Genetic Disorders and Biochemical Pathology Practice Questions

Q: In which of the following inheritance patterns is father-to-son transmission not observed?

X-linked recessive inheritance. ***X-linked recessive inheritance*** - In X-linked inheritance, females have two X chromosomes (XX) and males have one X and one Y chromosome (XY). A father always passes his **Y chromosome** to his son. - He passes his **X chromosome only to his daughters**. Therefore, a father cannot pass an X-linked trait directly to his son. *Autosomal dominant inheritance* - In autosomal dominant inheritance, a disease allele is located on a **non-sex chromosome (autosome)**. - Both males and females can be affected, and **father-to-son transmission is possible** if the father carries the dominant allele on an autosome. *Autosomal recessive inheritance* - This inheritance pattern also involves genes on **autosomes**. - A father can transmit a recessive allele to his son, though the son would only express the trait if he also inherits a recessive allele from his mother. **Father-to-son transmission of the allele is possible**. *Multifactorial inheritance* - This pattern involves the interaction of **multiple genes** and **environmental factors**. - As some of these genes are on autosomes, and environmental factors are independent of sex chromosomes, **father-to-son transmission is observed** for the genetic components.

Q: Congenital 17-hydroxylase deficiency leads to hypertension due to the accumulation of?

Deoxycorticosterone. ***Deoxycorticosterone*** - **17-hydroxylase deficiency** blocks the conversion of **pregnenolone** to **17-hydroxypregnenolone** and **progesterone** to **17-hydroxyprogesterone**, leading to an accumulation of precursors in the **mineralocorticoid pathway**. - This accumulation results in elevated levels of **deoxycorticosterone (DOC)**, a potent mineralocorticoid, which causes **sodium retention** and **hypertension**. *Cortisol* - **17-hydroxylase deficiency** prevents the synthesis of **cortisol**, as **17-hydroxyprogesterone** is a necessary intermediate. - Therefore, **cortisol levels are low**, not elevated, in this condition. *17-hydroxy pregnenediol* - **17-hydroxylase deficiency** directly impairs the formation of **17-hydroxypregnenolone** from **pregnenolone**. - Consequently, the levels of **17-hydroxypregnenolone** are very low or undetectable, not accumulated, in this disorder. *17-hydroxy progesterone* - The enzyme **17-hydroxylase** is required for the conversion of **progesterone** to **17-hydroxyprogesterone**. - Thus, the deficiency of this enzyme leads to **decreased levels of 17-hydroxyprogesterone**, rather than its accumulation.

Q: What is the type of inheritance in MELAS?

Mitochondrial. ***Mitochondrial*** - **MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes)** is caused by mutations in **mitochondrial DNA**. - **Mitochondrial inheritance** shows **maternal transmission** - the disease is passed from mothers to all of their children (both sons and daughters), but **only daughters can transmit it to the next generation** as sons do not pass on mitochondrial DNA. - This occurs because mitochondria are inherited exclusively from the egg (maternal), not from sperm. *X-linked Recessive* - **X-linked recessive disorders** primarily affect males, as they only have one X chromosome. - The disease is typically transmitted by carrier mothers to their sons, which is not characteristic of MELAS. *Autosomal Recessive* - In **autosomal recessive inheritance**, an individual must inherit two copies of the mutated gene (one from each parent) to be affected. - This pattern of inheritance does not explain the strict maternal transmission observed in MELAS. *X-linked Dominant* - **X-linked dominant disorders** can affect both males and females, but females are often more mildly affected. - All daughters of an affected father will inherit the condition, which differs from the maternal-only inheritance pattern of MELAS.

Q: Enzyme deficiencies are seen in genetic diseases such as?

