Retinal Manifestations of Maternally Inherited Diabetes and Deafness (MIDD)

From EyeWiki

All content on Eyewiki is protected by copyright law and the Terms of Service. This content may not be reproduced, copied, or put into any artificial intelligence program, including large language and generative AI models, without permission from the Academy.

Article initiated by:
Andreas Theocharis, MD, Agni Kakouri, MD, MBA, Romy Bejjani, MD, Leo A. Kim, MD, PhD
All contributors:
Andreas Theocharis, MD, Romy Bejjani, MD, Leo A. Kim, MD, PhD, Agni Kakouri, MD, MBA
Assigned editor:
Review:
Assigned status Update Pending
.


Disease Entity

Disease

Maternally inherited diabetes and deafness (MIDD) is a mitochondrial disorder characterized by diabetes mellitus and sensorineural hearing loss with maternal inheritance.[1] The most common genetic association is the m.3243A>G mitochondrial DNA variant in the mitochondrial tRNA leucine gene (MT-TL1 / tRNALeu(UUR)). The same variant is also associated with MELAS-spectrum presentations, resulting in many retina papers discussing “m.3243A>G–associated retinopathy.”[1][2] Retinal involvement is common and may prompt genetic testing, making ophthalmic findings relevant to diagnosis and multidisciplinary care.[3][4][5]

Epidemiology

Among patients initially diagnosed with type 2 diabetes, m.3243A>G-related disease is uncommon but represents a recognized cause of monogenic diabetes.[6] In the Dutch ophthalmic cohort, 25 of 29 m.3243A>G carriers (86%) had retinal abnormalities.[7] In large clinical series such as the French multicenter study, 86% of ophthalmologically examined MIDD patients had bilateral macular pattern dystrophy.[3][6] Visual symptoms and clinically significant retinopathy are often recognized in mid-adulthood, but age at onset is variable and asymptomatic or minimally symptomatic disease is well documented.[7][8][9]

Prevalence is likely underestimated because phenotype severity varies across tissues and families, maternal inheritance may be obscured, and blood heteroplasmy may be low even when retinal disease is present.[7][8]

Etiology and Genetics

Classic MIDD is associated with m.3243A>G in MT-TL1, although other rarer mitochondrial DNA variants have also been reported.[1] This same variant is associated with a spectrum that includes MELAS and MIDD, but phenotypic expression varies because heteroplasmy can differ substantially across tissues within the same person.[1][7] Maternal inheritance may be clinically obscured by variable expression and limited family history across relatives.[5][8]

Pathophysiology

Retinopathy in MIDD is predominantly localized at the level of the retinal pigment epithelium (RPE) and outer retina which are tissues with high metabolic demand and dense mitochondrial content.[10][11] Electrophysiologic and multimodal imaging studies support dysfunction of both the RPE-photoreceptor complex and outer retina, although the sequence may vary by eyes and disease stage.[10][11][12]

Clinically, this produces a recognizable pattern that often begins with subtle perifoveal or posterior pole pigmentary change and subretinal deposits, then progresses to nonfoveal chorioretinal atrophy. Central vision is only threatened when atrophy extends into the fovea.[7][10][12][13][14][15]

Diagnosis

History

MIDD has systemic manifestations that go beyond ocular findings. For this reason, historical clues that may raise suspicion for MIDD include:

  • Maternal family history of diabetes and/or hearing loss.[6]
  • Diabetes in a relatively lean or non-obese patient who does not fit a typical type 2 phenotype.[6]
  • Progression to insulin requirement out of proportion to the presumed diabetes subtype.[6]
  • Sensorineural hearing loss that predates or parallels diabetes.[6][8]
  • Renal involvement (including proteinuria and nephropathy) that may be misattributed to diabetes.[16]
  • Cardiac conduction abnormalities/cardiomyopathy and neurologic features in some patients.[6][17]

