Top

Neurological Sciences

Published in:

14-06-2022 | Magnetic Resonance Imaging | Original Article

Leber’s hereditary optic neuropathy plus dystonia caused by the mitochondrial ND1 gene m.4160 T > C mutation

Authors: Hong Ren, Yan Lin, Ying Li, Xiufang Zhang, Wei Wang, Xuebi Xu, Kunqian Ji, Yuying Zhao, Chuanzhu Yan

Published in: Neurological Sciences | Issue 9/2022

Abstract

Background

Leber’s hereditary optic neuropathy (LHON) is a common mitochondrial disease. More than 30 variants in the mitochondrial DNA (mtDNA) have been previously described in LHON. However, the pathogenicity of some variants remains unclear. Herein, we report a 19-year-old boy presenting unique LHON plus dystonia syndrome with the rare m.4136A > G and m.4160 T > C variants and elucidate the molecular pathomechanisms of the m.4160 T > C mutation.

Methods

We performed clinical, molecular genetic analysis, and biochemical investigation in the patient’s different tissues and cybrid cell lines.

Results

The optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) of the patient showed typical pathological changes—a significant decrease in the 17 thickness of the retinal nerve fiber layer (RNFL) and the ganglion cell complex (GCC). Brain magnetic resonance imaging (MRI) found noteworthy abnormal signals in the basal ganglia region. The genetic analysis revealed that the m.4160 T > C variant was heteroplasmic in the blood (80.2%), urine sediment (90.8%), and oral mucosal (81.7%) samples of the patient. In contrast, the m.4136A > G variant was homoplasmic in all available tissues. Biochemical and bioenergetic investigations showed decreased mitochondrial protein levels and mitochondrial respiration deficiency in cybrid cells harboring these variants.

Conclusions

This research provided more comprehensive data to help gain insight into the pathogenicity of the m.4160 T > C variant and broaden our view on the LHON plus phenotype.

Available only for authorised users

Leber T (1871) Ueber hereditäre und congenital-angelegte Sehnervenleiden. Albrecht von Graefes Archiv für Ophthalmologie 17:249–291. https://doi.org/10.1007/BF01694557CrossRef

Sitarz KS, Chinnery PF, Yu-Wai-Man P (2012) Disorders of the optic nerve in mitochondrial cytopathies: new ideas on pathogenesis and therapeutic targets. Curr Neurol Neurosci Rep 12:308–317. https://doi.org/10.1007/s11910-012-0260-0CrossRefPubMedPubMedCentral

Jurkute N, Majander A, Bowman R, Votruba M, Abbs S, Acheson J, Lenaers G, Amati-Bonneau P, Moosajee M, Arno G, Yu-Wai-Man P (2019) Clinical utility gene card for: inherited optic neuropathies including next-generation sequencing-based approaches. Eur J Human Gen : EJHG 27:494–502. https://doi.org/10.1038/s41431-018-0235-yCrossRef

Hohman TC (2017) Hereditary Retinal Dystrophy. In: Whitcup SM, Azar DT (eds) Pharmacologic therapy of ocular disease. Springer International Publishing, Cham, pp 337–367

Carelli V, Ross-Cisneros FN, Sadun AA (2004) Mitochondrial dysfunction as a cause of optic neuropathies. Prog Retin Eye Res 23:53–89. https://doi.org/10.1016/j.preteyeres.2003.10.003CrossRefPubMed

Priglinger C, Klopstock T, Rudolph G, Priglinger S (2019) Leber’s Hereditary Optic Neuropathy. Klin Monatsbl Augenheilkd 236:1271–1282. https://doi.org/10.1055/a-0972-1552CrossRefPubMed

Howell N, Kubacka I, Xu M, McCullough D (1991) Leber hereditary optic neuropathy: involvement of the mitochondrial ND1 gene and evidence for an intragenic suppressor mutation. Am J Hum Genet 48:935–942PubMedPubMedCentral

Wallace DC (1970) A new manifestation of Leber’s disease and a new explanation for the agency responsible for its unusual pattern of inheritance. Brain 93:121–132. https://doi.org/10.1093/brain/93.1.121CrossRefPubMed

Wilson J (1963) Leber’s hereditary optic atrophy: some clinical and aetiological considerations. Brain 86:347–362. https://doi.org/10.1093/brain/86.2.347CrossRefPubMed

10.

