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Genotype-phenotype correlations
Original research
Evaluation of the clinical, biochemical, genotype and prognosis of mut-type methylmalonic acidemia in 365 Chinese cases
  1. Lili Liang1,
  2. Shiying Ling1,
  3. Yue Yu1,
  4. Ruixue Shuai2,
  5. Wenjuan Qiu1,
  6. Huiwen Zhang1,
  7. Linghua Shen3,
  8. Shengnan Wu3,
  9. Haiyan Wei3,
  10. Yongxing Chen3,
  11. Chiju Yang4,
  12. Peng Xu4,
  13. Xigui Chen4,
  14. Hui Zou5,
  15. Jizhen Feng6,
  16. Tingting Niu7,
  17. Haili Hu8,
  18. Zhuwen Gong1,
  19. Ting Chen1,
  20. Xia Zhan1,
  21. Xuefan Gu1,
  22. Lianshu Han1
  1. 1 Department Of Pediatric Endocrinology/Genetics, Shanghai Institute For Pediatric Research, Xinhua Hospital Affiliated To Shanghai Jiao Tong University School Of Medicine, Shanghai, China
  2. 2 Department of Pediatrics, Shanghai Changzheng Hospital, Shanghai, China
  3. 3 Center of Neonatal Disease Screening, Henan Children's Hospital, Zhengzhou, Henan, China
  4. 4 Center of Neonatal Disease Screening, Jining Maternal and Child Health Care Hospital, Jining, China
  5. 5 Center of Neonatal Disease Screening, Jinan Maternal and Child Health Care Hospital, Jinan, China
  6. 6 Center of Neonatal Disease Screening, Shijiazhuang Maternal and Child Health Care Hospital, Shijiazhuang, China
  7. 7 Center of Neonatal Disease Screening, Shandong Maternal and Child Health Care Hospital, Jinan, China
  8. 8 Center of Neonatal Disease Screening, Hefei Maternal and Child Health Care Hospital, Hefei, China
  1. Correspondence to Dr Lianshu Han, Department of Pediatric Endocrinology/Genetics, Shanghai Jiao Tong University, Shanghai, China; hanlianshu{at}xinhuamed.com.cn

Abstract

Background Methylmalonic acidemia (MMA), which results from defects in methylmalonyl-CoA mutase (mut type) or its cofactor, is the most common inherited organic acid metabolic disease in China. This study aimed to investigate the phenotype and genotype of mut-type MMA in Chinese patients.

Methods We recruited 365 patients with mut-type MMA; investigated their disease onset, newborn screening (NBS) status, biochemical metabolite levels, gene variations and prognosis; and explored the relationship between phenotype and genotype.

Results There were 152 patients diagnosed by tandem mass spectrometry (MS/MS) expanded NBS, 209 patients diagnosed because of disease onset without NBS and 4 cases diagnosed because of sibling diagnosis. The median age of onset was 15 days old, with a variety of symptoms without specificity. Urinary levels of methylmalonic acid and methylcitric acid (MCA) decreased after treatment. Regarding the prognosis, among the 152 patients with NBS, 50.6% were healthy, 30.3% had neurocognitive impairment and/or movement disorders and 13.8% died. Among the 209 patients without NBS, 15.3% were healthy, 45.9% had neurocognitive impairment and/or movement disorders and 33.0% died. In total, 179 variants were detected in the MMUT gene, including 52 novel variations. c.729_730insTT, c.1106G>A, c.323G>A, c.914T>C and c.1663G>A were the five most frequent variations. The c.1663G>A variation led to a milder phenotype and better prognosis.

Conclusion There is a wide spectrum of variations in the MMUT gene with several common variations. Although the overall prognosis of mut-type MMA was poor, participation in MS/MS expanded NBS, vitamin B12 responsive and late onset are favourable factors for the prognosis.

  • mutation
  • neonatal screening
  • paediatrics
  • phenotype
  • genotype

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

https://doi.org/10.1136/jmg-2022-108682

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information.

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    Footnotes

    • LL and SL contributed equally.

    • Contributors LL, as the doctor of many of these patients, contributed to reorganise and analyse the clinical data of the patients, and drafted the manuscript. SL contributed to collect and reorganise the clinical data of the patients, and revised the manuscript. YY and RS contributed to arrange the clinical data of the patients. WQ, HZ, LS, SW, HW, YC, CY, PX, XC, HZ, JF, TN, HH and XG contributed to collect and treat the patients, and provided the clinical data. TC and XZ contributed to the detection of the blood acylcarnitines of the patients by tandem mass spectrometry and the urinary organic acids of the patients by gas chromatography-mass spectrometry. ZG contributed to gene variation analysis. LH, as the guarantor of the study and the doctor of most of the patients, contributed to the design of the research, treated the patients, provided the clinical data and revised the manuscript.

    • Funding This work was supported by the Scientific Research Project plan of Shanghai Municipal Health Commission (No. 202040448), the Scientific Research Project Plan of Shanghai Municipal Health Commission (No. 202140346) and the National Natural Science Foundation of China (No. 81600701).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.