Genetic Disorders and Biochemical Pathology Practice Questions

Q: 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?

X-linked recessive. ***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.

Q: Gene for the ryanodine receptor, mutation in which is responsible for malignant hyperthermia is located on which chromosome-

Chromosome 19. ***Chromosome 19*** - The gene encoding the **ryanodine receptor type 1 (RYR1)**, crucial for regulating calcium release from the sarcoplasmic reticulum, is located on **chromosome 19q13.1**. - Mutations in the **RYR1 gene** are the primary cause of **malignant hyperthermia susceptibility (MHS)**, an inherited disorder triggering a hypermetabolic crisis during exposure to certain anesthetics. *Chromosome 16* - Chromosome 16 is associated with various genetic conditions, such as **Crohn's disease**, **autosomal dominant polycystic kidney disease**, and certain forms of **epilepsy**. - However, it does not harbor the **RYR1 gene** or play a direct role in the etiology of malignant hyperthermia. *Chromosome 17* - Chromosome 17 contains genes linked to diseases like **Neurofibromatosis type 1**, **hereditary breast and ovarian cancer (BRCA1 gene)**, and **Smith-Magenis syndrome**. - It is not implicated in the genetic basis of **malignant hyperthermia**. *Chromosome 18* - Relevant disorders associated with chromosome 18 include **Edwards syndrome (Trisomy 18)** and **deletion 18q syndrome**. - This chromosome is not known to carry the **RYR1 gene** or contribute to the development of malignant hyperthermia.

Q: Most common deficient enzyme in Congenital adrenal hyperplasia:

21-hydroxylase deficiency. ***21-hydroxylase deficiency*** - This is by far the **most common cause** of congenital adrenal hyperplasia (CAH), accounting for about 90-95% of all cases. - Deficiency in 21-hydroxylase leads to impaired synthesis of **cortisol** and **aldosterone**, and an accumulation of androgen precursors. *18-hydroxylase deficiency* - This enzyme is crucial for the final step in **aldosterone synthesis**, specifically converting 18-hydroxycorticosterone to aldosterone. - Its deficiency would primarily impact **aldosterone production**, leading to salt wasting, but it is a very rare cause of CAH and does not affect cortisol synthesis directly. *3-beta-hydroxysteroid dehydrogenase deficiency* - This is a less common form of CAH that affects the synthesis of **glucocorticoids, mineralocorticoids, and androgens**. - It results in the accumulation of **dehydroepiandrosterone (DHEA)**, leading to varying degrees of virilization in females and undervirilization in males. *17-alpha hydroxylase deficiency* - This rare form of CAH impairs the production of **cortisol** and **androgens**, but it spares **aldosterone synthesis**. - Patients typically present with **hypertension** and **hypokalemia** due to excess mineralocorticoid activity, along with sexual developmental abnormalities.

Q: Defect in Menkes disease:

ATP7A (Copper-transporting ATPase). ***ATP7A (Copper-transporting ATPase)*** - **Menkes disease** is an X-linked recessive disorder characterized by a defect in the **ATP7A gene**, which encodes a copper-transporting ATPase. - This defect leads to impaired intestinal absorption and cellular transport of copper, resulting in **copper deficiency** in various tissues despite adequate dietary intake. *Prolyl oxidase* - **Prolyl oxidase** is involved in proline metabolism, and defects are not associated with Menkes disease. - Deficiency of this enzyme is usually linked to hyperprolinemia. *Prolyl hydroxylase* - **Prolyl hydroxylase** is an enzyme critical for the hydroxylation of proline residues in collagen, a step essential for collagen stability. - While collagen synthesis requires copper (for lysyl oxidase), a direct defect in prolyl hydroxylase is not the cause of Menkes disease. *Lysyl oxidase* - **Lysyl oxidase** is a copper-dependent enzyme required for the cross-linking of collagen and elastin, contributing to connective tissue strength. - Although lysyl oxidase activity is reduced in Menkes disease due to copper deficiency, the primary defect is in the **ATP7A transporter**, not the lysyl oxidase enzyme itself.

Q: In Zellweger syndrome, which of the following is absent?