F Nuber, J Schimpf, JP di Rago, D Tribouillard-Tanvier, V Procaccio, ML Martin-Negrier, A Trimouille, O Biner, C von Ballmoos, T Friedrich (2021) Biochemical consequences of two clinically relevant ND-gene mutations in Escherichia coli respiratory complex I, Sci Rep

11.

Grigorieff N (1998) Three-dimensional structure of bovine NADH:ubiquinone oxidoreductase (complex I) at 22 A in ice. J Mol Biol 277:1033–1046. https://doi.org/10.1006/jmbi.1998.1668CrossRefPubMed

12.

Bursle C, Riney K, Stringer J, Moore D, Gole G, Kearns LS, Mackey DA, Coman D (2018) Leber Hereditary Optic Neuropathy and Longitudinally Extensive Transverse Myelitis. In: Morava E, Baumgartner M, Patterson M, Rahman S, Zschocke J, Peters V (eds) JIMD Reports, vol 42. Springer. Berlin Heidelberg, Berlin, Heidelberg, pp 53–60

13.

van der Walt EM, Smuts I, Taylor RW, Elson JL, Turnbull DM, Louw R, van der Westhuizen FH (2012) Characterization of mtDNA variation in a cohort of South African paediatric patients with mitochondrial disease. Eur J Hum Genet 20:650–656. https://doi.org/10.1038/ejhg.2011.262CrossRefPubMedPubMedCentral

14.

Rieder MJ, Taylor SL, Tobe VO, Nickerson DA (1998) Automating the identification of DNA variations using quality-based fluorescence re-sequencing: analysis of the human mitochondrial genome. Nucleic Acids Res 26:967–973. https://doi.org/10.1093/nar/26.4.967CrossRefPubMedPubMedCentral

15.

Zhang M, Zhou X, Li C, Zhao F, Zhang J, Yuan M, Sun Y, Wang J, Tong Y, Liang M, Yang L, Cai W, Wang L, Qu J, Guan M (2010) Mitochondrial haplogroup M9a specific variant ND1 T3394C may have a modifying role in the phenotypic expression of the LHON-associated ND4 G11778A mutation. Mol Genet Metab 101:192–199. https://doi.org/10.1016/j.ymgme.2010.07.014CrossRefPubMed

16.

La Morgia C, Achilli A, Iommarini L, Barboni P, Pala M, Olivieri A, Zanna C, Vidoni S, Tonon C, Lodi R, Vetrugno R, Mostacci B, Liguori R, Carroccia R, Montagna P, Rugolo M, Torroni A, Carelli V (2008) Rare mtDNA variants in Leber hereditary optic neuropathy families with recurrence of myoclonus. Neurology 70:762–770. https://doi.org/10.1212/01.wnl.0000295505.74234.d0CrossRefPubMed

17.

Blanchette M, Kent WJ, Riemer C, Elnitski L, Smit AF, Roskin KM, Baertsch R, Rosenbloom K, Clawson H, Green ED, Haussler D, Miller W (2004) Aligning multiple genomic sequences with the threaded blockset aligner. Genome Res 14:708–715. https://doi.org/10.1101/gr.1933104CrossRefPubMedPubMedCentral

18.

Bacman S, Nissanka N, Moraes C (2020) Cybrid technology. Methods Cell Biol 155:415–439. https://doi.org/10.1016/bs.mcb.2019.11.025CrossRefPubMed

19.

Lin Y, Xu X, Zhao D, Liu F, Luo Y, Du J, Wang D, Ji K, Zhao Y, Yan C (2020) A novel m.11406 T > A mutation in mitochondrial ND4 gene causes MELAS syndrome. Mitochondrion 54:57–64. https://doi.org/10.1016/j.mito.2020.06.011CrossRefPubMed

20.

Zhang J, Ji Y, Lu Y, Fu R, Xu M, Liu X, Guan MX (2018) Leber’s hereditary optic neuropathy (LHON)-associated ND5 12338T > C mutation altered the assembly and function of complex I, apoptosis and mitophagy. Hum Mol Genet 27:1999–2011. https://doi.org/10.1093/hmg/ddy107CrossRefPubMed

21.

