Mitochondrial Myopathies

Slide 1 · Mitochondrial Myopathies

Molecular mechanisms · skeletal-muscle pathology · clinicogenetic syndromes

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Relate impaired mitochondrial ATP production to skeletal-muscle disease.

Contrast mtDNA and nuclear genetic inheritance.

Explain heteroplasmy, segregation and the threshold concept.

Recognize morphology and the named clinicogenetic syndromes.

Slide 3 · A mitochondrial myopathy is often systemic

Mitochondrial disease can involve many organs—not skeletal muscle alone.

Muscle weakness may coexist with neurologic, ocular or cardiac features.

Systemic manifestations are relevant when interpreting a muscle biopsy.

Clinical / conceptual emphasis

Organ involvement is not restricted to one tissue.

Slide 4 · Impaired ATP generation is a central mechanism

Genetic lesion

Impaired mitochondrial function

Reduced ATP generation

Tissue dysfunction

Schematic sequence; Arrows denote conceptual progression.

Slide 5 · Why skeletal muscle can be affected

Skeletal-muscle fibers depend on adequate cellular energy supply.

Mitochondrial defects can therefore produce a primary myopathic phenotype.

Clinical involvement is variable rather than confined to one muscle group.

Clinical / conceptual emphasis

Metabolic dysfunction can become structural and clinical muscle disease.

Slide 6 · From molecular defect to patient phenotype

Variant in relevant gene

Mitochondrial impairment

Susceptible tissue affected

Observed phenotype

Schematic sequence; Arrows denote conceptual progression.

Slide 7 · Two genomes contribute to mitochondrial function

NUCLEAR GENOME

MITOCHONDRIAL GENOME

Nuclear DNA

MtDNA

Mendelian inheritance

Maternal inheritance

Native vector schematic: Compartments are conceptual, not to anatomical scale.

Slide 8 · Mitochondrial proteins and tRNAs

Disorders need not arise from mutations in protein-coding mtDNA alone.

Mitochondrial tRNA genes are one source of pathogenic point mutations.

Altered mitochondrial metabolism is the common biologic theme.

Clinical / conceptual emphasis

Genetic lesion ≠ single obligatory clinical syndrome.

Slide 9 · Inheritance depends on the affected genome

Nuclear genome

Mendelian inheritance

Both parental genomes contribute

Multiple possible inheritance patterns

Mitochondrial genome

Maternal inheritance

Oocyte supplies embryonic mitochondria

Heteroplasmy may complicate phenotype

Slide 10 · Maternal inheritance of mtDNA

Mother

Father

Children receive mitochondria via the oocyte.

Schematic maternal inheritance only; No quantitative risk is represented.

Slide 11 · Why paternal mtDNA is not the usual source

Mitochondrial inheritance to oocyte origin.

A paternal family pattern should not automatically be classified as mtDNA inheritance.

Determine whether the causal locus is nuclear or mitochondrial.

Clinical / conceptual emphasis

Identify the gene location before interpreting a pedigree.

Slide 12 · Nuclear mutations require a separate framework

Nuclear disease gene

Typically two nuclear copies per somatic cell

Mendelian pedigree interpretation

Mitochondrial protein may still be affected

MtDNA variant

Many mitochondrial DNA copies per cell

Maternal inheritance

Heteroplasmy and cell-to-cell variance

Slide 13 · Inheritance pattern: A teaching decision

Locate affected gene

Nuclear DNA or mtDNA?

Apply inheritance pattern

Integrate phenotype

Schematic sequence; Arrows denote conceptual progression.

Slide 14 · A cell contains many mtDNA copies

Schematic: MtDNA copies within one cell

Many genome copies

Illustrative distribution; Marker counts do not represent measured mtDNA fractions.

Slide 15 · MtDNA copies partition during cell division

Parent cell

Daughter A

Daughter B

Random segregation can change the relative proportions.

Schematic only: No real copy numbers or quantitative segregation rates are implied.

Slide 16 · Heteroplasmy: Mixed mitochondrial genotypes

One cell can contain normal and altered mtDNA

One mtDNA population

Different mtDNA population

Schematic heteroplasmy; Number of symbols is not measured mutation burden.

