Analysis of a family with mitochondrial trifunctional protein deficiency caused by <em>HADHA</em> gene mutations

Yang,Jinling; Yuan,Dejian; Tan,Xiaohui; Zeng,Yexi; Tang,Ning; Chen,Dayu; Tan,Jianqiang; Cai,Ren; Huang,Jun; Yan,Tizhen

doi:10.3892/mmr.2021.12563

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

Authors:
- Jinling Yang
- Dejian Yuan
- Xiaohui Tan
- Yexi Zeng
- Ning Tang
- Dayu Chen
- Jianqiang Tan
- Ren Cai
- Jun Huang
- Tizhen Yan
View Affiliations

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, School of Forensic Medicine, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China, Newborn Screening Center, Huizhou Second Maternity and Child Health Care Hospital, Huizhou, Guangdong 516001, P.R. China
Published online on: December 8, 2021 https://doi.org/10.3892/mmr.2021.12563
Article Number: 47
Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1	Lotz-Havla AS, Röschinger W, Schiergens K, Singer K, Karall D, Konstantopoulou V, Wortmann SB and Maier EM: Fatal pitfalls in newborn screening for mitochondrial trifunctional protein (MTP)/long-chain 3-Hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. Orphanet J Rare Dis. 13:1222018. View Article : Google Scholar : PubMed/NCBI
2	Van Vliet P, Berden AE, van Schie MK, Bakker JA, Heringhaus C, de Coo IF, Langeveld M, Schroijen MA and Arbous MS: Peripheral neuropathy, episodic rhabdomyolysis, and hypoparathyroidism in a patient with mitochondrial trifunctional protein deficiency. JIMD Rep. 38:101–105. 2018. View Article : Google Scholar : PubMed/NCBI
3	Uchida Y, Izai K, Orii T and 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. View Article : Google Scholar : PubMed/NCBI
4	den Boer ME, Ijlst L, Wijburg FA, Oostheim W, van Werkhoven MA, van Pampus MG, Heymans HS and 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. View Article : Google Scholar : PubMed/NCBI
5	Karall D, Brunner-Krainz M, Kogelnig K, Konstantopoulou V, Maier EM, Möslinger D, Plecko B, Sperl W, Volkmar B and 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. 10:212015. View Article : Google Scholar : PubMed/NCBI
6	Wanders RJ, IJlst L, van Gennip AH, Jakobs C, de Jager JP, Dorland L, van Sprang FJ and 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. View Article : Google Scholar : PubMed/NCBI
7	Sykut-Cegielska J, Gradowska W, Piekutowska-Abramczuk D, Andresen BS, Olsen RK, Ołtarzewski M, Pronicki M, Pajdowska M, Bogdańska A, Jabłońska E, et al: 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. View Article : Google Scholar : PubMed/NCBI
8	Boutron A, Acquaviva C, Vianey-Saban C, de Lonlay P, de Baulny HO, Guffon N, Dobbelaere D, Feillet F, Labarthe F, Lamireau D, et al: 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. View Article : Google Scholar : PubMed/NCBI
9	Hong YB, Lee JH, Park JM, Choi YR, Hyun YS, Yoon BR, Yoo JH, Koo H, Jung SC, Chung KW and Choi BO: A compound heterozygous mutation in HADHB gene causes an axonal Charcot-Marie-tooth disease. BMC Med Genet. 14:1252013. View Article : Google Scholar : PubMed/NCBI
10	Fu X, Zheng F, Zhang Y, Bao X, Wang S, Yang Y and Xiong H: Mitochondrial trifunctional protein deficiency due to HADHB gene mutation in a Chinese family. Mol Genet Metab Rep. 5:80–84. 2015. View Article : Google Scholar : PubMed/NCBI
11	Bo R, Yamada K, Kobayashi H, Jamiyan P, Hasegawa Y, Taketani T, Fukuda S, Hata I, Niida Y, Shigematsu Y, et al: Clinical and molecular investigation of 14 Japanese patients with complete TFP deficiency: A comparison with caucasian cases. J Hum Genet. 62:809–814. 2017. View Article : Google Scholar : PubMed/NCBI
