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

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.

[1]  Zhi-Rong Liu,et al.  Identification and functional characterization of mutations within HADHB associated with mitochondrial trifunctional protein deficiency. , 2019, Mitochondrion.

[2]  Wenbin Zhu,et al.  A verification of the application of the non-derivatized mass spectrometry method in newborns screening of metabolic disorders , 2019, Medicine.

[3]  R. Horvath,et al.  HADHA and HADHB gene associated phenotypes - Identification of rare variants in a patient cohort by Next Generation Sequencing. , 2019, Molecular and cellular probes.

[4]  M. Gubar,et al.  Psychoanalysis of young children with autism spectrum disorders. An adaptation of technique in the approach to three cases , 2023, The International journal of psycho-analysis.

[5]  S. Wortmann,et al.  Fatal pitfalls in newborn screening for mitochondrial trifunctional protein (MTP)/long-chain 3-Hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency , 2018, Orphanet Journal of Rare Diseases.

[6]  N. Gorovenko,et al.  High Prevalence of c.1528G>C Rearrangement in Patients with Long Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency from Ukraine , 2018, Cytology and Genetics.

[7]  H. Yoo,et al.  Clinical and genetic characteristics of patients with fatty acid oxidation disorders identified by newborn screening , 2018, BMC Pediatrics.

[8]  J. Ronen,et al.  Acute Fatty Liver of Pregnancy: A Thorough Examination of a Harmful Obstetrical Syndrome and Its Counterparts , 2018, Cureus.

[9]  M. Langeveld,et al.  Peripheral Neuropathy, Episodic Rhabdomyolysis, and Hypoparathyroidism in a Patient with Mitochondrial Trifunctional Protein Deficiency. , 2017, JIMD reports.

[10]  T. Taketani,et al.  Clinical and molecular investigation of 14 Japanese patients with complete TFP deficiency: a comparison with Caucasian cases , 2017, Journal of Human Genetics.

[11]  S. Waisbren,et al.  Long-term outcome of expanded newborn screening at Boston children’s hospital: benefits and challenges in defining true disease , 2017, Journal of Inherited Metabolic Disease.

[12]  J. Hansen,et al.  Outcomes and genotype-phenotype correlations in 52 individuals with VLCAD deficiency diagnosed by NBS and enrolled in the IBEM-IS database. , 2016, Molecular genetics and metabolism.

[13]  X. Bao,et al.  Mitochondrial trifunctional protein deficiency due to HADHB gene mutation in a Chinese family☆ , 2015, Molecular genetics and metabolism reports.

[14]  S. Yamaguchi,et al.  Acute fatty liver of pregnancy associated with fetal mitochondrial trifunctional protein deficiency , 2015, The journal of obstetrics and gynaecology research.

[15]  Bale,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 , 2015, Genetics in Medicine.

[16]  B. Plecko,et al.  Clinical outcome, biochemical and therapeutic follow-up in 14 Austrian patients with Long-Chain 3-Hydroxy Acyl CoA Dehydrogenase Deficiency (LCHADD) , 2015, Orphanet Journal of Rare Diseases.

[17]  N. Brunetti‐Pierri,et al.  Child Neurology: Recurrent rhabdomyolysis due to a fatty acid oxidation disorder , 2014, Neurology.

[18]  H. Koo,et al.  A compound heterozygous mutation in HADHB gene causes an axonal Charcot-Marie-tooth disease , 2013, BMC Medical Genetics.

[19]  A. Munnich,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. , 2011, Molecular genetics and metabolism.

[20]  B. Andresen,et al.  Urgent metabolic service improves survival in long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency detected by symptomatic identification and pilot newborn screening , 2011, Journal of Inherited Metabolic Disease.

[21]  H. Waterham,et al.  Mitochondrial trifunctional protein deficiency with recurrent rhabdomyolysis. , 2009, Pediatric neurology.

[22]  R. Wanders,et al.  Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: Identification of a new inborn error of mitochondrial fatty acidβ-oxidation , 1990, Journal of Inherited Metabolic Disease.

[23]  B. Middleton,et al.  Reye syndrome—insights on causation and prognosis , 2001, Archives of disease in childhood.

[24]  R. Wanders,et al.  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 , 2000, Pediatric Research.

[25]  A. Palotie,et al.  Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency with the G1528C mutation: clinical presentation of thirteen patients. , 1997, The Journal of pediatrics.

[26]  T Hashimoto,et al.  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. , 1992, The Journal of biological chemistry.

[27]  B. Wilcken,et al.  Recurrent acute fatty liver of pregnancy associated with a fatty-acid oxidation defect in the offspring. , 1991, Gastroenterology.