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Year : 2022  |  Volume : 4  |  Issue : 1  |  Page : 55

Maternally inherited diabetes and deafness macular dystrophy

Hospital Centre Entre o Douro e Vouga, Santa Maria da Feira, Portugal

Date of Submission29-Aug-2022
Date of Decision08-Sep-2022
Date of Acceptance25-Sep-2022
Date of Web Publication22-Nov-2022

Correspondence Address:
Vitor Miranda
Hospital Centre Entre o Douro e Vouga, Santa Maria da Feira
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/pajo.pajo_47_22

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The m.3243A>G variant in the MTL1 gene is a DNA point mutation which has been shown to cause a variety of diseases including retinal abnormalities. We report on the ophthalmologic phenotype and systemic findings in a new patient with this mutation, presenting with sensorineural hearing loss, diabetes and macular dystrophy. We characterized the retinal phenotype with a multimodal approach and throughout the follow-up period we observed sustained centripetal progression of the areas of chorioretinal atrophy.

Keywords: Chorioretinal atrophy, m.3243A>G, mitochondrial retinal dystrophy, mitochondrial retinopathy, MTTL1 gene, retinal dystrophy

How to cite this article:
Miranda V, Aguiar C, Chibante-Pedro J, Ruao M. Maternally inherited diabetes and deafness macular dystrophy. Pan Am J Ophthalmol 2022;4:55

How to cite this URL:
Miranda V, Aguiar C, Chibante-Pedro J, Ruao M. Maternally inherited diabetes and deafness macular dystrophy. Pan Am J Ophthalmol [serial online] 2022 [cited 2023 Sep 27];4:55. Available from: https://www.thepajo.org/text.asp?2022/4/1/55/361716

  Introduction Top

Maternally inherited diabetes and deafness (MIDD) is a rare systemic disease with unknown prevalence, but it is estimated that as much as 1% of patients with diabetes mellitus (DM) diagnosis may have MIDD.[1],[2] In most cases (>85%), this disease is caused by a single-point mutation in the mitochondrial DNA, the m.3243A>G variant in the MT-TL1 gene.[1],[2],[3] Besides being associated with MIDD, this mutation has also been associated in the literature to mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS syndrome), a more severe systemic condition.

Most of the times, these patients have an undisturbed childhood and symptoms only start to arise in the second decade of life.[4] Almost all patients will develop bilateral neurosensorial deafness.[1] The majority develop a type of DM similar to DM type II. More than 80% of patients will develop a maculopathy which resembles pattern dystrophies, with variable severity due to the variability of the proportion of normal and mutated mitochondrial DNA across different individuals and even between individuals from the same family.

The most common maculopathy phenotype is the development of circumferentially oriented patches of parafoveal atrophy that coalesce over time but usually spare the fovea until late in the disease process. Mottling of the RPE (retinal pigment epithelium). with pale pigment epithelial deposits and pigment clumping may also be noted.

Electrophysiologic testing is characterized by a normal full field Retinal pigmented epithelium (RPE) but with localized areas of neuroretinal dysfunction in the multifocal ERG.[2],[5],[6] Microperimetry might be used to assess macular function across time, showing a good anatomical correlation to structural optical coherence tomography (OCT) imaging.[7] Fundus autofluorescence (FAF) shows well-marked areas of hypoautofluorescence corresponding to the patches of atrophy with diffused dotted hyperautofluorescence in the margins. Characteristically, FAF reveals much more widespread pigment abnormality than would be expected from fundoscopic appearance.[5],[6] Finally, mitochondrial genome sequencing can be used to confirm the diagnosis when there is a high clinical suspicion.

Hereby, we report on a new case of m.3243A>G-associated retinal dystrophy describing its ophthalmic manifestations and progression and aim at expanding the current literature and understanding of this rare disease.

  Case Report Top

A 39-year-old Caucasian female was referred from rheumatology to the retina department due to bilateral progressive vision loss. She had a history of dyslipidemia, arterial hypertension, recently diagnosed DM, and sensorineural hearing loss (SNHL) diagnosed since 3 years prior and treated with hearing prosthetics. She was being followed in rheumatology due to unspecific complaints of fatigue, arthralgias, and myalgias, without a diagnosis having been made and with normal blood workup for inflammatory and autoimmunity markers.

She had a family history of DM in her mother since early age (early 30s), and had 1 sister and 3 brothers, two of them also with DM. She had a healthy 14-year-old son. She had no known history of ophthalmologic or hearing disabilities.

At the first appointment, she complained of bilateral vision loss and trouble with adaptation to different light intensity environments since her late 20s. Her best-corrected visual acuity (BCVA) was 20/25 Snellen OU with a spherical equivalent correction of −2.75 diopters (D) in her right eye (RE) and −2.50 D in her left eye (LE). We present the temporal evolution of BCVA in [Table 1].
Table 1: Progression of best-corrected visual acuity and optical coherence tomography retinal thickness throughout the follow-up period

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Anterior segment examination, intraocular pressure, ocular motility, and alignment examination were unremarkable. Fundus examination showed macular and peripapillary areas of chorioretinal atrophy [Figure 1]a, [Figure 1]b, [Figure 1]c, [Figure 1]d which corresponded to areas of sharply demarcated outer retina atrophy and outer retina tubulations in OCT [Figure 2]a and [Figure 2]b. FAF showed the same well-demarcated areas with virtually absent autofluorescence and with hyperautofluorescent speckled margins [Figure 3]a, [Figure 3]b, [Figure 3]c, [Figure 3]d. Electrophysiologic study comprising ERG pattern, multifocal ERG, and full-field ERG identified evidence of bilateral severe macular dysfunction, without evidence of generalized retinal dysfunction. Microperimetry showed impaired macular function in the areas of atrophy.
Figure 1: (a-d) Widefield (OPTOS®) and posterior pole fundus color photography depicting the macular and peripappilary areas of atrophy, without involvement of the peripheral retina

