Clinical characteristics, biochemical metabolic biomarkers and genetic heterogeneity of 11 children with maple syrup urine disease_West China Medical Journal

Authors：

WANG Meiyi , PENG Minzhi , SHAO Yongxian , LIN Yunting , CAI Yanna , XU Jianan ,  LIU Li

Department of Genetics and Endocrinology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510623, P. R. China;

Corresponding author：

LIU Li, Email: liliuchina@qq.com

Keywords：

Maple syrup urine disease; gamma-glutamyltransferase; branched-chain amino acids; BCKDHB gene

DOI：

10.7507/1002-0179.202403293

Video：

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Objective To summarize and analyze the clinical data of maple syrup urine disease (MSUD) patients to explore the correlation among clinical phenotype, biochemical markers and genotype. Methods The clinical data of 11 children with MSUD who were admitted to Guangzhou Women and Children’s Medical Center of Guangzhou Medical University between January 2011 and October 2016 were retrospectively collected. According to the clinical symptoms and prognosis, they were divided into classic type group (n=6) and intermediate/thiamine-effective group (n=5). The differences in biochemical metabolic markers between the two groups were compared, and the correlation between genotype and phenotype was analyzed. Results Compared to the intermediate/thiamine-effective group, the blood gamma-glutamyltransferase (γ-GT) level in the classic type group was significantly higher [158.00 (122.80, 309.30) vs. 11.00 (10.50, 14.00) U/L, P=0.004], and the globulin [(15.55±3.45) vs. (24.26±4.37) g/L, P=0.018] and lactate [1.05 (0.98, 1.68) vs. 2.10 (1.75, 2.70) mmol/L, P=0.030] levels in the classic type group were significantly lower, while the levels of alanine aminotransferase, aspartate aminotransferase and total bile acid were not different between the two groups (P>0.05). The plasma concentrations of leucine in the classic type group were higher than that in the intermediate/thiamine-effective group [(3748.20 (3135.00, 4936.00) vs. 620.40 (531.20, 1150.00) μmol/L, P=0.004]. The γ-GT level was positively correlated with the leucine level (r_s=0.826, P=0.003), the leucine level was positively correlated with the iso-leucine level (r_s=0.827, P=0.003), and the iso-leucine level was positively correlated with the valine level (r_s=0.636, P=0.040). The results of gene sequencing showed that the 11 patients carried BCKDHA (n=4) and BCKDHB (n=7) gene mutations, respectively. Of these, 6 patients with BCKDHB gene mutations were classic type. Conclusion The prognosis of MSUD is closely correlated to blood γ-GT and branched-chain amino acids levels, as well as with genotype.

Citation： WANG Meiyi, PENG Minzhi, SHAO Yongxian, LIN Yunting, CAI Yanna, XU Jianan, LIU Li. Clinical characteristics, biochemical metabolic biomarkers and genetic heterogeneity of 11 children with maple syrup urine disease. West China Medical Journal, 2025, 40(1): 23-28. doi: 10.7507/1002-0179.202403293 Copy