Family history may be limited or even negative; retinal findings suggestive of MIDD should still prompt consideration of the disease despite limited information regarding family history .[4][5][8] Without recognition of the syndromic context, retinal and renal findings may be misattributed to typical diabetic microvascular disease.[16][18]

Physical Examination

Ophthalmic Manifestations

The most characteristic ocular finding is a macular pattern dystrophy/mitochondrial maculopathy associated with the m.3243A>G variant.[3][8][15] Ophthalmic studies have shown that macular pattern dystrophy is a common finding in MIDD and may occur even when diabetic retinopathy was mild or absent.[3]

The characteristic phenotype is usually bilateral and fairly symmetric.[3] Fundus examination may show:

  • Fine perifoveal or posterior pole RPE mottling. [7][8][15]
  • Pale yellow-white subretinal deposits at the level of the RPE. [7][8][15]
  • Perifoveal or pericentral chorioretinal abnormalities, with relative foveal sparing until later stages.[7][14][15]
  • Abnormalities extending beyond the macula or encircling the optic disc in more advanced grades.[7]

The aforementioned fundus findings may be more useful in hinting at MIDD than diabetic retinopathy, since the latter may be less severe than one would expect or even absent.

Clinical Staging

Retinal findings of MIDD associated with the m.3243A>G variant have been classified into a 4-grade classification proposed by de Laat et al, based on ophthalmoscopy, FAF, and OCT findings.[7] Increasing grade correlates with age and with reduced visual acuity.[7]

Table 1. Four Grades of Mitochondrial Retinal Dystrophy Associated with the m.3243A>G Mutation based on ophthalmoscopy, fundus autofluorescence (FAF), and OCT findings as proposed by de Laat et al.
Grade Mean Visual Acuity Ophthalmoscopy Fundus Autofluorescence Optical Coherence Tomography Fluorescein Angiography
1 20/20

(range, 20/25–20/16)

Very subtle pigment mottling confined to the central posterior pole; changes can be difficult to appreciate clinically Mild hypoautofluorescent mottling No obvious abnormalities Small hyperfluorescent spots
2 20/20

(range, 20/63–20/12.5)

Isolated or multifocal faintly white-yellowish or hyperpigmented subretinal deposits in posterior pole Yellow-white spots/flecks correspond to mostly increased FAF; decreased FAF in mildly atrophic areas Irregular thickening or attenuation of the line corresponding to the photoreceptor inner/outer segment (/ellipsoid) area; underlying RPE somewhat attenuated and irregular Hypofluorescence of spots/flecks on FA due to blockage of background fluorescence; hyperfluorescent window defects in mildly atrophic zones
3 20/25

(range, 20/40–20/16)

Appearance of ≥1 areas of well-delineated, profound chorioretinal (“geographic”) atrophy outside the fovea, in addition to grade 2 abnormalities Well-defined areas of absent autofluorescence due to atrophy of the lipofuscin-containing RPE in deeply atrophic areas Attenuated RPE cell layer and a markedly attenuated photoreceptor layer and external limiting membrane in areas of chorioretinal atrophy RPE window defects with visibility of the underlying larger choroidal vasculature and atrophy of the choriocapillaris
4 20/80

(range, 20/630–20/40)

Central fovea affected by profound chorioretinal atrophy Area of absent autofluorescence involving the fovea Atrophy of the outer retinal layers RPE window defect and atrophy of choriocapillaris in area of geographic atrophy
FA = fluorescein angiography; FAF = fundus autofluorescence; RPE = retinal pigment epithelium

Diagnostic Procedures

Multimodal Imaging

  • Color fundus photography is useful for baseline documentation of appearance and distribution of lesions and complements FAF/OCT in longitudinal follow-up.
  • FAF:
    • mottled hyper- and hypoautofluorescence in the posterior pole, with sharply demarcated hypoautofluorescence in established atrophy.[14][15]
    • abnormalities often extend beyond what is visible on color fundus examination.[15]
  • OCT:
    • early outer retinal irregularity with ellipsoid/interdigitation zone abnormalities overlying subretinal deposits.[10][12]
    • later RPE attenuation or loss, outer retinal thinning, and hypertransmission into the choroid in areas of atrophy.[10]
    • lesion-border changes such as hyporeflective wedges and, in advanced disease, outer retinal tubulations may be seen.[10]

