Mitochondrial Diseases
Learning objectives
- LO 1Explain what mitochondria do and why their failure can show up in any organ.
- LO 2Describe mtDNA, maternal inheritance and heteroplasmy, and recognize that mitochondrial disease can follow any inheritance pattern.
- LO 3Recognize the representative disorders (MELAS, PDH deficiency, MNGIE, Leigh syndrome, POLG1 spectrum): genetics, clinical picture and treatment.
MAPThe lecture is organized by inheritance pattern
LO 1Mitochondrial physiology
Q1. What are mitochondria, and what do they do?
- Intracellular organelle; 100s–1000s per cell, in every cell except mature RBCs (RBCs run on glycolysis)
- Maternally inherited; have their own genome
- Main job = metabolism: ATP by oxidative phosphorylation; hub of most metabolic pathways; also regulate apoptosis
Analogy — the power-plant blackout
Mitochondria are the city's power plants. In a blackout, the biggest power customers fail first: brain, muscle, heart, retina, ear, kidney tubules, liver, gut. That's why the disease looks like "anything."
Q2. What is primary vs secondary mitochondrial dysfunction?
Primary
- Genetic defect in a critical mitochondrial protein
- Gene can be in the nuclear OR mitochondrial genome
Secondary
- Infections
- Medications
- Other physiologic stressors (fever, fasting, surgery)
Step 1 — drugs that hurt mitochondria
- Valproate: inhibits respiratory chain; fatal liver failure in POLG/Alpers
- Barbiturates: inhibit complex I
- Aminoglycosides: deafness with 12S rRNA m.1555A>G
- NRTIs (zidovudine), linezolid: myopathy, lactic acidosis
Q3. What clinical features can mitochondrial disease cause?
"Anything, anywhere, anytime." Don't memorize the list; understand why each energy-hungry tissue fails.
| System | Features |
|---|---|
| Systemic | Lactic acidosis, short stature, fatigue, failure to gain weight |
| CNS | Myoclonus, generalized seizures, stroke, migraine, ataxia, intellectual disability, psychiatric disease |
| Muscle | Myopathy (hypotonia), CPEO, recurrent myoglobinuria, weakness/fatigue |
| Heart | Cardiomyopathy, conduction defects |
| Eye | Optic neuropathy, retinitis pigmentosa |
| Ear | High-frequency hearing loss, aminoglycoside-induced deafness |
| GI | Pseudo-obstruction, constipation, vomiting |
| Liver | Hypoglycemia, gluconeogenic defects, liver failure, cirrhosis |
| Kidney | Fanconi syndrome (proximal tubule) |
| Endocrine | Diabetes insipidus, hormonal dysfunction |
| Bone marrow | Anemia, pancytopenia |
High yield
Red flags: ≥3 unrelated organ systems (brain + muscle especially), worsening with illness or fasting, lactic acidosis, maternal family history.
Step 1
Lactate:pyruvate ratio: ETC defect → NADH piles up → pyruvate pushed to lactate → high L:P (>20). PDH deficiency → both rise together → normal L:P. Muscle biopsy: ragged red fibers (Gomori trichrome). Classic triad: deafness + diabetes mellitus + short stature.
ApplyLO 1 application questions
A1Which cell type has no mitochondria, and how does it make ATP?
A2Why does almost any mitochondrial defect raise blood lactate?
LO 2Mitochondrial genetics
Q1. What is unique about mitochondrial DNA?
| Feature | mtDNA |
|---|---|
| Size / shape | ≈16.5 kb, double-stranded, circular |
| Genes | 37: 22 tRNAs (distinct triplet code from nuclear DNA) · 2 rRNAs · 13 ETC subunits |
| Copies | 2–10 per mitochondrion → thousands per cell |
| Nuclear share | Most of the >1,000 mitochondrial proteins are nuclear-encoded |
Human mtDNA map
- 16,569 bp circle; tRNAs (yellow) scattered between protein genes
Memory tool
37 = 22 + 2 + 13: "22 tRNAs carry, 2 rRNAs build, 13 proteins burn." tRNA genes are the classic disease sites (MELAS tRNA-Leu, MERRF tRNA-Lys).
Step 1
Complex II (succinate dehydrogenase) is the only ETC complex with no mtDNA-encoded subunits.