1.	Sun WH, Wu BB, Wang YQ, et al. Identification of eight novel mutations in 11 Chinese patients with maple syrup urine disease. World J Pediatr, 2020, 16(4): 401-410.
2.	Knerr I, Colombo R, Urquhart J, et al. Expanding the genetic and phenotypic spectrum of branched-chain amino acid transferase 2 deficiency. J Inherit Metab Dis, 2019, 42(5): 809-817.
3.	国家卫生健康委官网. 国家卫健委: 完成我国首部罕见病诊疗指南发布. 中华医学信息导报, 2019(5): 7.
4.	Yang C, Linpeng S, Cao Y, et al. Identification of six novel mutations in five infants with suspected maple syrup urine disease based on blood and urine metabolism screening. Gene, 2019, 710: 9-16.
5.	Gupta D, Bijarnia-Mahay S, Saxena R, et al. Identification of mutations, genotype-phenotype correlation and prenatal diagnosis of maple syrup urine disease in Indian patients. Eur J Med Genet, 2015, 58(9): 471-478.
6.	Li X, Yang Y, Gao Q, et al. Clinical characteristics and mutation analysis of five Chinese patients with maple syrup urine disease. Metab Brain Dis, 2018, 33(3): 741-751.
7.	Yang J, Xiu J, Sun Y, et al. Three novel mutations of the BCKDHA, BCKDHB and DBT genes in Chinese children with maple syrup urine disease. J Pediatr Endocrinol Metab, 2021, 35(3): 303-312.
8.	Kiss O, Maizik J, Tamme K, et al. Diarrhea and elevation of plasma markers of cholestasis are common and often occur concomitantly in critically ill patients. J Crit Care, 2020, 60: 120-126.
9.	Whitfield JB. Gamma glutamyl transferase. Crit Rev Clin Lab Sci, 2001, 38(4): 263-355.
10.	Koenig G, Seneff S. Gamma-glutamyltransferase: a predictive biomarker of cellular antioxidant inadequacy and disease risk. Dis Markers, 2015, 2015: 818570.
11.	Hauschild TC, Guerreiro G, Mescka CP, et al. DNA damage induced by alloisoleucine and other metabolites in maple syrup urine disease and protective effect of l-carnitine. Toxicol In Vitro, 2019, 57: 194-202.
12.	Mescka CP, Rosa AP, Schirmbeck G, et al. L-carnitine prevents oxidative stress in the brains of rats subjected to a chemically induced chronic model of MSUD. Mol Neurobiol, 2016, 53(9): 6007-6017.
13.	Strauss KA, Carson VJ, Soltys K, et al. Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease): treatment, biomarkers, and outcomes. Mol Genet Metab, 2020, 129(3): 193-206.
14.	Xu J, Jakher Y, Ahrens-Nicklas RC. Brain branched-chain amino acids in maple syrup urine disease: implications for neurological disorders. Int J Mol Sci, 2020, 21(20): 7490.
15.	Li L, Mao X, Yang N, et al. Identification of gene mutations in six Chinese patients with maple syrup urine disease. Front Genet, 2023, 14: 1132364.
16.	Nguyen TTN, Vu CD, Nguyen NL, et al. Identification of novel mutations in BCKDHB and DBT genes in Vietnamese patients with maple sirup urine disease. Mol Genet Genomic Med, 2020, 8(8): e1337.
17.	Flaschker N, Feyen O, Fend S, et al. Description of the mutations in 15 subjects with variant forms of maple syrup urine disease. J Inherit Metab Dis, 2007, 30(6): 903-909.
18.	Khalifa OA, Imtiaz F, Ramzan K, et al. Genotype-phenotype correlation of 33 patients with maple syrup urine disease. Am J Med Genet A, 2020, 182(11): 2486-2500.
19.	Cavalli G, Heard E. Advances in epigenetics link genetics to the environment and disease. Nature, 2019, 571(7766): 489-499.
20.	Fang X, Zhu X, Feng Y, et al. Genetic analysis by targeted next-generation sequencing and novel variation identification of maple syrup urine disease in Chinese Han population. Sci Rep, 2021, 11(1): 18939.
21.	Ali EZ, Ngu LH. Fourteen new mutations of BCKDHA, BCKDHB and DBT genes associated with maple syrup urine disease (MSUD) in Malaysian population. Mol Genet Metab Rep, 2018, 17: 22-30.

