Mutations in Mitochondrial Genes Leber Hereditary Optic Neuropathy

Slide 1 · Mutations in mitochondrial genes

Leber hereditary optic neuropathy

Mitochondrial inheritance • Cellular bioenergetics • Optic neuropathy

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Distinguish maternal mtDNA inheritance from nuclear Mendelian transmission.

Explain heteroplasmy, random segregation, and tissue-specific threshold effects.

Link mitochondrial respiratory dysfunction to central visual failure.

Outline phenotype recognition, molecular testing, and family counseling.

Slide 3 · Two genetic compartments contribute to mitochondrial function

Nuclear genome

Biparental inheritance

Many mitochondrial proteins

Mitochondrial genome

Maternal inheritance

37 encoded genes

Nuclear chromosomes encode many mitochondrial proteins.

Mitochondrial DNA (mtDNA) encodes a smaller, essential set.

Pathogenic variants in either compartment can disturb oxidative phosphorylation.

Slide 4 · Why mitochondrial inheritance is non-Mendelian

Autosomal nuclear alleles are inherited from both parents.

The embryo normally receives its mitochondrial genome from the oocyte.

Transmission therefore follows the maternal line, not a dominant/recessive pedigree.

Slide 5 · Human mtDNA encodes 37 genes

13

Protein-coding

22

Mitochondrial tRNAs

2

Mitochondrial rRNAs

13 encode respiratory-chain polypeptides.

22 encode mitochondrial transfer RNAs.

2 encode mitochondrial ribosomal RNAs.

Slide 6 · Protein synthesis and respiration both require mtDNA products

MtDNA gene products

→

Mitochondrial translation / respiration

→

Cellular ATP availability

Mitochondrial tRNAs and rRNAs support translation within the organelle.

The 13 protein-coding genes contribute respiratory-chain subunits.

A genetic defect can therefore impair cellular energy production.

Slide 7 · Oxidative phosphorylation creates tissue vulnerability

Tissues with sustained ATP demand are susceptible to mitochondrial dysfunction.

The central nervous system, skeletal muscle, heart, liver, and kidneys.

The optic nerve is a clinically important example of neural susceptibility.

Slide 8 · Visual axons depend on intact energy metabolism

Macula

Central retinal representation

→

Ganglion cells

High-energy neurons

→

Papillomacular bundle

Vulnerable axons

→

Central vision

Visual acuity

Retinal ganglion cell axons transmit visual information to the brain.

A sustained mitochondrial energy deficit compromises neural survival.

Central visual function is especially affected in LHON.

Schematic

Slide 9 · Fertilization establishes maternal mtDNA transmission

OocytemtDNA + nucleus

Spermnuclear genome

Zygote: Maternal mtDNA

The ovum contributes the mitochondrial population to the zygote.

Paternal nuclear DNA is inherited; Paternal mtDNA is not normally transmitted.

Each child of a mother carrying an mtDNA variant can inherit it.

Schematic

Slide 10 · A maternal pedigree identifies the transmission route

Filled blue: MtDNA variant present Outlined: Variant not shown

Maternal mtDNA can reach sons and daughters

Individuals of either sex can inherit a maternal mtDNA variant.

Males do not transmit that variant to their children.

Female carriers can transmit it to sons and daughters.

Schematic

Slide 11 · An unaffected mother can transmit a pathogenic mtDNA variant

Filled blue: MtDNA variant present Outlined: Variant not shown

Maternal mtDNA can reach sons and daughters

Variant carriage and clinically manifest optic neuropathy are not equivalent.

Incomplete penetrance allows a mother to be asymptomatic.

Her descendants can nevertheless develop visual loss.

Schematic

Slide 12 · Affected fathers do not transmit LHON mtDNA variants

Filled blue: MtDNA variant present Outlined: Variant not shown

Variant-positive father → no paternal mtDNA transmission

A paternal history of visual loss does not create paternal mtDNA transmission.

The affected father can transmit his nuclear DNA normally.

LHON risk from that paternal mtDNA variant is not inherited by his children.

Schematic

Slide 13 · Transmission of a variant is not transmission of blindness

Filled blue: MtDNA variant present Outlined: Variant not shown

Maternal mtDNA can reach sons and daughters

All children of a homoplasmic maternal carrier may inherit the variant.

Not all variant-positive relatives develop optic neuropathy.

Sex, age, other genetic factors, and exposures influence expression.

