Details of Disease

Disease Name

Mitochondrial complex I deficiency

isolated mitochondrial respiratory chain complex I deficiency; isolated NADH-ubiquinone reductase deficiency; isolated NADH-CoQ reductase deficiency; isolated NADH-coenzyme Q reductase deficiency; complex 1 mitochondrial respiratory chain deficiency; NADH coenzyme Q reductase deficiency; isolated complex I deficiency

Definition

A type of mitochondrial disease charcterized by macrocephaly (large head) with progressive leukodystrophy, encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. The disease is caused by mutations in any of many genes and the inheritance pattern depends on the responsible gene.

Disease Hierarchy

DISCJSA1: Mitochondrial complex deficiency

DISWD40R: Disease

DIS13M7V: Mitochondrial complex I deficiency

Disease Identifiers

MONDO ID

MONDO_0100133

MESH ID

C537475

UMLS CUI

C1838979

OMIM ID

252010

MedGen ID

374101

Orphanet ID

2609

SNOMED CT ID

237988006

General Information of Disease (ID: DIS13M7V)

Molecular Interaction Atlas (MIA) of This Disease

Molecular Interaction Atlas (MIA)

This Disease Is Related to 5 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
NDUFAF2	TTCHGVF	Supportive	Autosomal recessive	[1]
NDUFB9	TTBYJ39	Supportive	Autosomal recessive	[2]
NDUFB9	TTBYJ39	moderate	Biomarker	[2]
NDUFA13	TTRU1NG	Strong	CausalMutation	[3]
NDUFAF2	TTCHGVF	Strong	Genetic Variation	[4]
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This Disease Is Related to 1 DTP Molecule(s)

Gene Name	DTP ID	Evidence Level	Mode of Inheritance	REF
SLC25A10	DTJYKDQ	Strong	Genetic Variation	[5]
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This Disease Is Related to 6 DME Molecule(s)

Gene Name	DME ID	Evidence Level	Mode of Inheritance	REF
NDUFS2	DEKX5CD	Supportive	Autosomal recessive	[6]
NDUFS3	DE741FI	Supportive	Autosomal recessive	[7]
NDUFS7	DEIW03B	Supportive	Autosomal recessive	[8]
NDUFS2	DEKX5CD	Strong	Biomarker	[9]
NDUFS3	DE741FI	Strong	Biomarker	[9]
NDUFS7	DEIW03B	Strong	GermlineCausalMutation	[8]
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⏷ Show the Full List of 6 DME(s)

This Disease Is Related to 37 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
SLC35G2	OTFBVS0P	Limited	Autosomal recessive	[10]
FOXRED1	OTYEB8YK	Supportive	Autosomal recessive	[11]
MT-ND1	OTCLGIXV	Supportive	Autosomal recessive	[12]
NDUFA1	OTKBUQXP	Supportive	Autosomal recessive	[13]
NDUFA11	OTZXD1UK	Supportive	Autosomal recessive	[14]
NDUFA6	OTEOIIOL	Supportive	Autosomal recessive	[15]
NDUFAF1	OTYK9JU6	Supportive	Autosomal recessive	[16]
NDUFAF2	OTC8QPRS	Supportive	Autosomal recessive	[1]
NDUFAF3	OT4MCB6W	Supportive	Autosomal recessive	[17]
NDUFAF4	OTWJ5B9M	Supportive	Autosomal recessive	[18]
NDUFAF5	OTN5V274	Supportive	Autosomal recessive	[19]
NDUFAF8	OT9EVJYG	Supportive	Autosomal recessive	[20]
NDUFB10	OTFLILEO	Supportive	Autosomal recessive	[21]
NDUFB3	OTDV12IF	Supportive	Autosomal recessive	[22]
NDUFB9	OTO3WI7S	Supportive	Autosomal recessive	[2]
NDUFS1	OTTIZDFR	Supportive	Autosomal recessive	[23]
NDUFS2	OTBT8KW9	Supportive	Autosomal recessive	[6]
NDUFS3	OTX61TQQ	Supportive	Autosomal recessive	[7]
NDUFS4	OTJKUYEE	Supportive	Autosomal recessive	[24]
NDUFS6	OT9IOONQ	Supportive	Autosomal recessive	[25]
NDUFS7	OTIRMB2O	Supportive	Autosomal recessive	[8]
NDUFS8	OTMEAWKO	Supportive	Autosomal recessive	[7]
NDUFV1	OTEVK4WW	Supportive	Autosomal recessive	[8]
NDUFV2	OTSZF7D6	Supportive	Autosomal recessive	[26]
NUBPL	OTQMCSXT	Supportive	Autosomal recessive	[27]
TIMMDC1	OTIK4I5R	Supportive	Autosomal recessive	[28]
TMEM126B	OT8JJ5TP	Supportive	Autosomal recessive	[29]
NDUFB8	OTW4A4Q0	moderate	Genetic Variation	[30]
AIFM1	OTKPWB7Q	Strong	Biomarker	[31]
ELAC2	OTY3BOF6	Strong	Biomarker	[32]
FMN1	OT9CID5R	Strong	Genetic Variation	[33]
GDAP1	OTQE1O25	Strong	Genetic Variation	[34]
ND2	OTG9OHOX	Strong	GermlineCausalMutation	[35]
NDUFAF6	OTRJMIGT	Strong	Genetic Variation	[36]
NDUFB11	OTFG5777	Strong	Genetic Variation	[37]
STXBP1	OTRYA8C3	Strong	Genetic Variation	[38]
ND3	OT1OC3K3	Definitive	GermlineCausalMutation	[39]
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⏷ Show the Full List of 37 DOT(s)

