A number sign (#) is used with this entry because of evidence that mitochondrial complex I deficiency nuclear type 20 (MC1DN20) is caused by homozygous or compound heterozygous mutation in the ACAD9 gene (611103) on chromosome 3q21.

MC1DN20 is an autosomal recessive multisystem disorder characterized by infantile onset of acute metabolic acidosis, hypertrophic cardiomyopathy, and muscle weakness associated with a deficiency of mitochondrial complex I activity in muscle, liver, and fibroblasts (summary by Haack et al., 2010).

For a discussion of genetic heterogeneity of mitochondrial complex I deficiency, see 252010.

Haack et al. (2010) reported 4 patients, including 2 sibs, with mitochondrial complex I deficiency. In the 2 sibs, the sister presented soon after birth with cardiorespiratory depression, hypertrophic cardiomyopathy, encephalopathy, and severe lactic acidosis, and died at 46 days of age. Compared to controls, complex I activity was reduced to 9 to 14% in patient muscle, 1% in patient liver, and 32 to 39% in patient fibroblasts. Complex V activity was reduced to 52% in patient muscle and 38% in patient liver. The complex I holoenzyme was reduced by 35% in mutant cells, suggesting either complex I instability or impaired assembly. Her brother, who presented at birth with hypotonia, cardiohypertrophy, and lactic acidosis, received vigorous treatment with riboflavin, which resulted in a favorable clinical response; he had no cognitive impairment and normal psychomotor development at 5 years of age. Two additional unrelated girls with the disorder were also reported: both had hypertrophic cardiomyopathy, encephalopathy, and lactic acidosis, and died at age 2 and 12 years, respectively. None of the patients had evidence of a defect in beta-oxidation of fatty acids.

Haack et al. (2012) reported a family in which 3 patients had hypertrophic cardiomyopathy, hypotonia, lactic acidosis, and exercise intolerance associated with complex I deficiency. Complex I activity was 3% of normal in muscle biopsy from 1 of the patients.

Clinical Variability

He et al. (2007) reported 3 cases of complex I deficiency presenting with episodic liver dysfunction during otherwise mild illnesses or cardiomyopathy, along with chronic neurologic dysfunction. Patient 1 was a 14-year-old previously healthy boy who died of a Reye-like episode and cerebellar stroke triggered by a mild viral illness and ingestion of aspirin. Findings on autopsy included diffuse hepatic microvesicular steatosis and some macrovesicular steatosis, which were interpreted as being consistent with Reye-like syndrome. Brain findings were notable for generalized edema with diffuse ventricular compression, acute left tonsillar herniation, and diffuse multifocal acute damage in the hippocampus. In addition, some abnormalities consistent with nonacute changes were seen, including a subacute right cerebellar hemispheric infarct and reduction in the number of neurons in several areas. Patient 2 was a 10-year-old girl who first presented at age 4 months with fulminant liver failure, and thereafter experienced recurrent episodes of acute liver dysfunction and hypoglycemia, with otherwise minor illnesses. Patient 3 was a 4.5-year-old girl who died of cardiomyopathy and whose sib also died of cardiomyopathy at age 22 months. Mild chronic neurologic dysfunction was reported. All 3 patients had biochemical findings suggestive of an unknown long-chain fat metabolism defect.

Dewulf et al. (2016) reported 9 additional patients, 7 girls and 2 boys, with complex I deficiency from 3 unrelated families. Most presented in the neonatal period with lactate acidosis and died in infancy. In addition to the previously reported hypertrophic cardiomyopathy, 5 of the patients (representing 2 families) had patent ductus arteriosus (PDA). Two sibs from family II presented in childhood with exercise intolerance and were clinically stable in their mid-20s under riboflavin treatment with mild left ventricular hypertrophy (LVH).

Haack et al. (2010) reported a boy who presented at birth with hypotonia, cardiohypertrophy, lactic acidosis, and mitochondrial complex I deficiency. He received vigorous treatment with riboflavin, which resulted in a favorable clinical response; he had no cognitive impairment and normal psychomotor development at 5 years of age.

