Mitochondrial Complex I Deficiency, Nuclear Type 17

A number sign (#) is used with this entry because of evidence that mitochondrial complex I deficiency nuclear type 17 (MC1DN17) is caused by homozygous or compound heterozygous mutation in the NDUFAF6 gene (612392) on chromosome 8q22.

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

Clinical Features

Pagliarini et al. (2008) reported 2 Lebanese sibs, born of consanguineous parents, who presented in infancy with focal seizures, decreased movement and strength, ataxia, lactic acidosis, and neuroimaging results consistent with Leigh syndrome. Biochemical studies showed complex I deficiency in liver, muscle, and fibroblasts.

Bianciardi et al. (2016) reported a 7-year-old boy, born of unrelated parents, with mitochondrial complex I deficiency and Leigh syndrome. After normal early development, the patient presented at 3.5 years of age with progressive gait and speech difficulties, dystonic movements, loss of fine motor abilities, and signal alterations in the brain affecting the caudate and putamina; he was unable to walk at age 7 years, but verbal comprehension appeared to be preserved.

Kohda et al. (2016) reported 4 unrelated children with mitochondrial complex I deficiency and Leigh syndrome. Clinical details were limited.

Molecular Genetics

In 2 Lebanese sibs, born of consanguineous parents, with mitochondrial complex I deficiency nuclear type 17 and Leigh syndrome, Pagliarini et al. (2008) identified a homozygous missense mutation in the NDUFAF6 gene (Q99R; 612392.0001) substitution in a highly conserved residue. The mutation was not present in 100 control Lebanese chromosomes.

In a 7-year-old boy, born of unrelated parents, with complex I deficiency and Leigh syndrome, Bianciardi et al. (2016) identified a heterozygous mutation in the NDUFAF6 gene (A178P; 612392.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was inherited from the unaffected father. The mutation was present at an unknown frequency in the dbSNP (build 142) database and at low frequencies in the ExAC (0.016%) and Exome Variant Server (0.017%) databases. A second pathogenic variant affecting the NDUFAF6 gene was not identified. Analysis of patient cells excluded nonsense-mediated mRNA decay as well as alterations in methylation of the NDUFAF6 promoter. Patient fibroblasts, but not skeletal muscle, showed decreased complex I activity and decreased assembly of complex I, which could be rescued by overexpression of wildtype NDUFAF6. RNA analysis showed an almost mono-allelic expression of the mutated allele in blood and fibroblasts from the patient, whereas there was biallelic expression in urine and buccal mucosa. Blood and fibroblasts from the father showed biallelic expression. Bianciardi et al. (2016) suggested that the second mutational event in the NDUFAF6 gene may be postmeiotic, affecting a nonexonic regulatory element and explaining the different tissue-specific expression, or that it may affect a specific protein

In 4 unrelated children with mitochondrial complex I deficiency and Leigh syndrome, Kohda et al. (2016) identified biallelic missense mutations in the NDUFAF6 gene (612392.0003-612392.0007). The mutations, which were found by high-throughput exome sequencing of 142 unrelated patients with childhood-onset mitochondrial respiratory chain complex deficiencies, segregated with the disorder in the families.