References

1	A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy. J Clin Invest. 2005 Oct;115(10):2784-92. doi: 10.1172/JCI26020.
2	Mutation screening of 75 candidate genes in 152 complex I deficiency cases identifies pathogenic variants in 16 genes including NDUFB9. J Med Genet. 2012 Feb;49(2):83-9. doi: 10.1136/jmedgenet-2011-100577. Epub 2011 Dec 26.
3	Mutation in NDUFA13/GRIM19 leads to early onset hypotonia, dyskinesia and sensorial deficiencies, and mitochondrial complex I instability. Hum Mol Genet. 2015 Jul 15;24(14):3948-55. doi: 10.1093/hmg/ddv133. Epub 2015 Apr 21.
4	Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy. Genet Med. 2016 Sep;18(9):898-905. doi: 10.1038/gim.2015.186. Epub 2016 Jan 21.
5	SLC25A10 biallelic mutations in intractable epileptic encephalopathy with complex I deficiency. Hum Mol Genet. 2018 Feb 1;27(3):499-504.
6	Clinical and molecular findings in children with complex I deficiency. Biochim Biophys Acta. 2004 Dec 6;1659(2-3):136-47. doi: 10.1016/j.bbabio.2004.09.006.
7	Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing. J Med Genet. 2012 Apr;49(4):277-83. doi: 10.1136/jmedgenet-2012-100846.
8	Natural disease course and genotype-phenotype correlations in Complex I deficiency caused by nuclear gene defects: what we learned from 130 cases. J Inherit Metab Dis. 2012 Sep;35(5):737-47. doi: 10.1007/s10545-012-9492-z. Epub 2012 May 30.
9	Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes.Brain. 2016 Nov 1;139(11):2844-2854. doi: 10.1093/brain/aww221.
10	Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
11	FOXRED1, encoding an FAD-dependent oxidoreductase complex-I-specific molecular chaperone, is mutated in infantile-onset mitochondrial encephalopathy. Hum Mol Genet. 2010 Dec 15;19(24):4837-47. doi: 10.1093/hmg/ddq414. Epub 2010 Sep 21.
12	Intragenic inversion of mtDNA: a new type of pathogenic mutation in a patient with mitochondrial myopathy. Am J Hum Genet. 2000 Jun;66(6):1900-4. doi: 10.1086/302927. Epub 2000 Apr 17.
13	X-linked NDUFA1 gene mutations associated with mitochondrial encephalomyopathy. Ann Neurol. 2007 Jan;61(1):73-83. doi: 10.1002/ana.21036.
14	Mitochondrial complex I deficiency caused by a deleterious NDUFA11 mutation. Ann Neurol. 2008 Mar;63(3):405-8. doi: 10.1002/ana.21332.
15	Bi-allelic Mutations in NDUFA6 Establish Its Role in Early-Onset Isolated Mitochondrial Complex I Deficiency. Am J Hum Genet. 2018 Oct 4;103(4):592-601. doi: 10.1016/j.ajhg.2018.08.013. Epub 2018 Sep 20.
16	Human CIA30 is involved in the early assembly of mitochondrial complex I and mutations in its gene cause disease. EMBO J. 2007 Jul 11;26(13):3227-37. doi: 10.1038/sj.emboj.7601748. Epub 2007 Jun 7.
17	Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause fatal neonatal mitochondrial disease. Am J Hum Genet. 2009 Jun;84(6):718-27. doi: 10.1016/j.ajhg.2009.04.020. Epub 2009 May 21.
18	C6ORF66 is an assembly factor of mitochondrial complex I. Am J Hum Genet. 2008 Jan;82(1):32-8. doi: 10.1016/j.ajhg.2007.08.003.
19	Mutation of C20orf7 disrupts complex I assembly and causes lethal neonatal mitochondrial disease. Am J Hum Genet. 2008 Oct;83(4):468-78. doi: 10.1016/j.ajhg.2008.09.009.
20	Pathogenic Bi-allelic Mutations in NDUFAF8 Cause Leigh Syndrome with an Isolated Complex I Deficiency. Am J Hum Genet. 2020 Jan 2;106(1):92-101. doi: 10.1016/j.ajhg.2019.12.001. Epub 2019 Dec 19.
