Mitochondrial Complex I Deficiency, Nuclear Type 26

A number sign (#) is used with this entry because of evidence that mitochondrial complex I deficiency nuclear type 26 (MC1DN26) is caused by homozygous mutation in the NDUFA9 gene (603834) on chromosome 12p13.

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

Clinical Features

Van den Bosch et al. (2012) reported a patient, born of consanguineous Kurdish parents, with mitochondrial complex I deficiency. After birth, the child developed respiratory and metabolic acidosis with increased serum lactate. Isolated complex I deficiency was found in muscle (29% of controls) and fibroblasts (11% of controls). He developed profound hearing loss, apneas associated with brainstem abnormalities, and retinitis pigmentosa. Brain MRI on day 6 showed diffuse loss of supratentorial white matter and brainstem volume with T2 hyperintensities of the basal nuclei, as well as a region of focal necrosis in the thalamus, all consistent with Leigh syndrome (see 256000). He became increasingly hypertonic with choreodystonic movements, and died of respiratory insufficiency at age 1 month.

Baertling et al. (2018) reported a patient, born of nonconsanguineous Chinese parents, with mitochondrial complex I deficiency. The patient was well until the age of 7 years when he developed progressive generalized dystonia. He also developed dysphagia, speech disturbance, and eventually severe dysarthria. He had no signs of intellectual deterioration. At age 28 years, he was diagnosed with axonal motor and sensory peripheral polyneuropathy with distal muscle wasting and depressed deep tendon reflexes. In his mid-forties, his clinical condition was stable. MRI of the brain showed a progressive bilateral putaminal signal alterations compatible with Leigh syndrome and atrophy of the left caudate nucleus.

Molecular Genetics

In a patient, born of consanguineous Kurdish parents, with mitochondrial complex I deficiency, van den Bosch et al. (2012) identified a homozygous missense mutation in the NDUFA9 gene (R321P; 603834.0001). The mutation was found by homozygosity mapping followed by candidate gene analysis.

In a patient, born of nonconsanguineous Chinese parents, with mitochondrial complex I deficiency, in whom mutations in genes known or predicted to cause the disorder were excluded, Baertling et al. (2018) identified homozygosity for a missense mutation in the NDUFA9 gene (R360C; 603834.0002). The mutation, which was found by whole-exome sequencing, was not present in the ExAC or 1000 Genomes Project databases or in an in-house database.