Skip to main content
Advertisement
  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Genetics
    • Neuroimmunology & Neuroinflammation
  • Specialty Sites
    • Equity, Diversity, and Inclusion
    • Innovations in Care Delivery
    • Without Borders
  • Collections
    • Topics A-Z
    • Residents & Fellows
    • Infographics
    • Patient Pages
    • Null Hypothesis
    • Translations
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit a Manuscript
    • Author Center

Advanced Search

Main menu

  • Neurology.org
  • Journals
    • Neurology
    • Clinical Practice
    • Genetics
    • Neuroimmunology & Neuroinflammation
  • Specialty Sites
    • Equity, Diversity, and Inclusion
    • Innovations in Care Delivery
    • Without Borders
  • Collections
    • Topics A-Z
    • Residents & Fellows
    • Infographics
    • Patient Pages
    • Null Hypothesis
    • Translations
  • Podcast
  • CME
  • About
    • About the Journals
    • Contact Us
    • Editorial Board
  • Authors
    • Submit a Manuscript
    • Author Center
  • Home
  • Articles
  • Issues

User menu

  • My Alerts
  • Log in

Search

  • Advanced search
Neurology Genetics
Home
A peer-reviewed clinical and translational neurology open access journal
  • My Alerts
  • Log in
Site Logo
  • Home
  • Articles
  • Issues

Share

October 2020; 6 (5) Clinical/Scientific NotesOpen Access

Expanding the clinical spectrum of the mitochondrial mutation A13084T in the ND5 gene

