An affected male does not have affected children but an affected female always has affected children. Type of inheritance?
Q4
Kinky hair disease is a disorder where an affected child has peculiar white stubby hair, does not grow, brain degeneration is seen and dies by age of two years. Mrs A is hesitant about having children because her two sisters had sons who died from kinky hair disease. Her mother's brother also died of the same condition. Which of the following is the possible mode of inheritance in her family?
Q5
A 4-year-old boy is brought to a pediatrician by his parents for a consultation after his teacher complained about his inability to focus or make friends at school. They mention that the boy does not interact well with others at home, school, or daycare. On physical examination, his vital signs are stable with normal weight, height, and head circumference for his age and sex. His general examination and neurologic examination are completely normal. A recent audiological evaluation shows normal hearing, and intellectual disability has been ruled out by a clinical psychologist. Which of the following investigations is indicated as part of his diagnostic evaluation at present?
Q6
A 16-year-old male presents to an ophthalmologist as a new patient with a complaint of blurry vision. He reports that over the past several months he has had increasing difficulty seeing the board from the back of the classroom at school. The patient is otherwise doing well in school and enjoys playing basketball. His past medical history is otherwise significant for scoliosis which is managed by an orthopedic surgeon. His family history is significant for a mother with type II diabetes mellitus, and a father who underwent aortic valve replacement last year. On physical exam, the patient is tall for his age and has long arms. He has 20 degrees of thoracic scoliosis, which is stable from previous exams. On slit-lamp examination, the patient is found to have bilateral upward lens subluxation and is prescribed corrective lenses.
Which of the following is the most likely etiology of this patient’s presentation?
Q7
A 12-year-old boy is brought by his mother to a neurologist for continuing evaluation of seizures. His seizures were previously well-controlled on medication but over the last month he has been having seizures several times per week. The boy is non-verbal and has had severe developmental delays and cognitive disability since birth. On exam, the boy is found to be enthusiastically playing with the toys in the office and laughing at almost any stimulus. Furthermore, his movements are found to be uncoordinated with a wide based gait. Previous genetic testing has revealed an abnormality in an E3 ubiquitin ligase gene. Compared to unaffected individuals, which of the following patterns of gene expression is most likely seen in this patient?
Q8
A 10-month-old boy is brought to the physician by his mother for evaluation of abnormal growth and skin abnormalities. His mother has also noticed that his eyes do not fully close when sleeping. He is at the 24th percentile for height, 17th percentile for weight, and 29th percentile for head circumference. Physical examination shows wrinkled skin, prominent veins on the scalp and extremities, and circumoral cyanosis. Genetic testing shows a point mutation in a gene that encodes for a scaffold protein of the inner nuclear membrane. The mutation causes a deformed and unstable nuclear membrane, which leads to premature aging. Which of the following is most likely to be the defective protein?
Q9
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?
Q10
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?
Single Gene Disorders US Medical PG Practice Questions and MCQs
Question 1: Which is not a feature of G6PD deficiency?
A. Presence of Heinz bodies
B. Males and females are equally affected (Correct Answer)
C. Absence of NADPH
D. Oxidative stress
Explanation: ***Males and females are equally affected***
- G6PD deficiency is an **X-linked recessive disorder**, meaning males are predominantly and more severely affected because they have only one X chromosome [2].
- Females are typically carriers and are less commonly affected, or may experience milder symptoms, due to **X-chromosome inactivation** (Lyonization).
*Presence of Heinz bodies*
- **Heinz bodies** are formed from denatured hemoglobin precipitates within red blood cells, a characteristic feature of **oxidative stress** in G6PD deficiency [2].
- These bodies are removed by the spleen, contributing to **hemolytic anemia**.
*Absence of NADPH*
- G6PD is the rate-limiting enzyme in the **pentose phosphate pathway**, which generates **NADPH** [1], [2].
- Without sufficient G6PD, the production of **NADPH** is severely impaired, leading to a deficiency in this critical reducing agent.
*Oxidative stress*
- **NADPH** is crucial for reducing **glutathione**, which in turn detoxifies reactive oxygen species [2].
