Mitochondrial Encephalomyopathies

Slide 1 · MitochondrialEncephalomyopathies

Energy failure, mitochondrial genetics and CNS pathology

Mitochondrial genomes • Tissue energy failure • Clinicopathologic syndromes

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain why mitochondrial dysfunction often affects neurons and skeletal muscle

Distinguish mitochondrial from nuclear genetic contributions

Interpret heteroplasmy, tissue lactate and cytochrome oxidase histochemistry

Correlate MELAS, MERRF and Leigh syndrome with characteristic pathology

Slide 3 · A family of disorders of energy generation

Primary defect

Impaired mitochondrial oxidative phosphorylation

CNS consequence

Neurons depend on mitochondrial ATP production

Systemic expression

Other energy-dependent tissues may be involved

Slide 4 · Encephalo- and myopathy are linked

Encephalopathy

Neurologic dysfunction may dominate the presentation

Energy-dependent CNS cells are vulnerable

Myopathy

Weakness or characteristic muscle changes may coexist

The same cellular energy system is affected

Slide 5 · Neuronal ATP demand explains CNS involvement

Oxidative phosphorylation

Major mechanism supplying neuronal ATP

Reduced ATP generation

Loss of energy available for neuronal function

Neurologic disease

Variable clinical and tissue injury

Slide 6 · Mitochondrial ATP synthesis is the shared pathway

Respiratory machinery

Mitochondrial proteins support oxidative phosphorylation

ATP production

Efficient energy generation for active cells

Affected tissues

Neurons and skeletal muscle are prominently vulnerable

Slide 7 · Disease mechanisms span two genomes

Mitochondrial DNA

Encodes a small set of proteins and mitochondrial RNAs

Mutations may produce maternal transmission

Nuclear DNA

Encodes most required mitochondrial proteins

Mutations may show Mendelian inheritance

Slide 8 · Mitochondrial DNA has a compact coding repertoire

13

Protein-coding genes

22

Transfer RNA genes

2

Ribosomal RNA genes

Slide 9 · Most mitochondrial components are nuclear encoded

Nuclear genome

Codes for most proteins needed for mitochondrial structure/function

Mitochondrial genome

Codes for 13 proteins and essential RNAs

Clinical consequence

An oxidative phosphorylation disorder need not follow maternal inheritance

Slide 10 · Maternal transmission follows organelle origin

Oocyte

Supplies embryonic mitochondria

Mitochondrial genome

Passed through the maternal lineage

Affected descendants

May show variable manifestations

Slide 11 · Nuclear mutations do not require maternal transmission

MtDNA-associated disease

Maternal transmission can be a clue

Interpret alongside clinical phenotype

Nuclear-gene disease

Mendelian patterns are possible

A negative maternal pattern does not exclude disease

Slide 12 · Pedigree pattern is a clue, not a diagnosis

Maternal clustering can support a mitochondrial-genome mechanism

Nuclear mutations can cause the same broad clinical category

Genetic heterogeneity prevents a single inheritance rule

Pair pedigree interpretation with tissue and molecular evidence

Slide 13 · Each cell contains many mitochondrial genomes

Copy number

Cells contain thousands of mitochondrial DNA copies

Distribution

Copies are not partitioned in fixed equal proportions

Consequence

Descendants of a cell may differ genetically

Slide 14 · Heteroplasmy: Mixed normal and mutant mtDNA

Lower mutant fraction

Higher mutant fraction

Wild-type mtDNA

Mutant mtDNA

Schematic mtDNA proportions (not measured)