Roberta Brusa, Eleonora Mauri, Laura Dell’Arti, Francesca Magri, Dario Ronchi, Valeria Minorini, Claudia Mainetti, Delia Gagliardi, Irene Faravelli, Megi Meneri, Nereo Bresolin, Francesco Viola, Stefania Corti, Giacomo Pietro Comi
First published September 15, 2020, DOI: https://doi.org/10.1212/NXG.0000000000000511
Roberta Brusa
From the Neurology Unit (R.B., E.M., F,M., D.R., M.M., N.B., S.C.); Ophthalmological Unit (L.D.A., V.M., C.M., F.V.), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico; Department of Pathophysiology and Transplantation (D.R., D.G., I.F., N.B., S.C., G.P.C.), Dino Ferrari Center, University of Milan; and Neuromuscular and Rare Diseases Unit (G.P.C.), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eleonora Mauri
From the Neurology Unit (R.B., E.M., F,M., D.R., M.M., N.B., S.C.); Ophthalmological Unit (L.D.A., V.M., C.M., F.V.), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico; Department of Pathophysiology and Transplantation (D.R., D.G., I.F., N.B., S.C., G.P.C.), Dino Ferrari Center, University of Milan; and Neuromuscular and Rare Diseases Unit (G.P.C.), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Laura Dell’Arti
From the Neurology Unit (R.B., E.M., F,M., D.R., M.M., N.B., S.C.); Ophthalmological Unit (L.D.A., V.M., C.M., F.V.), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico; Department of Pathophysiology and Transplantation (D.R., D.G., I.F., N.B., S.C., G.P.C.), Dino Ferrari Center, University of Milan; and Neuromuscular and Rare Diseases Unit (G.P.C.), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Francesca Magri
From the Neurology Unit (R.B., E.M., F,M., D.R., M.M., N.B., S.C.); Ophthalmological Unit (L.D.A., V.M., C.M., F.V.), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico; Department of Pathophysiology and Transplantation (D.R., D.G., I.F., N.B., S.C., G.P.C.), Dino Ferrari Center, University of Milan; and Neuromuscular and Rare Diseases Unit (G.P.C.), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Dario Ronchi
From the Neurology Unit (R.B., E.M., F,M., D.R., M.M., N.B., S.C.); Ophthalmological Unit (L.D.A., V.M., C.M., F.V.), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico; Department of Pathophysiology and Transplantation (D.R., D.G., I.F., N.B., S.C., G.P.C.), Dino Ferrari Center, University of Milan; and Neuromuscular and Rare Diseases Unit (G.P.C.), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Valeria Minorini
From the Neurology Unit (R.B., E.M., F,M., D.R., M.M., N.B., S.C.); Ophthalmological Unit (L.D.A., V.M., C.M., F.V.), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico; Department of Pathophysiology and Transplantation (D.R., D.G., I.F., N.B., S.C., G.P.C.), Dino Ferrari Center, University of Milan; and Neuromuscular and Rare Diseases Unit (G.P.C.), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Claudia Mainetti
From the Neurology Unit (R.B., E.M., F,M., D.R., M.M., N.B., S.C.); Ophthalmological Unit (L.D.A., V.M., C.M., F.V.), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico; Department of Pathophysiology and Transplantation (D.R., D.G., I.F., N.B., S.C., G.P.C.), Dino Ferrari Center, University of Milan; and Neuromuscular and Rare Diseases Unit (G.P.C.), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Delia Gagliardi
From the Neurology Unit (R.B., E.M., F,M., D.R., M.M., N.B., S.C.); Ophthalmological Unit (L.D.A., V.M., C.M., F.V.), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico; Department of Pathophysiology and Transplantation (D.R., D.G., I.F., N.B., S.C., G.P.C.), Dino Ferrari Center, University of Milan; and Neuromuscular and Rare Diseases Unit (G.P.C.), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Irene Faravelli
From the Neurology Unit (R.B., E.M., F,M., D.R., M.M., N.B., S.C.); Ophthalmological Unit (L.D.A., V.M., C.M., F.V.), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico; Department of Pathophysiology and Transplantation (D.R., D.G., I.F., N.B., S.C., G.P.C.), Dino Ferrari Center, University of Milan; and Neuromuscular and Rare Diseases Unit (G.P.C.), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Megi Meneri
From the Neurology Unit (R.B., E.M., F,M., D.R., M.M., N.B., S.C.); Ophthalmological Unit (L.D.A., V.M., C.M., F.V.), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico; Department of Pathophysiology and Transplantation (D.R., D.G., I.F., N.B., S.C., G.P.C.), Dino Ferrari Center, University of Milan; and Neuromuscular and Rare Diseases Unit (G.P.C.), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nereo Bresolin
From the Neurology Unit (R.B., E.M., F,M., D.R., M.M., N.B., S.C.); Ophthalmological Unit (L.D.A., V.M., C.M., F.V.), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico; Department of Pathophysiology and Transplantation (D.R., D.G., I.F., N.B., S.C., G.P.C.), Dino Ferrari Center, University of Milan; and Neuromuscular and Rare Diseases Unit (G.P.C.), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Francesco Viola
From the Neurology Unit (R.B., E.M., F,M., D.R., M.M., N.B., S.C.); Ophthalmological Unit (L.D.A., V.M., C.M., F.V.), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico; Department of Pathophysiology and Transplantation (D.R., D.G., I.F., N.B., S.C., G.P.C.), Dino Ferrari Center, University of Milan; and Neuromuscular and Rare Diseases Unit (G.P.C.), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stefania Corti
From the Neurology Unit (R.B., E.M., F,M., D.R., M.M., N.B., S.C.); Ophthalmological Unit (L.D.A., V.M., C.M., F.V.), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico; Department of Pathophysiology and Transplantation (D.R., D.G., I.F., N.B., S.C., G.P.C.), Dino Ferrari Center, University of Milan; and Neuromuscular and Rare Diseases Unit (G.P.C.), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Giacomo Pietro Comi
From the Neurology Unit (R.B., E.M., F,M., D.R., M.M., N.B., S.C.); Ophthalmological Unit (L.D.A., V.M., C.M., F.V.), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico; Department of Pathophysiology and Transplantation (D.R., D.G., I.F., N.B., S.C., G.P.C.), Dino Ferrari Center, University of Milan; and Neuromuscular and Rare Diseases Unit (G.P.C.), IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Full PDF
Citation
Expanding the clinical spectrum of the mitochondrial mutation A13084T in the ND5 gene
Roberta Brusa, Eleonora Mauri, Laura Dell’Arti, Francesca Magri, Dario Ronchi, Valeria Minorini, Claudia Mainetti, Delia Gagliardi, Irene Faravelli, Megi Meneri, Nereo Bresolin, Francesco Viola, Stefania Corti, Giacomo Pietro Comi
Neurol Genet Oct 2020, 6 (5) e511; DOI: 10.1212/NXG.0000000000000511