Tranchant C, Anheim M (2016) Movement disorders in mitochondrial diseases. Rev Neurol (Paris) 172:524–529. https://doi.org/10.1016/j.neurol.2016.07.003CrossRef

22.

Torroni A, Petrozzi M, D’Urbano L, Sellitto D, Zeviani M, Carrara F, Carducci C, Leuzzi V, Carelli V, Barboni P, De Negri A, Scozzari R (1997) Haplotype and phylogenetic analyses suggest that one European-specific mtDNA background plays a role in the expression of Leber hereditary optic neuropathy by increasing the penetrance of the primary mutations 11778 and 14484. Am J Hum Genet 60:1107–1121PubMedPubMedCentral

23.

Baradaran R, Berrisford JM, Minhas GS, Sazanov LA (2013) Crystal structure of the entire respiratory complex I. Nature 494:443–448. https://doi.org/10.1038/nature11871CrossRefPubMedPubMedCentral

24.

L Iommarini, A Ghelli, CV Tropeano, I Kurelac, G Leone, S Vidoni, A Lombes, M Zeviani, G Gasparre, AM Porcelli (2018) Unravelling the effects of the mutation m.3571insC/MT-ND1 on respiratory complexes structural organization, Int J Mol Sci 19 https://doi.org/10.3390/ijms19030764.

25.

Kim JY, Hwang JM, Park SS (2002) Mitochondrial DNA C4171A/ND1 is a novel primary causative mutation of Leber’s hereditary optic neuropathy with a good prognosis. Ann Neurol 51:630–634. https://doi.org/10.1002/ana.10177CrossRefPubMed

26.

Carelli V, Ghelli A, Ratta M, Bacchilega E, Sangiorgi S, Mancini R, Leuzzi V, Cortelli P, Montagna P, Lugaresi E, DegliEsposti M (1997) Leber’s hereditary optic neuropathy: biochemical effect of 11778/ND4 and 3460/ND1 mutations and correlation with the mitochondrial genotype. Neurology 48:1623–1632. https://doi.org/10.1212/wnl.48.6.1623CrossRefPubMed

27.

Vercellino I, Sazanov LA (2022) The assembly, regulation and function of the mitochondrial respiratory chain. Nat Rev Mol Cell Biol 23:141–161. https://doi.org/10.1038/s41580-021-00415-0CrossRefPubMed

28.

Gorman GS, Blakely EL, Hornig-Do H-T, Tuppen HAL, Greaves LC, He L, Baker A, Falkous G, Newman J, Trenell MI, Lecky B, Petty RK, Turnbull DM, McFarland R, Taylor RW (2015) Novel MTND1 mutations cause isolated exercise intolerance, complex I deficiency and increased assembly factor expression. Clin Sci 128:895–904. https://doi.org/10.1042/cs20140705CrossRef

29.

Ng YS, Lax NZ, Maddison P, Alston CL, Blakely EL, Hepplewhite PD, Riordan G, Meldau S, Chinnery PF, Pierre G, Chronopoulou E, Du A, Hughes I, Morris AA, Kamakari S, Chrousos G, Rodenburg RJ, Saris CGJ, Feeney C, Hardy SA, Sakakibara T, Sudo A, Okazaki Y, Murayama K, Mundy H, Hanna MG, Ohtake A, Schaefer AM, Champion MP, Turnbull DM, Taylor RW, Pitceathly RDS, McFarland R, Gorman GS (2018) MT-ND5 mutation exhibits highly variable neurological manifestations at low mutant load. EBioMedicine 30:86–93. https://doi.org/10.1016/j.ebiom.2018.02.010CrossRefPubMedPubMedCentral

30.

Blakely EL, de Silva R, King A, Schwarzer V, Harrower T, Dawidek G, Turnbull DM, Taylor RW (2005) LHON/MELAS overlap syndrome associated with a mitochondrial MTND1 gene mutation. Eur J Hum Genet 13:623–627. https://doi.org/10.1038/sj.ejhg.5201363CrossRefPubMed

31.