Slide 15 · Random mitochondrial segregation changes mutant load

Parent cell

Mix of wild-type and mutant mtDNA

Cell division

Mitochondria distributed stochastically

Daughter cells

Different mutant-to-wild-type proportions

Slide 16 · Heteroplasmy produces tissue-level mosaicism

Cell A

Lower proportion of mutant mtDNA

Cell B

Higher proportion of mutant mtDNA

Clinical result

Variable functional impairment within tissues

Slide 17 · A tissue threshold helps explain clinical onset

Variable mutant load

Heteroplasmy differs by cell and tissue

Functional threshold

Sufficiently high burden impairs ATP production

Symptomatic tissue

Vulnerability depends on tissue energy demand

Slide 18 · One mutation can produce different clinical phenotypes

One genetic variant

Mitochondrial leucine tRNA variant

Different manifestations

Isolated external ophthalmoplegia or severe MELAS

Slide 19 · A similar phenotype can result from different variants

Shared phenotype

Leigh syndrome

Multiple causes

Mutations in mtDNA or nuclear genes

Unifying dysfunction

Essential mitochondrial metabolic pathways

Slide 20 · Pleiotropy links neurologic and non-neurologic signs

Molecular defect

Disrupted mitochondrial energy generation

Multiple tissues

Brain, muscle and other organs

Combined phenotype

Neurologic and systemic manifestations

Slide 21 · Skeletal muscle can reveal systemic mitochondrial disease

Variable weakness may accompany CNS dysfunction

Serum creatine kinase can be elevated

Rhabdomyolysis is possible in some mitochondrial myopathies

Extraocular muscle involvement is a useful clinical clue

Slide 22 · External ophthalmoplegia signals an energy-sensitive muscle

Clinical sign

Chronic progressive external ophthalmoplegia

Muscle physiology

Extraocular muscles have very high mitochondrial content

Interpretation

Can be isolated or part of a multisystem syndrome

Slide 23 · Mitochondrial myopathy has characteristic structural changes

Light microscopy

Subsarcolemmal mitochondrial aggregates

Electron microscopy

Morphologically abnormal mitochondria

Histochemistry

Reduced activity of specific mitochondrial enzymes

Slide 24 · Ragged red fibers reflect mitochondrial accumulation

Abnormal mitochondria

Accumulation beneath the sarcolemma

Gomori trichrome

Reddish granular fiber periphery

Ragged red fiber

A structural clue to mitochondrial myopathy

Slide 25 · Ragged red fiber: What the stain indicates

Schematic muscle fiber (not a photomicrograph)