Schematic

Slide 14 · Heteroplasmy means mixed mitochondrial genotypes

Mostly wild-type

Mixed genotypes

Predominantly variant

A cell or tissue contains both wild-type and variant mtDNA.

The fraction of mutant mtDNA can differ among tissues.

Variant burden may influence the likelihood of dysfunction.

Schematic

Slide 15 · Homoplasmy does not guarantee clinical disease

Wild-type homoplasmy

Variant homoplasmy

Homoplasmy means mtDNA copies are predominantly of one genotype.

Many individuals carrying a major LHON variant are homoplasmic.

Clinical penetrance is nonetheless incomplete.

Schematic

Slide 16 · The threshold effect links burden to loss of function

Mutant burden / impairment

Tissue reserve

Clinical dysfunction

+

→

Mitochondrial dysfunction becomes clinically apparent only after a tissue-specific functional threshold is crossed.

Energy demand and physiological reserve influence that threshold.

This concept helps explain selective organ vulnerability.

Schematic

Slide 17 · Replicative segregation produces uneven mtDNA distributions

Parent cell with mixed mtDNA

Daughter cell A

Daughter cell B

Different mutant fractions after division

Normal and mutant mtDNA copies are not apportioned in fixed Mendelian ratios.

Daughter cells may receive different proportions of variant mtDNA.

Cellular lineages can therefore diverge in respiratory capacity.

Schematic

Slide 18 · Within-family severity can differ

Relatives may inherit the same maternally transmitted pathogenic variant.

Their degree of clinical visual loss may still differ greatly.

Mitochondrial segregation and incomplete penetrance provide different levels of explanation.

Slide 19 · Heteroplasmy is not the sole determinant of LHON risk

Common LHON variants often occur in a homoplasmic state.

Sex- and age-dependent penetrance remains important.

Additional genetic and environmental influences modify expression.

Slide 20 · Why the optic nerve is a key target

Macula

Central retinal representation

→

Ganglion cells

High-energy neurons

→

Papillomacular bundle

Vulnerable axons

→

Central vision

Visual acuity

Mitochondrial dysfunction reduces the ability to meet neuronal energy demand.

Retinal ganglion cells and their axons are especially vulnerable.

Damage to the papillomacular pathway produces loss of central vision.

Schematic

Slide 21 · Respiratory-chain dysfunction is the mechanistic bridge

Inner mitochondrial membrane

Complex I

→

Electron transport

→

Proton motive force

→

ATP synthase

The inner mitochondrial membrane contains the electron transport machinery.

Electron transfer supports the proton gradient used to synthesize ATP.

LHON-associated complex I variants disrupt this bioenergetic system.

Schematic

Slide 22 · Complex I is central to classical LHON

Mitochondrial inner membrane: Complex I

MT-ND1

M.3460G>A

MT-ND4

M.11778G>A

MT-ND6

M.14484T>C

Complex I participates in entry of electrons from NADH into the respiratory chain.

Three common LHON-associated mtDNA variants encode complex I subunits.

Mitochondrial bioenergetic dysfunction contributes to retinal ganglion cell injury.

Schematic

Slide 23 · Three mtDNA variants account for most classic LHON

Primary variant

Affected gene

Respiratory complex

M.11778G>A

MT-ND4

Complex I

M.3460G>A

MT-ND1

Complex I

M.14484T>C

MT-ND6

Complex I

M.11778G>A affects MT-ND4.

M.3460G>A affects MT-ND1.

M.14484T>C affects MT-ND6.

Slide 24 · M.11778G>A lies in MT-ND4

M.11778G>A

→

MT-ND4

This is a common primary LHON-associated pathogenic variant.

MT-ND4 encodes a mitochondrial complex I subunit.

Its identification supports the diagnosis in a compatible phenotype.

Slide 25 · M.3460G>A lies in MT-ND1

M.3460G>A

→

MT-ND1

The affected protein is a component of complex I.

Mitochondrial respiration may be measurably impaired.

Phenotypic severity still cannot be predicted from the variant alone.

Slide 26 · M.14484T>C lies in MT-ND6

M.14484T>C

→

MT-ND6

This classic mtDNA variant also affects complex I.

Visual recovery is relatively more frequent in some affected cohorts.

Prognosis remains individual and is not a deterministic gene-to-outcome rule.

Slide 27 · Mitochondrial variant notation should be read precisely

M.

Mitochondrial genome

11778

Reference position

G>A

Nucleotide substitution

The prefix “m.” denotes a mitochondrial sequence position.