Peroxisomes. ***Peroxisomes*** - **Zellweger syndrome** is an **autosomal recessive disorder** characterized by a severe reduction or absence of functional peroxisomes. - Peroxisomes are essential organelles involved in **lipid metabolism**, particularly the breakdown of very long-chain fatty acids (VLCFAs) and branched-chain fatty acids, leading to their accumulation in the blood and tissues. *Golgi apparatus* - The **Golgi apparatus** is an intact and functional organelle in Zellweger syndrome. - It plays a crucial role in modifying, sorting, and packaging proteins and lipids for secretion or delivery to other organelles, functions that remain unaffected in this condition. *Mitochondria* - **Mitochondria**, responsible for cellular respiration and ATP production, are present and functional in Zellweger syndrome. - While metabolic disturbances occur, they are not due to primary mitochondrial dysfunction. *ER* - The **endoplasmic reticulum (ER)**, a network of membranes involved in protein and lipid synthesis, is also intact and functional. - It is not directly implicated in the pathogenesis of Zellweger syndrome.

Q: Which of the following is the etiology of Werner syndrome?

Short telomere with damaged DNA and loss of helicase. ***Short telomere with damaged DNA and loss of helicase*** - **Werner syndrome** is an **autosomal recessive disorder** characterized by **premature aging** due to mutations in the *WRN* gene, which codes for a **RecQ-type DNA helicase**. - The dysfunctional helicase leads to defects in **DNA replication, repair, and transcription**, resulting in **genomic instability**, **damaged DNA**, and **accelerated telomere attrition** (short telomeres). *Increased length of telomere* - **Increased telomere length** is generally associated with a **reduced rate of cellular aging** and is not characteristic of Werner syndrome or other premature aging disorders. - In most aging processes and syndromes like Werner, **telomeres tend to shorten** over time due to incomplete replication and oxidative stress. *Increased advanced glycation end products* - **Advanced glycation end products (AGEs)** accumulate in various tissues during normal aging and in conditions like diabetes, contributing to vascular and organ damage. - While AGEs play a role in the broader aging process, they are not the primary underlying genetic defect or direct etiology of Werner syndrome, which is a **DNA repair disorder**. *Decreased lipid peroxidation* - **Lipid peroxidation** is a process by which **free radicals** attack lipids, leading to cellular damage and is often associated with oxidative stress and aging. - A **decrease in lipid peroxidation** would generally be considered protective against aging-related damage, which is the opposite of what is seen in Werner syndrome, where there's an accelerated aging phenotype and increased cellular stress.

Q: An affected male does not have affected children but an affected female always has affected children. Type of inheritance?

Mitochondrial. ***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.

Q: Which of the following is NOT a feature of mitochondrial inheritance?

Inheritance from both parents. ***Inheritance from both parents*** - **Mitochondrial DNA** is exclusively inherited from the **mother**, through the ovum. - Therefore, inheritance from both parents is not a characteristic of mitochondrial inheritance. *Maternal transmission* - This is a defining feature of **mitochondrial inheritance**, as all mitochondria in a zygote are derived from the mother's egg cell. - Both male and female offspring receive mitochondrial DNA solely from their mother. *Heteroplasmy* - This refers to the presence of **multiple variants** of mitochondrial DNA within the same cell or individual. - It's a common feature of mitochondrial diseases, leading to variable expressivity due to differing proportions of normal and mutated mtDNA. *High mutation rate* - **Mitochondrial DNA** has a significantly higher mutation rate compared to nuclear DNA. - This is due to the lack of protective histones, proximity to reactive oxygen species generated during oxidative phosphorylation, and less efficient DNA repair mechanisms within mitochondria.

Q: A 5-year-old presents with intellectual disability, self-mutilation, and hyperuricemia. What enzyme defect is most likely?

Hypoxanthine-guanine phosphoribosyltransferase (HGPRT). ***Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)*** - Deficiency of **HGPRT** an enzyme in the **purine salvage pathway** leads to **Lesch-Nyhan syndrome**, characterized by **hyperuricemia**, **self-mutilation**, **intellectual disability**, and **dystonia**. - The accumulation of **uric acid** due to defective salvage leads to the characteristic symptoms. *Adenosine deaminase deficiency* - This deficiency causes **severe combined immunodeficiency (SCID)** due to the accumulation of toxic metabolites in lymphocytes. - It does not typically present with **self-mutilation** or **hyperuricemia**. *Xanthine oxidase deficiency* - This deficiency leads to **xanthinuria**, characterized by **low uric acid levels** and an increased risk of **xanthine kidney stones**. - The clinical presentation does not include **intellectual disability** or **self-mutilation**. *Glucose-6-phosphatase deficiency* - This enzyme deficiency causes **Glycogen Storage Disease Type Ia (von Gierke disease)**, characterized by **hypoglycemia**, **lactic acidosis**, and **hepatomegaly**. - It is not associated with **self-mutilation** or the primary neurological/behavioral features seen in Lesch-Nyhan syndrome.

