Mitochondrial abnormalities are associated with which of the following conditions?
Q2
A muscle biopsy shows 'moth-eaten' fibers. Which histochemical finding would confirm mitochondrial myopathy?
Q3
Mark the false statement regarding mitochondrial DNA:
Q4
Muscle biopsy shows ragged red fibers on modified Gomori trichrome stain. Which enzyme defect is most likely?
Q5
Which disorder is associated with NARP syndrome, characterized by neuropathy, ataxia, and retinitis pigmentosa?
Q6
A 3-month-old girl with an immunodeficiency syndrome has been hospitalized for 1 month due to a severe pulmonary infection. Her family came to visit her daily in the beginning of her hospital stay; however, since their car broke down they have been unable to visit for the last 2 weeks. While the infection has now been resolved with proper treatment and supportive care, the girl's nurse is concerned that the patient is becoming increasingly withdrawn. Specifically, the nurse has noticed that since the family has stopped visiting, the girl seems to shy away from contact and sometimes even becomes unresponsive to verbal or visual cues. Which of the following is most likely true about this infant's condition?
Q7
A 59-year-old man comes to the clinic for an annual well-exam. He was lost to follow-up for the past 3 years due to marital issues but reports that he feels fine. The patient reports, “I feel tired but it is probably because I am getting old. I do feel a little feverish today - I think I got a cold.” His past medical history is significant for hypertension that is controlled with hydrochlorothiazide. He reports fatigue, congestion, cough, and night sweats. He denies any sick contacts, recent travel, weight changes, chest pain, or dizziness. His temperature is 101°F (38.3°C), blood pressure is 151/98 mmHg, pulse is 97/min, and respirations are 15/min. His laboratory values are shown below:
Hemoglobin: 13.5 g/dL
Hematocrit: 41%
Leukocyte count: 25,000/mm^3
Segmented neutrophils: 73%
Bands: 8%
Eosinophils: 1%
Basophils: 2%
Lymphocytes: 15%
Monocytes: 2%
Platelet count: 200,000/mm^3
What diagnostic test would be helpful in distinguishing this patient’s condition from pneumonia?
Q8
A 34-year-old man comes to the physician because of blurry vision and fatigue for 2 months. During this period, he has also had occasional bleeding from his gums after brushing his teeth. One month ago, he was diagnosed with deep vein thrombosis after returning from an overseas business meeting. His pulse is 118/min, respirations are 19/min, and blood pressure is 149/91 mm Hg. Pulse oximetry on room air shows an oxygen saturation of 97%. Examination shows bluish discoloration of the lips. The tip of the spleen is palpable 1 cm below the left costal margin. Sensory examination of the hands shows paresthesia. Hemoglobin concentration is 18 g/dL, hematocrit is 65%, leukocytes are 15,000/μL, and platelets are 470,000/μL. His serum erythropoietin concentration is decreased. Activation of which of the following is the most likely underlying cause of this patient's condition?
Q9
A 19-year-old woman is brought to the emergency room by her mother. She found her daughter pale, cold to the touch, and collapsed next to her bed earlier this morning. The patient has no previous medical or psychiatric history, but the mother does report that her daughter has not had her periods for the last 3 months. In the emergency department, the patient is alert and oriented. Her vitals include: blood pressure 80/60 mm Hg supine, heart rate 55/min. On physical examination, the patient appears pale and emaciated. A urine pregnancy test is negative. She is suspected of having an eating disorder. Which of the following treatment options would be contraindicated in this patient?
Q10
A 66-year-old woman comes to the physician because of a 1-week history of pruritic blister formation. Physical examination shows multiple 1–3 cm bullae on the palms, soles, lower legs, and inguinal folds. Gentle rubbing of the skin does not result in sloughing of the epidermis. Immunofluorescence studies of a perilesional skin biopsy specimen are most likely to show deposition of antibodies in which of the following areas?
Mitochondrial Disorders US Medical PG Practice Questions and MCQs
Question 1: Mitochondrial abnormalities are associated with which of the following conditions?
A. Krabbe's disease
B. Fabry disease
C. Leigh syndrome (Correct Answer)
D. Fanconi syndrome
Explanation: ***Fanconi syndrome***
- Fanconi syndrome is associated with **renal tubular dysfunction**, leading to **metabolic acidosis** and hypophosphatemia, often showing mitochondrial abnormalities [1].
