A Patient with Complex I Deficiency Caused by a Novel ACAD9 Mutation Not Responding to Riboflavin Treatment

Nouws, Jessica; Wibrand, Flemming; Brand, Mariël van den; Venselaar, Hanka; Dunø, Morten; Lund, Allan M.; Trautner, Simon; Nijtmans, Leo; Østergård, E.

doi:10.1007/8904_2013_242

Cited by 30 publications

(9 citation statements)

References 23 publications

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“…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. Nevertheless, non-responsive patients have been reported [ 41 ]. The surviving patients often develop delayed-onset neurologic or muscular symptoms [ 37 ].…”

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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“…Acyl‐CoA dehydrogenase 9 (ACAD9) also has a critical role in mitochondrial complex I (CI) assembly, and mutations in the ACAD9 gene cause mitochondrial disease with isolated CI deficiency . The major clinical presentation is rapidly progressive hypertrophic cardiomyopathy . Only a few patients (5 of the 24 published cases to date) had a mild phenotype with fatigability, exercise intolerance, and lactic acidosis.…”

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confidence: 99%

Severe defect in mitochondrial complex I assembly with mitochondrial DNA deletions in ACAD9‐deficient mild myopathy

et al. 2017

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“…According to Haack et al's studies, supplementation with riboflavin leads to assembly and stability of the ACAD enzymes and therefore significant increase in mitochondrial complex I activity [15]. While certain mutations have been found to be resistant to riboflavin, the majority of ACAD9 deficiency cases can be partially treated with riboflavin supplementation [24]. Our patient's ambulation and visual fixation did improve with the addition of these therapies.…”

Section: Discussionmentioning

confidence: 52%

An atypical presentation of ACAD9 deficiency: Diagnosis by whole exome sequencing broadens the phenotypic spectrum and alters treatment approach

Aintablian

Narayanan

Belnap

et al. 2017

Molecular Genetics and Metabolism Reports

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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 β-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.

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A Patient with Complex I Deficiency Caused by a Novel ACAD9 Mutation Not Responding to Riboflavin Treatment

Cited by 30 publications

References 23 publications

Human diseases associated with defects in assembly of OXPHOS complexes

Human diseases associated with defects in assembly of OXPHOS complexes

Severe defect in mitochondrial complex I assembly with mitochondrial DNA deletions in ACAD9‐deficient mild myopathy

An atypical presentation of ACAD9 deficiency: Diagnosis by whole exome sequencing broadens the phenotypic spectrum and alters treatment approach

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