- The lack of NADPH makes red blood cells vulnerable to **oxidative damage**, manifesting as hemolytic anemia upon exposure to oxidative agents [3].
Question 2: Duchenne muscular dystrophy is inherited as:
A. Autosomal dominant
B. Autosomal recessive
C. X-linked recessive (Correct Answer)
D. X-linked dominant
E. Mitochondrial inheritance
Explanation: ***X-linked recessive***
- Duchenne muscular dystrophy is primarily due to mutations in the **dystrophin gene**, located on the X chromosome, leading to X-linked recessive inheritance [1].
- Males are predominantly affected due to the presence of a single X chromosome, while females are carriers and may show mild symptoms [2].
*Autosomal dominant*
- This mode of inheritance involves only one copy of a mutated gene for the condition to manifest, which is not the case for Duchenne muscular dystrophy.
- Autosomal dominant disorders typically have a **vertical inheritance pattern**, unlike the skipped generations seen with X-linked recessive traits [2].
*X-linked dominant*
- In X-linked dominant conditions, both males and females can be affected, which contrasts with the severe male predominance observed in Duchenne muscular dystrophy cases.
- Female carriers of X-linked dominant disorders often experience more severe symptoms, which is not typical for this condition where females are usually asymptomatic carriers.
*Autosomal recessive*
- Autosomal recessive disorders require both copies of a gene to be mutated for the condition to be expressed, differing from the one-gene involvement in X-linked recessive disorders.
- Conditions that follow this pattern often arise in families with a history of consanguinity, which is not the primary inheritance scenario for Duchenne muscular dystrophy.
**References:**
[1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Peripheral Nerves and Skeletal Muscles, pp. 1244-1245.
[2] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, p. 151.
Question 3: An affected male does not have affected children but an affected female always has affected children. Type of inheritance?
A. Autosomal recessive
B. Mitochondrial (Correct Answer)
C. X linked recessive
D. X linked dominant
Explanation: ***Correct Option: Mitochondrial***
- This pattern describes **mitochondrial inheritance**, where all children of an **affected mother** inherit the condition because mitochondria are exclusively inherited from the ovum (maternal inheritance).
- An **affected father** cannot pass on the condition to his children, as sperm contribute only nuclear DNA and essentially no mitochondria.
- This is the **only inheritance pattern** where an affected male has no affected children while an affected female has all children affected.
*Incorrect Option: Autosomal recessive*
- This pattern would typically show affected individuals having unaffected parents (who are carriers) and both males and females being affected in equal proportions.
- It does not explain the complete absence of transmission from an affected father or universal transmission from an affected mother.
- An affected individual could have unaffected children if their partner is not a carrier.
*Incorrect Option: X linked recessive*
- In **X-linked recessive inheritance**, affected males cannot pass the trait to their sons, but all their daughters would be carriers (not affected).
- An affected mother would pass the trait to all her sons (affected) and make all her daughters carriers (not affected), which does not match the described pattern of all children being affected.
*Incorrect Option: X linked dominant*
- In **X-linked dominant inheritance**, an affected father passes the trait to all his daughters but none of his sons (contradicts "no affected children").
- An affected mother has a 50% chance of passing the trait to **each child**, which is inconsistent with all children of an affected female being affected.
Question 4: Kinky hair disease is a disorder where an affected child has peculiar white stubby hair, does not grow, brain degeneration is seen and dies by age of two years. Mrs A is hesitant about having children because her two sisters had sons who died from kinky hair disease. Her mother's brother also died of the same condition. Which of the following is the possible mode of inheritance in her family?
A. X-linked recessive (Correct Answer)
B. Autosomal dominant
C. X-linked dominant
D. Autosomal recessive
Explanation: ***X-linked recessive***
- Kinky hair disease (Menkes disease) is an **X-linked recessive disorder**, meaning that males are predominantly affected, and females are carriers.
- The pattern of inheritance in the family (sons of sisters, and a maternal uncle affected) is highly suggestive of **X-linked recessive inheritance**, as healthy female carriers can pass the gene to their sons.
*Autosomal dominant*
- In **autosomal dominant** inheritance, the disease would affect individuals in every generation, and both males and females would be affected equally.