- It can be linked to certain **toxins and genetic disorders**, affecting mitochondrial function, particularly in the context of renal cells.
*Fanconi syndrome*
- This option is a repeat and should not be considered separately; the proper acknowledgment of Fanconi syndrome is included in the correct answer.
- The condition itself is not missed but stated correctly under the correct answer.
*Krabbe's disease*
- Krabbe's disease primarily involves **galactocerebrosidase deficiency** and affects the central nervous system, not primarily linked to mitochondrial dysfunction [2].
- It presents with **neuropathy**, **global developmental delay**, and **progressive weakness**, which are distinct from mitochondrial disorders.
*Fabry disease*
- Fabry disease is caused by **alpha-galactosidase A deficiency**, leading to lysosomal accumulation, primarily affecting **vascular and renal systems**.
- Mitochondrial dysfunction is not a primary feature, making it distinguishable from mitochondrial abnormalities.
**References:**
[1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Peripheral Nerves and Skeletal Muscles, pp. 1246-1247.
[2] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. The Central Nervous System, pp. 1304-1305.
Question 2: 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 3: 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 4: Muscle biopsy shows ragged red fibers on modified Gomori trichrome stain. Which enzyme defect is most likely?
A. Complex IV
B. Complex II
C. Complex III
D. Complex I (Correct Answer)
Explanation: ***Complex I***
- **Ragged red fibers** on modified Gomori trichrome stain are the pathological hallmark of **mitochondrial myopathies** [1]
- **Complex I (NADH-CoQ reductase) deficiency** is the **most common cause** of mitochondrial disease, accounting for approximately 30-40% of all cases
- Complex I deficiency is the **most frequent cause of ragged red fibers** in muscle biopsies
- Associated clinical features include progressive muscle weakness, exercise intolerance, lactic acidosis, and encephalomyopathy (Leigh syndrome) [1]
- The ragged red appearance results from subsarcolemmal accumulation of abnormal mitochondria attempting to compensate for defective oxidative phosphorylation
*Complex II*
- **Complex II (succinate dehydrogenase) deficiency** is a relatively rare cause of mitochondrial myopathy
- More commonly associated with hereditary paraganglioma-pheochromocytoma syndromes and certain cancers
- Can cause ragged red fibers but is much less common than Complex I deficiency
- The only complex entirely encoded by nuclear DNA (not mitochondrial DNA)
*Complex III*
- **Complex III (ubiquinol-cytochrome c reductase) deficiency** is a rare cause of mitochondrial disease
- Can present with myopathy and ragged red fibers, but accounts for only a small percentage of mitochondrial disorders
- Associated with exercise intolerance and multisystem involvement when present
*Complex IV*
- **Complex IV (cytochrome c oxidase, COX) deficiency** can cause mitochondrial myopathy with ragged red fibers [1]
- However, it is **less common than Complex I deficiency** as a cause of ragged red fibers
- COX-deficient fibers can be identified using specific COX histochemical staining [1]
- Associated with Leigh syndrome and other encephalomyopathies, but not the **most likely** cause when ragged red fibers are present
**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 5: Which disorder is associated with NARP syndrome, characterized by neuropathy, ataxia, and retinitis pigmentosa?
A. Mitochondrial function disorder (Correct Answer)
B. Glycogen storage disorder
C. Lysosomal storage disorder
D. Lipid storage disorder
Explanation: ***Mitochondrial function disorder***
- NARP syndrome (Neurogenic weakness, Ataxia, Retinitis Pigmentosa) is caused by a specific point mutation in the **MT-ATP6 gene**, which encodes a subunit of the mitochondrial ATP synthase [1].
- This mutation leads to impaired mitochondrial energy production, affecting tissues with high energy demands, such as the **nervous system** and retina [1].
*Glycogen storage disorder*
- These disorders involve defects in enzymes responsible for **glycogen synthesis or degradation**, leading to abnormal glycogen accumulation in tissues [1].
- While they can cause muscle weakness and neurological symptoms, the specific constellation of **neuropathy, ataxia, and retinitis pigmentosa** is not characteristic of glycogenoses.
*Lysosomal storage disorder*
- These conditions result from deficiencies in lysosomal enzymes, causing the accumulation of **undigested macromolecules** within lysosomes.