Tay-Sachs disease. ***Tay-Sachs disease*** - Tay-Sachs disease is a **lysosomal storage disorder** caused by a deficiency of the enzyme **hexosaminidase A**. - This enzyme deficiency leads to the accumulation of **GM2 gangliosides** in neurons, resulting in progressive neurological degeneration. *Sickle Cell Anemia* - Sickle cell anemia is a **hemoglobinopathy** caused by a genetic mutation affecting the structure of the **beta-globin chain** of hemoglobin, leading to abnormal red blood cell shape. - It is not primarily due to an enzyme deficiency, but rather a structural protein defect. *Cystic Fibrosis* - Cystic fibrosis is caused by a mutation in the **CFTR gene**, which encodes a **chloride channel protein**. - This defect affects chloride transport across cell membranes, leading to thick, viscous secretions in various organs, not an enzyme deficiency. *Duchenne Muscular Dystrophy* - Duchenne muscular dystrophy is an **X-linked recessive disorder** characterized by a deficiency of the protein **dystrophin**. - Dystrophin is a structural protein essential for muscle cell integrity; its absence leads to progressive muscle degeneration, not an enzyme deficiency.

Q: In Marfan syndrome, the defect is in the gene encoding which protein?

Fibrillin I. ***Fibrillin I*** - Marfan syndrome arises from a defect in **fibrillin I**, which is essential for the proper formation of elastic fibers in connective tissue [1]. - This defect leads to symptoms affecting the **musculoskeletal**, **cardiovascular**, and **ocular systems** due to weakened connective tissue structure [1]. *Collagen* - While collagen is an important structural protein, it is not the primary defect in Marfan syndrome. - Disorders affecting collagen include **Ehlers-Danlos syndrome**, which presents with different clinical features such as hypermobility. *Fibrillin II* - Fibrillin II is related to different connective tissue conditions but is not involved in Marfan syndrome. - Its mutations are associated with **other disorders**, not the hallmark manifestations seen in Marfan. *Elastin* - Elastin provides elasticity in vascular and other tissues; however, it is not directly related to Marfan syndrome. - Conditions such as **Williams syndrome** involve elastin, but they present distinct clinical features from Marfan syndrome. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. With Illustrations By, pp. 35-36.

Q: Citrullinemia type I results from a deficiency of the

Argininosuccinate synthase. ***Argininosuccinate synthase*** - **Citrullinemia type I** is an **autosomal recessive disorder** characterized by a deficiency of the enzyme **argininosuccinate synthase**. - This enzyme is crucial in the **urea cycle**, catalyzing the conversion of **citrulline** and **aspartate** into **argininosuccinate**. Its deficiency leads to the accumulation of citrulline and ammonia. *Isocitrate dehydrogenase* - **Isocitrate dehydrogenase** is an enzyme involved in the **citric acid cycle** (Krebs cycle) and plays a role in energy production, not the urea cycle. - A deficiency in this enzyme would affect cellular respiration and lead to different metabolic disorders, unrelated to ammonia detoxification. *Pyruvate dehydrogenase* - **Pyruvate dehydrogenase** is a multi-enzyme complex that converts **pyruvate** to **acetyl-CoA**, linking glycolysis to the citric acid cycle. - Deficiency in pyruvate dehydrogenase leads to lactic acidosis and neurological problems, distinct from the hyperammonemia seen in citrullinemia. *Succinyl CoA synthase* - **Succinyl CoA synthase** (or succinate thiokinase) is another enzyme of the **citric acid cycle** that catalyzes the reversible reaction of succinyl-CoA to succinate. - Its deficiency would impair energy metabolism within the mitochondria and would not directly lead to the accumulation of citrulline or hyperammonemia.

Q: Xeroderma pigmentosum is caused by a group of closely related abnormalities in.

