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Mitochondrial trifunctional protein deficiency due to HADHB gene mutation in a Chinese family.

ABSTRACT: We report an 8-year-old girl with lower limb weakness since birth in whom mitochondrial trifunctional protein (MTP) deficiency, an autosomal recessive fatty acid oxidation disorder caused by HADHA or HADHB mutations, had not been definitively diagnosed before she was referred to our hospital. Repeated blood acylcarnitine analysis revealed slightly increased long-chain 3-OH-acylcarnitine levels; electromyography (EMG) suggested peripheral nerve injury; muscle biopsy confirmed a neurogenic lesion in muscle fibers, as shown by EMG. Analysis of the HADHB, which encodes long-chain 3-ketoacyl-CoA thiolase, one of the enzymes constituting mitochondrial trifunctional protein, identified homozygous missense mutation c.739C > T (p.R247C). Mitochondrial trifunctional protein deficiency is an extremely rare disorder and has not been reported in Chinese people to date. It is likely that neonatal onset, as seen in our patient, has not been reported for the neuromyopathic phenotype of mitochondrial trifunctional protein deficiency.

SUBMITTER: Fu X

PROVIDER: S-EPMC5471393 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Mitochondrial trifunctional protein deficiency due to HADHB gene mutation in a Chinese family.

Fu Xiaona X Zheng Feixia F Zhang Yao Y Bao Xinhua X Wang Shuang S Yang Yanling Y Xiong Hui H

Molecular genetics and metabolism reports 20151106

We report an 8-year-old girl with lower limb weakness since birth in whom mitochondrial trifunctional protein (MTP) deficiency, an autosomal recessive fatty acid oxidation disorder caused by HADHA or HADHB mutations, had not been definitively diagnosed before she was referred to our hospital. Repeated blood acylcarnitine analysis revealed slightly increased long-chain 3-OH-acylcarnitine levels; electromyography (EMG) suggested peripheral nerve injury; muscle biopsy confirmed a neur ...[more]

PMID: 28649548

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Project description: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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Mitochondrial trifunctional protein deficiency due to HADHB gene mutation in a Chinese family.

Publications

Mitochondrial trifunctional protein deficiency due to <i>HADHB</i> gene mutation in a Chinese family.

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