- Symptoms vary widely but typically involve progressive neurological degeneration, organomegaly, and skeletal abnormalities, without the classic NARP presentation.
*Lipid storage disorder*
- These disorders are characterized by the accumulation of **specific lipids** due to enzyme deficiencies involved in lipid metabolism.
- Examples include Gaucher disease and Niemann-Pick disease, which involve different clinical manifestations such as hepatosplenomegaly, bone crises, and various neurological issues, distinct from NARP syndrome.
Question 6: A 3-month-old girl with an immunodeficiency syndrome has been hospitalized for 1 month due to a severe pulmonary infection. Her family came to visit her daily in the beginning of her hospital stay; however, since their car broke down they have been unable to visit for the last 2 weeks. While the infection has now been resolved with proper treatment and supportive care, the girl's nurse is concerned that the patient is becoming increasingly withdrawn. Specifically, the nurse has noticed that since the family has stopped visiting, the girl seems to shy away from contact and sometimes even becomes unresponsive to verbal or visual cues. Which of the following is most likely true about this infant's condition?
A. The condition can be diagnosed in adults if it lasts > 6 months
B. The condition is significantly more common in boys
C. The condition is exclusively seen in girls
D. The condition should be reported to state authorities
E. The condition is reversible (Correct Answer)
Explanation: ***The condition is reversible***
- The infant is exhibiting symptoms of **anaclitic depression** or **hospitalism**, characterized by withdrawal, unresponsiveness, and lack of social engagement due to prolonged separation from primary caregivers.
- This condition is often **reversible** with proper intervention, such as reuniting the infant with their primary caregivers and providing supportive care.
*The condition can be diagnosed in adults if it lasts > 6 months*
- **Anaclitic depression** is a specific diagnosis primarily observed in **infants and young children** who experience prolonged separation from their primary attachment figures.
- While adults can experience depression, the specific symptom profile and etiological factors for anaclitic depression are distinct and not applied to adult diagnoses.
*The condition is significantly more common in boys*
- There is **no significant gender predilection** for anaclitic depression; it affects both boys and girls equally who experience similar environmental stressors.
- The development of this condition is primarily linked to the quality and consistency of early attachment relationships, not gender.
*The condition is exclusively seen in girls*
- **Anaclitic depression** is not exclusive to girls; it can affect **any infant** who experiences prolonged separation from their primary caregivers and lack of consistent emotional support.
- The case description only specifies a girl, but this does not imply gender exclusivity.
*The condition should be reported to state authorities*
- While the family's inability to visit is concerning, the infant's symptoms are best described as a consequence of **hospitalization and separation from caregivers**, not necessarily direct child abuse or neglect requiring state intervention.
- The focus should be on therapeutic interventions like facilitating family visits and providing consistent nursing care, rather than immediately involving child protective services.
Question 7: A 59-year-old man comes to the clinic for an annual well-exam. He was lost to follow-up for the past 3 years due to marital issues but reports that he feels fine. The patient reports, “I feel tired but it is probably because I am getting old. I do feel a little feverish today - I think I got a cold.” His past medical history is significant for hypertension that is controlled with hydrochlorothiazide. He reports fatigue, congestion, cough, and night sweats. He denies any sick contacts, recent travel, weight changes, chest pain, or dizziness. His temperature is 101°F (38.3°C), blood pressure is 151/98 mmHg, pulse is 97/min, and respirations are 15/min. His laboratory values are shown below:
Hemoglobin: 13.5 g/dL
Hematocrit: 41%
Leukocyte count: 25,000/mm^3
Segmented neutrophils: 73%
Bands: 8%
Eosinophils: 1%
Basophils: 2%
Lymphocytes: 15%
Monocytes: 2%
Platelet count: 200,000/mm^3
What diagnostic test would be helpful in distinguishing this patient’s condition from pneumonia?
A. Erythrocyte sedimentation rate
B. Magnetic resonance imaging of the chest
C. Leukocyte alkaline phosphatase (Correct Answer)
D. Presence of smudge cells
E. C-reactive protein
Explanation: ***Leukocyte alkaline phosphatase***
- This patient's symptoms (fatigue, fever, night sweats, **elevated leukocyte count** with a left shift) suggest a **myeloproliferative disorder** like **Chronic Myeloid Leukemia (CML)**, which can mimic infection.
