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

Abstract

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.

Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?

“…In anecdotal reports of patients with a predominance of myopathic features, alleviation of symptoms under riboflavin treatment has been reported [ 5 , 7 , 8 ]. Riboflavin is the precursor of flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), which are cofactors for complex I and numerous dehydrogenases involved in FAO.…”

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

“…Of the cases for which prenatal manifestations were sought after postnatal diagnosis, oligohydramnios and IUGR were the most commonly reported clinical signs, in 4 and 6 cases, respectively. Those manifestations were considered nonspecific by the authors [Aintablian et al, 2017;Repp et al, 2018]. Our 2 cases presented as well with IUGR detectable in the second trimester, which makes this ultrasonographic finding relatively frequent in the severe form of ACAD9 deficiency.…”

“…N, normal range. notypes with a large clinical spectrum and inconstant signs, from a severe form beginning at birth to a moderate phenotype with later onset [Aintablian et al, 2017;Repp et al, 2018]. Of those 70 cases, 22 patients presented features in the neonatal period (birth to 28 days), and only 9 of them were reported with prenatal manifestations.…”

Advances in the treatment of mitochondrial epilepsies

“…Affected patients typically have a good clinical response to riboflavin supplementation [15]. The most frequent clinical features associated with ACAD9 deficiency are hypertrophic cardiomyopathy, lactic acidosis and exercise intolerance, but seizures have been reported in occasional cases [16,17]. Mutations of AIFM1, encoding apoptosis inducing factor mitochondria associated 1, another flavoprotein required for complex I assembly, have been reported to cause riboflavinresponsive ataxia in two patients [18].…”