- This pattern of inheritance does not explain why only sons are dying and why sisters (who are likely carriers) are unaffected but have affected children.
*X-linked dominant*
- In **X-linked dominant** inheritance, affected fathers would pass the trait to all their daughters, and affected mothers would pass it to half of their children.
- The disease would also be more common in females, which contradicts the described pattern of only sons being affected and dying.
*Autosomal recessive*
- In **autosomal recessive** inheritance, both parents must be carriers for a child to be affected, and typically, there would be a 25% chance of recurrence in each pregnancy.
- This mode doesn't explain the observation of affected maternal uncles and sons from sisters, which points more directly to an X-linked pattern where females are carriers.
Question 5: A 4-year-old boy is brought to a pediatrician by his parents for a consultation after his teacher complained about his inability to focus or make friends at school. They mention that the boy does not interact well with others at home, school, or daycare. On physical examination, his vital signs are stable with normal weight, height, and head circumference for his age and sex. His general examination and neurologic examination are completely normal. A recent audiological evaluation shows normal hearing, and intellectual disability has been ruled out by a clinical psychologist. Which of the following investigations is indicated as part of his diagnostic evaluation at present?
A. Magnetic resonance imaging (MRI) of brain
B. Electroencephalography
C. No further testing is needed
D. Positron Emission Tomography (PET) scanning of head
E. Autism spectrum disorder screening and developmental assessment (Correct Answer)
Explanation: ***Autism spectrum disorder screening and developmental assessment***
- The clinical presentation (inability to focus, difficulty making friends, poor social interaction across multiple settings) is **highly suggestive of Autism Spectrum Disorder (ASD)**.
- After ruling out **hearing impairment and intellectual disability**, the next appropriate step is **formal ASD screening using validated tools** such as the **Modified Checklist for Autism in Toddlers (M-CHAT)**, **Autism Diagnostic Observation Schedule (ADOS)**, or **Autism Diagnostic Interview-Revised (ADI-R)**.
- According to **AAP guidelines**, when developmental concerns suggestive of ASD are identified, formal screening and comprehensive developmental assessment are **essential components of the diagnostic evaluation**.
- ASD diagnosis is primarily **clinical**, based on standardized screening tools and developmental assessments, not neuroimaging or electrophysiological studies.
*No further testing is needed*
- This is **incorrect** because the patient has not yet undergone **formal ASD-specific screening and developmental assessment**.
- While hearing and intellectual disability have been ruled out, **diagnostic confirmation of ASD** requires structured evaluation using validated assessment tools.
- Simply observing symptoms without formal screening is inadequate for establishing an ASD diagnosis.
*Magnetic resonance imaging (MRI) of brain*
- Brain MRI is **not routinely indicated** for ASD diagnosis as it typically shows **normal findings** in children with ASD.
- Neuroimaging is reserved for cases with **focal neurological signs, regression, or atypical features** suggesting structural abnormalities.
- This patient has a **normal neurological examination**, making MRI unnecessary.
*Electroencephalography*
- EEG is indicated only when there is suspicion of **seizure disorder** or other specific neurological conditions.
- The patient has a **normal neurological examination** with no seizure-like symptoms, making EEG unnecessary at this stage.
*Positron Emission Tomography (PET) scanning of head*
- PET scans are **not part of routine ASD diagnostic workup** and are typically used in research settings or for evaluating specific metabolic or neoplastic conditions.
- The **radiation exposure and invasiveness** make PET scanning inappropriate for initial diagnostic evaluation in a child with developmental concerns.
Question 6: A 16-year-old male presents to an ophthalmologist as a new patient with a complaint of blurry vision. He reports that over the past several months he has had increasing difficulty seeing the board from the back of the classroom at school. The patient is otherwise doing well in school and enjoys playing basketball. His past medical history is otherwise significant for scoliosis which is managed by an orthopedic surgeon. His family history is significant for a mother with type II diabetes mellitus, and a father who underwent aortic valve replacement last year. On physical exam, the patient is tall for his age and has long arms. He has 20 degrees of thoracic scoliosis, which is stable from previous exams. On slit-lamp examination, the patient is found to have bilateral upward lens subluxation and is prescribed corrective lenses.