OCTA and adaptive optics findings have been reported, but current diagnosis still relies mainly on clinical examination, FAF, OCT, and genetics.[10][12]

Electrophysiology and Visual Fields

Multifocal ERG can show localized macular dysfunction that corresponds to areas of FAF abnormalities, even when full-field ERG is normal, supporting that early disease is often focal and primarily macular/central retinopathy rather than panretinal.[11]

Visual field testing is useful when symptoms are present or atrophy is approaching the fovea. Reported defects include paracentral scotomas, cecocentral scotoma, enlarged blind spots, and reduced sensitivity corresponding to areas of atrophy.[12][15][19]

Laboratory/Genetic Testing

Definitive diagnosis requires molecular detection of a pathogenic mitochondrial DNA variant, most commonly m.3243A>G.[1][17] Because heteroplasmy varies by tissue, blood testing alone may be falsely negative; if clinical suspicion remains high despite negative blood testing, additional testing from other tissues, particularly urinary epithelial cells, should be considered.[7][17]

It is important that the retinal phenotype does not merely get labeled as a pattern dystrophy.[4][5] It should trigger systemic review and genetics referral because the ocular finding may be the entry point to diagnosis for the patient and affected maternal relatives.[4][5][8]

Differential Diagnosis

  • Other pattern dystrophies (PRPH2-related and others)
    • May look similar clinically but MIDD is favored when there is characteristic accompanying phenotype, inheritance pattern and posterior pole imaging findings.[13]
  • Age-related macular degeneration
    • MIDD patients are often younger, and the lesion pattern is typically perifoveal/peripapillary with a distinctive FAF phenotype.[7][13][15]
  • Central areolar choroidal dystrophy
    • Can enter the differential diagnosis, but systemic findings and the characteristic MIDD retinal phenotype help distinguish the disorders.[13]
  • Late-onset Stargardt spectrum disease
    • May overlap phenotypically and should remain in the differential diagnosis.[7]
  • Diabetic macular disease
    • Mild diabetic retinopathy may coexist, but it does not explain the bilateral pattern-dystrophy-like posterior pole changes typical of MIDD.[3][16]

A major pitfall is assuming that macular atrophy or pattern-like deposits in a diabetic patient are typical diabetic changes or AMD, rather than mitochondrial retinopathy.[4][5][16][17] Choroidal neovascularization is not a characteristic feature in the reported MIDD retinal cohorts and phenotype series cited here.[7][14][15] Cystoid macular changes have been reported in isolated cases and are not part of the typical core phenotype.[20]

Management

Ophthalmic Management

There is no proven ocular treatment that alters the natural history of MIDD-associated retinopathy.[13][14] Management is therefore centered on documentation, monitoring, counseling, and systemic referral.

  • Document baseline best-corrected visual acuity, dilated fundus findings, FAF, and OCT.[7][14]
  • Regular follow-up with multimodal imaging (especially FAF and OCT) to document atrophy progression over time.[14]
  • Counsel patients regarding the often slow progression of atrophy and the possibility of preserved central vision until later stages in many cases.[9][14]

Medical Follow-up and Systemic Coordination

The ophthalmologist may be the first clinician to suspect MIDD, so systemic coordination is part of good retinal care.