Slide 17 · Random segregation creates tissue variability

Descendant cell groups may differ

Cell population A

Cell population B

Cell population C

Illustrative clonal variation after random segregation; No quantitative rates asserted.

Slide 18 · A threshold governs disease expression

Conceptual mutation burden

Below a functional threshold

Function may be preserved

Exceeds a functional threshold

Susceptible cells may show disease

No numerical threshold is asserted. This is a qualitative disease model.

Slide 19 · A tissue-level threshold matters

At-risk muscle tissue: A mixture of cells

Cells need not share the same functional state.

Schematic tissue heterogeneity; Colors are illustrative, not measured proportions.

Slide 20 · Why the same mutation can yield different disease

Same mtDNA lesion

Different burden / distribution

Different vulnerable organs

Different phenotype

Schematic sequence; Arrows denote conceptual progression.

Slide 21 · Integrated mitochondrial disease model

Genetic architecture

Two genomes and heterogeneous inheritance

Cellular energy deficit

Reduced mitochondrial ATP generation

Multisystem expression

Muscle and other organs can be affected

Conceptual summary; Categories are not quantitative or exhaustive.

Slide 22 · The clinical entry point may be weakness

Skeletal-muscle weakness is one possible presentation.

Robbins does not assign a single obligatory distribution of weakness.

The clinical pattern must be interpreted alongside extra-muscular findings.

Clinical / conceptual emphasis

Weakness is compatible with mitochondrial disease, but is not specific.

Slide 23 · Serum creatine kinase may be elevated

Elevation of serum creatine kinase is one recognized manifestation.

An elevated CK indicates muscle injury rather than a unique mitochondrial cause.

The textbook does not provide a diagnostic CK cutoff for this category.

Clinical / conceptual emphasis

Laboratory findings support a phenotype; They do not determine its gene.

Slide 24 · Rhabdomyolysis is a possible presentation

Mitochondrial dysfunction

Susceptible skeletal muscle

Severe muscle injury

Rhabdomyolysis

Schematic sequence; Arrows denote conceptual progression.

Slide 25 · Muscle involvement is anatomically variable

What may vary

Distribution of muscle weakness

Presence or absence of rhabdomyolysis

Degree of CK elevation

A useful clinical clue

Extraocular muscle involvement

Chronic progressive ophthalmoplegia

Associated systemic manifestations

Slide 26 · Extraocular muscle involvement is conspicuous

Extraocular muscles

CPEO may be isolated or syndromic.

Symbolic eye diagram; Not an anatomical drawing or clinical photograph.

Slide 27 · The extraocular ATP hypothesis is uncertain

High mitochondrial density

Possibly high ATP requirement

Sensitivity to energy failure

Ophthalmoplegia

Proposed mechanism, not proven explanation

Slide 28 · Chronic progressive external ophthalmoplegia

Chronic progressive external ophthalmoplegia (CPEO) is common in mitochondrial disease.

CPEO can occur alone or as part of a multisystem syndrome.

The ocular phenotype by itself does not define a unique mtDNA variant.

Clinical / conceptual emphasis

CPEO describes a clinical phenotype, not one molecular diagnosis.

Slide 29 · Isolated versus syndromic ophthalmoplegia

Isolated CPEO

Ophthalmoplegia as predominant finding

Can reflect mtDNA point mutation or deletion

A phenotype, not a standalone genotype

Syndromic CPEO

Ophthalmoplegia with other organ involvement

Consider features of MELAS or Kearns–Sayre

Search for a coherent multisystem pattern

Slide 30 · Case 1: Progressive ocular muscle disease

Clinical reasoning prompt

A patient has gradually progressive extraocular muscle weakness.

A mitochondrial myopathy enters the differential diagnosis.

Question: Is ophthalmoplegia alone sufficient to name a specific mutation?

Slide 31 · Case 1: Interpret the phenotype correctly

Interpretation

No: Chronic progressive ophthalmoplegia is not mutation-specific.

The same genetic lesion can produce distinct clinical syndromes.

Assess the broader clinical pattern and select appropriate confirmatory studies.

Slide 32 · Muscle biopsy: The principal morphologic lesion

Myofiber cytoplasm

Subsarcolemmal aggregates

Sarcolemma

Schematic illustration — not a clinical specimen or microscopic image.

