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Post-mortem Diagnosis of Heme Oxygenase-1 Deficiency by Whole Exome Sequencing in an Iranian Child.

ABSTRACT: Heme oxygenase-1 (HO-1) is an inducible enzyme involved in the catalysis of heme conversion into biliverdin. We describe a patient with a novel stop-gain mutation in the HMOX1 coding sequence resulting in HO-1 deficiency. A 17-month-old female with fever, tachypnea, and signs of respiratory distress was referred to our center. Four admissions ensued during the eight months follow up. At the first admission, she had massive pericardial effusion without any laboratory findings for tuberculosis, viral infectionsor malignancies.An abdominal ultrasound examination confirmed hepatomegaly.Laboratory findings showed leukocytosis, thrombocytosis, hemolytic anemia, elevated inflammatory markers, increased levels of the hepatic transferase, triglycerides and ferritin as well as decreased level of fibrinogen. Other laboratory investigations were negative blood cultures, normal bone marrow aspiration, and normal serology viral infections. Immunodeficiency and auto-inflammatory syndromes were ruled out. Hepatic biopsy showed iron deposits. The patient was initiated on corticosteroids; however, her clinical condition was progressively deteriorated, and she died of recurrent fever, bleeding, heart failure, and ascites. Post-mortem whole exome sequencing revealed a homozygous mutation (exon3: c.A610T, p.K204X) on the HMOX1 gene. The parents were found to be heterozygous for that mutation. The laboratory findings and clinical features of our patient were somehow similar to that of HO-1 deficient cases reported previously, as well as Hmox1 knocked out mice. We speculate that the clinical manifestations of HO-1 deficient patients can be partially dependent on the type of mutation they inherit.

SUBMITTER: Tahghighi F

PROVIDER: S-EPMC7305464 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Post-mortem Diagnosis of Heme Oxygenase-1 Deficiency by Whole Exome Sequencing in an Iranian Child.

Tahghighi Fatemeh F Parvaneh Nima N Ziaee Vahid V

International journal of molecular and cellular medicine 20190101 4

Heme oxygenase-1 (HO-1) is an inducible enzyme involved in the catalysis of heme conversion into biliverdin. We describe a patient with a novel stop-gain mutation in the <i>HMOX1</i> coding sequence resulting in HO-1 deficiency. A 17-month-old female with fever, tachypnea, and signs of respiratory distress was referred to our center. Four admissions ensued during the eight months follow up. At the first admission, she had massive pericardial effusion without any laboratory findings for tuberculo ...[more]

PMID: 32587840

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Project description:Acyl-CoA dehydrogenase 9 (ACAD9), linked to chromosome 3q21.3, is one of a family of multimeric mitochondrial flavoenzymes that catalyze the degradation of fatty acyl-CoA from the carnitine shuttle via ?-oxidation (He et al. 2007). ACAD9, specifically, is implicated in the processing of palmitoyl-CoA and long-chain unsaturated substrates, but unlike other acyl-CoA dehydrogenases (ACADs), it has a significant role in mitochondrial complex I assembly (Nouws et al. 2010 & 2014). Mutations in this enzyme typically cause mitochondrial complex I deficiency, as well as a mild defect in long chain fatty acid metabolism (Haack et al. 2010, Kirby et al. 2004, Mcfarland et al. 2003, Nouws et al. 2010 & 2014). The clinical phenotype of ACAD9 deficiency and the associated mitochondrial complex I deficiency reflect this unique duality, and symptoms are variable in severity and onset. Patients classically present with cardiac dysfunction due to hypertrophic cardiomyopathy. Other common features include Leigh syndrome, macrocephaly, and liver disease (Robinson et al. 1998). We report the case of an 11-month old girl presenting with microcephaly, dystonia, and lactic acidosis, concerning for a mitochondrial disorder, but atypical for ACAD9 deficiency. Muscle biopsy showed mitochondrial proliferation, but normal mitochondrial complex I activity. The diagnosis of ACAD9 deficiency was not initially considered, due both to these findings and to her atypical presentation. Biochemical assay for ACAD9 deficiency is not clinically available. Family trio-based whole exome sequencing (WES) identified 2 compound heterozygous mutations in the ACAD9 gene. This discovery led to optimized treatment of her mitochondrial dysfunction, and supplementation with riboflavin, resulting in clinical improvement. There have been fewer than 25 reported cases of ACAD9 deficiency in the literature to date. We review these and compare them to the unique features of our patient. ACAD9 deficiency should be considered in the differential diagnosis of patients with lactic acidosis, seizures, and other symptoms of mitochondrial disease, including those with normal mitochondrial enzyme activities. This case demonstrates the utility of WES, in conjunction with biochemical testing, for the appropriate diagnosis and treatment of disorders of energy metabolism.

Dataset Information

Post-mortem Diagnosis of Heme Oxygenase-1 Deficiency by Whole Exome Sequencing in an Iranian Child.

Publications

Post-mortem Diagnosis of Heme Oxygenase-1 Deficiency by Whole Exome Sequencing in an Iranian Child.

Similar Datasets

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