Mitochondrial Complex I Deficiency, Nuclear Type 2

A number sign (#) is used with this entry because of evidence that mitochondrial complex I deficiency nuclear type 2 (MC1DN2) is caused by homozygous or compound heterozygous mutation in the NDUFS8 gene (602141) on chromosome 11q13.

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

Clinical Features

Loeffen et al. (1998) reported a patient with mitochondrial complex I deficiency manifesting as Leigh syndrome (see 256000). The patient presented at age 5 weeks with poor feeding and episodes of apnea and cyanosis. The symptoms, which had existed since the first day of life, escalated in the course of an acute gastroenteritis. The parents were nonconsanguineous. Cardiac examination revealed a moderate hypertrophic obstructive cardiomyopathy. CT scan of the brain showed extensive white matter hypodensity, mild ventricular enlargement, and hypodense symmetric lesions in putamen and mesencephalon. The disorder progressed, leading to death at the age of 11 weeks from cardiorespiratory failure.

Procaccio and Wallace (2004) reported a patient with late onset of mitochondrial complex I deficiency manifesting as Leigh syndrome. The patient first developed walking difficulties at age 7 years, which progressed to balance impairment, dysarthria, mild dystonic posture, and nystagmus. Brain imaging showed bilateral symmetric lesions in the putamen. Complex I activity in the patient's skeletal muscle and lymphoblasts was reduced to 31% and 43% of controls, respectively.

Haack et al. (2012) reported 3 patients, including 2 sibs, with complex I deficiency. The unrelated patient had mitochondrial encephalopathy, hypertrophic cardiomyopathy, hypotonia, and respiratory insufficiency. respectively. Both sibs had Leigh syndrome, hypotonia, and lactic acidosis; one had seizures and the other had hypertrophic cardiomyopathy.

Molecular Genetics

In a patient with mitochondrial complex I deficiency manifesting as Leigh syndrome, Loeffen et al. (1998) identified compound heterozygous mutations in the NDUFS8 gene (P79L, 602141.0001 and R102H, 602141.0002). These were the first mutations identified in a nuclear-encoded component of the respiratory chain complex I.

In a patient with late onset of mitochondrial complex I deficiency manifesting as Leigh syndrome, Procaccio and Wallace (2004) identified compound heterozygous mutations in the NDUFS8 gene (P85L, 602141.0003 and R138H, 602141.0004).

In a patient with complex I deficiency, Haack et al. (2012) identified compound heterozygous mutations in the NDUFS8 gene (R77W, 602141.0005 and A149D, 602141.0006). Each unaffected parent was heterozygous for 1 of the mutations. In 2 sibs with MC1DN2, Haack et al. (2012) identified a homozygous mutation in the NDUFS8 gene (E63Q; 602141.0007).