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MIDD (maternally inherited diabetes, deafness and maculopathy): for professionals


Overview

Prevalence0.5-1% of all cases of diabetes
InheritanceMaternally inherited (mitochondrial)
Genes Involved (OMIM No.)MT-TL1 gene (OMIM: #590050)
SymptomsReduced visual acuity, Nyctalopia, Difficulty adapting to bright conditions, Sensorineural hearing impairment, Short stature, Proximal limb myopathy
Ocular FeaturesEarly cataracts
Maculopathy
Pattern Dystrophy-like alterations
RPE Atrophy
Subretinal deposits
Systemic FeaturesDiabetes mellitus, , Cardiovascular issues, Renal failure, Gastrointestinal disease, Increased risk of miscarriage
Key InvestigationsOcular
Fundoscopy:
Optical Coherence Tomography (OCT)
Fundus Autofluorescence (FAF)
Electroretinogram (ERG)
Electro-oculogram (EOG)
Systemic
Audiometry Metabolic studies
Cardiovascular assessments (ECG, echocardiography)
Renal function tests
Endocrine evaluations
Molecular DiagnosisWhole genome sequencing with retinal panel
ManagementOcular: Regular ophthalmic monitoring, Intravitreal anti-VEGF injections for macular oedema, Low vision services

Systemic: Diabetes management, Audiology support, Cardiovascular monitoring, Renal monitoring, Nutritional support, Physical and occupational therapy, Endocrine management

Genetic counselling, family planning advice, prenatal testing, preimplantation genetic diagnosis
Current ResearchResearch focused on understanding molecular mechanisms, developing gene therapies, and improving diagnostic techniques

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Clinical phenotype

MIDD (maternally inherited diabetes, deafness and maculopathy) is a mitochondrial disorder characterised by diabetes mellitus, sensorineural hearing impairment, and a distinctive maculopathy. It is primarily caused by a mutation in the MT-TL1 gene.1,2

Presenting features

Ocular:

  • Reduced visual acuity3
  • Nyctalopia and Difficulty Adapting to Bright Conditions
  • Early Cataracts: Cataracts may develop earlier than usual in patients with MIDD, contributing to visual impairment.4

Systemic

  • Diabetes mellitus: Typically presents in the fourth decade of life but can range from ages 10 to 70. Often characterised by decreased insulin secretion.3
  • Sensorineural hearing impairment: Usually bilateral, affecting high-frequency ranges, with a gradual onset.
  • Short stature and proximal limb myopathy: Common physical manifestations.
  • Cardiovascular issues: Left ventricular hypertrophy and other cardiac complications.
  • Renal failure: Patients may develop renal issues, including proteinuria.
  • Gastrointestinal disease: Various gastrointestinal complications are associated with MIDD.
  • Increased risk of miscarriage: Particularly noted in affected females.

Fundus

  • Maculopathy: Characterised by pattern dystrophy-like changes and RPE atrophy, primarily at the posterior pole and surrounding the optic disc. The fovea often remains relatively preserved, aiding in the maintenance of central vision.5
  • Pattern Dystrophy-like Alterations: Visualised as irregular pigmentary changes, these are best seen using fundus autofluorescence (FAF), showing a speckled pattern of increased and decreased autofluorescence.
  • RPE Atrophy: Progresses over time, manifesting as hypo-autofluorescent areas on FAF.
  • Subretinal Deposits: Early stages show these as hyper-autofluorescent areas on FAF, which later contribute to atrophic changes.

Genetics

Gene: MT-TL1 (Mitochondrially encoded tRNA leucine 1, OMIM: #590050). The m.3243A>G variant is present in 85% of patients.

  • Inheritance Pattern: Maternally inherited (mitochondrial), with penetrance depending on heteroplasmy
  • Effect: This variation disrupts mitochondrial protein synthesis, leading to impaired oxidative phosphorylation and diverse clinical manifestations, ranging from diabetes and hearing loss to various ocular abnormalities.6,
  • Heteroplasmy: Heteroplasmy refers to the presence of more than one type of mitochondrial DNA (mtDNA) within a cell or individual. In the context of mitochondrial disorders such as MIDD, heteroplasmy plays a crucial role in the expression and severity of the disease.7
  • Impact on clinical manifestation:
    • Threshold effect: The severity and range of symptoms in MIDD depend on the heteroplasmy level, i.e., the proportion of mtDNA carrying the m.3243A>G mutation. A higher heteroplasmy level typically correlates with more severe clinical manifestations. For example, individuals with higher proportions of mutated mtDNA in their pancreatic beta cells are more likely to develop diabetes.
    • Tissue-specific heteroplasmy: Different tissues may have varying levels of heteroplasmy, contributing to the heterogeneity of symptoms in MIDD. For instance, the cochlea may have a higher heteroplasmy level than the retina, leading to more pronounced hearing loss compared to visual symptoms in some patients.
    • Age-related decline: The level of mutated mtDNA can change over time, often decreasing in blood cells with age. This decline can affect the accuracy of genetic testing if only blood samples are used, making it necessary to test other tissues such as muscle or urine epithelial cells for a definitive diagnosis.

Further information about each gene can be found on OMIM and Medline Plus.

