Mitochondrial Diseases — MCQs
A muscle biopsy shows 'moth-eaten' fibers. Which histochemical finding would confirm mitochondrial myopathy?
Mark the false statement regarding mitochondrial DNA:
Mitochondrial DNA inheritance is transmitted from:
What is the mechanism of cyanide poisoning?
In the electron transport chain, electrons travel from which energy state to which energy state?
A 48-year-old right-handed man was admitted with a 3-day history of brief generalized tonic-clonic seizures, muscle weakness, a 3-month history of weight loss with increasing difficulty in eating, and a 1-week history of word finding difficulties and speech apraxia with reduced fine motor skills. He had a diagnosis of type 2 diabetes mellitus, epilepsy, and a history of a left temporal lobe infarct 3 years ago. MRI of the brain showed bilateral cortical-based signal abnormality with associated edema, with corresponding diffusion hyperintensity. MR spectroscopy showed a lactate doublet peak. HPE of muscle biopsy was shown below. What is the most probable diagnosis?
What is the function of Complex I in the electron transport chain?
Muscle biopsy shows ragged red fibers on modified Gomori trichrome stain. Which enzyme defect is most likely?
A 34-year-old, G1P0, presents for genetic counseling at 12 weeks' gestation. The patient has two sisters and a brother; her father has hemophilia. Her siblings are not affected, but she has a nephew who is affected. What is the inheritance pattern of this disorder?
Identify the pattern of inheritance shown below.
Mitochondrial Diseases Indian Medical PG Practice Questions and MCQs
Question 1: A muscle biopsy shows 'moth-eaten' fibers. Which histochemical finding would confirm mitochondrial myopathy?
- A. Ragged red fibers on MGT (Correct Answer)
- B. Type 1 fiber predominance
- C. Rimmed vacuoles
- D. Nemaline rods
Explanation: ***Ragged red fibers on MGT*** - The presence of **ragged red fibers** on a **modified Gomori trichrome (MGT) stain** is the histological hallmark of **mitochondrial myopathies**. - These fibers represent abnormal accumulation of **dysfunctional mitochondria** beneath the sarcolemma. *Type 1 fiber predominance* - While some myopathies may show type 1 fiber predominance, it is a **non-specific finding** and does not confirm mitochondrial myopathy. - It can be seen in various conditions, including **neurogenic atrophy** or some **congenital myopathies**. *Rimmed vacuoles* - **Rimmed vacuoles** are characteristic of **inclusion body myositis** (IBM) and some **distal myopathies**. - They are not a specific finding for mitochondrial myopathy. *Nemaline rods* - **Nemaline rods** are pathognomonic for **nemaline rod myopathy**, a distinct form of congenital myopathy. - They are composed of **actin filament aggregates** and are unrelated to mitochondrial dysfunction.
Question 2: Mark the false statement regarding mitochondrial DNA:
- A. AGA and AGG are stop codons in mitochondrial DNA
- B. Kearns-Sayre Syndrome is a large deletion in mitochondrial DNA
- C. Does not show heteroplasmy (Correct Answer)
- D. 1% of cellular DNA, 13 proteins of respiratory chain
Explanation: ***Does not show heteroplasmy*** - This statement is false because **mitochondrial DNA (mtDNA)** commonly exhibits **heteroplasmy**, meaning the presence of more than one type of mitochondrial genome within a cell or individual. - **Heteroplasmy** arises due to the presence of both normal and mutated mtDNA, which can be passed down from the mother. *AGA and AGG are stop codons in mitochondrial DNA* - This statement is true; in the **universal genetic code**, AGA and AGG code for **arginine**, but in **human mitochondrial DNA**, they serve as **stop codons**. - This is an example of the **differences** in genetic code interpretation between the nuclear genome and the mitochondrial genome. *Kearns-Sayre Syndrome is a large deletion in mitochondrial DNA* - This statement is true; **Kearns-Sayre Syndrome** is a well-known mitochondrial disorder caused by a **large single deletion** in the mitochondrial DNA. - This deletion often leads to chronic progressive **external ophthalmoplegia**, **retinal pigmentary degeneration**, and **cardiac conduction defects**. *1% of cellular DNA, 13 proteins of respiratory chain* - This statement is true; **mitochondrial DNA constitutes** approximately **1% of the total cellular DNA** by mass. - It codes for **13 essential proteins** that are part of the **electron transport chain** (respiratory chain) complexes in the mitochondrion, along with ribosomal RNAs (rRNAs) and transfer RNAs (tRNAs).