1. Sun WH, Wu BB, Wang YQ, et al. Identification of eight novel mutations in 11 Chinese patients with maple syrup urine disease. World J Pediatr, 2020, 16(4): 401-410.
2. Knerr I, Colombo R, Urquhart J, et al. Expanding the genetic and phenotypic spectrum of branched-chain amino acid transferase 2 deficiency. J Inherit Metab Dis, 2019, 42(5): 809-817.
3. 国家卫生健康委官网. 国家卫健委: 完成我国首部罕见病诊疗指南发布. 中华医学信息导报, 2019(5): 7.
4. Yang C, Linpeng S, Cao Y, et al. Identification of six novel mutations in five infants with suspected maple syrup urine disease based on blood and urine metabolism screening. Gene, 2019, 710: 9-16.
5. Gupta D, Bijarnia-Mahay S, Saxena R, et al. Identification of mutations, genotype-phenotype correlation and prenatal diagnosis of maple syrup urine disease in Indian patients. Eur J Med Genet, 2015, 58(9): 471-478.
6. Li X, Yang Y, Gao Q, et al. Clinical characteristics and mutation analysis of five Chinese patients with maple syrup urine disease. Metab Brain Dis, 2018, 33(3): 741-751.
7. Yang J, Xiu J, Sun Y, et al. Three novel mutations of the BCKDHA, BCKDHB and DBT genes in Chinese children with maple syrup urine disease. J Pediatr Endocrinol Metab, 2021, 35(3): 303-312.
8. Kiss O, Maizik J, Tamme K, et al. Diarrhea and elevation of plasma markers of cholestasis are common and often occur concomitantly in critically ill patients. J Crit Care, 2020, 60: 120-126.
9. Whitfield JB. Gamma glutamyl transferase. Crit Rev Clin Lab Sci, 2001, 38(4): 263-355.
10. Koenig G, Seneff S. Gamma-glutamyltransferase: a predictive biomarker of cellular antioxidant inadequacy and disease risk. Dis Markers, 2015, 2015: 818570.
11. Hauschild TC, Guerreiro G, Mescka CP, et al. DNA damage induced by alloisoleucine and other metabolites in maple syrup urine disease and protective effect of l-carnitine. Toxicol In Vitro, 2019, 57: 194-202.
12. Mescka CP, Rosa AP, Schirmbeck G, et al. L-carnitine prevents oxidative stress in the brains of rats subjected to a chemically induced chronic model of MSUD. Mol Neurobiol, 2016, 53(9): 6007-6017.
13. Strauss KA, Carson VJ, Soltys K, et al. Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease): treatment, biomarkers, and outcomes. Mol Genet Metab, 2020, 129(3): 193-206.
14. Xu J, Jakher Y, Ahrens-Nicklas RC. Brain branched-chain amino acids in maple syrup urine disease: implications for neurological disorders. Int J Mol Sci, 2020, 21(20): 7490.
15. Li L, Mao X, Yang N, et al. Identification of gene mutations in six Chinese patients with maple syrup urine disease. Front Genet, 2023, 14: 1132364.
16. Nguyen TTN, Vu CD, Nguyen NL, et al. Identification of novel mutations in BCKDHB and DBT genes in Vietnamese patients with maple sirup urine disease. Mol Genet Genomic Med, 2020, 8(8): e1337.
17. Flaschker N, Feyen O, Fend S, et al. Description of the mutations in 15 subjects with variant forms of maple syrup urine disease. J Inherit Metab Dis, 2007, 30(6): 903-909.
18. Khalifa OA, Imtiaz F, Ramzan K, et al. Genotype-phenotype correlation of 33 patients with maple syrup urine disease. Am J Med Genet A, 2020, 182(11): 2486-2500.
19. Cavalli G, Heard E. Advances in epigenetics link genetics to the environment and disease. Nature, 2019, 571(7766): 489-499.
20. Fang X, Zhu X, Feng Y, et al. Genetic analysis by targeted next-generation sequencing and novel variation identification of maple syrup urine disease in Chinese Han population. Sci Rep, 2021, 11(1): 18939.
21. Ali EZ, Ngu LH. Fourteen new mutations of BCKDHA, BCKDHB and DBT genes associated with maple syrup urine disease (MSUD) in Malaysian population. Mol Genet Metab Rep, 2018, 17: 22-30.

West China Medical Journal

Clinical characteristics, biochemical metabolic biomarkers and genetic heterogeneity of 11 children with maple syrup urine disease

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