21	Mutations in the accessory subunit NDUFB10 result in isolated complex I deficiency and illustrate the critical role of intermembrane space import for complex I holoenzyme assembly. Hum Mol Genet. 2017 Feb 15;26(4):702-716. doi: 10.1093/hmg/ddw431.
22	Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Sci Transl Med. 2012 Jan 25;4(118):118ra10. doi: 10.1126/scitranslmed.3003310.
23	Novel mutations in the NDUFS1 gene cause low residual activities in human complex I deficiencies. Mol Genet Metab. 2010 Jul;100(3):251-6. doi: 10.1016/j.ymgme.2010.03.015. Epub 2010 Mar 21.
24	Demonstration of a new pathogenic mutation in human complex I deficiency: a 5-bp duplication in the nuclear gene encoding the 18-kD (AQDQ) subunit. Am J Hum Genet. 1998 Feb;62(2):262-8. doi: 10.1086/301716.
25	NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency. J Clin Invest. 2004 Sep;114(6):837-45. doi: 10.1172/JCI20683.
26	Mutant NDUFV2 subunit of mitochondrial complex I causes early onset hypertrophic cardiomyopathy and encephalopathy. Hum Mutat. 2003 Jun;21(6):582-6. doi: 10.1002/humu.10225.
27	High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency. Nat Genet. 2010 Oct;42(10):851-8. doi: 10.1038/ng.659. Epub 2010 Sep 5.
28	Genetic diagnosis of Mendelian disorders via RNA sequencing. Nat Commun. 2017 Jun 12;8:15824. doi: 10.1038/ncomms15824.
29	Mutations in Complex I Assembly Factor TMEM126B Result in Muscle Weakness and Isolated Complex I Deficiency. Am J Hum Genet. 2016 Jul 7;99(1):208-16. doi: 10.1016/j.ajhg.2016.05.022. Epub 2016 Jun 30.
30	NDUFB8 Mutations Cause Mitochondrial Complex I Deficiency in Individuals with Leigh-like Encephalomyopathy. Am J Hum Genet. 2018 Mar 1;102(3):460-467. doi: 10.1016/j.ajhg.2018.01.008. Epub 2018 Feb 8.
31	The variability of the harlequin mouse phenotype resembles that of human mitochondrial-complex I-deficiency syndromes.PLoS One. 2008 Sep 15;3(9):e3208. doi: 10.1371/journal.pone.0003208.
32	A homozygous splicing mutation in ELAC2 suggests phenotypic variability including intellectual disability with minimal cardiac involvement.Orphanet J Rare Dis. 2016 Oct 21;11(1):139. doi: 10.1186/s13023-016-0526-8.
33	Genetic diversity of NDUFV1-dependent mitochondrial complex I deficiency.Eur J Hum Genet. 2018 Nov;26(11):1582-1587. doi: 10.1038/s41431-018-0209-0. Epub 2018 Jul 5.
34	Mitochondrial complex I deficiency in GDAP1-related autosomal dominant Charcot-Marie-Tooth disease (CMT2K).Neurogenetics. 2009 Apr;10(2):145-50. doi: 10.1007/s10048-008-0166-9. Epub 2008 Dec 17.
35	Nonsense mutations in mitochondrial DNA associated with myalgia and exercise intolerance.Neurology. 2005 Mar 22;64(6):1091-2. doi: 10.1212/01.WNL.0000154471.33156.55.
36	Compound heterozygous missense and deep intronic variants in NDUFAF6 unraveled by exome sequencing and mRNA analysis.J Hum Genet. 2018 May;63(5):563-568. doi: 10.1038/s10038-018-0423-1. Epub 2018 Mar 12.
37	A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies. PLoS Genet. 2016 Jan 7;12(1):e1005679. doi: 10.1371/journal.pgen.1005679. eCollection 2016 Jan.
38	A novel de novo STXBP1 mutation is associated with mitochondrial complex I deficiency and late-onset juvenile-onset parkinsonism.Neurogenetics. 2015 Jan;16(1):65-7. doi: 10.1007/s10048-014-0431-z. Epub 2014 Nov 25.
39	De novo mutations in the mitochondrial ND3 gene as a cause of infantile mitochondrial encephalopathy and complex I deficiency. Ann Neurol. 2004 Jan;55(1):58-64. doi: 10.1002/ana.10787.