Horvath R, Reilmann R, Holinski-Feder E, Ringelstein EB, Klopstock T (2008) The role of complex I genes in MELAS: a novel heteroplasmic mutation 3380G>A in ND1 of mtDNA. Neuromuscul Disord 18:553–556. https://doi.org/10.1016/j.nmd.2008.05.002CrossRefPubMed

32.

Finsterer J, Stollberger C, Gatterer E (2018) Wolff-Parkinson-White syndrome and noncompaction in Leber’s hereditary optic neuropathy due to the variant m.3460G>A. J Int Med Res 46:2054–2060. https://doi.org/10.1177/0300060518765846CrossRefPubMedPubMedCentral

33.

Malfatti E, Bugiani M, Invernizzi F, de Souza CF, Farina L, Carrara F, Lamantea E, Antozzi C, Confalonieri P, Sanseverino MT, Giugliani R, Uziel G, Zeviani M (2007) Novel mutations of ND genes in complex I deficiency associated with mitochondrial encephalopathy. Brain 130:1894–1904. https://doi.org/10.1093/brain/awm114CrossRefPubMed

34.

Carreño-Gago L, Gamez J, Cámara Y, Alvarez de la Campa E, Aller-Alvarez JS, Moncho D, Salvado M, Galan A, de la Cruz X, Pinós T, García-Arumí E (2017) Identification and characterization of the novel point mutation m.3634A>G in the mitochondrial MT-ND1 gene associated with LHON syndrome. Biochim Biophys Acta Mol Basis Dis 1863:182–187. https://doi.org/10.1016/j.bbadis.2016.09.002CrossRefPubMed

35.

Yang J, Zhu Y, Tong Y, Chen L, Liu L, Zhang Z, Wang X, Huang D, Qiu W, Zhuang S, Ma X (2009) Confirmation of the mitochondrial ND1 gene mutation G3635A as a primary LHON mutation. Biochem Biophys Res Commun 386:50–54. https://doi.org/10.1016/j.bbrc.2009.05.127CrossRefPubMed

36.

Valente L, Piga D, Lamantea E, Carrara F, Uziel G, Cudia P, Zani A, Farina L, Morandi L, Mora M, Spinazzola A, Zeviani M, Tiranti V (2009) Identification of novel mutations in five patients with mitochondrial encephalomyopathy. Biochim Biophys Acta 1787:491–501. https://doi.org/10.1016/j.bbabio.2008.10.001CrossRefPubMed

37.

Spangenberg L, Graña M, Greif G, Suarez-Rivero JM, Krysztal K, Tapié A, Boidi M, Fraga V, Lemes A, Gueçaimburú R, Cerisola A, Sánchez-Alcázar JA, Robello C, Raggio V, Naya H (2016) 3697G>A in MT-ND1 is a causative mutation in mitochondrial disease. Mitochondrion 28:54–59. https://doi.org/10.1016/j.mito.2016.03.006CrossRefPubMed

38.

DM Kirby, R McFarland, A Ohtake, C Dunning, MT Ryan, C Wilson, D Ketteridge, DM Turnbull, DR Thorburn, RW Taylor (2004) Mutations of the mitochondrial ND1 gene as a cause of MELAS, J Med Genet

39.

Valentino ML, Barboni P, Ghelli A, Bucchi L, Rengo C, Achilli A, Torroni A, Lugaresi A, Lodi R, Barbiroli B, Dotti M, Federico A, Baruzzi A, Carelli V (2004) The ND1 gene of complex I is a mutational hot spot for Leber’s hereditary optic neuropathy. Ann Neurol 56:631–641. https://doi.org/10.1002/ana.20236CrossRefPubMed

40.

Ammar M, Tabebi M, Sfaihi L, Alila-Fersi O, Maalej M, Felhi R, Chabchoub I, Keskes L, Hachicha M, Fakhfakh F, Mkaouar-Rebai E (2016) Mutational screening in patients with profound sensorineural hearing loss and neurodevelopmental delay: description of a novel m.3861A > C mitochondrial mutation in the MT-ND1 gene. Biochem Biophys Res Commun 474:702–708. https://doi.org/10.1016/j.bbrc.2016.05.014CrossRefPubMed

41.