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Permissions

Make Comment

See Comments

Downloads
115

Share

  • Article
  • Figures & Data
  • Info & Disclosures
Loading

Our group previously published about a patient with a LS/MELAS (Leigh syndrome/mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) overlap phenotype associated with a novel mitochondrial mutation in the ND5 gene.1 At that time, his 38-year-old mother presented only migraine and asymptomatic bilateral optic atrophy, without other neurologic signs or symptoms. Headache attacks, occurring about twice a month, were localized mainly in the right frontoparietal region, sometimes associated with nausea or vomit or phonophotophobia, and were responsive to nonsteroidal anti-inflammatory drugs. She carried lower levels of heteroplasmy of the same A13084T mutation (57% in lymphocytes and 48% in fibroblasts) compared with her son (82% in blood and 72% in fibroblasts).

At 53 years of age, she was admitted to our hospital to treat the recent worsening of migraine attacks in terms of frequency (up to 12 a month) and severity. Neurologic examination was unremarkable, including manual visual field by confrontation. Ophthalmologic examination revealed visual acuity loss, which onset was not exactly datable. Visual acuity was 20/32 in the right eye (oculus dexter [OD]) and 20/40 in the left eye (oculus sinister [OS]). Fundoscopy confirmed known bilateral optic disc pallor and excavation, with major involvement of the temporal sectors (figure, A). Intraocular pressure was 16 mm Hg bilaterally. Computerized visual field analysis showed a moderate-severe defect in the superotemporal sector in the OD and centrocecal scotoma in the OS (figure, B). No retinal abnormalities were detected at infrared and autofluorescence retinoscopy (figure, C), whereas optical coherence tomography showed a diffused macular ganglion cell layer thinning and a retinal nerve fiber layer atrophy of the temporal sectors bilaterally (figure, D). Visual evoked response to flash stimulation was reduced in amplitude in the OS, with a markedly increased latency, and normal in the OD. Serum lactate was slightly elevated (1.6 mmol/L; normal values <1.3 mmol/mol), and folate levels were mildly reduced (3.5 μg/L; normal range 4.6–18.7 μg/L). The remaining blood tests, including thyroid and liver functions, were otherwise normal. We performed a brain MRI with gadolinium that also included studies of orbits and cerebral vessels. Subcortical white matter carried nonspecific hyperintensities in T2 sequences, but no signs of previous stroke-like lesions were detected. No optic nerve or chiasm abnormalities were seen on scans. Arteries of the circle of Willis were normally represented.

Figure
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure Neuro-ophthalmologic evaluations

Fundus color image showing bilateral optic disc pallor and excavation, with main involvement of the temporal sectors (A). Humphrey automatic visual field analysis 30-2 revealing a superotemporal defect in the OD and centrocecal scotoma in the OS (B). No retinal abnormalities were detected at IR and autofluorescence (C, OS upper row, OD lower row), whereas OCT showed a diffused macular ganglion cell layer thinning and a RNFL atrophy of the temporal sectors (D, OS upper row, OD lower row). IR = infrared retinoscopy; OCT = optical coherence tomography; OD = oculus dexter; OS = oculus sinister; RNFL = retinal nerve fiber layer.

