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Cited by 12Metabolism and Genetic DisordersMitochondrial Function and PathologyGenomics and Rare Diseases

Analysis of a family with mitochondrial trifunctional protein deficiency caused by HADHA gene mutations

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Yang, Jinling, Yuan, Dejian, Tan, Xiaohui, Zeng, Yexi, Tang, Ning, Chen, Dayu, Tan, Jianqiang, Cai, Ren +2 more·2021·Molecular Medicine Reports
DOI 10.3892/mmr.2021.12563PMC PMC8674702
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Abstract

Mitochondrial trifunctional protein (MTP) deficiency (MTPD; MIM 609015) is a metabolic disease of fatty acid oxidation. MTPD is an autosomal recessive disorder caused by mutations in the HADHA gene, encoding the α‑subunit of a trifunctional protease, or in the HADHB gene, encoding the β‑subunit of a trifunctional protease. To the best of our knowledge, only two cases of families with MTPD due to HADHB gene mutations have been reported in China, and the HADHA gene mutation has not been reported in a Chinese family with MTPD. The present study reported the clinical characteristics and compound heterozygous HADHA gene mutations of two patients with MTPD in the Chinese population. The medical history, routine examination data, blood acyl‑carnitine analysis results, results of pathological examination after autopsy and family pedigree map were collected for patients with MTPD. The HADHA gene was analyzed by Sanger sequencing or high‑throughput sequencing, the pathogenicity of the newly discovered variant was interpreted by bioinformatics analysis, and the function of the mutated protein was modeled and analyzed according to 3D structure. The two patients with MTPD experienced metabolic crises and died following an infectious disease. Lactate dehydrogenase, creatine kinase (CK), CK‑MB and liver enzyme abnormalities were observed in routine examinations. Tandem mass spectrometry revealed that long‑chain acyl‑carnitine was markedly elevated in blood samples from the patients with MTPD. The autopsy results for one child revealed fat accumulation in the liver and heart. Next‑generation sequencing detected compound heterozygous c.703C>T (p.R235W) and c.2107G>A (p.G703R) mutations in the HADHA gene. The mother did not have acute fatty liver during pregnancy with the two patients. Using amniotic fluid prenatal diagnostic testing, the unborn child was confirmed to carry only c.2107G>A (p.G703R). Molecular mechanistic analysis indicated that the two variants affected the conformation of the α‑subunit of the MTP enzyme complex, and consequently affected the stability and function of the enzyme complex. The present study comprehensively analyzed the cases, including exome sequencing and protein structure analysis and, to the best of our knowledge, describes the first observation of compound heterozygous mutations in the HADHA gene underlying this disorder in China. The clinical phenotypes of the two heterozygous variants of the HADHA gene are non‑lethal. The present study may improve understanding of the HADHA gene mutation spectrum and clinical phenotype in the Chinese population.