Which of the following is the most likely etiology of this patient’s presentation?
A. Extra copy of sex chromosome
B. Mutation of gene on chromosome 15 (Correct Answer)
C. Mutation of COL5A1 or COL5A2
D. Defective metabolism of methionine
E. Mutation of RET proto-oncogene
Explanation: ***Mutation of gene on chromosome 15***
- The patient's presentation with **tall stature**, **long arms** (dolichostenomelia), **scoliosis**, and **bilateral upward lens subluxation** are classic features of **Marfan syndrome**.
- Marfan syndrome is an autosomal dominant disorder caused by a mutation in the *FBN1* gene located on **chromosome 15**, which encodes for **fibrillin-1**, a glycoprotein essential for connective tissue formation.
*Extra copy of sex chromosome*
- An extra copy of a sex chromosome, such as in **Klinefelter syndrome (XXY)**, is associated with tall stature and disproportionately long limbs, but it typically presents with **hypogonadism**, infertility, and learning difficulties, not lens subluxation or significant scoliosis as the primary features.
- Patients with Klinefelter syndrome often have a **eunuchoid body habitus** and gynecomastia, which are not described in this patient.
*Mutation of COL5A1 or COL5A2*
- Mutations in *COL5A1* or *COL5A2* are associated with **Ehlers-Danlos syndrome (classical type)**, which primarily features **skin hyperextensibility**, delayed wound healing, and **joint hypermobility**.
- While some forms of Ehlers-Danlos can have ocular involvement (e.g., easy bruising, scleral fragility), **lens subluxation** and the specific tall, slender build with scoliosis are not characteristic clinical features.
*Defective metabolism of methionine*
- A defective metabolism of methionine is characteristic of **homocystinuria**, an autosomal recessive disorder.
- Homocystinuria also causes **tall stature**, **scoliosis**, and **lens subluxation**, but the subluxation is typically **downward and inward**, differentiating it from the upward subluxation seen in Marfan syndrome. Patients also have an increased risk of **thromboembolic events** and **intellectual disability**.
*Mutation of RET proto-oncogene*
- Mutations of the *RET* proto-oncogene are associated with **Multiple Endocrine Neoplasia type 2 (MEN2)**.
- MEN2 presents with specific endocrine tumors such as **medullary thyroid carcinoma**, **pheochromocytoma**, and **parathyroid hyperplasia**, and does not involve the skeletal or ocular abnormalities described in this patient.
Question 7: A 12-year-old boy is brought by his mother to a neurologist for continuing evaluation of seizures. His seizures were previously well-controlled on medication but over the last month he has been having seizures several times per week. The boy is non-verbal and has had severe developmental delays and cognitive disability since birth. On exam, the boy is found to be enthusiastically playing with the toys in the office and laughing at almost any stimulus. Furthermore, his movements are found to be uncoordinated with a wide based gait. Previous genetic testing has revealed an abnormality in an E3 ubiquitin ligase gene. Compared to unaffected individuals, which of the following patterns of gene expression is most likely seen in this patient?
A. Abnormally increased expression of the gene from the maternal chromosome
B. Abnormally decreased expression of the gene from the maternal chromosome (Correct Answer)
C. Abnormally decreased expression of the gene from both chromosomes
D. Abnormally decreased expression of the gene from the paternal chromosome
E. Abnormally increased expression of the gene from the paternal chromosome
Explanation: ***Abnormally decreased expression of the gene from the maternal chromosome***
- This patient's symptoms (non-verbal, severe developmental delays, cognitive disability, seizures, uncoordinated movements, wide-based gait, inappropriate laughter, and an abnormality in an E3 ubiquitin ligase gene) are characteristic of **Angelman syndrome**.
- Angelman syndrome is typically caused by a deletion or mutation on the **maternally inherited copy of chromosome 15q11-q13**, specifically affecting the *UBE3A* gene, which is an E3 ubiquitin ligase. This leads to reduced or absent expression of the *UBE3A* gene in critical brain regions where only the maternal allele is expressed.
*Abnormally increased expression of the gene from the maternal chromosome*
- Angelman syndrome is caused by a **loss of function** of the maternally inherited *UBE3A* gene, not an increase in its expression.