Peripheral mitochondrial aggregates

Reddish granular subsarcolemmal pattern on Gomori trichrome

Slide 26 · Electron microscopy can show abnormal mitochondria

Ultrastructural examination may disclose mitochondrial abnormalities

Concentric membranous rings are described figure

Rhomboid paracrystalline inclusions may occur

These observations are morphologic, not a stand-alone genotype

Slide 27 · Cytochrome c oxidase activity is a functional marker

Mitochondrial dysfunction

Loss of enzyme activity in some disorders

Nonfixed tissue

Histochemical assessment of cytochrome oxidase

Interpretation

Functional evidence complementing morphology

Slide 28 · An unremarkable biopsy does not exclude disease

Some patients

Show ragged red fibers or enzyme loss

Histochemical abnormality is supportive

Other patients

Lack conspicuous muscle morphologic changes

Enzyme assays or genetic analysis may be required

Slide 29 · Impaired oxidative metabolism is reflected in lactate

Reduced oxidative ATP generation

Metabolic energetic impairment

Tissue lactate

Often elevated in CNS mitochondrial disease

Diagnostic evidence

Supports—but does not alone define—the disorder

Slide 30 · MR spectroscopy can demonstrate elevated tissue lactate

Biochemical signal

Increased lactate associated with energy failure

Imaging method

Spectroscopic imaging of involved tissues

Interpretation

A physiologic clue in the appropriate clinical setting

Slide 31 · Diagnostic assessment must integrate evidence

Phenotype and pedigree

Neurologic, muscle and family features

Metabolic and tissue studies

Lactate, histochemistry, morphology

Molecular evaluation

Variants in mitochondrial or nuclear DNA

Slide 32 · Three recognizable clinical patterns

MELAS

Stroke-like episodes, lactic acidosis and encephalomyopathy

MERRF

Myoclonus and ragged red fibers, often with ataxia

Leigh syndrome

Infantile psychomotor arrest and symmetric destructive CNS lesions

Slide 33 · MELAS: Clinical meaning of the acronym

M

Mitochondrial

E

Encephalomyopathy

LA

Lactic acidosis

S

Stroke-like episodes

Slide 34 · MELAS causes recurrent acute neurologic episodes

Recurrent episodes of acute neurologic dysfunction are characteristic

Cognitive changes may develop

The presentation occurs in the context of systemic mitochondrial dysfunction

Clinical episodes should be interpreted together with metabolic findings

Slide 35 · Lactic acidosis and weakness anchor MELAS systemically

CNS

Acute neurologic dysfunction and cognitive disturbance

Muscle / metabolism

Weakness and lactic acidosis

Slide 36 · MELAS can produce infarct-like tissue destruction

Neuropathology

Infarcts may be found

Associated findings

Vascular proliferation can accompany lesions

Additional change

Focal calcification may be present

Slide 37 · Vascular proliferation and calcification in MELAS

Disease context

Mitochondrial encephalomyopathy

Parenchymal observation

Infarcts may occur

Associated morphology

Vascular proliferation ± focal calcification

Slide 38 · MELAS is often associated with a leucine tRNA gene

Frequent association

Mutation in the mitochondrial leucine tRNA gene

Textbook designation

MTTL1 in the supplied Robbins text

Interpretation

A common association, not a universal genotype

Slide 39 · MELAS illustrates variable expressivity

Same variant

Mitochondrial leucine tRNA change

Phenotypic range

Isolated ophthalmoplegia or MELAS

Slide 40 · MELAS: A clinicopathologic synthesis

Recurrent neurologic attacks

With cognitive alteration

Muscle and metabolism

Weakness and lactic acidosis

Neuropathology

Infarcts ± vascular proliferation/calcification

Slide 41 · MERRF: A neuromuscular–epileptic phenotype

M

Myoclonic

E

Epilepsy

RRF

Ragged red fibers

Maternal

Maternally transmitted syndrome

Slide 42 · MERRF combines myoclonus with mitochondrial myopathy

Neurologic

Myoclonus, a seizure manifestation

Muscle

Myopathy with ragged red fibers

Slide 43 · Ataxia in MERRF correlates with cerebellar neuron loss

Cerebellar neuronal loss

Recognized pathology in MERRF

Disrupted coordination

Functional consequence

Ataxia

A common clinical feature

Slide 44 · MERRF may damage spinal white matter tracts

Affected tissue

White matter tracts in spinal cord

Morphologic change

Degeneration

Clinical context

Additional neurological dysfunction with ataxia

Slide 45 · Most MERRF cases involve mitochondrial tRNA genes

Genetic substrate

Pathogenic variants in mitochondrial tRNA genes

Transmission

Commonly maternal

Phenotype

Myoclonus, myopathy, ataxia

Slide 46 · Ragged red fibers support MERRF but are not exclusive

MERRF

Uses ragged red fibers in its syndrome name

Other disorders

Mitochondrial myopathies can also show mitochondrial aggregates

Slide 47 · MERRF links muscle and CNS pathology

Mitochondrial tRNA defect

Disrupted mitochondrial function

Muscle involvement

Ragged red myofibers

Neural involvement

Myoclonus, cerebellar loss, tract degeneration

Slide 48 · Leigh syndrome: A severe early-life disorder

Typical onset

Infancy

Early course

Psychomotor development arrests

Systemic metabolism

Lactic acidemia commonly occurs

Slide 49 · Leigh syndrome has a broad neurologic presentation

Feeding difficulties can be prominent

Seizures may develop

