Mitochondrial Complex I Deficiency, Nuclear Type 11

A number sign (#) is used with this entry because of evidence that mitochondrial complex I deficiency nuclear type 11 (MC1DN11) is caused by compound heterozygous mutation in the NDUFAF1 gene (606934) on chromosome 15q15.

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

Clinical Features

Dunning et al. (2007) reported a patient with mitochondrial complex I deficiency manifest as cardioencephalomyopathy. He presented at age 11 months with failure to thrive and developed severe cardiac failure due to hypertrophic cardiomyopathy in association with a viral illness at age 15 months. He had developmental delay, lactic acidosis, and hypotonia. He was diagnosed with Wolff-Parkinson-White syndrome (194200) at age 3, cortical visual dysfunction at age 7, and pigmentary retinopathy at age 11. At age 20, he had mild to moderate intellectual disability and myopathy.

Fassone et al. (2011) reported a French infant with fatal infantile hypertrophic cardiomyopathy and isolated complex I deficiency. The patient presented at age 6.5 months in cardiogenic shock with metabolic acidosis after a respiratory viral infection. Echocardiogram showed pericardial effusion, biventricular hypertrophy, and left ventricular dysfunction. Skeletal muscle biopsy showed increased lipid deposition and accumulation of enlarged and abnormal mitochondria and an isolated severe deficiency of complex I activity (25% of controls). She died soon after, despite aggressive treatment. Postmortem examination showed an enlarged globular heart and myocardial hypertrophy with foci of myofiber loss and replacement fibrosis. Liver histology showed macrovesicular steatosis, but respiratory chain enzymes in the liver were normal. Fassone et al. (2011) noted that both their patient and the patient reported by Dunning et al. (2007) developed hypertrophic cardiomyopathy in infancy after a viral illness, but the latter patient had a multisystem disorder and showed much longer survival. Correct diagnosis of mitochondrial cardiomyopathy is critical for genetic counseling.

Molecular Genetics

Dunning et al. (2007) reported a patient with mitochondrial complex I deficiency manifest as cardioencephalomyopathy who was compound heterozygous for 2 mutations in the NDUFAF1 (T207P, 606934.0001 and K253R, 606934.0002).

Fassone et al. (2011) identified compound heterozygosity for 2 mutations in the NDUFAF1 gene (R211C, 606934.0003 and G245R, 606934.0004) in a French infant with fatal infantile hypertrophic cardiomyopathy and isolated complex I deficiency. Each unaffected parent was heterozygous for 1 of the mutations, which were not found in 240 control alleles.