Mitochondrial Complex I Deficiency, Nuclear Type 5

A number sign (#) is used with this entry because of evidence that mitochondrial complex I deficiency nuclear type 5 (MC1DN5) is caused by homozygous or compound heterozygous mutation in the NDUFS1 gene (157655) on chromosome 2q33.

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

Clinical Features

Benit et al. (2001) described patients with mitochondrial complex I deficiency and mutation in the NDUFS1 gene. One proband had unrelated healthy parents and was normal until age 4 months, when he developed psychomotor retardation with hypotonia. At age 7 months, he presented with nystagmus and bilateral optic atrophy. Leukodystrophy, lactic acidosis, and hyperlactatorachia were noted. He died at age 10 months. An older sister with similar findings died at age 7 months, and an older brother developed 2 episodes of ataxia and mild psychomotor retardation at age 2 years. In another family the proband, offspring of healthy unrelated parents, was normal until age 2 months, when he presented with growth retardation, axial hypotonia, hepatomegaly, and persistent hyperlactatemia. Magnetic resonance imaging showed hyperintensity of basal ganglia. The child later developed macrocytic anemia and dystonia. He died suddenly at age 5 months. His older sister presented with growth retardation, macrocytic anemia, and metabolic acidosis at age 3 months and died shortly thereafter in an acute episode of hyperlactatemia.

Martin et al. (2005) reported a Spanish child with complex I deficiency and features of Leigh syndrome (see 256000) with mutation in the NDUFS1 gene. At 8.5 months of age, she was hospitalized for recurrent vomiting, hypotonia, and growth retardation. Other findings included irritability, horizontal nystagmus, hyperreflexia, and bilateral lesions in the substantia nigra and midbrain. There was increased lactic acid in serum and CSF. Her status worsened and she died at age 14 months. A younger brother with a similar clinical picture died at age 8 months. Biochemical studies showed that skeletal muscle complex I activity was reduced to 25% normal values.

Hoefs et al. (2010) reported 4 patients from 3 families with severe mitochondrial complex I deficiency and very low complex I activity (less than 30% of normal) who had biallelic mutations in the NDUFS1 gene. All patients had a severe, progressive disease course resulting in death in childhood due to neurologic disability. Brain MRI performed in 2 patients showed severe and progressive white matter abnormalities. Hoefs et al. (2010) suggested that patients with very low complex I deficiency should specifically be screened for NDUFS1 mutations.

Ferreira et al. (2011) reported 2 sibs, born of consanguineous parents, with complex I deficiency due to mutation in the NDUFS1 gene. The patients had a neurodegenerative disorder of the white matter beginning around the first year of life. One showed loss of early developmental milestones and the other showed early delayed psychomotor development and irritability. Both had dystonic posturing, difficulty swallowing, and increased lactate in bodily fluids. Although there were episodes of deterioration, there was also some improvement in symptoms with age. Brain MRI showed progressive cavitating leukoencephalopathy with multiple cystic lesions in the white matter. Muscle biopsy of 1 sib showed significantly decreased complex I activity (45% of controls) and a decreased amount of complex I subunits. Reduced fully assembled complex I was seen in mitochondria isolated from fibroblasts from the other sib, but only under stress conditions. Modeling of the mutation in yeast showed that reduced complex I activity was due mainly to decreased accumulation of fully assembled active complex I in the membrane and not to diminished activity of the mutant enzyme.

Molecular Genetics

In 3 of 36 patients with isolated mitochondrial complex I deficiency, Benit et al. (2001) identified 5 different point mutations and 1 large-scale deletion in the NDUFS1 gene (see, e.g., 157655.0001-157655.0003).

Martin et al. (2005) reported a Spanish child with complex I deficiency and features of Leigh syndrome caused by a homozygous mutation in the NDUFS1 gene (L231V; 157655.0004).

In 4 patients from 3 families with severe mitochondrial complex I deficiency and very low complex I activity (less than 30% of normal), Hoefs et al. (2010) identified 5 different biallelic mutations in the NDUFS1 gene (see, e.g., 157655.0006-157655.0008). Patient cells also showed decreased amounts of assembled complex I and accumulation of subcomplexes, indicating disturbance in the assembly or stability of complex I. Hoefs et al. (2010) suggested that patients with very low complex I deficiency should be specifically screened for NDUFS1 mutations.

Ferreira et al. (2011) reported 2 sibs, born of consanguineous parents, with complex I deficiency due to a homozygous mutation in the NDUFS1 gene (T595A; 157655.0005).