- A **low Leukocyte Alkaline Phosphatase (LAP) score** is characteristic of CML, while an **elevated LAP score** is seen in bacterial infections (like pneumonia) and leukemoid reactions.
*Erythrocyte sedimentation rate*
- **ESR** is a general marker of **inflammation** and can be elevated in both pneumonia and various hematologic malignancies.
- It does not specifically differentiate between inflammatory processes due to infection versus a myeloproliferative disorder.
*Magnetic resonance imaging of the chest*
- While MRI can detect pulmonary infiltrates suggestive of pneumonia, it is **not typically the first-line imaging** for pneumonia and would not specifically differentiate it from a hematologic malignancy.
- **Chest X-ray or CT scan** would be more appropriate for initial pulmonary evaluation, but neither directly helps distinguish between infection and leukemia without other clinical data.
*Presence of smudge cells*
- **Smudge cells** (fragile lymphocytes) are characteristic of **Chronic Lymphocytic Leukemia (CLL)**.
- This patient's **leukocyte differential** shows a predominance of neutrophils and bands, not lymphocytes, making CLL less likely.
*C-reactive protein*
- **CRP** is another **acute phase reactant** that is elevated in response to inflammation, including infections like pneumonia.
- Similar to ESR, a high CRP level would not specifically distinguish between an infectious process and a myeloproliferative disorder.
Question 8: A 34-year-old man comes to the physician because of blurry vision and fatigue for 2 months. During this period, he has also had occasional bleeding from his gums after brushing his teeth. One month ago, he was diagnosed with deep vein thrombosis after returning from an overseas business meeting. His pulse is 118/min, respirations are 19/min, and blood pressure is 149/91 mm Hg. Pulse oximetry on room air shows an oxygen saturation of 97%. Examination shows bluish discoloration of the lips. The tip of the spleen is palpable 1 cm below the left costal margin. Sensory examination of the hands shows paresthesia. Hemoglobin concentration is 18 g/dL, hematocrit is 65%, leukocytes are 15,000/μL, and platelets are 470,000/μL. His serum erythropoietin concentration is decreased. Activation of which of the following is the most likely underlying cause of this patient's condition?
A. Serine/threonine kinase
B. Antiapoptotic molecule
C. Nonreceptor tyrosine kinase (Correct Answer)
D. Transcription factor
E. Cytokine receptor
Explanation: ***Nonreceptor tyrosine kinase***
- This patient's symptoms (blurry vision, fatigue, gum bleeding, deep vein thrombosis, splenomegaly, **elevated hemoglobin, hematocrit, leukocytes, and platelets**, and **decreased erythropoietin**) are highly suggestive of **polycythemia vera**.
- Polycythemia vera is a myeloproliferative neoplasm characterized by a mutation in the **JAK2 gene**, which encodes a **nonreceptor tyrosine kinase**. This mutation leads to constitutive activation of the JAK-STAT pathway, resulting in uncontrolled proliferation of myeloid cells independent of growth factors.
*Serine/threonine kinase*
- While serine/threonine kinases are involved in various cellular signaling pathways, their constitutive activation is not the primary underlying cause of polycythemia vera.
- Mutations in serine/threonine kinases are more commonly associated with other conditions, such as certain cancers, but not specifically with the **JAK2 V617F mutation** characteristic of PV.
*Antiapoptotic molecule*
- Activation of antiapoptotic molecules plays a role in the survival of cancer cells, but it is a downstream effect rather than the primary initiating event in polycythemia vera.
- The **JAK2 mutation** leads to increased cell proliferation and reduced apoptosis indirectly by enhancing survival signals.
*Transcription factor*
- Transcription factors regulate gene expression, and their dysregulation can contribute to various diseases, including cancers. However, the direct activation of a transcription factor is not the root cause of polycythemia vera.
- The **JAK-STAT pathway** ultimately affects transcription factors, but the initial genetic defect is in the JAK2 kinase.
*Cytokine receptor*
- Cytokine receptors bind cytokines and initiate signaling cascades, often involving JAK kinases. While cytokine receptor signaling is hyperactive in polycythemia vera, the primary defect is not in the receptor itself but in the downstream **JAK2 kinase**.
- The **JAK2 V617F mutation** causes **cytokine-independent activation** of the signaling pathway, meaning the cells don't need external cytokines to proliferate.