Nucleotide excision repair mechanism. ***Nucleotide excision repair*** - Xeroderma pigmentosum results from defects in **nucleotide excision repair (NER)**, crucial for repairing DNA damage caused by UV light [1]. - Patients are highly sensitive to **sunlight**, presenting with skin changes like pigmentation and increased risk of skin cancers [1]. - UV radiation causes cross-linking of pyrimidine residues, preventing normal DNA replication, and several proteins are involved in nucleotide excision repair [1]. - With excessive sun exposure, the capacity of the nucleotide excision repair pathway can be overwhelmed, leading to error-prone repair mechanisms that result in genomic mutations [2]. *SOS repair* - SOS repair is a **bacterial response** to severe DNA damage and not related to xeroderma pigmentosum. - It is not involved in the repair processes in human cells, particularly in response to UV damage. *Base excision repair* - Base excision repair primarily addresses minor **DNA base damage**, not the bulky lesions caused by UV exposure seen in xeroderma pigmentosum. - The molecular mechanics differ, and mutations in base excision repair do not lead to the symptoms characteristic of this condition. *Mismatch repair* - Mismatch repair corrects errors that occur during DNA replication, such as base pair mismatches, which are unrelated to UV-induced damage. - Deficiencies in this pathway lead to **Lynch syndrome**, not xeroderma pigmentosum. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Neoplasia, pp. 322-323. [2] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Neoplasia, pp. 332-333.

Q: A 3-year-old child was brought to the emergency room with complaints of hematuria after accidental ingestion of naphthalene balls, which indicates:

G6PD deficiency. ***G6PD deficiency*** - Ingestion of naphthalene balls (mothballs) contains **naphthalene**, a potent oxidant known to trigger **hemolysis** in individuals with G6PD deficiency. - This hemolysis leads to the rapid destruction of red blood cells, causing **hemoglobinuria** which manifests as gross hematuria or **dark urine**. *Purpura* - Purpura refers to **purple skin lesions** resulting from bleeding under the skin, often associated with platelet disorders or vasculitis. - While naphthalene exposure can cause hemolysis, purpura is **not the primary or direct symptom** of naphthalene-induced hemolytic anemia. *Black water fever* - Black water fever is a severe complication of **malaria** (especially *Plasmodium falciparum*) characterized by widespread intravascular hemolysis and **dark brown/black urine** due to hemoglobinuria. - It is **caused by malarial infection**, not naphthalene ingestion, although both can present with dark urine due to hemolysis. *Hereditary spherocytosis* - This is an **inherited disorder** of red blood cell membranes, leading to fragile, spherical red blood cells that are prematurely destroyed in the spleen. - While it causes chronic hemolytic anemia, it is a **genetic condition** and not triggered by acute ingestion of oxidants like naphthalene.

Q: Which of the following conditions is characterized by depletion of mitochondrial DNA?

Mitochondrial DNA depletion syndrome. ***Mitochondrial DNA depletion syndrome*** - This syndrome is directly characterized by a significant **reduction in the copy number of mitochondrial DNA (mtDNA)** in affected tissues, leading to impaired mitochondrial function. - The depletion results in a broad spectrum of clinical manifestations, including **neurological, hepatic, and myopathic symptoms**, depending on the specific gene mutation involved (e.g., POLG, DGUOK, TK2, SUCLA2). *Leigh syndrome* - Leigh syndrome is a severe neurological disorder characterized by **psychomotor regression and brain lesions** in specific areas (basal ganglia, brainstem). - While some cases can involve mtDNA depletion (e.g., POLG mutations), Leigh syndrome is a **clinical diagnosis** defined by its characteristic neuropathological features, not specifically by the mechanism of mitochondrial dysfunction. - Most cases result from **defects in oxidative phosphorylation enzymes** or specific mtDNA point mutations rather than quantitative mtDNA depletion. *Mitochondrial myopathy* - Mitochondrial myopathies are a heterogeneous group of disorders primarily affecting skeletal muscle, characterized by **muscle weakness, exercise intolerance**, and sometimes "ragged red fibers" on biopsy. - They can be caused by various genetic defects, including **point mutations or large deletions** in mtDNA, but are **not specifically characterized by mtDNA depletion** as the defining feature. *Mitochondrial encephalomyopathy* - Mitochondrial encephalomyopathies are broader disorders involving multiple organ systems, particularly the brain and muscle, due to mitochondrial dysfunction. - Examples include MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes), which is caused by specific **mtDNA point mutations** (commonly m.3243A>G), rather than a quantitative reduction in mtDNA copy number.