Question 3: Mitochondrial DNA inheritance is transmitted from:
- A. Father
- B. Grandmother
- C. Grandfather
- D. Mother (Correct Answer)
Explanation: ***Mother*** - **Mitochondrial DNA (mtDNA)** is exclusively inherited from the mother. - This is because the **egg cell** contributes the cytoplasm, including mitochondria, to the zygote, while the sperm primarily contributes nuclear DNA. *Father* - The father primarily contributes **nuclear DNA** during fertilization. - While sperm do contain mitochondria, these are typically **degraded** or excluded from the fertilized egg. *Grandmother* - This option confuses **lineage** with **direct transmission**. - The question asks about immediate parental transmission, which is from the **mother**, not the grandmother. - While mtDNA follows a maternal lineage (grandmother → mother → child), the direct source is always the mother. *Grandfather* - A grandfather does not transmit mtDNA to his offspring. - The inheritance pathway for mtDNA is strictly **maternal**.
Question 4: What is the mechanism of cyanide poisoning?
- A. Inhibition of cytochrome oxidase (Correct Answer)
- B. Inhibition of complex I
- C. Inhibition of cytochrome C
- D. Inhibition of carbonic anhydrase
Explanation: ***Inhibition of cytochrome oxidase*** - Cyanide rapidly binds to the **ferric iron (Fe3+)** in the **heme a3 component of cytochrome c oxidase** (Complex IV) in the mitochondrial electron transport chain. - This binding completely inhibits the enzyme's ability to transfer electrons to oxygen, thereby **halting cellular respiration** and ATP production. *Inhibition of complex I* - **Rotenone** and **barbiturates** are known inhibitors of **Complex I** (NADH dehydrogenase), not cyanide. - While inhibition of Complex I also disrupts the electron transport chain, it is not the primary mechanism of cyanide toxicity. *Inhibition of cytochrome C* - **Cytochrome C** is an electron carrier between Complex III and Complex IV, but it is not the direct target of cyanide. - Cytochrome C itself is not inhibited; rather, its function is compromised because **cytochrome c oxidase (Complex IV)**, which accepts electrons from it, is inhibited by cyanide. *Inhibition of carbonic anhydrase* - **Carbonic anhydrase**, an enzyme involved in CO2 transport and pH regulation, is inhibited by drugs like **acetazolamide**. - Its inhibition does not directly affect the mitochondrial electron transport chain or cause the rapid cellular hypoxia seen in cyanide poisoning.
Question 5: In the electron transport chain, electrons travel from which energy state to which energy state?
- A. From high energy to low energy state (Correct Answer)
- B. Two way
- C. One way irrespective of the potential
- D. From low to high redox potential
Explanation: ***From high to low potential (high energy to low energy)*** - In the electron transport chain, electrons move from carriers with **lower (more negative) reduction potentials** (higher energy state) to carriers with **higher (more positive) reduction potentials** (lower energy state). - This "downhill" energy movement releases energy that is used to pump protons and synthesize ATP. - **Key concept**: Low redox potential = High energy; High redox potential = Low energy. - Electrons flow spontaneously from **more negative to more positive redox potential**, which represents movement from **high to low energy state**. *One way irrespective of the potential* - Electron flow is indeed **unidirectional** in the electron transport chain, but it is NOT independent of potential. - The flow is entirely **dependent on the redox potential gradient** between successive carriers. - Electrons move specifically due to the thermodynamically favorable reduction potential differences. *Two way* - The electron transport chain is a **strictly unidirectional process** under normal physiological conditions. - Electrons flow in one direction: from NADH/FADH₂ through the complexes to molecular oxygen. - There is **no backward or reversible flow** of electrons along the chain. *From low to high redox potential* - While electrons do move from **low (more negative) to high (more positive) redox potential** in terms of voltage values, this is from **high energy to low energy** state. - This option is technically correct regarding redox potential values but may confuse the energy relationship. - The question asks about energy state movement, and thermodynamically, electrons move "downhill" from high to low energy.