Slide 33 · What “ragged red” signifies

Mitochondrial aggregates

Peripheral fiber distribution

Reddish granules on Gomori stain

Schematic sequence; Arrows denote conceptual progression.

Slide 34 · Gomori trichrome is a morphology stain

No conspicuous aggregate

Ragged red pattern

Gomori trichrome pattern comparison — schematic only, not stained tissue.

Slide 35 · Subsarcolemmal position is diagnostically relevant

A peripheral rim of aggregates

Beneath the sarcolemma

Schematic cross section of a muscle fiber; Not a microscopy image.

Slide 36 · Mitochondrial accumulation in a myofiber

Conceptual comparison fiber

Affected fiber

Conceptual pattern distribution, not a specimen or observed fiber frequency.

Slide 37 · Ultrastructure may reveal abnormal mitochondria

Concentric membranous rings

Paracrystalline inclusion

Schematic illustration — not a patient electron micrograph.

Slide 38 · Concentric rings on electron microscopy

Enlarged native-vector depiction

Concentric intramitochondrial membranous rings

Schematic; “phonograph record” appearance Fig. 27.13.

Slide 39 · Paracrystalline inclusions are another EM clue

Enlarged native-vector depiction

Rhomboid inclusion with ordered internal pattern

Schematic only; Not an electron micrograph.

Slide 40 · Mitochondrial enzyme histochemistry

Cytochrome oxidase histochemistry (conceptual)

Some fibers may show deficient enzyme activity.

Hypothetical staining concept; No patient material or observed counts.

Slide 41 · A morphologically normal biopsy may not exclude disease

Some mitochondrial disorders lack conspicuous histologic changes.

Enzymatic assays or genetic analysis may be needed to establish diagnosis.

Do not demand ragged red fibers in every clinically compatible case.

Clinical / conceptual emphasis

Absent ragged red fibers ≠ excluded mitochondrial disease.

Slide 42 · Three complementary lines of evidence

Morphology

Visible tissue phenotype

Enzyme activity

Functional mitochondrial evidence

Genetic analysis

Causative genetic information

Conceptual summary; Categories are not quantitative or exhaustive.

Slide 43 · Morphology, biochemistry and genetics differ

Method

Gomori trichrome or ultrastructure

Visible mitochondrial accumulation or structural abnormality

May be absent in some disorders

Principal information

Cytochrome oxidase / genetic assays

Enzyme activity or pathogenic genetic basis

May clarify otherwise inconspicuous disease

Slide 44 · A genotype does not uniquely specify a phenotype

One mtDNA mutation

Variable genetic / tissue context

Distinct organ involvement

Different syndromes

Schematic sequence; Arrows denote conceptual progression.

Slide 45 · Leucine tRNA: One mutation, different outcomes

Mitochondrial leucine tRNA point mutation

Isolated CPEO

MELAS

One lesion type can be associated with more than one clinical phenotype.

Slide 46 · CPEO and MELAS can share a point mutation

Isolated CPEO

Predominantly extraocular weakness

Chronic progressive ophthalmoplegia

May present without the described multisystem syndrome

MELAS phenotype

Encephalomyopathy

Lactic acidosis

Stroke-like episodes

Slide 47 · MELAS: Unpack the name

MELAS

M: Mitochondrial.

E: Encephalomyopathy.

LA: Lactic acidosis; S: Stroke-like episodes.

Slide 48 · MtDNA deletions can also yield different syndromes

MtDNA deletion

Isolated CPEO

Kearns–Sayre syndrome

One lesion type can be associated with more than one clinical phenotype.

Slide 49 · Kearns–Sayre syndrome: Characteristic features

Ophthalmoplegia

Chronic progressive extraocular weakness

Retinal degeneration

Pigmentary degeneration of retina

Complete heart block

Severe cardiac conduction manifestation

Conceptual summary; Categories are not quantitative or exhaustive.

Slide 50 · CPEO versus Kearns–Sayre

Isolated CPEO

Chronic external ophthalmoplegia

No defining retinal / conduction triad supplied

Narrower phenotype

Kearns–Sayre syndrome

Chronic external ophthalmoplegia

Pigmentary retinal degeneration

Complete heart block

Slide 51 · Case 2: Eye, retina and cardiac conduction

Clinical reasoning prompt

A patient has progressive external ophthalmoplegia.