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Key investigations

Ocular

  1. Ophthalmic Examination: Comprehensive assessment including visual acuity, intraocular pressure, and anterior and posterior segment examination.
  2. Fundoscopy: Essential for identifying pattern dystrophy-like changes and RPE atrophy.8
  3. Optical Coherence Tomography (OCT): Key for visualising subretinal deposits, ellipsoid zone loss, and outer retinal tubulations.9
  4. Fundus Autofluorescence (FAF): Reveals the speckled pattern of autofluorescence, indicating areas of RPE atrophy and subretinal deposits.5
  5. Electrophysiological Testing:
    • Electroretinogram (ERG): Typically normal full-field ERG; abnormal pattern and multifocal ERGs consistent with macular dysfunction.10
    • Electro-oculogram (EOG): May show reduced light peak to dark trough ratio, suggesting RPE dysfunction.
  6. Genetic Testing: whole genome sequencing with retinal panel

Systemic

  1. Audiometry: To assess sensorineural hearing loss.11
  2. Metabolic Studies: Including serum lactate levels.
  3. Cardiovascular Assessments: ECG and echocardiography to evaluate for cardiomyopathy and conduction defects.
  4. Renal Function Tests: Monitoring for proteinuria and assessing kidney function.
  5. Endocrine Evaluations: Monitoring glucose levels and insulin secretion to manage diabetes effectively.

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Diagnosis

Combining clinical evaluation, imaging studies, and genetic testing ensures an accurate diagnosis of MIDD. A multidisciplinary approach involving paediatricians, geneticists, cardiologists, nephrologists, and ophthalmologists is required for comprehensive evaluation of patients with suspected MIDD.

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Differential Diagnoses

Differential diagnoses include other mitochondrial disorders, diabetic retinopathy, and age-related macular degeneration.

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Management

MIDD requires a comprehensive and multidisciplinary management approach.

Ocular

  1. Regular ophthalmic monitoring: To monitor disease progression and identify complications promptly.
  2. Intravitreal injections: For treating cystoid macular oedema.2
  3. Low vision services: To support visual rehabilitation.

Systemic

  1. Diabetes Management: Utilising insulin secretagogues; avoiding metformin due to the risk of lactic acidosis.
  2. Audiology: Early referral and fitting of hearing aids; avoiding ototoxic medications.
  3. Cardiovascular Monitoring: Comprehensive cardiac workup to assess heart failure and cardiomyopathy risks.
  4. Renal Monitoring: Early treatment with ACE inhibitors if proteinuria is present.
  5. Nutritional Support: Ensuring adequate nutrition and addressing any deficiencies.
  6. Physical and Occupational Therapy: Sessions to improve motor skills and muscle strength.
  7. Paediatric Neurologist: For managing neurodevelopmental issues.
  8. Endocrinology: For managing hormonal imbalances.

Family management and counselling

Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis.

Emotional and social support

Genetic counsellors and Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients and their parents in clinic. They provide emotional and practical support to help patients and parents deal with the diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.

Related links

Referral to a specialist centre

In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive comprehensive management of their condition (genetic testing and genetic counselling) and to have the opportunity to participate in clinical research. In the UK, patient can also be referred to the Mitochondrial services in Queens Square, London.

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Current research

Current research on the management of maternally inherited diabetes and deafness (MIDD) focuses on addressing mitochondrial dysfunction and its systemic effects. Studies are exploring the use of coenzyme Q10 (CoQ10), a mitochondrial enhancer, to improve mitochondrial function and reduce oxidative stress. CoQ10 supplementation has shown potential in ameliorating symptoms associated with mitochondrial disorders by enhancing cellular energy production.12

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Further information and support

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References

  1. W. Reardon, M.E. Pembrey, R.C. Trembath, R.J.M. Ross, M.G. Sweeney, A.E. Harding, et al. Diabetes mellitus associated with a pathogenic point mutation in mitochondrial DNA. Lancet, 340 (1992), pp. 1376-1379
  2. Ferreira CR, van Karnebeek CDM, Vockley J, Blau N. A proposed nosology of inborn errors of metabolism. Genet Med. 2019;21(1):102-6.
  3. Murphy R, Turnbull DM, Walker M, Hattersley AT. Clinical features, diagnosis and management of maternally inherited diabetes and deafness (MIDD) associated with the 3243A>G mitochondrial point mutation. Diabet Med. 2008;25:383-99.
  4. de Laat P, Rodenburg RR, Roeleveld N, Koene S, Smeitink JA, Janssen MC. Six-year prospective follow-up study in 151 carriers of the mitochondrial DNA 3243 A>G variant. J Med Genet. 2020. jmedgenet-2019-106800.
  5. 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(5):623-9.
  6. Michaelides M, Jenkins SA, Bamiou DE, Sweeney MG, Davis MB, Luxon L, 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):320-8.
  7. Robinson KN, Terrazas S, Giordano-Mooga S, Xavier NA. The role of heteroplasmy in the diagnosis and management of maternally inherited diabetes and deafness. Endocr Pract. 2020;26(2):241-6.
  8. Müller PL, Treis T, Pfau M, Esposti SD, Alsaedi A, Maloca P, et al. Progression of retinopathy secondary to maternally inherited diabetes and deafness—evaluation of predicting parameters. Am J Ophthalmol. 2020;213:134-44.
  9. 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):467-72.
  10. 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(7):2355-60.
  11. 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;218:136-47.
  12. Suzuki S, Hinokio Y, Ohtomo M, Hirai M, Hirai A, Chiba M, et al. The effects of coenzyme Q10 treatment on maternally inherited diabetes mellitus and deafness, and mitochondrial DNA 3243 (A to G) mutation. Diabetologia. 1998;41(5):584-8.

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Updated on June 3, 2024
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