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Figure 2: (a and b) Structural OCT imaging depicting the areas of sharply demarcated atrophy in en-face near-infrared reflectance imagens and which corresponds to outer retinal atrophy and outer retinal tubulations in OCT section imagens. OCT: Optical coherence tomography

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Figure 3: (a-d) Widefield (OPTOS®) and posterior pole fundus autofluorescence showing only macular and peripappilary involvement with well demarcated areas with almost no autofluorescence and with speckled hyperautofluorescent margins

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Based on the clinical findings, a genetic study with sequencing of the PRPH 2 and TEAD1 genes and study of the 3243A>G variant in the mitochondrial DNA was requested: the PRPH 2 gene has been implied in cases of choroidal centroareolar dystrophy, adult vitelliform dystrophy, and other pattern dystrophies; the TEAD1 gene has been implied in cases of choroidal peripapillary dystrophy; and the m.3243A>G variant has been implied in cases of Kearns–Sayre syndrome and MIDD syndrome.

While the PRPH 2 and TEAD1 study was normal, the genetic study detected the mitochondrial DNA m.3243A>G heteroplasmic variant in the MTTL1 gene. There are no known ophthalmologic manifestations in the patient's maternal ancestry or in the patient's offspring (a 13-year-old boy) and it is still unknown at this stage if they are carriers of the mutation or if it is a de novo mutation.

This diagnosis explains the macular dystrophy observed in this patient, as well as the SNHL and the recently diagnosed DM. It might also account for her unspecific and prolonged complaints of fatigue, since fatigue is a hallmark symptom of mitochondrial diseases. Although DM is a highly prevalent disease in our population and it is unknown whether the mother has the mutation, we speculate that the high frequency of DM is this patient's family – mother and two brothers, all with diagnosis having been made before 40 years of age – might be at least in part attributable to the m.3243A>G mutation.

The patient, now 42-year-old, maintains regular follow-up in our retina department, and throughout this period, we observed sustained centripetal progression of the areas of chorioretinal atrophy, with almost half a disc-diameter of progression in some directions [Table 1] and [Figure 4]. Her BCVA has deteriorated to 20/50 in her RE due to partial foveal involvement and is preserved in her LE (so far).
Figure 4: Progression of chorioretinal atrophy throughout the follow-up period

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  Discussion Top

The 3243A>G mutation in the MTL1 gene represents the most frequent point mutation among patients affected by MIDD. As is the norm in mitochondrial diseases, there is ample phenotypic variation due to heteroplasmy and mitotic segregation, with a variable mutation load in different members of the same family and even in the same individual from tissue to tissue. As such, this mutation has been associated with variable degrees of macular dystrophy, from a mild salt-and-pepper maculopathy to severe atrophic disease,[8] but in most cases, the fovea is spared until late in the disease process. Possible differential diagnosis includes centroareolar choroidal dystrophy, peripapillary choroidal dystrophy, age-related macular degeneration, and late-onset Stargardt disease.

We described a new case of MIDD-associated macular dystrophy caused by the 3243A>G mutation in mitochondrial DNA, highlighting the most prominent clinical and multimodal features. There are currently no therapeutic approaches to this disease, and patients should be carefully monitored and instructed of their prognosis.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Maternally Inherited Diabetes and Deafness. Orphanet. Available from: https://Www.Orpha.Net. 7 august 2022.  Back to cited text no. 1
Schachat AP, Wilkinson CP, Hinton DR, Sadda SR, Wiedemann P. Ryan's Retina. 6th ed., Vol. 44. Elsevier; 2018. p. 954-89. 978-0-323-40197-5.  Back to cited text no. 2
Feigl B, Morris CP. Visual function and risk genotypes in maternally inherited diabetes and deafness. Can J Ophthalmol 2013;48:e111-4.  Back to cited text no. 3
Sánchez-Gutiérrez V, García-Montesinos J, Pardo-Muñoz A. Dos hermanas con distrofia macular causada por la mutación 3243A and gt G Del ADN mitocondrial. Arch Soc Esp Oftalmol 2016;91:240-4.  Back to cited text no. 4
Rath PP, Jenkins S, Michaelides M, Smith A, Sweeney MG, Davis MB, et al. Characterisation of the macular dystrophy in patients with the A3243G mitochondrial DNA point mutation with fundus autofluorescence. Br J Ophthalmol 2008;92:623-9.  Back to cited text no. 5
Bellmann C, Neveu MM, Scholl HP, Hogg CR, Rath PP, Jenkins S, et al. Localized retinal electrophysiological and fundus autofluorescence imaging abnormalities in maternal inherited diabetes and deafness. Invest Ophthalmol Vis Sci 2004;45:2355-60.  Back to cited text no. 6
Rohrschneider K, Bültmann S, Springer C. Use of fundus perimetry (microperimetry) to quantify macular sensitivity. Prog Retin Eye Res 2008;27:536-48.  Back to cited text no. 7
de Laat P, Smeitink JA, Janssen MC, Keunen JE, Boon CJ. Mitochondrial retinal dystrophy associated with the m. 3243A and gt; G mutation. Ophthalmology 2013;120:2684-96.  Back to cited text no. 8


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1]


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