Lethal Neonatal Progression of Fetal Cardiomegaly Associated to ACAD9 Deficiency

Lagoutte-Renosi, Jennifer; Ségalas-Milazzo, Isabelle; Crahès, Marie; Renosi, Florian; Menu-Bouaouiche, Laurence; Torre, Stéphanie; Rio, Marlène; Marret, Stéphane; Brasse‐Lagnel, Carole; Laquerrière, Annie; Bekri, Soumeya

doi:10.1007/8904_2015_499

Cited by 11 publications

(4 citation statements)

References 26 publications

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“…All patients had a reduction in CI enzymatic activity and assembly. Severe neonatal presentations [ 38 ] and multiorgan involvement, with liver and kidney damage [ 39 ], broaden the phenotypic spectrum of ACAD9 disease. Most of the ACAD9 mutant cells and patients respond to riboflavin treatment, with partial correction of CI deficiency and clinical improvement [ 35 , 40 ], possibly because ACAD9 is an FADH 2 -dependent acyl-CoA dehydrogenase.…”

Section: Human Diseases Associated With CI Deficiency (Mim 252010)mentioning

confidence: 99%

Human diseases associated with defects in assembly of OXPHOS complexes

Ghezzi

Zeviani

2018

Essays in Biochemistry

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The structural biogenesis and functional proficiency of the multiheteromeric complexes forming the mitochondrial oxidative phosphorylation system (OXPHOS) require the concerted action of a number of chaperones and other assembly factors, most of which are specific for each complex. Mutations in a large number of these assembly factors are responsible for mitochondrial disorders, in most cases of infantile onset, typically characterized by biochemical defects of single specific complexes. In fact, pathogenic mutations in complex-specific assembly factors outnumber, in many cases, the repertoire of mutations found in structural subunits of specific complexes. The identification of patients with specific defects in assembly factors has provided an important contribution to the nosological characterization of mitochondrial disorders, and has also been a crucial means to identify a huge number of these proteins in humans, which play an essential role in mitochondrial bioenergetics. The wide use of next generation sequencing (NGS) has led to and will allow the identifcation of additional components of the assembly machinery of individual complexes, mutations of which are responsible for human disorders. The functional studies on patients’ specimens, together with the creation and characterization of in vivo models, are fundamental to better understand the mechanisms of each of them. A new chapter in this field will be, in the near future, the discovery of mechanisms and actions underlying the formation of supercomplexes, molecular structures formed by the physical, and possibly functional, interaction of some of the individual respiratory complexes, particularly complex I (CI), III (CIII), and IV (CIV).

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Section: Human Diseases Associated With CI Deficiency (Mim 252010)mentioning

confidence: 99%

Human diseases associated with defects in assembly of OXPHOS complexes

Ghezzi

Zeviani

2018

Essays in Biochemistry

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“…The two fetuses reported here share phenotypic presentations with individual 1 and 2 from the study by Feichtinger et al, 3 namely IUGR, oligo/anhydramnios, generalized edema, cardio/hepatomegaly, cortical hemorrhages, and preterm birth within 20 to 34 weeks of gestation. Studies of other mitochondrial diseases caused by pathogenic variants in, for example, ACAD9 , POLG , COQ9 , and FBXL4 , have shown prenatal onset of mitochondrial disease with intrauterine growth retardation, lactic acidosis, cardiomegaly, anemia, renal abnormalities, dysmorphic facial features, cerebellar hypoplasia and often preterm, or shortly thereafter, fatality 13‐16 . However, the large variability in phenotypic presentation, the large number of genes involved in mitochondrial function, and the unknown prenatal phenotype for most mitochondrial diseases highlights the utility of exome/genome sequencing in the diagnostic workup.…”

Section: Discussionmentioning

confidence: 99%

A novel homozygous variant in C1QBP causes severe IUGR, edema, and cardiomyopathy in two fetuses

et al. 2021

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The C1QBP protein (complement component 1 Q subcomponent‐binding protein), encoded by the C1QBP gene, is a multifunctional protein predominantly localized in the mitochondrial matrix. Biallelic variants have previously been shown to give rise to combined respiratory‐chain deficiencies with variable phenotypic presentation, severity, and age at onset, from intrauterine with a mostly lethal course, to a late‐onset mild myopathy. We present two fetuses, one male and one female, of first‐cousin parents, with severe intrauterine growth retardation, oligo/anhydramnios, edema, and cardiomyopathy as the most prominent prenatal symptoms. Both fetuses showed no copy number variants by chromosome microarray analysis. Analysis of a fibroblast culture from one of the fetuses showed deficiency of respiratory chain complex IV, and using exome sequencing, we identified homozygosity for a novel variant in C1QBP in both fetuses. To our knowledge, only six patients with pathogenic variants in C1QBP have been reported previously and with this report, we add a novel pathogenic variant in C1QBP found in two related fetuses.

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“…A single case of type I mitochondrial complex deficiency has been reported with antenatal biventricular non-compaction associated with congenital complete heart block [Dhar et al, 2015], but the underlying genetic etiology for this case was not determined. Three other cases with pathogenic variants in ACAD9 had fetal cardiac findings, one of them cardiomegaly [Lagoutte-Renosi et al, 2015] and the other two dysrythmias [Repp et al, 2018]. Interestingly, the case with prenatal cardiomegaly also showed growth retardation detected as early as at 22 weeks' gestation.…”

Section: Prenatal Cardiac Findingsmentioning

confidence: 96%

Severe Antenatal Hypertrophic Cardiomyopathy Secondary to ACAD9-Related Mitochondrial Complex I Deficiency

Dubucs¹,

Aziza

Sartor

et al. 2022

Mol Syndromol

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Introduction: Antenatal presentation of hypertrophic cardiomyopathy (HCM) is rare. We describe familial recurrence of antenatal HCM associated with intrauterine growth restriction and the diagnostic process undertaken. Methods: Two pregnancies with antenatal HCM were followed up. Biological assessment including metabolic analyses, genetic analyses, and respiratory chain study was performed. We describe the clinical course of these two pregnancies, antenatal manifestations as well as specific histopathological findings, and review the literature. Results: The assessment revealed a deficiency in complex I of the respiratory chain and two likely pathogenic variations in the ACAD9 gene. Discussion and Conclusion: Antenatal HCM is rare and a diagnosis is not always made. In pregnancies presenting with cardiomyopathy and intrauterine growth restriction, ACAD9 deficiency should be considered as one of the potential underlying diagnoses, and ACAD9 molecular testing should be included among other prenatal investigations.

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Lethal Neonatal Progression of Fetal Cardiomegaly Associated to ACAD9 Deficiency

Cited by 11 publications

References 26 publications

Human diseases associated with defects in assembly of OXPHOS complexes

Human diseases associated with defects in assembly of OXPHOS complexes

A novel homozygous variant in C1QBP causes severe IUGR, edema, and cardiomyopathy in two fetuses

Severe Antenatal Hypertrophic Cardiomyopathy Secondary to ACAD9-Related Mitochondrial Complex I Deficiency

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