Mitochondrial Complex I Deficiency, Nuclear Type 3

A number sign (#) is used with this entry because of evidence that mitochondrial complex I deficiency nuclear type 3 (MC1DN3) is caused by homozygous or compound heterozygous mutation in the NDUFS7 gene (601825) on chromosome 19p13.

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

Clinical Features

Smeitink and van den Heuvel (1999) described 2 brothers with complex I deficiency and features of Leigh syndrome (see 256000) confirmed postmortem. One brother presented with feeding problems, dysarthria, and ataxia at age 26 months; the other presented with vomiting at age 11 months. The course was progressive, especially after infection. Lactic acid concentration was normal in blood, urine, and cerebrospinal fluid (slight increase in cerebrospinal fluid). Magnetic resonance imaging showed symmetrical hypodensities in both sibs, who died at ages 3.5 and 5 years.

Lebon et al. (2007) reported a girl, born to consanguineous Tunisian parents, with severe complex I deficiency manifesting as Leigh syndrome. Her development was normal until age 15 months when she presented with muscular weakness, with delayed onset of walking. She also presented trunk hypotonia. During a pulmonary infection episode, a progressive deterioration was noted with fever and hepatomegaly. Brain magnetic resonance imaging showed bilateral putaminal lesions. Metabolic workup showed high plasma lactate concentration. Her neurologic state deteriorated quickly and brain cerebral MRI detected a high T2 signal intensity in the putamen, the white matter, and the brainstem.

Lebon et al. (2007) reported 2 brothers, born of consanguineous Turkish parents, with complex I deficiency and Leigh syndrome resulting in death in infancy. The older brother thrived normally until the age of 4 months when he presented with an acute episode of respiratory distress after which he became floppy, comatose and presented generalized tonic-clonic seizures with metabolic acidosis, hyperlactatemia, and elevated lactate/pyruvate molar ratios. He had severe trunk and limb hypotonia, with episodes of trunk hyperextension, dystonic limb movements, and brisk tendon reflexes. Brain MRI showed severe hyperintensity of the basal ganglia, brainstem, internal capsulae and frontal atrophy. His condition progressively worsened with episodes of polypnea, tachycardia, hypo/hyperthermia and painful paroxystic episodes ascribed to brainstem and thalamus involvement, respectively. He became comatous and he died at 5 months of age. His brother had a similar clinical course and died at 6 months of age.

Molecular Genetics

In 2 brothers with complex I deficiency and features of Leigh syndrome confirmed postmortem, Smeitink and van den Heuvel (1999) identified a missense mutation in the NDUFS7 gene (V122M; 601825.0001).

In a girl, born to consanguineous Tunisian parents, with severe complex I defect and Leigh syndrome, Lebon et al. (2007) identified homozygosity for a missense mutation in the NDUFS7 gene (R145H; 601825.0002). The parents were heterozygous carriers for the mutation, which was not detected in over 100 healthy controls of Tunisian origin.

In 2 brothers, born of consanguineous Turkish parents, with complex I deficiency and Leigh syndrome, Lebon et al. (2007) identified a homozygous splice site mutation in the NDUFS7 gene (601825.0003).