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Licensed Unlicensed Requires Authentication Published by De Gruyter December 19, 2019

Analysis of five cases of hypermethioninemia diagnosed by neonatal screening

Zhilei Zhang, Yanyun Wang, Dingyuan Ma, Wei Cheng, Yun Sun and Tao Jiang



Hypermethioninemia is a group of diseases with elevated plasma methionine (Met) caused by hereditary and non-hereditary factors, although it could also be caused by administration of the amino acid Met. Among these, the disease caused by methionine adenosyltransferase (MAT) I/III deficiency is the most common, and is characterized by persistent, isolated hypermethioninemia as well as slightly elevated homocysteine. S-adenosylmethionine is the product of Met, which can be used as a direct methyl donor of many substances, such as choline and nucleotide, and essential in the development of the body. Among the patients, most have no symptoms, and a small number have central nervous system complications with high levels of plasma Met, including mental retardation, cognitive impairment and special breathing odor.


In this study, five cases of MAT I/III deficiency were diagnosed and retrospectively analyzed among 220,000 newborns. Patients with high Met levels received a Met-restricted diet treatment.

Results and conclusions

MAT I/III deficiency is a common reason for Met elevation in neonatal screening by tandem mass spectrometry (MS/MS), which needs long-term follow-up except for these patients with explicitly benign mutations.

Corresponding authors: Yun Sun and Tao Jiang, Center of Genetic Medicine, The Affiliated Obstetrics and Gynecology Hospital with Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Jiangsu, No. 123, Tianfei Xiang, Mochou Road, Nanjing, China, Phone: +13951621263 (Y. Sun); +13952001972 (T. Jiang)


This paper was completed in March, 2019. And I thank all participants.

  1. Author contributions: ZZL and SY conceptualized and designed the study, completed the experiment, led the review process and drafted the initial manuscript; SY reviewed all articles; WYY is responsible for the physical examination and follow-up of children; MDY is responsible for the genetic detection; and CW assisted to complete the experiment. All authors made substantial contributions to revising the manuscript. SY is responsible for the review and language editing. JT is responsible for the overall content. All authors read and approved the final manuscript.

  2. Research funding: None declared.

  3. Employment or leadership: None declared.

  4. Honorarium: None declared.

  5. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

  6. Informed consent: Informed consent was obtained from all individual participants included in the study.


1. Kim YM, Kim JH, Choi J, Gu-Hwan K, Kim JM, et al. Determination of autosomal dominant or recessive methionine adenosyltransferase I/III deficiencies based on clinical and molecular studies. Mol Med 2016;22:147–55.10.2119/molmed.2015.00254Search in Google Scholar

2. Blom HJ, Davidson AJ, Finkelstein JD, Luder AS, Bernardini I, et al. Persistent hypermethioninaemia with dominant inheritance. J Inherit Metab Dis 1992;15:188–97.10.1007/BF01799629Search in Google Scholar

3. Muriello MJ, Viall S, Bottiglieri T, Cusmano-Ozog K, Ferreira CR. Confirmation that MAT1A p.Ala259Val mutation causes autosomal dominant hypermethioninemia. Mol Genet Metab Rep 2017;13:9–12.10.1016/j.ymgmr.2017.07.004Search in Google Scholar

4. Martins E, Marcao A, Bandeira A, Fonseca H, Nogueira C, et al. Methionine adenosyltransferase I/III deficiency in Portugal: high frequency of a dominantly inherited form in a small area of Douro high lands. JIMD Rep 2012;6:107–12.10.1007/8904_2011_124Search in Google Scholar

5. Nashabat M, Al-Khenaizan S, Alfadhel M. Methionine adenosyltransferase I/III deficiency: beyond the central nervous system manifestations. Ther Clin Risk Manag 2018;14:225–9.10.2147/TCRM.S151732Search in Google Scholar

6. Nagao M, Tanaka T, Furujo M. Spectrum of mutations associated with methionine adenosyltransferase I/III deficiency among individuals identified during newborn screening in Japan. Mol Genet Metab 2013;110:460–4.10.1016/j.ymgme.2013.10.013Search in Google Scholar

7. Marcao A, Couce ML, Nogueira C, Fonseca H, Ferreira F, et al. Newborn screening for homocystinuria revealed a high frequency of MAT I/III deficiency in Iberian Peninsula. JIMD Rep 2015;20:113–20.10.1007/8904_2014_400Search in Google Scholar

8. Chien YH, Chiang SC, Huang A, Hwu W. Spectrum of hypermethioninemia in neonatal screening. Early Hum Dev 2005;81:529–33.10.1016/j.earlhumdev.2004.11.005Search in Google Scholar

9. Petrossian TC, Clarke SG. Uncovering the human methyltransferasome. Mol Cell Proteomics 2011;10:M110.000976.10.1074/mcp.M110.000976Search in Google Scholar

10. Schweinberger BM, Wyse AT. Mechanistic basis of hypermethioninemia. Amino Acids 2016;48:2479–89.10.1007/s00726-016-2302-4Search in Google Scholar

11. Chamberlin ME, Ubagai T, Mudd SH, Thomas J, Pao VY, et al. Methionine adenosyltransferase I/Iii deficiency: novel mutations and clinical variations. Am J Hum Genet 2000;66:347–35.10.1086/302752Search in Google Scholar

12. Mudd SH, Tangerman A, Stabler SP, Allen RH, Wagner C, et al. Maternal methionine adenosyltransferase I/III deficiency: reproductive outcomes in a woman with four pregnancies. J Inherit Metab Dis 2003;26:443–58.10.1023/A:1025121326959Search in Google Scholar

13. Furujo M, Kinoshita M, Nagao M, Kubo T. S-adenosylmethionine treatment in methionine adenosyltransferase deficiency: a case report. Mol Genet Metab 2012;105:516–8.10.1016/j.ymgme.2011.11.192Search in Google Scholar

14. Karas Kuzelicki N. S-adenosyl methionine in the therapy of depression and other psychiatric disorders. Drug Dev Res 2016;77:346–56.10.1002/ddr.21345Search in Google Scholar

15. Couce ML, Bóveda MD, Balmaseda E, Vives I, Castiñeiras DE, et al. Clinical and metabolic findings in patients with methionine adenosyltransferase I/III deficiency detected by newborn screening. Mol Genet Metab 2013;110:218–21.10.1016/j.ymgme.2013.08.003Search in Google Scholar

16. Chien YH, Abdenur JE, Baronio F, Bannick AA, Corrales F, et al. Mudd’s disease (Mat I/III Deficiency): a survey of data for mat1a homozygotes and compound heterozygotes. Orphanet J Rare Dis 2015;10:99.10.1186/s13023-015-0321-ySearch in Google Scholar

17. Markham GD, Pajares MA. Structure-function relationships in methionine adenosyltransferases. Cell Mol Life Sci 2009;66:636–48.10.1007/s00018-008-8516-1Search in Google Scholar

Received: 2019-06-24
Accepted: 2019-10-14
Published Online: 2019-12-19
Published in Print: 2020-01-28

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