The letters specify the reference and substituted nucleotide.

Gene symbols such as MT-ND4 identify the affected mtDNA-encoded subunit.

Slide 28 · Energy deficit and oxidative stress contribute to cell injury

Complex I dysfunction

→

Bioenergetic stress

→

Ganglion-cell injury

Complex I dysfunction perturbs oxidative phosphorylation.

Altered redox homeostasis and reactive oxygen species can accompany this dysfunction.

Degeneration of retinal ganglion cells ultimately interrupts visual signaling.

Slide 29 · The papillomacular bundle explains central visual loss

Macula

Central retinal representation

→

Ganglion cells

High-energy neurons

→

Papillomacular bundle

Vulnerable axons

→

Central vision

Visual acuity

Macular retinal ganglion cell axons project through the optic nerve.

Injury to these fibers impairs high-acuity central visual function.

Peripheral visual function may initially be relatively better preserved.

Schematic

Slide 30 · Anatomic localization: Retina to optic nerve

Photoreceptor layer

Light detection

→

Interneurons

Signal processing

→

Ganglion cells

Action potentials

→

Optic nerve

Axon bundle

Photoreceptors detect light; Retinal circuits relay signals to ganglion cells.

Ganglion cell axons form the optic nerve.

LHON is an optic neuropathy, not primarily a photoreceptor degeneration.

Schematic

Slide 31 · Functional loss precedes overt chronic optic atrophy

Carrier / early

Possible subtle changes

Subacute

Central failure; Variable disc appearance

Chronic

Axonal thinning; Disc pallor

Acute LHON may have conspicuous optic-disc vascular findings—or a relatively normal fundus.

Ganglion cell dysfunction reduces central acuity and produces a central scotoma.

Chronic degeneration eventually produces visible optic atrophy.

Schematic

Slide 32 · LHON is a neurodegenerative optic neuropathy

The defining clinical event is acquired central visual impairment.

Loss is typically painless and subacute.

The disease commonly affects both eyes, often sequentially.

Slide 33 · Age at onset is concentrated in young adulthood

The ma genetics section describes typical onset at 15–35 years.

The Robbins eye chapter describes 10–30 years; These are descriptive ranges.

Presentation outside these intervals is possible and does not exclude LHON.

Slide 34 · Visual loss is often sequential but ultimately bilateral

Eye 1

Eye 2

One eye may become symptomatic first.

The second eye commonly becomes involved after an interval.

Purely persistent unilateral optic neuropathy should trigger reassessment.

Schematic

Slide 35 · Central and centrocecal scotomas are characteristic

Normal central field

Central scotoma

Patients lose central field sensitivity corresponding to macular projections.

The blind region may extend toward the physiologic blind spot.

Perimetry helps quantify the functional deficit.

Schematic

Slide 36 · Dyschromatopsia often accompanies central visual loss

Color discrimination is frequently impaired in optic nerve disease.

Testing complements acuity and visual field examination.

These findings are supportive, not independently diagnostic of LHON.

Slide 37 · Acute fundus abnormalities can be subtle

Subacute / active

Chronic / atrophic

Reported findings include disc hyperemia and peripapillary nerve-fiber swelling.

Telangiectatic vessels and vascular tortuosity may be present.

A normal-appearing disc does not exclude acute LHON.

Schematic optic-disc appearances — not photographs

Schematic

Slide 38 · Optic-disc hyperemia is not true inflammatory edema

Acute LHON can produce a pseudoedematous peripapillary appearance.

Clinical interpretation requires correlation with pain, vision, OCT, and other findings.

Do not diagnose inflammatory optic neuritis on disc appearance alone.

Slide 39 · Chronic LHON progresses to optic atrophy

Subacute / active

Chronic / atrophic

Long-standing retinal ganglion cell injury reduces optic-nerve fibers.

Optic disc pallor becomes a prominent structural clue.

The degree of atrophy must be interpreted alongside function and disease stage.

Schematic optic-disc appearances — not photographs

Schematic

Slide 40 · Optical coherence tomography interrogates neural structure

Early RNFL thickening

RNFL

Retinal tissue (schematic)

Chronic RNFL loss

RNFL

Retinal tissue (schematic)

Retinal nerve fiber layer (RNFL) thickness reflects ganglion-cell axon integrity.

Macular ganglion cell measurements assess neuronal loss.

Serial OCT complements—but cannot replace—clinical and molecular diagnosis.