Extraocular muscle palsies may occur

Weakness with hypotonia is characteristic

Slide 50 · Leigh syndrome preferentially affects deep CNS structures

Brainstem nuclei

Typically involved

Thalamus

Typically involved

Hypothalamus

Typically involved

Slide 51 · Leigh lesions are often bilaterally symmetric

Schematic paired distribution: Not an anatomical section

Left side

Right side

Brainstem nuclei

Brainstem nuclei

Thalamus

Thalamus

Hypothalamus

Hypothalamus

Usually symmetric lesions involving characteristic deep structures

Slide 52 · Leigh histology shows destructive spongiform lesions

Parenchyma

Multifocal areas of tissue destruction

Background

Spongiform appearance

Vessels

Associated vascular proliferation

Slide 53 · Leigh has marked nuclear and mtDNA heterogeneity

Mitochondrial DNA

Some disease-causing mutations reside in mtDNA

Nuclear DNA

Many mutations affecting mitochondrial metabolism are also implicated

Slide 54 · Classic infantile Leigh disease is often rapidly progressive

Textbook description emphasizes the severe infantile presentation

Psychomotor arrest accompanies multiple brainstem / deep gray manifestations

Death usually within 1–2 years in this classic presentation

The statement should not be generalized to every molecularly defined phenotype

Slide 55 · Leigh: Pathology explains its clinical localization

Symmetric brainstem / deep nuclei

Multifocal spongiform destructive injury

Ocular, feeding, motor functions

Neural pathways and nuclei affected

Infantile neurologic syndrome

Palsies, feeding problems, hypotonia, seizures

Slide 56 · Compare hallmark manifestations across syndromes

Feature

MELAS

MERRF

Leigh

Dominant presentation

Stroke-like episodes

Myoclonus / myopathy

Infantile psychomotor arrest

Metabolic feature

Lactic acidosis

Oxidative dysfunction

Lactic acidemia

Structural clue

Infarcts, vascular change

Ragged red fibers

Symmetric spongiform lesions

Slide 57 · Anatomical pattern helps separate phenotypes

Syndrome

Typical anatomic clue

Underlying tissue change

MELAS

Brain parenchyma

Infarcts ± vascular proliferation

MERRF

Cerebellum and spinal tracts

Neuronal loss; tract degeneration

Leigh

Brainstem / thalamus / hypothalamus

Symmetric destructive spongiform lesions

Slide 58 · Genetic patterns differ even with one mechanism

Pattern

Relevant example

Diagnostic implication

Maternal mtDNA

MERRF; common MELAS variant

Maternal history may help

Nuclear-gene variants

Some Leigh cases

Nonmaternal pedigrees possible

Heteroplasmy

Across mtDNA disorders

Variation within families and tissues

Slide 59 · Different kinds of evidence answer different questions

Phenotype

Which organs and functions are involved?

Morphology / biochemistry

Is mitochondrial dysfunction plausible?

Molecular testing

Which genome and variant are implicated?

Slide 60 · Three common diagnostic over-interpretations

“Always maternal”

Incorrect: Nuclear genes also cause mitochondrial disease

“Normal biopsy excludes”

Incorrect: Some disorders lack overt muscle morphology

“One mutation = one syndrome”

Incorrect: Genotype–phenotype mapping is complex

Slide 61 · Teaching case: Episodic neurologic dysfunction

A patient has recurrent acute neurologic episodes and cognitive changes

Muscle weakness accompanies elevated lactate

Neuropathology documents infarct-like changes with vascular proliferation

Which of the three syndromes is most strongly suggested?

Slide 62 · Case resolution: MELAS

MELAS

Recurrent stroke-like neurologic dysfunction is the discriminating clue

Lactic acidosis and muscle involvement strengthen the pattern

The infarct-type pathology and vascular changes match the Robbins description

Slide 63 · Teaching case: Myoclonus with abnormal muscle stain

Myoclonic epilepsy develops with a myopathy

Muscle biopsy shows subsarcolemmal red granularity on Gomori trichrome

Ataxia and cerebellar neuronal loss are documented

Identify the clinicopathologic syndrome.

Slide 64 · Case resolution: MERRF

MERRF

Myoclonus plus ragged red fibers identifies the classic syndrome

Ataxia corresponds to cerebellar neuronal loss

Mitochondrial tRNA mutations are associated with most cases

Slide 65 · Teaching case: Infantile regression with symmetric lesions

An infant develops feeding difficulty, hypotonia and psychomotor arrest

Lactic acidemia is present

Symmetric brainstem and thalamic spongiform destructive lesions are identified

Which syndrome best explains this combination?

Slide 66 · Case resolution: Leigh syndrome

Leigh syndrome

Infantile neurologic deterioration and lactic acidemia fit the syndrome

Symmetric deep gray and brainstem involvement is highly characteristic

Both nuclear and mitochondrial gene defects are possible

Slide 67 · Principles to retain

Defective oxidative phosphorylation links neurologic and muscle disease

Both nuclear and mitochondrial genomes can be causal

Heteroplasmy helps explain variable tissue expression

MELAS, MERRF and Leigh have distinguishing clinicopathologic patterns

Slide 68 · Primary reading

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

Chapter 28: The Central Nervous System — Mitochondrial Encephalomyopathies, pp. 1174–1175.

Chapter 27: Peripheral Nerves and Skeletal Muscles — Mitochondrial Myopathies, pp. 1123–1125.