Question 6: A 48-year-old right-handed man was admitted with a 3-day history of brief generalized tonic-clonic seizures, muscle weakness, a 3-month history of weight loss with increasing difficulty in eating, and a 1-week history of word finding difficulties and speech apraxia with reduced fine motor skills. He had a diagnosis of type 2 diabetes mellitus, epilepsy, and a history of a left temporal lobe infarct 3 years ago. MRI of the brain showed bilateral cortical-based signal abnormality with associated edema, with corresponding diffusion hyperintensity. MR spectroscopy showed a lactate doublet peak. HPE of muscle biopsy was shown below. What is the most probable diagnosis?
- A. Myotonic dystrophy
- B. Duchenne muscular dystrophy
- C. MELAS disease (Correct Answer)
- D. Becker's muscular dystrophy
Explanation: ***MELAS disease*** - The clinical picture of **seizures**, **muscle weakness**, **stroke-like episodes** (indicated by cortical signal abnormalities and prior infarct), **weight loss**, and **speech difficulties** are characteristic features of MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes). - The **lactate doublet peak on MR spectroscopy** confirms lactic acidosis, a hallmark of mitochondrial disorders, and the muscle biopsy showing **ragged red fibers** (as depicted in the image) is pathognomonic for MELAS. *Myotonic dystrophy* - Characterized by **myotonia** (delayed muscle relaxation), **muscle wasting**, and involvement of other systems such as cataracts and cardiac conduction defects. - While it causes muscle weakness, it does not typically present with stroke-like episodes, lactic acidosis, or the specific MRI findings seen in this case. *Duchenne muscular dystrophy* - This is an **X-linked recessive disorder** primarily affecting young boys, causing progressive muscle degeneration and weakness, typically starting in early childhood. - It would not present with adult-onset stroke-like episodes, lactic acidosis, or the neurological features described in this patient. *Becker's muscular dystrophy* - It is a milder variant of Duchenne muscular dystrophy with a later onset and slower progression, but it also primarily affects skeletal and cardiac muscles. - Like Duchenne, it does not typically cause stroke-like episodes, lactic acidosis, or the specific MRI and spectroscopy findings observed in this patient.
Question 7: What is the function of Complex I in the electron transport chain?
- A. NADH - CoQ reductase (Correct Answer)
- B. CoQ - cytochrome C reductase
- C. Cytochrome-C oxidase
- D. None of the options
Explanation: ***NADH - CoQ reductase*** - Complex I, also known as **NADH dehydrogenase**, transfers electrons from **NADH** to **Coenzyme Q (CoQ)**. - This process oxidizes NADH to NAD+ and pumps protons from the **mitochondrial matrix** to the **intermembrane space**, contributing to the proton gradient. - Complex I is the entry point for electrons from NADH into the electron transport chain and generates approximately **4 H+ ions** pumped per 2 electrons. *CoQ - cytochrome C reductase* - This describes the function of **Complex III**, not Complex I. - Complex III (cytochrome bc1 complex) transfers electrons from **reduced CoQ (ubiquinol)** to **cytochrome c**. - It also contributes to proton pumping via the Q-cycle mechanism. *Cytochrome-C oxidase* - This describes the function of **Complex IV**, not Complex I. - Complex IV transfers electrons from **cytochrome c** to **molecular oxygen (O2)**, forming water (H2O). - It is the terminal enzyme of the electron transport chain and pumps protons across the membrane. *None of the options* - This option is incorrect because Complex I clearly functions as **NADH - CoQ reductase**. - Each complex (I, II, III, and IV) has distinct enzymatic functions in the electron transport chain, and Complex I's role is well-established.
Question 8: Muscle biopsy shows ragged red fibers on modified Gomori trichrome stain. Which enzyme defect is most likely?
