ORPHA: 255241; DO: 0112078;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8q22.1 | Mitochondrial complex I deficiency, nuclear type 17 | 618239 | Autosomal recessive | 3 | NDUFAF6 | 612392 |
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.
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.
Catania et al. (2018) reported 4 patients from 3 families with MC1DN17, including the patient previously described by Bianciardi et al. (2016). Two affected sibs had normal early development, but presented with psychomotor abnormalities at 21 and 12 months of age. Brain MRI showed bilateral T2-hyperintensities in the caudate and putamen in 1 sib, and bilateral T2-hyperintensities in the dentate nucleus and superior cerebellar peduncles in the other. Cognitive impairment was spared in both sibs. The fourth patient presented at 5 years of age with gait and coordination abnormalities, which progressed to include extrapyramidal symptoms. Brain MRI at 7 years of age showed bilateral T2-hyperintense signals in the putamen.
Baide-Mairena et al. (2019) described 3 Spanish sibs with MC1DN17. Early developmental milestones were normal, and all 3 sibs walked between 12 and 15 months of age. Neurologic abnormalities presented between 17 months and 2.5 years and progressed to generalized dystonia, loss of ambulation, and significant oromandibular and bulbar involvement. No acute encephalopathic episodes occurred. In 2 of the sibs, plasma amino acids, lactate, and urine organic acids were normal; these were not tested in the third sib. MRI showed caudate and putamen abnormalities in 2 sibs, and only putamen abnormalities in the third. MR spectroscopy in 1 sib showed a lactate peak in the caudate and putamen. Nerve conduction studies in 1 sib showed a peripheral demyelinating neuropathy.
Johnstone et al. (2020) reported a 27-year-old man (proband B) with MC1DN17. At age 4 years, he and his 3-year-old sister developed neurologic symptoms, including tiptoeing and dystonia, 4 weeks after experiencing high fever in the setting of a viral illness. A brain MRI in the brother showed cavitary lesions of the putamina. At age 27 years, he had normal cognition but was significantly impaired by generalized dystonia. He had no additional episodes of acute neurologic or metabolic decompensation after the original episode. No clinical follow-up of the sister was provided.
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. 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 children from 3 southern Italian families with MC1DN17 manifesting as Leigh syndrome, including the patient reported by Bianciardi et al. (2016), Catania et al. (2018) identified compound heterozygosity for mutations in the NDUFAF6 gene: A178P (612392.0002) and a splice site mutation (612392.0009). Haplotype analysis showed that all 4 patients shared the same haplotype in the NDUFAF6 genomic region, indicating that they likely have common NDUFAF6 alleles rather than independent mutational events.
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.
In 3 Spanish sibs with MC1DN17 manifesting as Leigh syndrome, Baide-Mairena et al. (2019) identified compound heterozygous missense mutations in the NDUFAF6 gene: I124T (612392.0005) and a 5-bp deletion (612392.0010). The mutations, which were found by next-generation sequencing of a Leigh syndrome-focused gene panel, were validated by Sanger sequencing. Studies in fibroblasts of one of the sibs showed decreased mitochondrial ATP, NDUFAF6 mRNA and protein expression, mitochondrial complex I expression, and complex I activity via in-gel activity staining. Studies in muscle homogenates from 2 of the sibs showed decreased mitochondrial complex I activity by in-gel activity staining compared to control. Transduction of wildtype NDUFAF6 into patient fibroblasts rescued complex I assembly and in-gel activity.
In a Hispanic brother (proband B) and sister with MC1DN17 manifesting as mild Leigh syndrome, Johnstone et al. (2020) identified compound heterozygous mutations in the NDUFAF6 gene (612392.0005 and 612392.0011). The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.
Baide-Mairena, H., Gaudo, P., Marti-Sanchez, L., Emperador, S., Sanchez-Montanez, A., Alonso-Luengo, O., Correa, M., Grau, A. M., Ortigoza-Escobar, J. D., Artuch, R., Vazquez, E., Del Toro, M., Garrido-Perez, N., Ruiz-Pesini, E., Montoya, J., Bayona-Bafaluy, M. P., Perez-Duenas, B. Mutations in the mitochondrial complex I assembly factor NDUFAF6 cause isolated bilateral striatal necrosis and progressive dystonia in childhood. Molec. Genet. Metab. 126: 250-258, 2019. [PubMed: 30642748] [Full Text: https://doi.org/10.1016/j.ymgme.2019.01.001]
Bianciardi, L., Imperatore, V., Fernandez-Vizarra, E., Lopomo, A., Falabella, M., Furini, S., Galluzzi, P., Grosso, S., Zeviani, M., Renieri, A., Mari, F., Frullanti, E. Exome sequencing coupled with mRNA analysis identifies NDUFAF6 as a Leigh gene. Molec. Genet. Metab. 119: 214-222, 2016. [PubMed: 27623250] [Full Text: https://doi.org/10.1016/j.ymgme.2016.09.001]
Catania, A., Ardissone, A., Verrigni, D., Legati, A., Reyes, A., Lamantea, E., Diodato, D., Tonduti, D., Imperatore, V., Pinto, A. M., Moroni, I., Bertini, E., Robinson, A., Carrozzo, R., Zeviani, M., Ghezzi, D. Compound heterozygous missense and deep intronic variants in NDUFAF6 unraveled by exome sequencing and mRNA analysis. J. Hum. Genet. 63: 563-568, 2018. [PubMed: 29531337] [Full Text: https://doi.org/10.1038/s10038-018-0423-1]
Johnstone, T., Wang, J., Ross, D., Balanda, N., Huang, Y., Godfrey, R., Groden, C., Barton, B. R., Gahl, W., Toro, C., Malicdan, M. C. V. Biallelic variants in two complex I genes cause abnormal splicing defects in probands with mild Leigh syndrome. Molec. Genet. Metab. 131: 98-106, 2020. [PubMed: 33097395] [Full Text: https://doi.org/10.1016/j.ymgme.2020.09.008]
Kohda, M., Tokuzawa, Y., Kishita, Y., Nyuzuki, H., Moriyama, Y., Mizuno, Y., Hirata, T., Yatsuka, Y., Yamashita-Sugahara, Y., Nakachi, Y., Kato, H., Okuda, A., and 23 others. A comprehensive genomic analysis reveals the genetic landscape of mitochondrial respiratory chain complex deficiencies. PLoS Genet. 12: e1005679, 2016. Note: Electronic Article. [PubMed: 26741492] [Full Text: https://doi.org/10.1371/journal.pgen.1005679]
Pagliarini, D. J., Calvo, S. E., Chang, B., Sheth, S. A., Vafai, S. B., Ong, S.-E., Walford, G. A., Sugiana, C., Boneh, A., Chen, W. K., Hill, D. E., Vidal, M., Evans, J. G., Thorburn, D. R., Carr, S. A., Mootha, V. K. A mitochondrial protein compendium elucidates complex I disease biology. Cell 134: 112-123, 2008. [PubMed: 18614015] [Full Text: https://doi.org/10.1016/j.cell.2008.06.016]