Mitochondrial Complex I Deficiency, Nuclear Type 12

A number sign (#) is used with this entry because of evidence that mitochondrial complex I deficiency nuclear type 12 (MC1DN12) is caused by mutation in the NDUFA1 gene (300078) on chromosome Xq24.

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

Clinical Features

Fernandez-Moreira et al. (2007) reported 2 unrelated Spanish male patients with complex I deficiency nuclear type 12. The first patient was conceived via in vitro fertilization with an anonymous donor from a sperm bank. Developmental delay was noted at 4 months, and he later developed axial hypotonia, nystagmus, generalized choreoathetosis, and decreased reflexes. MRI showed bilateral lesions within the brain consistent with Leigh syndrome (see 256000). He developed an abnormal breathing pattern and died at age 14 months. His eldest brother, conceived via a different biologic father, had a similar disease course with death at age 19 months. The patient had psychomotor delay from 6 months of age, delayed language, and generalized hypotonia. At 9 years, he developed myoclonic epilepsy but remained clinically stable. Muscle and fibroblast complex I activities were 30% and 70%, respectively. Further studies showed impaired complex I assembly and stability. The patient's unaffected mother was heterozygous for the mutation.

Potluri et al. (2009) reported 2 first-cousin males, related by the maternal line, with a progressive neurodegenerative disorder and complex I deficiency. Muscle biopsies showed significantly decreased complex I activity (5-10% of normal).

Mayr et al. (2011) reported a girl with a very mild form of complex I deficiency. She had normal psychomotor development and was only symptomatic during intercurrent illnesses.

Molecular Genetics

In 2 unrelated Spanish male patients with complex I deficiency, Fernandez-Moreira et al. (2007) identified different hemizygous mutations in the NDUFA1 gene (G8R, 300078.0001 and R37S, 300078.0002, respectively). The former patient had a severe presentation consistent with Leigh syndrome (see 256000) and early death. The latter patient had developmental delay and myoclonic epilepsy. In both cases, the unaffected mother was heterozygous for the mutation.

Potluri et al. (2009) identified a hemizygous mutation in the NDUFA1 gene (G32R; 300078.0003) in 2 first-cousin males, related by the maternal line, with complex I deficiency. Mayr et al. (2011) identified heterozygosity for the G32R substitution in the NDUFA1 gene in a girl with a very mild form of complex I deficiency. There was decreased complex I staining in muscle only, and muscle cDNA showed predominant expression of the mutant allele (72%); in addition, the patient had higher expression of the paternal AR receptor in muscle, indicating skewed X inactivation. The G32R variant in the NDUFA1 gene was later reclassified as a variant of unknown significance.

Animal Model

Qi et al. (2004) created a mouse model of severe complex I deficiency by targeted disruption of the mRNA of a complex I subunit, Ndufa1, using ribozymes. In vitro complex I activity was reduced by more than 80%, and reactive oxygen species were increased by 21 to 24% in cells from affected mice. The mice showed damage to the optic nerve and retina. Adeno-associated viral delivery of the human SOD2 gene (147460) resulted in suppression of optic nerve degeneration and rescue of retinal ganglion cells. The findings suggested that reactive oxygen species contributed to retinal cell death and optic nerve damage in mice with complex I deficiency and that expression of SOD2 attenuated the disease process.