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References 27 · Cited by 12

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  1. [1]Lotz-Havla AS Röschinger W Schiergens K Singer K Karall D Konstantopoulou V Wortmann SB Maier EM Fatal pitfalls in newborn screening for mitochondrial trifunctional protein (MTP)/long-chain 3-Hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency Orphanet J Rare Dis 13 122 2018 10.1186/s13023-018-0875-6 30029694 PMC6053800 · DOI
  2. [2]Van Vliet P Berden AE van Schie MK Bakker JA Heringhaus C de Coo IF Langeveld M Schroijen MA Arbous MS Peripheral neuropathy, episodic rhabdomyolysis, and hypoparathyroidism in a patient with mitochondrial trifunctional protein deficiency JIMD Rep 38 101 105 2018 10.1007/8904_2017_37 28685493 PMC5874207 · DOI
  3. [3]Uchida Y Izai K Orii T Hashimoto T Novel fatty acid beta-oxidation enzymes in rat liver mitochondria. II. Purification and properties of enoyl-coenzyme A (CoA) hydratase/3-hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase trifunctional protein J Biol Chem 267 1034 1041 1992 10.1016/S0021-9258(18)48391-3 1730633 · DOI
  4. [4]den Boer ME Ijlst L Wijburg FA Oostheim W van Werkhoven MA van Pampus MG Heymans HS Wanders RJ Heterozygosity for the common LCHAD mutation (1528g>c) is not a major cause of HELLP syndrome and the prevalence of the mutation in the dutch population is low Pediatr Res 48 151 154 2000 10.1203/00006450-200008000-00006 10926288 · DOI
  5. [5]Karall D Brunner-Krainz M Kogelnig K Konstantopoulou V Maier EM Möslinger D Plecko B Sperl W Volkmar B Scholl-Bürgi S Clinical outcome, biochemical and therapeutic follow-up in 14 Austrian patients with long-chain 3-Hydroxy Acyl CoA dehydrogenase deficiency (LCHADD) Orphanet J Rare Dis 10 21 2015 10.1186/s13023-015-0236-7 25888220 PMC4407779 · DOI
  6. [6]Wanders RJ IJlst L van Gennip AH Jakobs C de Jager JP Dorland L van Sprang FJ Duran M Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: Identification of a new inborn error of mitochondrial fatty acid beta-oxidation J Inherit Metab Dis 13 311 314 1990 10.1007/BF01799383 2122092 · DOI
  7. [7]Sykut-Cegielska J Gradowska W Piekutowska-Abramczuk D Andresen BS Olsen RK Ołtarzewski M Pronicki M Pajdowska M Bogdańska A Jabłońska E Urgent metabolic service improves survival in long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency detected by symptomatic identification and pilot newborn screening J Inherit Metab Dis 34 185 195 2011 10.1007/s10545-010-9244-x 21103935 · DOI
  8. [8]Boutron A Acquaviva C Vianey-Saban C de Lonlay P de Baulny HO Guffon N Dobbelaere D Feillet F Labarthe F Lamireau D Comprehensive cDNA study and quantitative analysis of mutant HADHA and HADHB transcripts in a French cohort of 52 patients with mitochondrial trifunctional protein deficiency Mol Genet Metab 103 341 348 2011 10.1016/j.ymgme.2011.04.006 21549624 · DOI
  9. [9]Hong YB Lee JH Park JM Choi YR Hyun YS Yoon BR Yoo JH Koo H Jung SC Chung KW Choi BO A compound heterozygous mutation in HADHB gene causes an axonal Charcot-Marie-tooth disease BMC Med Genet 14 125 2013 10.1186/1471-2350-14-125 24314034 PMC4029087 · DOI
  10. [10]Fu X Zheng F Zhang Y Bao X Wang S Yang Y Xiong H Mitochondrial trifunctional protein deficiency due to HADHB gene mutation in a Chinese family Mol Genet Metab Rep 5 80 84 2015 10.1016/j.ymgmr.2015.10.015 28649548 PMC5471393 · DOI
  11. [11]Bo R Yamada K Kobayashi H Jamiyan P Hasegawa Y Taketani T Fukuda S Hata I Niida Y Shigematsu Y Clinical and molecular investigation of 14 Japanese patients with complete TFP deficiency: A comparison with caucasian cases J Hum Genet 62 809 814 2017 10.1038/jhg.2017.52 28515471 · DOI
  12. [12]Liu ZR Dong HL Ma Y Wu ZY Identification and functional characterization of mutations within HADHB associated with mitochondrial trifunctional protein deficiency Mitochondrion 49 200 205 2019 10.1016/j.mito.2019.09.004 31521624 · DOI
  13. [13]Tyni T Palotie A Viinikka L Valanne L Salo MK von Döbeln U Jackson S Wanders R Venizelos N Pihko H Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency with the G1528C mutation: Clinical presentation of thirteen patients J Pediatr 130 67 76 1997 10.1016/S0022-3476(97)70312-3 9003853 · DOI
  14. [14]Barvinska O Olkhovych N Gorovenko N High prevalence of c.1528G>C rearrangement in patients with long chain 3-Hydroxyacyl-CoA dehydrogenase deficiency from Ukraine Cytol Genet 52 198 203 2018 10.3103/S0095452718030027 · DOI
  15. [15]Glasgow JF Middleton B Reye syndrome-insights on causation and prognosis Arch Dis Child 85 351 353 2001 10.1136/adc.85.5.351 11668090 PMC1718987 · DOI
  16. [17]Scheuerman O Wanders RJ Waterham HR Dubnov-Raz G Garty BZ Mitochondrial trifunctional protein deficiency with recurrent rhabdomyolysis Pediatr Neurol 40 465 467 2009 10.1016/j.pediatrneurol.2008.12.017 19433283 · DOI
  17. [18]Zheng Y Chen Y Qiu X Chen W Lin Q Zeng Y Zhao H Zhu W A verification of the application of the non-derivatized mass spectrometry method in newborns screening of metabolic disorders Medicine (Baltimore) 98 e15500 2019 10.1097/MD.0000000000015500 31083189 PMC6531236 · DOI
  18. [19]Terrone G Ruoppolo M Brunetti-Pierri N Cozzolino C Scolamiero E Parenti G Romano A Andria G Salvatore F Frisso G Child Neurology: Recurrent rhabdomyolysis due to a fatty acid oxidation disorder Neurology 82 e1 e4 2014 10.1212/01.wnl.0000438217.31437.72 24379101 · DOI
  19. [20]Landau YE Waisbren SE Chan LM Levy HL Long-term outcome of expanded newborn screening at Boston children's hospital: Benefits and challenges in defining true disease J Inherit Metab Dis 40 209 218 2017 10.1007/s10545-016-0004-4 28054209 · DOI
  20. [21]Diebold I Schön U Horvath R Schwartz O Holinski-Feder E Kölbel H Abicht A HADHA and HADHB gene associated phenotypes-identification of rare variants in a patient cohort by next generation sequencing Mol Cell Probes 44 14 20 2019 10.1016/j.mcp.2019.01.003 30682426 · DOI
  21. [22]Pena LD van Calcar SC Hansen J Edick MJ Vockley CW Leslie N Cameron C Mohsen AW Berry SA Arnold GL Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database Mol Genet Metab 118 272 281 2016 10.1016/j.ymgme.2016.05.007 27209629 PMC4970910 · DOI
  22. [23]Kang E Kim YM Kang M Heo SH Kim GH Choi IH Choi JH Yoo HW Lee BH Clinical and genetic characteristics of patients with fatty acid oxidation disorders identified by newborn screening BMC Pediatr 18 103 2018 10.1186/s12887-018-1069-z 29519241 PMC5842515 · DOI
  23. [24]Ibdah JA Acute fatty liver of pregnancy: An update on pathogenesis and clinical implications World J Gastroenterol 12 7397 7404 2006 10.3748/wjg.v12.i46.7397 17167825 PMC4087582 · DOI
  24. [25]Ronen J Shaheen S Steinberg D Justus KR Acute fatty liver of pregnancy:A thorough examination of a harmful obstetrical syndrome and its counterparts Cureus 10 e2164 2018 29644153 PMC5889153
  25. [26]Schoeman MN Batey RG Wilcken B Recurrent acute fatty liver of pregnancy associated with a fatty-acid oxidation defect in the offspring Gastroenterology 100 544 548 1991 10.1016/0016-5085(91)90228-D 1985050 · DOI
  26. [27]Kobayashi T Minami S Mitani A Tanizaki Y Booka M Okutani T Yamaguchi S Ino K Acute fatty liver of pregnancy associated with fetal mitochondrial trifunctional protein deficiency J Obstet Gynaecol Res 41 799 802 2015 10.1111/jog.12609 25420603 · DOI