12	Liu ZR, Dong HL, Ma Y and Wu ZY: Identification and functional characterization of mutations within HADHB associated with mitochondrial trifunctional protein deficiency. Mitochondrion. 49:200–205. 2019. View Article : Google Scholar : PubMed/NCBI
13	Tyni T, Palotie A, Viinikka L, Valanne L, Salo MK, von Döbeln U, Jackson S, Wanders R, Venizelos N and 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. View Article : Google Scholar : PubMed/NCBI
14	Barvinska O, Olkhovych N and 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. View Article : Google Scholar
15	Glasgow JF and Middleton B: Reye syndrome-insights on causation and prognosis. Arch Dis Child. 85:351–353. 2001. View Article : Google Scholar : PubMed/NCBI
16	Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, et al: Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology. Genet Med. 17:405–424. 2015. View Article : Google Scholar : PubMed/NCBI
17	Scheuerman O, Wanders RJ, Waterham HR, Dubnov-Raz G and Garty BZ: Mitochondrial trifunctional protein deficiency with recurrent rhabdomyolysis. Pediatr Neurol. 40:465–467. 2009. View Article : Google Scholar : PubMed/NCBI
18	Zheng Y, Chen Y, Qiu X, Chen W, Lin Q, Zeng Y, Zhao H and Zhu W: A verification of the application of the non-derivatized mass spectrometry method in newborns screening of metabolic disorders. Medicine (Baltimore). 98:e155002019. View Article : Google Scholar : PubMed/NCBI
19	Terrone G, Ruoppolo M, Brunetti-Pierri N, Cozzolino C, Scolamiero E, Parenti G, Romano A, Andria G, Salvatore F and Frisso G: Child Neurology: Recurrent rhabdomyolysis due to a fatty acid oxidation disorder. Neurology. 82:e1–e4. 2014. View Article : Google Scholar : PubMed/NCBI
20	Landau YE, Waisbren SE, Chan LM and 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. View Article : Google Scholar : PubMed/NCBI
21	Diebold I, Schön U, Horvath R, Schwartz O, Holinski-Feder E, Kölbel H and 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. View Article : Google Scholar : PubMed/NCBI
22	Pena LD, van Calcar SC, Hansen J, Edick MJ, Vockley CW, Leslie N, Cameron C, Mohsen AW, Berry SA, Arnold GL, et al: 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. View Article : Google Scholar : PubMed/NCBI
23	Kang E, Kim YM, Kang M, Heo SH, Kim GH, Choi IH, Choi JH, Yoo HW and Lee BH: Clinical and genetic characteristics of patients with fatty acid oxidation disorders identified by newborn screening. BMC Pediatr. 18:1032018. View Article : Google Scholar : PubMed/NCBI
24	Ibdah JA: Acute fatty liver of pregnancy: An update on pathogenesis and clinical implications. World J Gastroenterol. 12:7397–7404. 2006. View Article : Google Scholar : PubMed/NCBI
25	Ronen J, Shaheen S, Steinberg D and Justus KR: Acute fatty liver of pregnancy:A thorough examination of a harmful obstetrical syndrome and its counterparts. Cureus. 10:e21642018.PubMed/NCBI
26	Schoeman MN, Batey RG and Wilcken B: Recurrent acute fatty liver of pregnancy associated with a fatty-acid oxidation defect in the offspring. Gastroenterology. 100:544–548. 1991. View Article : Google Scholar : PubMed/NCBI
27	Kobayashi T, Minami S, Mitani A, Tanizaki Y, Booka M, Okutani T, Yamaguchi S and Ino K: Acute fatty liver of pregnancy associated with fetal mitochondrial trifunctional protein deficiency. J Obstet Gynaecol Res. 41:799–802. 2015. View Article : Google Scholar : PubMed/NCBI