Question 9: A 19-year-old woman is brought to the emergency room by her mother. She found her daughter pale, cold to the touch, and collapsed next to her bed earlier this morning. The patient has no previous medical or psychiatric history, but the mother does report that her daughter has not had her periods for the last 3 months. In the emergency department, the patient is alert and oriented. Her vitals include: blood pressure 80/60 mm Hg supine, heart rate 55/min. On physical examination, the patient appears pale and emaciated. A urine pregnancy test is negative. She is suspected of having an eating disorder. Which of the following treatment options would be contraindicated in this patient?
A. Olanzapine
B. Bupropion (Correct Answer)
C. Cognitive-behavioral therapy
D. Selective serotonin reuptake inhibitors
E. High caloric food
Explanation: ***Bupropion***
- **Bupropion** is contraindicated in patients with **anorexia nervosa** or **bulimia nervosa** due to the increased risk of **seizures**.
- Patients with eating disorders often have electrolyte imbalances and metabolic derangements, which further lower the seizure threshold.
*Olanzapine*
- **Olanzapine**, an atypical antipsychotic, can be used in patients with anorexia nervosa to help with **weight gain** and reduce rigid thinking patterns.
- It is particularly useful when significant **anxiety** or **psychotic features** are present, which can exacerbate the eating disorder.
*Cognitive-behavioral therapy*
- **Cognitive-behavioral therapy (CBT)** is a cornerstone of treatment for eating disorders, including anorexia nervosa.
- It helps patients identify and change distorted thoughts and behaviors related to food, weight, and body image.
*Selective serotonin reuptake inhibitors*
- **SSRIs** may be used in anorexia nervosa, primarily after **weight restoration**, to address co-occurring **depression** or **anxiety disorders**.
- They are generally not effective for acute weight gain but can prevent relapse and treat underlying mood disturbances.
*High caloric food*
- Providing **high-caloric food** and nutritional rehabilitation is essential in managing anorexia nervosa to reverse the state of **malnutrition**.
- This must be done carefully to avoid **refeeding syndrome**, a potentially fatal shift in fluid and electrolytes that can occur with rapid refeeding.
Question 10: A 66-year-old woman comes to the physician because of a 1-week history of pruritic blister formation. Physical examination shows multiple 1–3 cm bullae on the palms, soles, lower legs, and inguinal folds. Gentle rubbing of the skin does not result in sloughing of the epidermis. Immunofluorescence studies of a perilesional skin biopsy specimen are most likely to show deposition of antibodies in which of the following areas?
A. In dermal papillae
B. Between epidermal keratinocytes
C. No staining
D. In dermal vessel walls
E. At the dermoepidermal junction (Correct Answer)
Explanation: ***At the dermoepidermal junction***
- This presentation of **tense bullae** on flexural surfaces in an elderly patient, with a negative **Nikolsky's sign** (no epidermal sloughing with rubbing), is classic for **bullous pemphigoid**.
- **Direct immunofluorescence** in bullous pemphigoid typically reveals linear deposits of **IgG** and/or **C3** at the **dermoepidermal junction (basement membrane zone)**.
*In dermal papillae*
- Deposition in dermal papillae is characteristic of **dermatitis herpetiformis**, which typically presents with intensely pruritic papules and vesicles, often on extensor surfaces.
- The morphology and distribution of lesions in this patient (large bullae on palms, soles, inguinal folds) are not consistent with dermatitis herpetiformis.
*Between epidermal keratinocytes*
- Deposition of autoantibodies (IgG) between epidermal keratinocytes is a hallmark of **pemphigus vulgaris**, resulting in suprabasal blistering and a positive **Nikolsky's sign**.
- This patient exhibits **tense bullae** and a **negative Nikolsky's sign**, which rules out pemphigus vulgaris.
*No staining*
- The presence of pruritic blister formation in an elderly patient strongly suggests an autoimmune bullous disease, for which direct immunofluorescence is a key diagnostic tool.
- A lack of staining would indicate a non-immunological cause of blistering or a different type of dermatological condition, which is unlikely given the clinical picture.
*In dermal vessel walls*
- Immune complex deposition in dermal vessel walls is characteristic of diseases like **leukocytoclastic vasculitis**, which presents with palpable purpura rather than tense bullae.
- The clinical presentation of pruritic bullae in this patient is inconsistent with a vasculitis.
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