- A. Complex II
- B. Complex I (Correct Answer)
- C. Complex III
- D. Complex IV
Explanation: ***Complex I*** - **Complex I (NADH dehydrogenase) deficiency** is the **most common respiratory chain defect** causing mitochondrial myopathy with ragged red fibers - Accounts for approximately **30-40% of mitochondrial respiratory chain disorders** - **Ragged red fibers** on modified Gomori trichrome stain result from abnormal **subsarcolemmal accumulation of mitochondria** - Clinically presents with **progressive myopathy, exercise intolerance, lactic acidosis**, and may include encephalomyopathy (MELAS syndrome) [1] *Complex IV* - **Complex IV (cytochrome c oxidase/COX) deficiency** is another important cause of mitochondrial myopathy with ragged red fibers - While significant, it is **less common than Complex I deficiency** as a cause of RRF - COX-negative fibers can be identified by specific histochemical staining [1] *Complex III* - **Complex III (ubiquinol-cytochrome c oxidoreductase) deficiency** can cause mitochondrial myopathy - Less frequently associated with prominent ragged red fibers compared to Complex I or IV deficiencies - May present with exercise intolerance and myoglobinuria *Complex II* - **Complex II (succinate dehydrogenase) deficiency** is the rarest cause of mitochondrial myopathy among the respiratory chain complexes - More commonly associated with **paragangliomas and pheochromocytomas** (familial paraganglioma syndromes) - Ragged red fibers are uncommon in isolated Complex II deficiency **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. The Central Nervous System, pp. 1305-1306.
Question 9: A 34-year-old, G1P0, presents for genetic counseling at 12 weeks' gestation. The patient has two sisters and a brother; her father has hemophilia. Her siblings are not affected, but she has a nephew who is affected. What is the inheritance pattern of this disorder?
- A. X-linked inheritance (Correct Answer)
- B. Autosomal recessive
- C. Mitochondrial inheritance
- D. Multifactorial inheritance
Explanation: ***X-linked inheritance*** - Hemophilia is an **X-linked recessive disorder** - An affected father passes his X chromosome mutation to **all daughters**, making them **obligate carriers** (not affected but carry the gene) - The affected nephew (son of patient's sister) confirms the patient's sister is a carrier who passed the affected X chromosome to her son - Classic pattern: affected males, carrier females, skips generations through female carriers *Autosomal recessive* - Would require both parents to be carriers for offspring to be affected - An affected father would pass one mutant allele to all children, but this wouldn't make daughters obligate carriers unless mother also carried the gene - Pattern of father → carrier daughter → affected grandson is not typical of autosomal recessive inheritance *Mitochondrial inheritance* - Only transmitted from mother to **all children** regardless of gender - Affected father **cannot** pass mitochondrial disorders to offspring - Would show maternal transmission pattern with all children of affected mothers being affected *Multifactorial inheritance* - Involves combination of multiple genes and environmental factors - Does not follow clear Mendelian pattern - The distinct single-gene pattern (affected father, carrier daughters, affected male grandchild) indicates X-linked recessive, not multifactorial
Question 10: Identify the pattern of inheritance shown below.
- A. X linked Dominant inheritance
- B. Y linked Inheritance
- C. X linked Recessive inheritance
- D. Mitochondrial inheritance (Correct Answer)
Explanation: ***Mitochondrial inheritance*** - This pedigree shows **maternal inheritance**, where all children of an affected mother are affected, but none of the children of an affected father are affected. This is characteristic of mitochondrial inheritance as mitochondrial DNA is exclusively inherited from the mother. - The trait is passed from the **affected mother** to all her offspring regardless of sex. *X linked Dominant inheritance* - In X-linked dominant inheritance, affected fathers pass the trait to **all their daughters**, and no sons. This pattern is not observed here, as affected fathers do not pass the trait to any of their children. - Affected mothers can pass the trait to both sons and daughters, but affected males also pass to all daughters, which is absent. *Y linked Inheritance* - Y-linked inheritance would show transmission only from **father to son**. This pedigree shows affected females as well, and affected fathers do not pass the trait to their sons in the observed pattern. - No instances of father-to-son transmission are observed in the parts of the pedigree where the father is affected. *X linked Recessive inheritance* - X-linked recessive inheritance typically shows more affected **males than females**, and affected fathers cannot pass the trait to their sons. Daughters of affected fathers are carriers if the mother is not affected. - There is no transmission from affected fathers to any of their offspring in the observed pedigree.
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