Moslemi AR, Darin N, Tulinius M, Wiklund LM, Holme E, Oldfors A (2008) Progressive encephalopathy and complex I deficiency associated with mutations in MTND1. Neuropediatrics 39:24–28. https://doi.org/10.1055/s-2008-1076739CrossRefPubMed

42.

CD Wray, MW Friederich, D du Sart, S Pantaleo, J Smet, C Kucera, L Fenton, G Scharer, R Van Coster, JLK Van Hove (2013) A new mutation in MT-ND1 m.3928G>C p.V208L causes Leigh disease with infantile spasms, Mitochondrion

43.

Lin J, Zhao CB, Lu JH, Wang HJ, Zhu WH, Xi JY, Lu J, Luo SS, Ma D, Wang Y, Xiao BG, Lu CZ (2014) Novel mutations m.3959G>A and m.3995A>G in mitochondrial gene MT-ND1 associated with MELAS. Mitochondrial DNA 25:56–62. https://doi.org/10.3109/19401736.2013.779259CrossRefPubMed

44.

Cristina Pereira1* (2019) Vedolin3, F.V. , 5, C.F.d.S. , Cláudia Lorea3,7, C.N.a.L. Vilarinho1, Leigh syndrome due to mtDNA pathogenic variants, https://doi.org/10.1590/2326-4594-JIEMS-2018-0003

45.

La Morgia C, Caporali L, Gandini F, Olivieri A, Toni F, Nassetti S, Brunetto D, Stipa C, Scaduto C, Parmeggiani A, Tonon C, Lodi R, Torroni A, Carelli V (2014) Association of the mtDNA m.4171C>A/MT-ND1 mutation with both optic neuropathy and bilateral brainstem lesions. BMC Neurol 14:116. https://doi.org/10.1186/1471-2377-14-116CrossRefPubMedPubMedCentral

46.

Bet L, Bresolin N, Moggio M, Meola G, Prelle A, Schapira AH, Binzoni T, Chomyn A, Fortunato F, Cerretelli P et al (1990) A case of mitochondrial myopathy, lactic acidosis and complex I deficiency. J Neurol 237:399–404. https://doi.org/10.1007/bf00314729CrossRefPubMed

47.

Musumeci O, Andreu AL, Shanske S, Bresolin N, Comi GP, Rothstein R, Schon EA, DiMauro S (2000) Intragenic inversion of mtDNA: a new type of pathogenic mutation in a patient with mitochondrial myopathy. Am J Hum Genet 66:1900–1904. https://doi.org/10.1086/302927CrossRefPubMedPubMedCentral

Title: Leber’s hereditary optic neuropathy plus dystonia caused by the mitochondrial ND1 gene m.4160 T > C mutation
Authors: Hong Ren
Yan Lin
Ying Li
Xiufang Zhang
Wei Wang
Xuebi Xu
Kunqian Ji
Yuying Zhao
Chuanzhu Yan
Publication date: 14-06-2022
Publisher: Springer International Publishing
Keywords: Magnetic Resonance Imaging
Magnetic Resonance Imaging
Dystonia
Published in: Neurological Sciences / Issue 9/2022
Print ISSN: 1590-1874
Electronic ISSN: 1590-3478
DOI: https://doi.org/10.1007/s10072-022-06165-x

At a glance: The STEP trials

Springer Medicine

Leber’s hereditary optic neuropathy plus dystonia caused by the mitochondrial ND1 gene m.4160 T > C mutation

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 9/2022

Side effects of long-term oral anti-seizure drugs on thyroid hormones in patients with epilepsy: a systematic review and network meta-analysis

Multiple sclerosis in patients with hereditary spastic paraplegia: a case report and systematic review

Sex influences clinical phenotype in frontotemporal dementia

SARS-CoV-2 vaccination, Parkinson’s disease, and other movement disorders: case series and short literature review

Relationship between neutrophil to lymphocyte ratio and intracranial hemorrhage in stroke

Significance and clinical suggestions for the somatosensory evoked potentials increased in amplitude revealed by a large sample of neurological patients