ACAD9 – acyl-CoA dehydrogenase 9 deficiency

Acyl-CoA dehydrogenase 9 (ACAD9) is a mitochondrial flavoenzyme with dual functions in long-chain fatty acid β-oxidation and assembly of oxidative phosphorylation complex I ([PMID:21057504]). Biallelic variants in ACAD9 cause autosomal recessive acyl-CoA dehydrogenase 9 deficiency, characterized by impaired complex I assembly and variable fatty acid oxidation defects.

Genetic evidence includes >24 probands from at least 15 unrelated families, with compound heterozygous and homozygous missense, splice, and loss-of-function variants segregating with disease ([PMID:28070495]; [PMID:20929961]). In a consanguineous kindred, two siblings homozygous for c.1594C>T (p.Arg532Trp) exhibited complex I deficiency responsive to riboflavin. Segregation of biallelic variants in multiple families supports autosomal recessive inheritance.

Clinical presentations are heterogeneous. An index 11-month–old presented with microcephaly, dystonia, and lactic acidosis despite normal complex I activity in muscle ([PMID:28070495]). Another adult with c.398G>A (p.Ser133Asn) manifested hypertrophic cardiomyopathy, myopathy, seizures, and intellectual disability, successfully treated with riboflavin and resulting in a normal pregnancy ([PMID:33204590]).

The variant spectrum now exceeds 50 pathogenic alleles including missense substitutions (e.g., p.Arg414Cys), canonical splice-site changes (c.1030-1G>T), and frameshift/truncating alleles ([PMID:25721401]; [PMID:23836383]). Recurrent p.Arg414Cys has been reported in multiple families with both severe cardiomyopathy and mild myopathy.

Functional studies demonstrate that wild-type ACAD9 restores complex I activity in patient fibroblasts, whereas mutant proteins fail to rescue enzyme function, confirming a loss-of-function mechanism ([PMID:20929961]; [PMID:21057504]). Mouse models with tissue-specific Acad9 deletion recapitulate neonatal cardiomyopathy and muscle weakness, validating the pathogenic role of ACAD9 deficiency ([PMID:34556413]).

Some pathogenic variants, such as Ala220Thr, do not respond to riboflavin in vitro and are associated with early lethality, indicating allelic heterogeneity in therapeutic response ([PMID:23996478]).

In summary, robust genetic and functional data classify the ACAD9–acyl-CoA dehydrogenase 9 deficiency association as Strong. Autosomal recessive inheritance, segregation in multiple families, concordant biochemical and rescue assays, and animal models underpin diagnostic and therapeutic decision-making. Key Take-home: ACAD9 testing should be integrated into the evaluation of mitochondrial disease, and riboflavin therapy trialed when biallelic loss-of-function variants are identified.

References

• Brain : a journal of neurology • 2011 • Riboflavin-responsive oxidative phosphorylation complex I deficiency caused by defective ACAD9: new function for an old gene. PMID:20929961
• Nature genetics • 2010 • Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency. PMID:21057504
• Molecular genetics and metabolism reports • 2017 • An atypical presentation of ACAD9 deficiency: Diagnosis by whole exome sequencing broadens the phenotypic spectrum and alters treatment approach. PMID:28070495
• JIMD reports • 2020 • Successful pregnancy in a patient with mitochondrial cardiomyopathy due to ACAD9 deficiency. PMID:33204590
• Human molecular genetics • 2015 • Complex I assembly function and fatty acid oxidation enzyme activity of ACAD9 both contribute to disease severity in ACAD9 deficiency. PMID:25721401
• JIMD reports • 2014 • A Patient with Complex I Deficiency Caused by a Novel ACAD9 Mutation Not Responding to Riboflavin Treatment. PMID:23996478
• Molecular genetics and metabolism • 2021 • Development and characterization of a mouse model for Acad9 deficiency. PMID:34556413

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