The examination identifies pigmentary retinal degeneration and complete heart block.

Question: Which named mitochondrial syndrome best fits this cluster?

Slide 52 · Case 2: The syndromic diagnosis

Interpretation

The three-feature cluster is characteristic of Kearns–Sayre syndrome.

This syndrome to mtDNA deletions.

The pattern illustrates why ophthalmoplegia must be evaluated in clinical context.

Slide 53 · Myoclonic epilepsy with ragged red fibers

MERRF is another named mitochondrial disease.

It among diseases caused by point mutations in mtDNA.

Its name links a neurologic syndrome to a classic muscle-pathology feature.

Clinical / conceptual emphasis

MERRF: A named mitochondrial syndrome with mtDNA point mutations.

Slide 54 · Leber hereditary optic neuropathy

Leber hereditary optic neuropathy is a mitochondrial disease example.

It among disorders associated with mtDNA point mutations.

Its presence in the list reinforces the potential importance of non-muscle organs.

Clinical / conceptual emphasis

A mitochondrial disease phenotype may be dominated by extra-muscular findings.

Slide 55 · Leigh syndrome is genetically heterogeneous

Nuclear gene mutation

MtDNA mutation

Leigh syndrome

Multiple genes in either genome converge on mitochondrial metabolic dysfunction.

Slide 56 · Leigh syndrome: Common pathway, diverse genes

Many different genes

MtDNA or nuclear genome

Disrupted mitochondrial metabolism

Leigh syndrome

Schematic sequence; Arrows denote conceptual progression.

Slide 57 · Clinical syndromes: Pattern comparison

Entity

Core association

Genetic note

CPEO

Chronic progressive external ophthalmoplegia

May be isolated or syndromic

MELAS

Encephalomyopathy, lactic acidosis, stroke-like episodes

MtDNA point mutation example

Kearns–Sayre

Ophthalmoplegia, retina, complete heart block

Associated with mtDNA deletions

MERRF

Myoclonic epilepsy with ragged red fibers

MtDNA point mutations

Leber optic neuropathy

Optic neuropathy phenotype

MtDNA point mutations

Leigh syndrome

Subacute necrotizing encephalopathy

MtDNA and nuclear mutations

Slide 58 · Use morphology without overspecifying genotype

Clinical pattern

Ocular, muscle and other organ findings

Tissue phenotype

Tissue accumulation or enzyme defect

Molecular evidence

MtDNA or nuclear variant

Conceptual summary; Categories are not quantitative or exhaustive.

Slide 59 · Clinical and tissue evidence must be integrated

Clinical phenotype

Morphology, if informative

Enzyme / genetic evidence

Integrated interpretation

Schematic sequence; Arrows denote conceptual progression.

Slide 60 · A common diagnostic pitfall

Absence of ragged red fibers does not rule out mitochondrial disease.

A classic clinical syndrome may remain recognizable even with subtle morphology.

Robbins expressly allows enzyme- or genetics-based diagnosis.

Clinical / conceptual emphasis

Histologic visibility and molecular disease are not synonymous.

Slide 61 · Case 3: Same mutation, divergent presentation

Clinical reasoning prompt

Two patients are found to share a pathogenic mtDNA point mutation.

One has isolated CPEO; The other has MELAS-type multisystem features.

Question: Must one diagnosis be incorrect?

Slide 62 · Case 3: What explains divergence?

Interpretation

No: Different phenotypes may arise from a shared mitochondrial variant.

Robbins offers the leucine tRNA point-mutation example.

Heteroplasmy and tissue threshold effects supply a mechanistic framework.

Slide 63 · Synthesis: Five defensible conclusions

Many mitochondrial mutations interfere with ATP generation.

Nuclear and mitochondrial genes yield different inheritance patterns.

Heteroplasmy, segregation and tissue thresholds complicate expression.

Ragged red fibers are characteristic but not universal.

CPEO, MELAS, Kearns–Sayre, MERRF, LHON and Leigh illustrate clinical diversity.

Slide 64 · Primary reference and source limitations

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. (2026).

Chapter 27, “Peripheral Nerves and Skeletal Muscles,” pp. 1123–1125.

Source: project-provided Markdown extraction; no original chapter PDF was available.

Microscopic figures here are native educational schematics, not patient specimens.