Q2. What does a maternal-inheritance pedigree look like?
| Parent with an mtDNA mutation | Children |
|---|---|
| Mother | All children inherit it (sons and daughters), with variable severity |
| Father | None (sperm mitochondria are lost after fertilization) |
Maternal transmission
- mtDNA marker passes only through mothers
High yield
Passed only through females, both sexes affected, affected men never transmit, severity varies within a sibship → mitochondrial. Contrast XLR (affected father → all daughters carriers) and AD (male-to-male transmission possible).
Q3. What are homoplasmy, heteroplasmy, threshold and bottleneck?
| Term | Meaning |
|---|---|
| Homoplasmy | All mtDNA copies in a cell are the same (all normal or all mutant) |
| Heteroplasmy | A mix of normal and mutant mtDNA in a cell or tissue |
| Threshold | Symptoms only when the mutant fraction passes a tissue-specific level (30% mutant → none? 70% → symptoms?) |
| Tissue variation | Heteroplasmy differs tissue to tissue and shifts with cell division |
| Bottleneck | Only a small, random sample of mom's mitochondria enters each egg → a mildly affected mother can have a severely affected child |
Homoplasmy vs heteroplasmy
- 30% mutant = no symptoms? 70% = symptoms?
Bottleneck
- Eggs get 80%, 50% or 20% mutant → severe, mild, none
High yield
Variable severity of the same mtDNA mutation within one family = heteroplasmy (not anticipation, imprinting or locus heterogeneity).
Analogy — the bag of marbles
Mom's egg precursor holds a bag of red (mutant) and green (normal) marbles. Each egg grabs a small random handful. One child gets mostly red, a sibling mostly green.
Trap — counseling
A woman with a heteroplasmic mtDNA point mutation passes it to all offspring, but CVS/amniocentesis can't reliably predict severity: heteroplasmy shifts during development and differs between tissues.
Q4. Can mitochondrial disease be inherited any other way?
- Yes: because most mitochondrial proteins are nuclear-encoded, disease can be maternal, X-linked, autosomal recessive (most common!) or autosomal dominant
- Affected siblings with healthy parents and a mitochondrial phenotype → think AR nuclear
In-house exam
Autosomal recessive nuclear genes are the most common cause of mitochondrial disease.
ApplyLO 2 application questions
A1A man and a woman each have LHON. What is the risk to each one's children?
A2A patient has mild cramps; his maternal aunt has deafness and CPEO; biopsy shows a variable % of mutant mtDNA across fibers. Principle?
LO 3Representative disorders
Q1. MELAS: who gets it, and what are "ATP strokes"?
Mitochondrial Encephalopathy, Lactic Acidosis, Stroke-like episodes.
Clinical
- Childhood onset
- First: non-specific neuro symptoms: seizures, headaches, altered consciousness, transient hemiparesis or blindness
- Then progressive motor, visual and cognitive decline
- Lactic acidosis; myopathy
- Stroke-like episodes = "ATP strokes, not clot strokes"
Genetics & treatment
- mtDNA: 80% in MT-TL1 (tRNA-Leu); common mutation m.3243A>G
- Maternal inheritance; heteroplasmy and tissue distribution shape the phenotype
- "Cocktail": CoQ10, carnitine, creatine, lipoic acid (supportive)
- Arginine during acute stroke-like events
In-house exam
3-year-old with a seizure after 3 days of fever, months of regression, ↑ lactate in blood and CSF, an occipital cortical lesion → MELAS, maternal inheritance.
High yield — MELAS vs ischemic stroke
Young patient, no vascular risk factors, lesion crosses arterial territories (often occipital), lactate high, triggered by illness, maternal relatives with varied symptoms → metabolic "ATP stroke."
Memory tool
Why arginine? Arginine → nitric oxide → vasodilation → more blood and nutrients to the stressed brain. The cocktail = cofactors that "support a stressed mitochondrion," not a cure.
Q2. PDH deficiency: why X-linked, and why a ketogenic diet?