Qualitative layer representation — not acquired OCT measurements

Schematic

Slide 41 · OCT appearance depends on disease stage

Early RNFL thickening

RNFL

Retinal tissue (schematic)

Chronic RNFL loss

RNFL

Retinal tissue (schematic)

Early RNFL swelling may coexist with developing ganglion-cell dysfunction.

Later RNFL thinning reflects established axonal loss.

Stage-aware interpretation prevents misreading edema as preserved health.

Qualitative layer representation — not acquired OCT measurements

Schematic

Slide 42 · Visual fields and OCT answer different questions

Perimetry measures vision function: A central/centrocecal defect.

OCT measures retinal and peripapillary structure.

Agreement increases confidence in localization to the optic-nerve pathway.

Slide 43 · A typical clinical sequence can be staged

Carrier / early

Possible subtle changes

Subacute

Central failure; Variable disc appearance

Chronic

Axonal thinning; Disc pallor

Carrier state: Pathogenic variant present, with or without subtle ocular findings.

Subacute phase: Central visual failure with variable disc features.

Chronic phase: Persistent field deficit and optic-disc atrophy.

Schematic

Slide 44 · Male predominance does not mean X-linked inheritance

Males are affected more frequently than females among variant carriers.

Both sexes inherit the maternal mitochondrial genome.

The sex bias concerns penetrance, not the route of gene transmission.

Slide 45 · Penetrance limits individual risk prediction

Filled blue: MtDNA variant present Outlined: Variant not shown

Maternal mtDNA can reach sons and daughters

A pathogenic variant is necessary in classical mtDNA-associated LHON.

Presence of the variant alone cannot determine future visual loss.

Family counseling must convey uncertainty rather than a fixed personal prognosis.

Schematic

Slide 46 · A negative family history does not exclude LHON

Filled blue: MtDNA variant present Outlined: Variant not shown

Maternal mtDNA can reach sons and daughters

Maternal relatives may carry the variant without symptoms.

Smaller pedigrees may contain no previously recognized affected individuals.

Molecular testing can resolve uncertainty despite an uninformative pedigree.

Schematic

Slide 47 · Extraocular findings occur in some affected families

Cardiac conduction abnormalities and minor neurologic features.

GeneReviews also lists tremor, peripheral neuropathy, and movement disorders.

Such findings require clinical evaluation and should not be assumed in every case.

Slide 48 · LHON phenotypes are heterogeneous

Classic LHON predominantly affects the optic nerves.

A minority of patients display additional neurologic or cardiac features.

Atypical systemic involvement warrants broader mitochondrial and neurologic assessment.

Slide 49 · Recognize the clinical pattern before ordering genetic tests

Painless central failure

→

Bilateral optic neuropathy

→

Consider LHON

Young adult with painless subacute central vision loss.

Sequential or simultaneous bilateral optic neuropathy.

Maternal inheritance, when present, strengthens suspicion.

Slide 50 · Core ophthalmic assessment localizes the deficit

Best-corrected visual acuity and color vision.

Central visual-field evaluation with perimetry.

Fundus examination and OCT of RNFL/ganglion-cell layers.

Slide 51 · Initial molecular testing targets common mtDNA variants

Primary variant

Affected gene

Respiratory complex

M.11778G>A

MT-ND4

Complex I

M.3460G>A

MT-ND1

Complex I

M.14484T>C

MT-ND6

Complex I

Test m.11778G>A, m.3460G>A, and m.14484T>C.

These variants account for approximately 90% of cases in GeneReviews.

Ensure the laboratory assay reports mitochondrial variant nomenclature clearly.

Slide 52 · If primary-variant testing is negative

Three variants absent

→

Extended mtDNA analysis

→

Evaluate alternatives

Reassess the clinical localization and other treatable etiologies.

Consider comprehensive mtDNA sequencing or an inherited optic-neuropathy panel.

Interpret any detected variant using clinical and molecular evidence together.

Slide 53 · A variant of uncertain significance is not a diagnosis

Sequence variation may be benign, pathogenic, or uncertain.

A VUS must not be treated as molecular confirmation.

Phenotype, segregation, functional evidence, and expert interpretation matter.

Slide 54 · LHON and inflammatory optic neuritis are not synonyms

LHON usually causes painless central failure, often progressing to the second eye.

Typical demyelinating optic neuritis may involve pain with eye movements.

History, examination, imaging, and clinical course guide differentiation.

Slide 55 · Consider nutritional and toxic optic neuropathies

Central visual loss may result from nutritional deficits or toxic exposure.

