Genetic Disorders and Biochemical Pathology Practice Questions

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: The enzyme deficient in Galactosemia is:-

Galactose-1-phosphate uridyltransferase (GALT). ***Galactose-1-phosphate uridyltransferase (GALT)*** - Deficiency of **GALT** leads to the accumulation of **galactose-1-phosphate** in tissues, which is toxic and causes the symptoms of **classical galactosemia**. - This enzyme is crucial for the second step in the Leloir pathway, converting **galactose-1-phosphate** and UDP-glucose into UDP-galactose and glucose-1-phosphate. *Sphingomyelinase (associated with Niemann-Pick disease)* - Deficiency in **sphingomyelinase** causes the accumulation of **sphingomyelin**, leading to **Niemann-Pick disease**, characterized by hepatosplenomegaly and neurological deterioration. - This enzyme is involved in the catabolism of lipids, distinct from carbohydrate metabolism. *Glucocerebrosidase (associated with Gaucher's disease)* - Deficiency of **glucocerebrosidase** results in the accumulation of **glucocerebroside**, leading to **Gaucher's disease**, which affects the spleen, liver, bone marrow, and sometimes the brain. - This is a lysosomal storage disorder involving glycosphingolipids, not galactose metabolism. *Hexosaminidase (associated with Tay-Sachs disease)* - Deficiency of **hexosaminidase A** causes the accumulation of **GM2 ganglioside**, resulting in **Tay-Sachs disease**, a severe neurodegenerative disorder. - This enzyme primarily functions in the breakdown of gangliosides, which are complex lipids, not galactose.

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: A child presented with abdominal distension, hepatomegaly, doll like facies and recurrent episodes of hypoglycemia. Which of the following is the most likely diagnosis?

Von Gierke disease. ***Von Gierke disease*** - **Von Gierke disease** (Glycogen Storage Disease Type I) is characterized by **hepatomegaly**, **abdominal distension**, **severe hypoglycemia**, and a distinct "doll-like" facies due to fat deposits. - This condition results from a deficiency in **glucose-6-phosphatase**, impairing the liver's ability to release glucose, leading to glycogen accumulation and the described symptoms. *Down syndrome* - **Down syndrome** (Trisomy 21) is a chromosomal disorder associated with intellectual disability, characteristic facial features, and congenital heart defects, but not typically with these metabolic symptoms. - While children with Down syndrome may have various health issues, recurrent severe hypoglycemia and hepatomegaly to this extent are not characteristic features of the syndrome itself. *Lesch-Nyhan syndrome* - **Lesch-Nyhan syndrome** is an X-linked recessive disorder of purine metabolism, leading to overproduction of uric acid, severe neurological dysfunction, and self-mutilation. - It does not present with hepatomegaly, abdominal distension, or the recurrent episodes of hypoglycemia seen in this case. *Menkes disease* - **Menkes disease** is an X-linked recessive disorder of copper transport, leading to copper deficiency and affecting various organs, including the brain, hair, and connective tissue. - Key features include sparse, brittle, "steely" hair (`pili torti`), neurodegeneration, and developmental delay, which are distinct from the metabolic presentation described.

Q: An infant presented with vomiting, malnutrition, blue eyes, blonde hair & fair skin. On investigation, Guthrie test was positive. All are true regarding this disease EXCEPT:

Hypopigmentation due to tryptophan deficiency. ***Hypopigmentation due to tryptophan deficiency*** - The characteristic **hypopigmentation** (fair skin, blonde hair, blue eyes) in **phenylketonuria (PKU)** is due to **tyrosine deficiency**, not tryptophan deficiency. - **Phenylalanine hydroxylase (PAH)** deficiency leads to accumulation of phenylalanine, which cannot be converted to **tyrosine**. - **Tyrosine** is the precursor for **melanin synthesis** via the enzyme **tyrosinase**, so tyrosine deficiency results in decreased melanin production and hypopigmentation. *Phenyl acetate positive in urine* - In **phenylketonuria (PKU)**, **phenylalanine** accumulates and is shunted to alternative metabolic pathways, leading to the production and excretion of **phenylacetate, phenylpyruvate, and phenyllactate** in the urine. - The presence of these metabolites gives the urine a characteristic **mousey or musty odor**. *Mental retardation is present* - If **phenylketonuria (PKU)** is left untreated, the accumulation of **phenylalanine** is neurotoxic and leads to severe, **irreversible intellectual disability** and **developmental delay**. - Early detection through newborn screening (the **Guthrie test** detects elevated blood phenylalanine) and dietary phenylalanine restriction are crucial to prevent this outcome. *Due to PAH enzyme defect* - **Phenylketonuria (PKU)** is primarily caused by a deficiency in the enzyme **phenylalanine hydroxylase (PAH)**, which is responsible for converting phenylalanine to tyrosine. - This **autosomal recessive genetic disorder** leads to the accumulation of phenylalanine in the blood and tissues, causing the clinical manifestations.

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.

Question 1

Defect in Menkes disease:

Accepted Answer

ATP7A (Copper-transporting ATPase)

Answer

Prolyl oxidase

Answer

Prolyl hydroxylase

Answer

Lysyl oxidase

Question 2

In Zellweger syndrome, which of the following is absent?

Accepted Answer

Peroxisomes

Answer

Golgi apparatus

Answer

Mitochondria

Answer

ER

Question 3

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 4

The enzyme deficient in Galactosemia is:-

Accepted Answer

Galactose-1-phosphate uridyltransferase (GALT)

Answer

Sphingomyelinase

Answer

Glucocerebrosidase

Answer

Hexosaminidase

Question 5

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 6

A child presented with abdominal distension, hepatomegaly, doll like facies and recurrent episodes of hypoglycemia. Which of the following is the most likely diagnosis?

Accepted Answer

Von Gierke disease

Answer

Down syndrome

Answer

Lesch-Nyhan syndrome

Answer

Menkes disease

Question 7

An infant presented with vomiting, malnutrition, blue eyes, blonde hair & fair skin. On investigation, Guthrie test was positive. All are true regarding this disease EXCEPT:

Accepted Answer

Hypopigmentation due to tryptophan deficiency

Answer

Phenyl acetate positive in urine

Answer

Mental retardation is present

Answer

Due to PAH enzyme defect

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

How does the defective nucleotide excision repair (NER) mechanism in Xeroderma pigmentosum (XP) patients contribute to their increased risk of skin cancer?

Accepted Answer

Failure to repair UV-induced DNA damage leading to mutations.

Answer

Increased oxidative DNA damage resulting in breaks.

Answer

Impaired mismatch repair causing replication errors.

Answer

Defective base excision repair leading to abasic sites.

Genetic Disorders and Biochemical Pathology — MCQs

Genetic Disorders and Biochemical Pathology — MCQs

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