- PDH links glycolysis to the TCA cycle (pyruvate → acetyl-CoA); a multi-enzyme complex
- Cofactors: thiamine, α-lipoic acid, FAD, NAD, CoA
- Gene PDHA1 is X-linked, but males and females can be affected (skewed X-inactivation in brain); complete loss is fatal early in both
- Clinical: psychomotor delay, hypotonia, progressive encephalopathy (incl. Leigh) with early death, brain malformations; occasional cardiomyopathy, liver
- Treatment: ketogenic diet (ketones → acetyl-CoA after the block = alternate brain fuel); cofactors help only if some enzyme activity remains
PDH = the gateway
- Pyruvate → acetyl-CoA → TCA
PDH deficiency MRI
- Brain malformations / breakdown
Memory tool
PDH cofactors: "Tender Loving Care For Nancy" = Thiamine (B1), Lipoic acid, CoA (B5), FAD (B2), NAD (B3). Same five as α-ketoglutarate dehydrogenase.
Trap
X-linked ≠ "boys only": the slide says male and female can be affected. And carbohydrate loads worsen lactic acidosis in PDH deficiency.
Step 1
PDH deficiency → ↑ lactate and pyruvate (normal L:P ratio), ↑ alanine. Arsenic inhibits lipoic acid.
Q3. MNGIE: how does a nuclear gene damage mtDNA?
Mitochondrial NeuroGastroIntestinal Encephalopathy.
- Onset in adolescence (variable)
- Severe GI dysmotility, cachexia, nausea, vomiting, constipation, incontinence; peripheral neuropathy; ophthalmoplegia/ptosis
- Cause: thymidine phosphorylase deficiency (TYMP), a nuclear-encoded, cytoplasmic protein → autosomal recessive
- Massive ↑ thymidine → disrupts mtDNA replication (which needs tight nucleotide control) → progressive accumulation of mtDNA mutations
Memory tool
MNGIE = "My Nerves, Gut, Intestines, Eyes": neuropathy, gut dysmotility, cachexia, ptosis/ophthalmoplegia.
Analogy — the flooded supply room
mtDNA replication is a printer that needs exactly the right ink mix. Thymidine phosphorylase deficiency floods the room with one color (thymidine) and the copies come out full of errors.
Q4. Leigh syndrome: what is it, and why do so many genes cause it?
- Progressive neurologic degeneration starting at 3–12 months
- Decompensation with each catabolic stress (infection, fasting)
- Hypotonia, spasticity, chorea, ataxia, peripheral neuropathy; cardiomyopathy
- Brainstem and/or basal ganglia disease; ↑ lactate in blood or CSF (MRS lactate peak)
- Genetic heterogeneity: many genes → one disease ("the brain showing us the mitochondria aren't working")
| Complex | mtDNA-encoded | Nuclear-encoded |
|---|---|---|
| I | MTND3, MTND5, MTND6 | NDUFV1, NDUFS1, S3, S4, S7, S8 |
| II | — | SDHA (flavoprotein subunit A) |
| III | — | BCS1L (assembly) |
| IV | MTCO3 | COX10, COX15, SCO2, SURF1 (assembly of complex IV) |
| V | MTATP6 | — |
| Other | — | PDH (X-linked) |
Leigh imaging
- Basal ganglia lesions (top); MRS lactate peak (bottom)
Management: no specific treatment · sodium bicarbonate for acidosis · antiepileptics but avoid valproic acid and barbiturates (inhibit the respiratory chain) · mitochondrial cocktail trial · hospice care.
In-house exam
7-month-old regresses after a viral illness; MRI symmetric basal ganglia/brainstem lesions; CSF lactate ↑ → Leigh. Avoid valproate and barbiturates.
Memory tool
Leigh = "Lots of genes, Lactate, Little ones, Lentiform (basal ganglia)."
Q5. POLG1: how does one gene cause many diseases?
- POLG1 = mtDNA polymerase γ, critical for mtDNA replication and repair; 3 domains (polymerase, exonuclease, linker) with some genotype–phenotype correlation
- Continuum of overlapping phenotypes varying in severity, organ and age of onset; all originally described separately
- Diagnosed by direct mutation detection or mtDNA depletion; no specific effective therapy
- Phenotypic heterogeneity: one gene → many diseases
| Phenotype | Features |
|---|---|
| Leigh disease | CNS imaging findings; rapid deterioration in childhood |
| Alpers | Seizures, neurologic regression, liver dysfunction or failure |
| MEMSA | Myoclonic epilepsy, myopathy, sensory ataxia |
| ANS | Ataxia neuropathy spectrum |
| AR and AD PEO | Progressive external ophthalmoplegia (adults) |
In-house exam
Leigh = genetic heterogeneity (many genes → one disease). POLG1 = phenotypic heterogeneity (one gene → many diseases). Easy to flip on the exam.