  • Prompt referral to endocrinology/genetic counseling when MIDD is suspected.[4][17]
  • Recommend audiology evaluation and renal/cardiac screening as these can affect prognosis and counseling.[6][16]
  • Avoid attributing renal disease or other organ involvement automatically to conventional diabetes alone.[16]
  • Encourage evaluating family members when maternal inheritance is suspected, because ophthalmic findings may help uncover affected relatives.[8]

Complications

Progressive nonfoveal-to-foveal chorioretinal atrophy is the main ocular complication.[7][10][14] Paracentral scotoma may precede loss of central visual acuity.[12][15]

Rare cystoid macular changes have been reported in isolated cases and are not part of the typical core phenotype.[20]

Prognosis

Visual prognosis can vary among affected individuals. Many patients maintain useful central vision for a prolonged period, consistent with typical foveal sparing in earlier stages.[7][14]

Longitudinal data confirm progression rather than stability. Atrophic lesions enlarge over time on FAF, and the mean enlargement rate in the Müller progression series was 2.33 mm2/year.[14]

Pooled visual-acuity data suggest that visual acuity is generally better in patients aged 50 years or younger than in older patients, while longitudinal imaging studies indicate that vision becomes more vulnerable once atrophy approaches or involves the fovea.[7][9][14]

References

Add text here

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Van Den Ouweland JMW, Lemkes HHPJ, Trembath RC, et al. Maternally inherited diabetes and deafness is a distinct subtype of diabetes and associates with a single point mutation in the mitochondrial tRNA Leu(UUR) gene. Diabetes. 1994;43(6):746-751. doi:10.2337/diab.43.6.746
  2. ↑ Van Den Ouweland JMW, Lemkes HHPJ, Ruitenbeek W, et al. Mutation in mitochondrial tRNALeu(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nat Genet. 1992;1(5):368-371. doi:10.1038/ng0892-368
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Massin P, Virally-Monod M, Vialettes B, et al. Prevalence of macular pattern dystrophy in maternally inherited diabetes and deafness. Ophthalmology. 1999;106(9):1821-1827. doi:10.1016/S0161-6420(99)90356-1
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 Bryan JM, Rojas CN, Mirza RG. Macular findings expedite accurate diagnosis of MIDD in a young female patient with newly diagnosed diabetes. Am J Ophthalmol Case Rep. 2022;27:101578. doi:10.1016/j.ajoc.2022.101578
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Strauss DS, Freund KB. Diagnosis of maternally inherited diabetes and deafness (mitochondrial A3243G mutation) based on funduscopic appearance in an asymptomatic patient. Br J Ophthalmol. 2012;96(4):604-604. doi:10.1136/bjophthalmol-2011-300004
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 Guillausseau PJ, Massin P, Dubois-LaForgue D, et al. Maternally Inherited Diabetes and Deafness: A Multicenter Study. Ann Intern Med. 2001;134(9_Part_1):721-728. doi:10.7326/0003-4819-134-9_Part_1-200105010-00008
  7. ↑ 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 7.11 7.12 7.13 7.14 7.15 7.16 7.17 7.18 De Laat P, Smeitink JAM, Janssen MCH, Keunen JEE, Boon CJF. Mitochondrial retinal dystrophy associated with the m.3243A>G mutation. Ophthalmology. 2013;120(12):2684-2696. doi:10.1016/j.ophtha.2013.05.013
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8 8.9 Michaelides M, Jenkins SA, Bamiou DE, et al. Macular Dystrophy Associated With the A3243G Mitochondrial DNA Mutation: Distinct Retinal and Associated Features, Disease Variability, and  Characterization of Asymptomatic Family Members. Arch Ophthalmol. 2008;126(3):320-328. doi:10.1001/archopht.126.3.320