Q: Which of the following is a common genetic mutation leading to hypoxia-induced polycythemia in patients with chronic mountain sickness?

VHL gene mutation. ***VHL gene mutation*** - **Von Hippel-Lindau (VHL) gene mutations** are associated with **Chuvash polycythemia**, a form of **primary familial congenital polycythemia (PFCP)**, which mimics chronic mountain sickness at normoxia by causing overproduction of red blood cells due to impaired **HIF-1α degradation**. - The VHL protein is a component of the **ubiquitin ligase complex** that targets **HIF-1α** for degradation under normoxic conditions. Dysfunction of VHL leads to constitutive activation of HIF-1α, over-expression of **erythropoietin (EPO)**, and subsequent **polycythemia** even at normal oxygen levels. *EGFR gene mutation* - **EGFR mutations** are commonly found in non-small cell lung cancer and are associated with tumor growth and response to targeted therapies, but they are not directly involved in the pathogenesis of **polycythemia** or its response to hypoxia. - These mutations primarily affect **cell proliferation and survival** pathways in cancerous cells, rather than erythropoiesis. *JAK2 V617F mutation* - The **JAK2 V617F mutation** is a hallmark of **myeloproliferative neoplasms (MPNs)**, particularly **polycythemia vera (PV)**, leading to constitutive activation of the JAK-STAT pathway and uncontrolled erythropoiesis independent of erythropoietin. - While it causes **polycythemia**, this is typically considered a primary, acquired bone marrow disorder, not directly linked to the hypoxia-sensing pathway dysregulation seen in **chronic mountain sickness**. *HIF1α gene mutation* - While **HIF-1α** is central to the hypoxic response, direct activating mutations in the **HIF1α gene** itself are generally not the most common genetic cause of **hypoxia-induced polycythemia** in humans. - The dysregulation typically occurs upstream, often through mutations in the **VHL gene**, which controls HIF-1α stability.

Question 1

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?

Accepted Answer

X-linked recessive

Answer

Autosomal dominant

Answer

X-linked dominant

Answer

Autosomal recessive

Question 2

Gene for the ryanodine receptor, mutation in which is responsible for malignant hyperthermia is located on which chromosome-

Accepted Answer

Chromosome 19

Answer

Chromosome 16

Answer

Chromosome 17

Answer

Chromosome 18

Question 3

Most common deficient enzyme in Congenital adrenal hyperplasia:

Accepted Answer

21-hydroxylase deficiency

Answer

18-hydroxylase deficiency

Answer

3-beta-hydroxysteroid dehydrogenase deficiency

Answer

17-alpha hydroxylase deficiency

Question 4

Defect in Menkes disease:

Accepted Answer

ATP7A (Copper-transporting ATPase)

Answer

Prolyl oxidase

Answer

Prolyl hydroxylase

Answer

Lysyl oxidase

Question 5

In Zellweger syndrome, which of the following is absent?

Accepted Answer

Peroxisomes

Answer

Golgi apparatus

Answer

Mitochondria

Answer

ER

Question 6

Which of the following is the etiology of Werner syndrome?

Accepted Answer

Short telomere with damaged DNA and loss of helicase

Answer

Increased length of telomere

Answer

Increased advanced glycation end products

Answer

Decreased lipid peroxidation

Question 7

An affected male does not have affected children but an affected female always has affected children. Type of inheritance?

Accepted Answer

Mitochondrial

Answer

Autosomal recessive

Answer

X linked recessive

Answer

X linked dominant

Question 8

Which of the following is NOT a feature of mitochondrial inheritance?

Accepted Answer

Inheritance from both parents

Answer

Maternal transmission

Answer

Heteroplasmy

Answer

High mutation rate

Question 9

A 5-year-old presents with intellectual disability, self-mutilation, and hyperuricemia. What enzyme defect is most likely?

Accepted Answer

Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)

Answer

Adenosine deaminase deficiency

Answer

Xanthine oxidase deficiency

Answer

Glucose-6-phosphatase deficiency

Question 10

Which of the following is a common genetic mutation leading to hypoxia-induced polycythemia in patients with chronic mountain sickness?

Accepted Answer

VHL gene mutation

Answer

EGFR gene mutation

Answer

JAK2 V617F mutation

Answer

HIF1α gene mutation

Genetic Disorders and Biochemical Pathology — MCQs

Genetic Disorders and Biochemical Pathology — MCQs

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