The transmission pattern of complex I deficiency nuclear type 20 in the families reported by Haack et al. (2010) and Haack et al. (2012) was consistent with autosomal recessive inheritance.

In 4 patients, including 2 sibs, with mitochondrial complex I deficiency nuclear type 20, Haack et al. (2010) identified compound heterozygosity for 2 mutations in the ACAD9 gene (611103.0002-611103.0006, respectively). The authors demonstrated the efficacy of exome sequencing, in combination with a functional cell assay, for elucidating the molecular basis of complex I deficiency

Among 3 patients with complex I deficiency, He et al. (2007) identified a 4-bp insertion 44 bp upstream of the first ATG of the ACAD9 gene on 1 allele (611103.0001) of patient 1. Only a minimal signal corresponding to this insertion was visible when fragments amplified from cDNA made from patient liver mRNA were directly sequenced, suggesting a transcriptional defect in this allele. Although a minimal amount of ACAD9 antigen was detected in samples from patient 1, it was thought probably enzymatically inactive, since none was appropriately targeted to mitochondria. Instead, residual ACAD9 protein in this patient was predominantly cytoplasmic. He et al. (2007) stated that the complexity of the ACAD9 gene and its transcripts hindered their ability to elucidate the molecular defect in the 3 remaining ACAD9 alleles (from patients 1 and 2) available for examination; no frozen blood or tissue samples from patient 3 were available for study. Patient 1 presented with a Reye-like episode after aspirin ingestion during a viral illness, a presentation frequently reported in LCHAD deficiency (HADHA; 600890) and MCAD deficiency (ACADM; 607008). He et al. (2007) suggested that ACAD9 deficiency should be considered if other beta-oxidation defects are not identified.

In affected members of a family with mitochondrial complex I deficiency characterized by hypertrophic cardiomyopathy, Haack et al. (2012) identified a homozygous mutation in the ACAD9 gene (611103.0006). The mutation was identified by exome sequencing.

Dewulf et al. (2016) reported 9 additional patients from 3 unrelated families with novel mutations in ACAD9. Two sibs who were compound heterozygous for 2 missense mutations (611103.0007-611013.0008) were more mildly affected, presenting in midchildhood and still doing well in their 20s under riboflavin treatment.

By in vitro functional expression assays in E. coli, Schiff et al. (2015) evaluated the ACAD enzymatic dehydrogenase activity of 16 pathogenic ACAD9 mutations identified in 24 patients with ACAD9 deficiency. All mutations were found in patients with complex I deficiency, but ACAD enzyme activity varied from nondetectable to normal levels, and did not correlate with the complex I defect. However, there was a significant inverse correlation between residual ACAD enzymatic dehydrogenase activity and phenotypic severity of ACAD9-deficient patients. These results indicated that ACAD9 plays a physiologic role in fatty acid oxidation in cells where it is strongly expressed and suggested that the fatty acid oxidation defect contributes to the severity of the phenotype in ACAD9-deficient patients. Schiff et al. (2015) suggested that treatment of patients with ACAD9 deficiency should aim at counteracting both complex I and fatty acid oxidation dysfunctions.

Sinsheimer et al. (2021) developed and characterized whole-body, cardiac-specific, and skeletal muscle-specific homozygous Acad9 knockout mouse models. The whole-body Acad9 knockout caused embryonic lethality. In heart tissue from the cardiac-specific Acad9 knockout mice, ECSIT (608388) and ACADVL (609575) expression was undetectable, and ACADM (607008) expression was reduced compared to wildtype. In heart tissue from the cardiac-specific Acad9 knockout mice, complex I and respiratory chain supercomplexes were undetectable, and cardiac mitochondria did not respond to substrates that drive complex I. At day 14 of life, the mutant mice had cardiomyopathy with thickened atrial and ventricular walls and reduced ejection fraction. Based on the detection of cardiac dysfunction so early in life, Sinsheimer et al. (2021) hypothesized that the cardiac disease started in utero. The muscle-specific Acad9 knockout mice had impaired exercise tolerance at 2 to 6 months of age and elevated baseline and post-exercise blood lactate levels.