Our findings pointed out to a phenotype similar to Leber hereditary optic neuropathy (LHON), not previously diagnosed because the patient did not perform further evaluations in the past years nor reported ocular symptoms so far. Idebenone (dosage 90 mg trice a day) was added to the treatment with coenzyme Q10 (dosage 50 mg twice a day).2 Because LHON may be associated with arrhythmias and mitochondriopathies with cardiac involvement, we performed ECG, echocardiogram, and 24-hour ECG monitoring, resulted all normal. Frequency of headache episodes responded partially to riboflavin 200 mg twice a day.3 Clinical evaluation and ophthalmologic assessments, performed 1 year later, were substantially stable.

Here, we describe the mitochondrial A13084T mutation in the ND5 gene, still not reported in other families, in association with a LHON-like presentation and migraine, in addition to the previously described LS/MELAS phenotype.1 ND5 is a mtDNA gene encoding for the nicotinamide adenine dinucleotide dehydrogenase 5, part of the complex I of the respiratory chain in mitochondria, which mutations have been so far associated with MELAS, LHON, Leigh syndrome (LS), and overlap syndromes (MELAS/LS, MELAS/LHON/LS, MELAS/Chronic Progressive External Ophthalmoplegia, MELAS/Myoclonic Epilepsy with Ragged-Red Fibers).4,5

LHON, usually affecting young men, is typically characterized by bilateral and painless loss of vision, with centrocecal scotoma, prominent temporal optic nerve atrophy, and selective degeneration of retinal ganglion cells,2 as occurred in our patient. However, our patient did not complain of acute or subacute visual loss. In the literature, heteroplasmy has been reported in 10%–15% of LHON cases with levels above 70%,6 which are higher compared with those found in our patient. We speculate that lower heteroplasmy levels and female sex may be responsible for the milder presentation of visual loss in our patient, although further observation is needed to confirm this theory.

Despite being a common disorder in the population, a higher prevalence of migraine has been reported in several mitochondrial disorders, probably because of impaired oxidative metabolism in the CNS.7

In conclusion, our findings expand the spectrum of phenotypes arising from the A13084T mutation. We support the role of ND5 as a candidate gene for LHON or LHON-like presentations. Moreover, we suggest periodic evaluations in paucisymptomatic or asymptomatic carriers to detect subclinical signs of optic atrophy.

Study funding

The project received partial support from the Italian Ministry of Health to G.P. Comi.

Disclosure

All the authors reported no disclosures. Go to Neurology.org/NG for full disclosures.

Acknowledgments

The authors gratefully thank the Associazione Centro Dino Ferrari for its support.

Appendix Authors

Footnotes

  • Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article.

  • ↵* These authors equally contributed to the article.

  • The Article Processing charge was funded by authors.

  • Received May 1, 2020.
  • Accepted in final form June 11, 2020.
  • Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