- Increased expression would not lead to the neurodevelopmental deficits seen in Angelman syndrome.
*Abnormally decreased expression of the gene from both chromosomes*
- While there is decreased expression of the functional *UBE3A* gene, the paternal allele is normally **silenced** in specific brain regions relevant to Angelman syndrome pathogenesis due to **genomic imprinting**. Therefore, the issue is with the maternal allele.
- If both chromosomes had decreased expression, it would imply a different genetic mechanism or a more severe, potentially lethal, condition.
*Abnormally decreased expression of the gene from the paternal chromosome*
- In the brain regions relevant to Angelman syndrome, the paternal *UBE3A* allele is normally **silenced** due to genomic imprinting. Therefore, its decreased expression would not be an abnormal finding or contribute to the pathology.
- Problems with the paternal allele in this region are associated with **Prader-Willi syndrome**, which has a different clinical presentation (e.g., hypotonia, hyperphagia, obesity).
*Abnormally increased expression of the gene from the paternal chromosome*
- The paternal *UBE3A* allele is normally **silenced** in the relevant brain regions; therefore, an increased expression would be abnormal but is not the genetic basis of Angelman syndrome.
- Angelman syndrome is caused by the **loss or absence of functional maternal *UBE3A*** expression, not altered paternal expression.
Question 8: A 10-month-old boy is brought to the physician by his mother for evaluation of abnormal growth and skin abnormalities. His mother has also noticed that his eyes do not fully close when sleeping. He is at the 24th percentile for height, 17th percentile for weight, and 29th percentile for head circumference. Physical examination shows wrinkled skin, prominent veins on the scalp and extremities, and circumoral cyanosis. Genetic testing shows a point mutation in a gene that encodes for a scaffold protein of the inner nuclear membrane. The mutation causes a deformed and unstable nuclear membrane, which leads to premature aging. Which of the following is most likely to be the defective protein?
A. Vimentin
B. Lamin (Correct Answer)
C. Plectin
D. Nesprin
E. Desmin
Explanation: ***Lamin***
- The clinical presentation with **accelerated aging** symptoms (wrinkled skin, prominent veins, abnormal growth percentiles, lagophthalmos/difficulty closing eyes) combined with a defect in a **scaffold protein** of the **inner nuclear membrane** is diagnostic of **Hutchinson-Gilford Progeria Syndrome (HGPS)**.
- **Lamins** (specifically Lamin A/C) are intermediate filaments that form the **nuclear lamina**, the primary structural scaffold underlying the inner nuclear membrane, and mutations in the **LMNA gene** cause progeria and other laminopathies.
- The mutation typically produces progerin, an abnormal lamin protein that destabilizes the nuclear envelope leading to premature cellular senescence.
*Vimentin*
- **Vimentin** is an intermediate filament primarily found in **mesenchymal cells** and plays a role in cell shape, integrity, and motility within the **cytoplasm**.
- Defects in vimentin are not associated with disorders of the nuclear membrane or premature aging syndromes.
*Plectin*
- **Plectin** is a **cytoskeletal linker protein** that cross-links intermediate filaments to each other, to microtubules, and to actin filaments, reinforcing cellular stability.
- While important for cellular integrity, plectin is a **cytoplasmic protein**, not a component of the inner nuclear membrane scaffold.
*Nesprin*
- **Nesprins** (Nuclear Envelope Spectrin-repeat Proteins) are components of the **Linker of Nucleoskeleton and Cytoskeleton (LINC) complex**, bridging the nuclear lamina to the cytoskeleton at the **outer nuclear membrane**.
- While nesprins interact with the nuclear envelope, they are not the primary scaffold protein of the **inner nuclear membrane** itself (that role belongs to lamins), and mutations in nesprins are associated with muscular dystrophies, not progeria.
*Desmin*
- **Desmin** is an intermediate filament found predominantly in **muscle cells** (cardiac, skeletal, and smooth muscle), forming a scaffold that connects myofibrils to each other and to the sarcolemma.
- Mutations in desmin are associated with **myopathies** and **cardiomyopathies**, not with defects in the inner nuclear membrane or premature aging.
Question 9: 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 10: 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.
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