Robbins specifically mentions toxic injury such as methanol exposure.

A complete exposure, medication, alcohol, and nutrition history is necessary.

Slide 56 · MRI is often an exclusion tool, not an LHON biomarker

MRI may be normal in typical LHON.

Atypical deficits require evaluation for compressive, inflammatory, and other causes.

Do not infer that an abnormal MRI automatically proves a mitochondrial etiology.

Slide 57 · A safe diagnostic pathway prioritizes reversible disorders

Clinical localization

→

Exclude urgent mimics

→

MtDNA genetic testing

Establish optic-neuropathy localization and characterize the clinical pattern.

Exclude urgent treatable mimics based on symptoms and examination.

Confirm a pathogenic mtDNA variant with appropriately selected testing.

Slide 58 · Patient vignette: Bilateral central loss

Constructed educational vignette

A 22-year-old develops painless central blur in one eye; The fellow eye deteriorates weeks later.

Perimetry reveals bilateral central scotomas.

An unaffected mother reports a brother who developed severe visual loss.

Slide 59 · Interpretation: Localize before labeling the pedigree

Optic-neuropathy pattern

→

Maternal-line history

→

Molecular evaluation

Sequential painless central loss supports an optic neuropathy.

The maternal uncle suggests, but does not prove, maternal transmission.

Targeted testing for primary LHON mtDNA variants is appropriate.

Slide 60 · Pedigree exercise: Variant carrier and children

Constructed educational vignette

A woman carries a pathogenic LHON mtDNA variant but has normal vision.

Her son and daughter are healthy at the time of consultation.

Which family members may transmit the mtDNA variant to the next generation?

Slide 61 · Pedigree answer: Follow mtDNA, not symptom status

Filled blue: MtDNA variant present Outlined: Variant not shown

Maternal mtDNA can reach sons and daughters

Maternal transmission can occur without maternal visual impairment.

A variant-carrying daughter can pass it to her children.

A variant-carrying son cannot pass it through paternal mtDNA.

Schematic

Slide 62 · Genetic counseling separates three distinct questions

Transmission: Which relatives can inherit the variant?

Penetrance: Who is likely to develop optic neuropathy?

Severity: How much visual impairment might occur?

Slide 63 · Risk reduction and clinical support are distinct

Avoiding smoking is particularly important for known carriers.

GeneReviews recommends moderation of alcohol and avoidance of binge drinking.

Functional support requires vision rehabilitation and individualized follow-up.

Slide 64 · Management is primarily multidisciplinary

Neuro-ophthalmology

→

Clinical genetics

→

Low-vision rehabilitation

Neuro-ophthalmology evaluates progression and competing diagnoses.

Clinical genetics explains inheritance and reproductive implications.

Low-vision services and rehabilitation address functional disability.

Slide 65 · Disease-modifying treatment requires contextual evidence

Idebenone has a region-specific regulatory history and evidence of benefit in some patients.

Effect depends on timing and patient characteristics; Responses are variable.

Therapeutic decisions require current local specialist guidance, not a generic textbook algorithm.

Slide 66 · Gene-directed strategies remain an evolving field

Pathogenic MT-ND4 variant

→

Experimental gene delivery

→

Functional outcome evaluation

Investigational approaches attempt to restore mitochondrial respiratory function.

Trials have focused on allotopic delivery of MT-ND4 for selected genotypes.

Do not equate promising study signals with universally established therapy.

Slide 67 · Three high-yield distinctions

Maternal transmission ≠ clinical penetrance.

Heteroplasmy threshold ≠ sufficient explanation of all LHON cases.

Central optic neuropathy ≠ primary disease of retinal photoreceptors.

Slide 68 · Integrating genotype, tissue vulnerability, and phenotype

Complex I dysfunction

→

Bioenergetic stress

→

Ganglion-cell injury

Maternal mtDNA variant can alter respiratory-chain function.

Energy-demanding retinal ganglion cells are susceptible to injury.

Loss of ganglion-cell axons creates bilateral central optic neuropathy.

Slide 69 · Selected references

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. (2026). Chapter 5, pp. 156–157.

Robbins, Cotran & Kumar. Other Optic Neuropathies section (eye chapter).

Yu-Wai-Man P, Chinnery PF. Leber Hereditary Optic Neuropathy. GeneReviews (2021 update).

Ambika S, Srilekha S. Systematic review of LHON. Indian J Ophthalmol (2026).