References

  1. 1.↵
    1. Crimi M,
    2. Galbiati S,
    3. Moroni I, et al
    . A missense mutation in the mitochondrial ND5 gene associated with a Leigh-MELAS overlap syndrome. Neurology 2003;60:1857–1861.
    OpenUrl
  2. 2.↵
    1. Carelli V,
    2. Carbonelli M,
    3. de Coo IF, et al
    . International Consensus Statement on the Clinical and Therapeutic Management of Leber hereditary optic neuropathy. J Neuroophthalmol 2017;37:371–381.
    OpenUrl
  3. 3.↵
    High-dose riboflavin treatment is efficacious in migraine prophylaxis: an open study in a tertiary care centre. PubMed - NCBI [online]. Available at: www.ncbi.nlm.nih.gov/pubmed/15257686. Accessed March 18, 2019.
  4. 4.↵
    1. Ng YS,
    2. Lax NZ,
    3. Maddison P, et al
    . MT-ND5 mutation exhibits highly variable neurological manifestations at Low mutant Load. EBioMedicine 2018;30:86–93.
    OpenUrl
  5. 5.↵
    1. Seong MW,
    2. Choi J,
    3. Park SS,
    4. Kim JY,
    5. Hwang J-M
    . Novel MT-ND5 gene mutation identified in Leber's hereditary optic neuropathy patient using mitochondrial genome sequencing. J Neurol Sci 2017;375:301–303.
    OpenUrl
  6. 6.↵
    1. Chinnery PF,
    2. Andrews RM,
    3. Turnbull DM,
    4. Howell NN
    . Leber hereditary optic neuropathy: does heteroplasmy influence the inheritance and expression of the G11778A mitochondrial DNA mutation? Am J Med Genet 2001;98:235–243.
    OpenUrlCrossRefPubMed
  7. 7.↵
    1. Vollono C,
    2. Primiano G,
    3. Della Marca G,
    4. Losurdo A,
    5. Servidei S
    . Migraine in mitochondrial disorders: prevalence and characteristics. Cephalalgia 2018;38:1093–1106.
    OpenUrl

Letters: Rapid online correspondence

No comments have been published for this article.
Comment

NOTE: All contributors' disclosures must be entered and current in our database before comments can be posted. Enter and update disclosures at http://submit.ng.neurology.org. Exception: replies to comments concerning an article you originally authored do not require updated disclosures.

  • Stay timely. Submit only on articles published within the last 8 weeks.
  • Do not be redundant. Read any comments already posted on the article prior to submission.
  • 200 words maximum.
  • 5 references maximum. Reference 1 must be the article on which you are commenting.
  • 5 authors maximum. Exception: replies can include all original authors of the article.
  • Submitted comments are subject to editing and editor review prior to posting.

More guidelines and information on Letters

Compose Comment

More information about text formats

Plain text

  • No HTML tags allowed.
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.
Author Information
NOTE: The first author must also be the corresponding author of the comment.
First or given name, e.g. 'Peter'.
Your last, or family, name, e.g. 'MacMoody'.
Your email address, e.g. higgs-boson@gmail.com
Your role and/or occupation, e.g. 'Orthopedic Surgeon'.
Your organization or institution (if applicable), e.g. 'Royal Free Hospital'.
Publishing Agreement
NOTE: All authors, besides the first/corresponding author, must complete a separate Letters Submission Form and provide via email to the editorial office before comments can be posted.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.

Vertical Tabs

You May Also be Interested in

Back to top
  • Article
    • Study funding
    • Disclosure
    • Acknowledgments
    • Appendix Authors
    • Footnotes
    • References
  • Figures & Data
  • Info & Disclosures

Related Articles

  • No related articles found.

Topics Discussed

  • Optic nerve
  • Mitochondrial disorders
  • Visual loss

Alert Me

  • Alert me when eletters are published
Advertisement
Neurology Genetics: 7 (3)

Articles

  • Articles
  • Issues
  • Popular Articles

About

  • About the Journals
  • Ethics Policies
  • Editors & Editorial Board
  • Contact Us
  • Advertise

Submit

  • Author Center
  • Submit a Manuscript
  • Information for Reviewers
  • AAN Guidelines
  • Permissions

Subscribers

  • Subscribe
  • Sign up for eAlerts
  • RSS Feed
Site Logo
  • Visit neurology Template on Facebook
  • Follow neurology Template on Twitter
  • Visit Neurology on YouTube
  • Neurology
  • Neurology: Clinical Practice
  • Neurology: Genetics
  • Neurology: Neuroimmunology & Neuroinflammation
  • AAN.com
  • AANnews
  • Continuum
  • Brain & Life
  • Neurology Today

Wolters Kluwer Logo

Neurology: Genetics | Online ISSN: 2376-7839

© 2021 American Academy of Neurology

  • Privacy Policy
  • Feedback
  • Advertise