, Kalas TA, Naylor EW (2002) The application of tandem mass spectrometry to neonatal screening for inherited disorders of intermediary metabolism. Annu Rev Genomics Hum Genet 3:17–45PubMedCrossRefGoogle Scholar
  9. Comeau AM, Larson C, Eaton RB (2004) Integration of new genetic diseases into statewide newborn screening: New England experience. Am J of Med Genet Part C-Sem in Med Genet 125C(1):35–41CrossRefGoogle Scholar
  10. El-Said MF, Badii R, Bessisso MS et al (2006) A common mutation in the CBS gene explains a high incidence of homocystinuria in the Qatari population. Hum Mutat 27(7):719PubMedCrossRefGoogle Scholar
  11. Frazier D, Millington D, McCandless S et al (2006) The tandem mass spectrometry newborn screening experience in North Carolina: 1997–2005. J Inherit Metab Dis 29(1):76–85PubMedCrossRefGoogle Scholar
  12. Gan-Schreier H, Kebbewar M, Fang-Hoffmann J et al (2010) Newborn population screening for classic homocystinuria by determination of total homocysteine from Guthrie cards. J Pediatr 156(3):427–433PubMedCrossRefGoogle Scholar
  13. Hoffmann GF, von KR, Klose D et al (2004) Frequencies of inherited organic acidurias and disorders of mitochondrial fatty acid transport and oxidation in Germany. Eur J Pediatr 163(2):76–80PubMedCrossRefGoogle Scholar
  14. Khneisser I, Adib SM, Megarbane A, Lukacs Z (2008) International cooperation in the expansion of a newborn screening programme in Lebanon: a possible model for other programmes. J Inherit Metab Dis 31(Suppl 2):S441–S446PubMedCrossRefGoogle Scholar
  15. Kolker S, Garbade SF, Boy N et al (2007) Decline of acute encephalopathic crises in children with glutaryl-CoA dehydrogenase deficiency identified by newborn screening in Germany. Pediatr Res 62(3):357–363PubMedCrossRefGoogle Scholar
  16. Kolker S, Christensen E, Leonard JV et al (2011) Diagnosis and management of glutaric aciduria type I–revised recommendations. J Inherit Metab Dis 34(3):677–694PubMedCrossRefPubMedCentralGoogle Scholar
  17. Kyllerman M, Skjeldal OH, Lundberg M et al (1994) Dystonia and dyskinesia in glutaric aciduria type I: clinical heterogeneity and therapeutic considerations. Mov Disord 9(1):22–30PubMedCrossRefGoogle Scholar
  18. a Marca G, Malvagia S, Casetta B, Pasquini E, Donati MA, Zammarchi E (2008) Progress in expanded newborn screening for metabolic conditions by LC-MS/MS in Tuscany: update on methods to reduce false tests. J Inherit Metab Dis 31:S395–S404Google Scholar
  19. Lindner M, Abdoh G, Fang-Hoffmann J et al (2007) Implementation of extended neonatal screening and a metabolic unit in the state of Qatar: developing and optimizing strategies in cooperation with the neonatal screening center in Heidelberg. J Inherit Metab Dis 30(4):522–529PubMedCrossRefGoogle Scholar
  20. Loukas YL, Soumelas GS, Dotsikas Y et al (2010) Expanded newborn screening in Greece: 30 months of experience. J InheritMetab Dis 33(Suppl 3):341–348CrossRefGoogle Scholar
  21. Lund AM, Hougaard DM, Simonsen H et al (2012) Biochemical screening of 504,049 newborns in Denmark, the Faroe islands and Greenland - experience and development of a routine program for expanded newborn screening. Mol Genet Metab 107(3):281–293PubMedCrossRefGoogle Scholar
  22. Millington DS, Kodo N, Norwood DL, Roe CR (1990) Tandem mass spectrometry: a new method for acylcarnitine profiling with potential for neonatal screening for inborn errors of metabolism. J Inherit Metab Dis 13(3):321–324PubMedCrossRefGoogle Scholar
  23. Moammar H, Cheriyan G, Mathew R, Al-Sannaa N (2010) Incidence and patterns of inborn errors of metabolism in the Eastern Province of Saudi Arabia, 1983-2008. Ann Saudi Med 30(4):271–277PubMedCrossRefPubMedCentralGoogle Scholar