Q: Which gene is mutated in Waardenburg syndrome?

PAX3 gene. ***PAX3 gene*** - Mutations in the **PAX3 gene** are the most common cause of **Waardenburg syndrome type 1 (WS1)** and **type 3 (WS3)**. - The PAX3 gene is crucial for the development of **melanocytes** and structures derived from the **neural crest**, explaining the characteristic pigmentary abnormalities and craniofacial features of the syndrome. *PAX2 gene* - Mutations in the **PAX2 gene** are primarily associated with conditions affecting **kidney and ear development**, such as **renal-coloboma syndrome**. - It plays a critical role in **renal and optic nerve development**, which are generally not the primary features of Waardenburg syndrome. *PAX6 gene* - The **PAX6 gene** is a master control gene for **eye development** and is associated with conditions like **aniridia** (absence of the iris). - Its mutations typically lead to severe ocular malformations, which are distinct from the general presentation of Waardenburg syndrome. *PAX9 gene* - **PAX9 gene** mutations are linked to **tooth agenesis** or **oligodontia**, affecting the development and eruption of teeth. - This gene is particularly involved in **odontogenesis** and craniofacial development, but not typically in the pigmentary or hearing defects seen in Waardenburg syndrome.

Question 1

In which of the following inheritance patterns is father-to-son transmission not observed?

Accepted Answer

X-linked recessive inheritance

Answer

Autosomal dominant inheritance

Answer

Autosomal recessive inheritance

Answer

Multifactorial inheritance

Question 2

Congenital 17-hydroxylase deficiency leads to hypertension due to the accumulation of?

Accepted Answer

Deoxycorticosterone

Answer

Cortisol

Answer

17-hydroxypregnenolone

Answer

17-hydroxy progesterone

Question 3

What is the type of inheritance in MELAS?

Accepted Answer

Mitochondrial

Answer

X-linked Recessive

Answer

Autosomal Recessive

Answer

X-linked Dominant

Question 4

Enzyme deficiencies are seen in genetic diseases such as?

Accepted Answer

Tay-Sachs disease

Answer

Sickle Cell Anemia

Answer

Cystic Fibrosis

Answer

Duchenne Muscular Dystrophy

Question 5

In Marfan syndrome, the defect is in the gene encoding which protein?

Accepted Answer

Fibrillin I

Answer

Fibrillin II

Answer

Elastin

Answer

Collagen

Question 6

Citrullinemia type I results from a deficiency of the

Accepted Answer

Argininosuccinate synthase

Answer

Isocitrate dehydrogenase

Answer

Pyruvate dehydrogenase

Answer

Succinyl CoA synthase

Question 7

Xeroderma pigmentosum is caused by a group of closely related abnormalities in.

Accepted Answer

Nucleotide excision repair mechanism

Answer

SOS repair mechanism

Answer

Mismatch repair mechanism

Answer

Base excision repair mechanism

Question 8

A 3-year-old child was brought to the emergency room with complaints of hematuria after accidental ingestion of naphthalene balls, which indicates:

Accepted Answer

G6PD deficiency

Answer

Purpura

Answer

Black water fever

Answer

Hereditary spherocytosis

Question 9

Which of the following conditions is characterized by depletion of mitochondrial DNA?

Accepted Answer

Mitochondrial DNA depletion syndrome

Answer

Leigh syndrome

Answer

Mitochondrial myopathy

Answer

Mitochondrial encephalomyopathy

Question 10

Which gene is mutated in Waardenburg syndrome?

Accepted Answer

PAX3 gene

Answer

PAX2 gene

Answer

PAX6 gene

Answer

PAX9 gene

Genetic Disorders and Biochemical Pathology — MCQs

Genetic Disorders and Biochemical Pathology — MCQs

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