Genetic Disorders and Biochemical Pathology — MCQs

Genetic Disorders and Biochemical Pathology Indian Medical PG Practice Questions and MCQs

Question 761: Congenital 17-hydroxylase deficiency leads to hypertension due to the accumulation of?

A. Deoxycorticosterone (Correct Answer)
B. Cortisol
C. 17-hydroxypregnenolone
D. 17-hydroxy progesterone

Explanation: ***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.

Question 762: Which of the following statements regarding phenylketonuria (PKU) is false?

A. Blood phenyl alanine level >20 mg/dl causes severe disease
B. Neurological symptoms are due to deficiency of phenylalanine hydroxylase. (Correct Answer)
C. Method of choice for screening is blood phenylalanine by Guthrie's test.
D. PKU is caused by a deficiency of phenylalanine hydroxylase.

Explanation: ***Neurological symptoms are due to deficiency of phenylalanine hydroxylase.*** - This statement is **FALSE** - it confuses the cause with the mechanism. - Neurological symptoms in PKU are caused by the **accumulation of phenylalanine and its toxic metabolites** (such as phenylpyruvate, phenyllactate, and phenylacetate) in the brain, not directly by the enzyme deficiency itself. - The deficiency of **phenylalanine hydroxylase** is the underlying cause, but the **toxic buildup** is what damages the developing brain, leading to intellectual disability, seizures, and behavioral problems. *Blood phenyl alanine level >20 mg/dl causes severe disease* - This statement is **TRUE**. - Blood phenylalanine levels **>20 mg/dL** are diagnostic of **classical PKU**, which causes severe disease if untreated. - Normal phenylalanine levels are 1-2 mg/dL; levels >20 mg/dL require strict dietary management to prevent neurological damage. *Method of choice for screening is blood phenylalanine by Guthrie's test.* - This statement is **TRUE** in the traditional context taught for medical exams. - The **Guthrie bacterial inhibition assay** measures blood phenylalanine from a heel prick and has been the standard newborn screening method for decades. - While modern laboratories increasingly use **tandem mass spectrometry (MS/MS)**, the Guthrie test remains a validated and widely taught screening method. *PKU is caused by a deficiency of phenylalanine hydroxylase.* - This statement is **TRUE**. - **Phenylketonuria (PKU)** is an autosomal recessive disorder caused by mutations in the **PAH gene**, leading to deficiency of the enzyme **phenylalanine hydroxylase**. - This enzyme normally converts phenylalanine to tyrosine; its absence leads to phenylalanine accumulation.

Question 763: What is the type of inheritance in MELAS?

A. X-linked Recessive
B. Autosomal Recessive
C. Mitochondrial (Correct Answer)
D. X-linked Dominant

Explanation: ***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.

Question 764: In Marfan syndrome, the defect is in the gene encoding which protein?

A. Fibrillin I (Correct Answer)
B. Fibrillin II
C. Elastin
D. Collagen

Explanation: ***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.

Question 765: Enzyme deficiencies are seen in genetic diseases such as?

A. Tay-Sachs disease (Correct Answer)
B. Sickle Cell Anemia
C. Cystic Fibrosis
D. Duchenne Muscular Dystrophy

Explanation: ***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.

Question 766: A 3-year-old child was brought to the emergency room with complaints of hematuria after accidental ingestion of naphthalene balls, which indicates:

A. Purpura
B. Black water fever
C. G6PD deficiency (Correct Answer)
D. Hereditary spherocytosis

Explanation: ***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.

Question 767: Citrullinemia type I results from a deficiency of the

A. Isocitrate dehydrogenase
B. Argininosuccinate synthase (Correct Answer)
C. Pyruvate dehydrogenase
D. Succinyl CoA synthase

Explanation: ***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.

Question 768: Xeroderma pigmentosum is caused by a group of closely related abnormalities in.

A. Nucleotide excision repair mechanism (Correct Answer)
B. SOS repair mechanism
C. Mismatch repair mechanism
D. Base excision repair mechanism

Explanation: ***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.

Question 769: Which of the following is a cause of macrocytic anemia?

A. Phenylketonuria
B. Lesch-Nyhan disease
C. Orotic aciduria (Correct Answer)
D. Abetalipoproteinemia

Explanation: ***Lesh nyhan disease*** - Lesh Nyhan disease primarily affects uric acid metabolism and is associated with **self-mutilating behavior**, not directly leading to macrocytic anemia. - Macrocytic anemia typically involves an **imbalance in red blood cell production** due to deficiencies in vitamins or other factors, which are not features of this condition. *Transcobalamine deficiency* - This deficiency leads to impaired transport of **cobalamin (Vitamin B12)**, resulting in **macrocytic anemia** due to ineffective erythropoiesis [2]. - Patients will often present with symptoms related to **B12 deficiency**, including neurological manifestations [2]. *Abetalipoproteinemia* - It is characterized by the inability to absorb lipids, leading to deficiencies in **fat-soluble vitamins** (A, D, E, K) and subsequent **macrocytic anemia** due to vitamin deficiencies, particularly vitamin E. - Common findings include **retinitis pigmentosa** and neurological symptoms, indicative of vitamin deficiencies. *Orotic aciduria* - This condition is due to a defect in **pyrimidine synthesis**, leading to **macrocytic anemia** because of ineffective erythropoiesis from uridine deficiency [1]. - Patients usually exhibit **growth retardation** and other metabolic issues related to the inability to synthesize nucleotides effectively [1]. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Red Blood Cell and Bleeding Disorders, pp. 656-657. [2] Cross SS. Underwood's Pathology: A Clinical Approach. 6th ed. Common Clinical Problems From Blood And Bone Marrow Disease, pp. 593-594.

Question 770: Which of the following conditions is characterized by depletion of mitochondrial DNA?

A. Leigh syndrome
B. Mitochondrial myopathy
C. Mitochondrial encephalomyopathy
D. Mitochondrial DNA depletion syndrome (Correct Answer)

Explanation: ***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.

Practice by Chapter

Single Gene Disorders

Practice Questions

Biochemical Diagnosis of Genetic Disorders

Practice Questions

Inborn Errors of Metabolism

Practice Questions

Lysosomal Storage Diseases

Practice Questions

Glycogen Storage Diseases

Practice Questions

Disorders of Lipoprotein Metabolism

Practice Questions

Disorders of Purine and Pyrimidine Metabolism

Practice Questions

Hemoglobinopathies

Practice Questions

Porphyrias

Practice Questions

Biochemical Markers for Disease Diagnosis

Practice Questions

Newborn Screening for Genetic Disorders

Practice Questions

Enzyme Replacement Therapy

Practice Questions

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