  24. Nennstiel-Ratzel U, Luders A, Blankenstein O, et al (2010) Deutsche Gesellschaft fur neugeborenenscreening E.V. National Screening Report Germany: years 2004–2007; 2008; 2009; 2010. Retrieved from Date accessed 10.07.13.
  25. Niu DM, Chien YH, Chiang CC et al (2010) Nationwide survey of extended newborn screening by tandem mass spectrometry in Taiwan. J Inherit Metab Dis 33(Suppl 2):S295–S305PubMedCrossRefGoogle Scholar
  26. NNSGRC (2013) National newborn screening and global resource center: US newborn screening programme (1991–2000 cumulative; and 2001, 2002, 2003, 2004, 2005, 2006) Retrieved from: (May 2013Google Scholar
  27. Pandor A, Eastham J, Beverley C, Chilcott J, Paisley S (2004) Clinical effectiveness and cost-effectiveness of neonatal screening for inborn errors of metabolism using tandem mass spectrometry: a systematic review. Health Technology Assessment 8(12): iii-NaNGoogle Scholar
  28. Quental S, Vilarinho L, Martins E et al (2010) Incidence of maple syrup urine disease in Portugal. Mol Genet Metab 100(4):385–387PubMedCrossRefGoogle Scholar
  29. Rashed MS, Rahbeeni Z, Ozand PT (1999) Application of electrospray tandem mass spectrometry to neonatal screening. Semin Perinatol 23(2):183–193PubMedCrossRefGoogle Scholar
  30. Sahai I, Zytkowicz T, Rao KS, Lakshmi KA, Eaton RB, Akella RR (2011) Neonatal screening for inborn errors of metabolism using tandem mass spectrometry: experience of the pilot study in Andhra Pradesh, India. Indian J Pediatr 78(8):953–960PubMedCrossRefGoogle Scholar
  31. Sander J, Sander S, Steuerwald U et al (2005) Neonatal screening for defects of the mitochondrial trifunctional protein. Mol Genet Metab 85(2):108–114PubMedCrossRefGoogle Scholar
  32. Tiwana SK, Rascati KL, Park H (2012) Cost-effectiveness of expanded newborn screening in Texas (Provisional abstract). Value Health 15:613–621PubMedCrossRefGoogle Scholar
  33. Wilcken B, Wiley V, Hammond J, Carpenter K (2003) Screening newborns for inborn errors of metabolism by tandem mass spectrometry. N Engl J Med 348(23):2304–2312PubMedCrossRefGoogle Scholar
  34. Wilcken B, Haas M, Joy P et al (2009) Expanded newborn screening: outcome in screened and unscreened patients at age 6 years. Pediatrics 124(2):e241–e248PubMedCrossRefGoogle Scholar
  35. Williams JG, Higgins JP, Brayne CE (2006) Systematic review of prevalence studies of autism spectrum disorders. Arch Dis Child 91(1):8–15PubMedCrossRefPubMedCentralGoogle Scholar
  36. Wilson C, Kerruish NJ, Wilcken B, Wiltshire E, Webster D (2007) The failure to diagnose inborn errors of metabolism in New Zealand: the case for expanded newborn screening. N ZMed J 120(1262):1–11Google Scholar
  37. Yap S, Naughten E (1998) Homocystinuria due to cystathionine beta-synthase deficiency in Ireland: 25 years’ experience of a newborn screened and treated population with reference to clinical outcome and biochemical control. J Inherit Metab Dis 21(7):738–747PubMedCrossRefGoogle Scholar
  38. Yoon H-R, Lee KR, Kang S et al (2005) Screening of newborns and high-risk group of children for inborn metabolic disorders using tandem mass spectrometry in south Korea: a three-year report. Clin Chim Acta 354(1–2):167–180PubMedCrossRefGoogle Scholar

Copyright information

© SSIEM 2014

Authors and Affiliations

  • Sowmiya Moorthie
    • 1
    Email author
  • Louise Cameron
    • 1
  • Gurdeep S. Sagoo
    • 1
  • Jim R. Bonham
    • 2
  • Hilary Burton
    • 1
  1. 1.PHG FoundationCambridgeUK
  2. 2.Clinical ChemistrySheffield Children’s NHS Foundation TrustSheffieldUK

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