  9. ↑ 9.0 9.1 9.2 Coussa RG, Sohn EH, Han IC, Parikh S, Traboulsi EI. Mitochondrial DNA A3243G variant-associated retinopathy: a meta-analysis of the clinical course of visual acuity and correlation with systemic manifestations. Ophthalmic Genet. 2021;42(4):420-430. doi:10.1080/13816810.2021.1907598
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 10.6 10.7 Müller PL, Maloca P, Webster A, Egan C, Tufail A. Structural Features Associated With the Development and Progression of RORA Secondary to Maternally Inherited Diabetes and Deafness. Am J Ophthalmol. 2020;218:136-147. doi:10.1016/j.ajo.2020.05.023
  11. ↑ 11.0 11.1 11.2 Bellmann C, Neveu MM, Scholl HPN, et al. Localized Retinal Electrophysiological and Fundus Autofluorescence Imaging Abnormalities in Maternal Inherited Diabetes and Deafness. Invest Ophthalmol Vis Sci. 2004;45(7):2355-2360. doi:10.1167/iovs.03-1090
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 Oishi N, Kubota D, Nakamoto K, et al. Multimodal imaging analysis of macular dystrophy in patient with maternally inherited diabetes and deafness (MIDD) with m.3243A>G mutation. Ophthalmic Genet. 2021;42(3):304-311. doi:10.1080/13816810.2021.1881978
  13. ↑ 13.0 13.1 13.2 13.3 13.4 Coussa RG, Parikh S, Traboulsi EI. Mitochondrial DNA A3243G variant-associated retinopathy: Current perspectives and clinical implications. Surv Ophthalmol. 2021;66(5):838-855. doi:10.1016/j.survophthal.2021.02.008
  14. ↑ 14.00 14.01 14.02 14.03 14.04 14.05 14.06 14.07 14.08 14.09 14.10 14.11 Müller PL, Treis T, Pfau M, et al. Progression of Retinopathy Secondary to Maternally Inherited Diabetes and Deafness – Evaluation of Predicting Parameters. Am J Ophthalmol. 2020;213:134-144. doi:10.1016/j.ajo.2020.01.013
  15. ↑ 15.00 15.01 15.02 15.03 15.04 15.05 15.06 15.07 15.08 15.09 15.10 Rath PP, Jenkins S, Michaelides M, et al. Characterisation of the macular dystrophy in patients with the A3243G mitochondrial DNA point mutation with fundus autofluorescence. Br J Ophthalmol. 2008;92(5):623-629. doi:10.1136/bjo.2007.131177
  16. ↑ 16.0 16.1 16.2 16.3 16.4 16.5 Massin P, Dubois-Laforgue D, Meas T, et al. Retinal and renal complications in patients with a mutation of mitochondrial DNA at position 3,243 (maternally inherited diabetes and deafness). A case–control study. Diabetologia. 2008;51(9):1664-1670. doi:10.1007/s00125-008-1073-1
  17. ↑ 17.0 17.1 17.2 17.3 17.4 Cardenas-Robledo S, Saber Tehrani A, Blume G, Kattah JC. Visual, Ocular Motor, and Cochleo-Vestibular Loss in Patients With Heteroplasmic, Maternally-Inherited Diabetes Mellitus and Deafness (MIDD), 3243 Transfer RNA Mutation. J Neuroophthalmol. 2016;36(2):134-140. doi:10.1097/WNO.0000000000000340
  18. ↑ Naing A, Kenchaiah M, Krishnan B, et al. Maternally inherited diabetes and deafness (MIDD): Diagnosis and management. J Diabetes Complications. 2014;28(4):542-546. doi:10.1016/j.jdiacomp.2014.03.006
  19. ↑ Romano F, Cozzi M, Staurenghi G, Salvetti AP. Multimodal retinal imaging of m.3243A>G associated retinopathy. Am J Ophthalmol Case Rep. 2022;26:101411. doi:10.1016/j.ajoc.2022.101411
  20. ↑ 20.0 20.1 Qian CX, Branham K, Khan N, Lundy SK, Heckenlively JR, Jayasundera T. Cystoid macular changes on optical coherence tomography in a patient with maternally inherited diabetes and deafness (MIDD)-associated macular dystrophy. Ophthalmic Genet. 2017;38(5):467-472. doi:10.1080/13816810.2016.1253106
Retrieved from "https://eyewiki.org/w/index.php?title=Retinal_Manifestations_of_Maternally_Inherited_Diabetes_and_Deafness_(MIDD)&oldid=127482"
The Academy uses cookies to analyze performance and provide relevant personalized content to users of our website.
Learn more
Powered by MediaWiki
Powered by Canasta
Powered by Semantic MediaWiki