Mitochondrial Complex I Deficiency, Nuclear Type 7

A number sign (#) is used with this entry because of evidence that mitochondrial complex I deficiency nuclear type 7 (MC1DN7) is caused by homozygous mutation in the NDUFV2 gene (600532) on chromosome 18p11.

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

Clinical Features

Benit et al. (2003) reported a male infant, born to first-cousin parents of African ancestry, with isolated complex I deficiency. The patient presented at 5 days of life with hypertrophic cardiomyopathy, truncal hypotonia, and encephalopathy.

Pagniez-Mammeri et al. (2009) reported a patient (patient 1) with MC1DN7 who presented with hypertrophic cardiomyopathy and encephalopathy.

Cameron et al. (2015) reported 5 patients from 2 unrelated families with MC1DN7. Two infant sibs in 1 family presented with hypertrophic cardiomyopathy and lactic acidosis and died in the first days or months of life. Muscle and fibroblasts tissues from the patients showed increased lactate:pyruvate ratios and/or isolated complex I deficiency. Brain imaging of 1 of the patients did not show evidence of Leigh syndrome. Three sibs in a second family with isolated complex I deficiency presented in infancy with seizures and developmental regression. Other variable features included spasticity, microcephaly, nystagmus, and optic atrophy. Brain imaging in these patients showed progressive brain atrophy and changes in the basal ganglia consistent with Leigh syndrome. One died at age 10 year, 1 was in a vegetative state by age 3 and was still alive at age 32, and the third died at 19 months of age.

Molecular Genetics

In a male infant, born to first-cousin parents of African ancestry, with isolated complex I deficiency, Benit et al. (2003) identified a 4-bp deletion of nucleotides 5 to 8 at the 5-prime end of IVS2 of the NDUFV2 gene, resulting in skipping of exon 2 (600532.0002). Benit et al. (2003) stated that whereas mutations in a number of genes encoding complex I subunits result in neurologic symptoms, hypertrophic cardiomyopathy and encephalopathy have been described previously only with a mutation in NDUFS2 (Loeffen et al., 2001; see 602985.0001).

Pagniez-Mammeri et al. (2009) identified a homozygous 4-bp deletion (IVS2+5_+8delGTAA) in the NDUFV2 gene (600532.0002) in a patient (patient 1) with MC1DN7 who presented with hypertrophic cardiomyopathy and encephalopathy. The mutation was the same as that reported by Benit et al. (2003) in an unrelated individual.

In 2 infant sibs with lethal MC1DN7 manifest as hypertrophic cardiomyopathy, Cameron et al. (2015) identified compound heterozygosity for 2 mutations in the NDUFV2 gene (c.IVS2+1delGTAA, 600532.0002 and c.669_670insG, 600532.0003). The mutations were found by whole-exome sequencing. Patient mitochondria showed 25% residual NDUFV2 protein levels compared to controls. Two sibs from another family with MC1DN7 manifest as early-onset seizures and Leigh syndrome were subsequently found to be homozygous for the c.IVS2+1delGTAA mutation by direct sequencing of the gene in 10 additional families. Parental DNA was not studied in either family.