Authors
Yang, J., Yuan, D., Tan, X., Zeng, Y., Tang, N., Chen, D., Tan, J., Cai, R., Huang, J., & Yan, T.
Affiliations
  • Newborn Screening Center, Department of Medical Genetics, Key Laboratory of Prevention and Control of Birth Defects, Liuzhou Maternity and Child Health Care Hospital, Affiliated Maternity Hospital and Affiliated Children's Hospital of Guangxi University of Science and Technology, Liuzhou, Guangxi 545000, P.R. China
  • Guangxi University of Science and Technology (CN)
  • Southern Medical University (CN)
  • Newborn Screening Center, Huizhou Second Maternity and Child Health Care Hospital, Huizhou, Guangdong 516001, P.R. China
Corresponding author
Yan, Tizhen
ORCID
Venue
Molecular Medicine Reports
Publisher
Spandidos Publications
Published
2021-12-08
Volume
25
Issue
2
ISSN
  • 1791-2997 (ISSN-L)
  • 1791-3004
DOI
10.3892/mmr.2021.12563
PMC
PMC8674702
OpenAlex
W4200534650
Cited by
12
References
27
Citations by year
2026: 2 · 2025: 2 · 2024: 4 · 2023: 3 · 2022: 1
FWCI
1.41
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Molecular Medicine Reports (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
mitochondrial trifunctional protein deficiency, compound heterozygosity, fatty acid oxidation disorders, acylcarnitines, metabolic crisis, protein structure modeling, autosomal recessive inheritance
MeSH terms
Child, Preschool, Female, Genetic Testing, Heterozygote, Humans, Infant, Lipid Metabolism, Inborn Errors, Male, Models, Molecular, Multienzyme Complexes, Mutation, Cardiomyopathies, Nervous System Diseases, Pedigree, Phenotype, Protein Conformation, Rhabdomyolysis, Mitochondrial Myopathies, Genetic Predisposition to Disease, Asian People, Mitochondrial Trifunctional Protein, Mitochondrial Trifunctional Protein, alpha Subunit

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