Mitochondrial Complex I Deficiency, Nuclear Type 15

A number sign (#) is used with this entry because of evidence that mitochondrial complex I deficiency nuclear type 15 (MC1DN15) is caused by homozygous mutation in the C6ORF66 gene (NDUFAF4; 611776) on chromosome 6q16.

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

Clinical Features

Saada et al. (2008) reported 6 patients, 5 of whom were from a consanguineous Arab Muslim family, with mitochondrial complex I deficiency who presented in infancy with devastating encephalomyopathy or antenatal cardiomyopathy. There were 9 affected members in the Arab Muslim family, but tissue was available for only 5 for enzymatic and molecular testing. All affected family presented soon after birth with severe metabolic acidosis and very high plasma-lactate levels. Three patients died at 2-5 days of age from intractable acidosis. Patients who survived longer were repeatedly admitted because of exacerbation of the acidosis during intercurrent infections. Generalized muscle hypotonia was noted soon after birth, and failure to thrive, irritability, paucity of spontaneous movements, dystonic posturing during crying, nystagmus, failure to interact with the surroundings and lack of eye contact were evident at 6 months. At age 16 months, one patient had spastic tone with quadriplegic involvement, thoracic kyphosis, and reduced range of motion at the knees and hips. Brain MRI of this patient revealed severe atrophy of both gray and white matter, with demyelination, most prominent at the anterior aspects of the brain; the cerebellum, basal ganglia, pons, and medulla were severely atrophic. Physical examination of the oldest surviving patient, age 7 years, was similar, with kyphosis and multiple contractures.

Baertling et al. (2017) reported a boy, born of consanguineous Pakistani parents, with MC1DN15. He presented at 7 months of age with global developmental delay, irritability, and hypotonia. Brain imaging showed signal alterations in the basal ganglia consistent with Leigh syndrome. EEG showed generalized slowing with multifocal spikes. Laboratory studies showed increased serum and CSF lactate, and patient-derived fibroblasts showed isolated mitochondrial complex I deficiency. Two years later, the patient had profound developmental delay, episodic seizures, and was tube-fed.

Molecular Genetics

In 5 affected members of an Arab Muslim consanguineous family with mitochondrial complex I deficiency manifesting as infantile mitochondrial encephalopathy and in an unrelated patient who presented with antenatal cardiomyopathy, Saada et al. (2008) identified homozygosity for a missense mutation in the C6ORF66 gene (L65P; 611776.0001).

In a boy, born of consanguineous Pakistani parents, with MC1DN15, Baertling et al. (2017) identified a homozygous missense mutation in the NDUFAF4 gene (A3P; 611776.0002). The mutation was found by whole-exome sequencing. Patient fibroblasts showed absence of NDUFAF4, abnormal stoichiometry of supercomplexes, and impaired assembly of complex I with accumulation of some modules and not others. Complementation of patient cells with wildtype NDUFAF4 rescued the complex I deficiency and assembly defect.