High yield
Valproate + POLG = acute liver failure. Children with refractory seizures and regression are tested for POLG1 before mitochondria-toxic antiepileptics.
Q6. Which classic mitochondrial syndromes does Step 1 add?
| Syndrome | Genetics | Hallmarks |
|---|---|---|
| MERRF | mtDNA tRNA-Lys (m.8344A>G), maternal | Myoclonic epilepsy with ragged red fibers; ataxia, myopathy, hearing loss |
| LHON | mtDNA complex I (ND4), maternal | Young men; acute painless bilateral central vision loss |
| Kearns-Sayre | Single large mtDNA deletion, sporadic | Onset <20: CPEO + pigmentary retinopathy + heart block |
| Pearson | Large mtDNA deletion, sporadic | Infants: sideroblastic anemia + exocrine pancreatic insufficiency; can evolve to KSS |
| Aminoglycoside deafness | 12S rRNA m.1555A>G | Irreversible deafness after one course |
Step 1 — sorters
- Ragged red trio: MERRF, MELAS, Kearns-Sayre
- Ophthalmoplegia: KSS (+ retinopathy + heart block, <20) · POLG PEO (adult) · MNGIE (+ GI + neuropathy)
- Vision: LHON = optic neuropathy · KSS/MERRF = retinopathy · MELAS = cortical blindness
ApplyLO 3 application questions
A1A 2-month-old girl has hypotonia and corpus callosum agenesis; lactate and pyruvate are both ↑ with a normal L:P ratio. Enzyme, inheritance and diet?
A2A 19-year-old has pseudo-obstruction, 20 kg weight loss, ptosis and neuropathy; plasma thymidine is very high. Diagnosis and inheritance?
A3A child with refractory seizures and regression develops liver failure after starting valproate. Gene?
IDImage ID
Image 1 — circle
Image 2 — pedigree
Image 3 — cells
Image 4 — eggs
Image 5 — pathway
Image 6 — MRI / MRS
MCQExam-style questions
1A 3-year-old has a tonic-clonic seizure after 3 days of fever and 3 months of motor regression. Lactate is ↑ in blood and CSF; MRI shows a left occipital cortical lesion that doesn't fit a vascular territory. Inheritance pattern?
2Which gene type carries most MELAS mutations?
3During an acute stroke-like episode in MELAS, which therapy is given?
4A woman has a heteroplasmic mtDNA point mutation and mild symptoms. Which statement about her children is correct?
5Affected family members carry the same mtDNA mutation but range from mild cramps to severe encephalopathy. Best explanation?
6What is the most common inheritance pattern of mitochondrial disease?
7An infant girl has hypotonia, brain malformations, and ↑ lactate and pyruvate with a normal L:P ratio. Which treatment is most effective?
8A 17-year-old has severe GI dysmotility, cachexia, ptosis and peripheral neuropathy. Plasma thymidine is markedly elevated. Defective protein?
9A 7-month-old regresses after each viral illness. MRI shows symmetric basal ganglia and brainstem lesions; CSF lactate is ↑. Which antiseizure drug should be avoided?
10Leigh syndrome can result from mutations in complex I, II, III, IV, V or PDH genes. This illustrates:
11A child with refractory seizures and developmental regression develops acute liver failure after starting valproate. Most likely gene?
12How many genes does human mtDNA encode, and which group is largest?
!Where sources disagree
| Item | In-house | Step 1 / standard references |
|---|---|---|
| Primary dysfunction | Exam notes: "abnormality in mitochondrial DNA" | Slides: defect in the nuclear or mitochondrial genome |
| POLG phenotype variation | Exam notes: due to heteroplasmy | POLG1 is nuclear; variation reflects genotype/domain and which tissues accumulate mtDNA damage |
| Leigh inheritance | Class notes: "autosomal recessive" | Slides: all inheritance types (mtDNA, AR, X-linked PDH) |
| Endocrine feature | Diabetes insipidus | Diabetes mellitus is the classic Step 1 association |
| Sperm mitochondria | Exam notes: "burned out" | Tagged and destroyed in the zygote |
| mtDNA size | ≈16.5 kb | 16,569 bp |