Genetic Disorders and Biochemical Pathology — MCQs

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

Question 611: In sickle cell anaemia, what is the underlying genetic defect?

A. A base insertion in DNA
B. A base deletion in DNA
C. A base substitution in DNA (Correct Answer)
D. None of the above

Explanation: Sickle cell anemia (SCA) is a classic example of a **missense mutation**, which is a type of **point mutation** involving a base substitution in the DNA sequence. ### Why Option C is Correct: The molecular basis of SCA involves a single base substitution in the **$\beta$-globin gene** located on chromosome 11. Specifically, the triplet codon **GAG** (which codes for Glutamic acid) is mutated to **GUG** (which codes for Valine) at the **6th position** of the $\beta$-chain. * **The Change:** Adenine (A) is replaced by Thymine (T) in the DNA template (transcribed as Uracil in mRNA). * **The Result:** Glutamic acid (a polar, hydrophilic amino acid) is replaced by Valine (a non-polar, hydrophobic amino acid). This creates a "sticky patch" on the hemoglobin molecule (HbS), leading to polymerization under deoxygenated conditions and the characteristic "sickling" of RBCs. ### Why Other Options are Incorrect: * **Options A & B (Insertion/Deletion):** These mutations typically cause a **frameshift**, altering the entire reading frame of the genetic code from the point of mutation. This usually results in a non-functional protein or a premature stop codon (nonsense mutation), which is seen in certain types of Thalassemia, but not in Sickle Cell Anemia. ### NEET-PG High-Yield Pearls: * **Inheritance:** Autosomal Recessive. * **Electrophoresis:** On alkaline electrophoresis, HbS moves **slower** than HbA toward the anode (due to the loss of negative charge from Glutamic acid). * **Protective Effect:** Heterozygotes (Sickle cell trait) show resistance to *Plasmodium falciparum* malaria. * **Diagnosis:** Solubility test (screening) and Hb Electrophoresis/HPLC (confirmatory).

Question 612: A 6-month-old child presents with episodes of vomiting after ingesting fruit juice. Which of the following enzyme deficiencies is likely?

A. Aldolase (Correct Answer)
B. Fructokinase
C. Glucose 6-phosphatase
D. Hexokinase

Explanation: **Explanation:** The clinical presentation of vomiting after the ingestion of fruit juice (which contains fructose) in a 6-month-old infant is a classic hallmark of **Hereditary Fructose Intolerance (HFI)**. This condition typically manifests when weaning begins and the infant is introduced to fruits or sweetened formulas. **1. Why Aldolase B is correct:** HFI is caused by a deficiency of **Aldolase B**. In the liver, fructose is converted to Fructose-1-Phosphate (F1P) by fructokinase. Aldolase B is responsible for cleaving F1P into DHAP and glyceraldehyde. When Aldolase B is deficient, **Fructose-1-Phosphate accumulates** intracellularly. This "traps" inorganic phosphate, leading to ATP depletion, inhibition of glycogenolysis, and gluconeogenesis, resulting in severe hypoglycemia, vomiting, and jaundice. **2. Why other options are incorrect:** * **Fructokinase:** Deficiency causes **Essential Fructosuria**. This is a benign, asymptomatic condition where fructose is excreted in the urine. It does not cause vomiting or metabolic distress. * **Glucose 6-phosphatase:** Deficiency leads to **Von Gierke Disease (GSD Type I)**. While it causes severe hypoglycemia, it is triggered by fasting, not specifically by fruit juice ingestion. * **Hexokinase:** This enzyme has a low affinity for fructose and is not the primary pathway for fructose metabolism in the liver; its deficiency does not present with these symptoms. **High-Yield NEET-PG Pearls:** * **The "Trapping" Mechanism:** Accumulation of F1P is the toxic event in HFI. * **Diagnosis:** Reducing sugars in urine (Clinitest positive) but a negative glucose oxidase test (Dipstick negative). * **Treatment:** Strict avoidance of fructose, sucrose (glucose + fructose), and sorbitol. * **Mnemonic:** "Fructose is **B**ad" = Aldolase **B** deficiency.

Question 613: Deficiency in spliceosomal components (snRNPs) leads to which type of disorder?

A. Sickle cell anemia
B. Thalassemia (Correct Answer)
C. Marfan syndrome
D. Ehlers-Danlos syndrome

Explanation: **Explanation:** The correct answer is **Thalassemia**. This disorder is frequently caused by mutations that affect the **splicing of pre-mRNA**. **1. Why Thalassemia is Correct:** The production of hemoglobin chains requires precise removal of introns from pre-mRNA by the **spliceosome** (a complex of small nuclear ribonucleoproteins or **snRNPs**). In many cases of $\beta$-thalassemia, mutations occur at the splice donor or acceptor sites (e.g., GT-AG rule). These mutations lead to "cryptic" splice site activation or exon skipping, resulting in non-functional mRNA and a subsequent deficiency in globin chain synthesis. **2. Why Other Options are Incorrect:** * **Sickle Cell Anemia:** This is caused by a **missense mutation** (point mutation) in the $\beta$-globin gene, where Glutamic acid is replaced by Valine at the 6th position. It is a qualitative defect, not a splicing defect. * **Marfan Syndrome:** This is an autosomal dominant connective tissue disorder caused by mutations in the **FBN1 gene** (encoding Fibrillin-1), typically involving missense or nonsense mutations. * **Ehlers-Danlos Syndrome:** This group of disorders results from defects in **collagen synthesis or processing** (e.g., deficiency of lysyl hydroxylase or procollagen peptidase), not mRNA splicing. **Clinical Pearls for NEET-PG:** * **Systemic Lupus Erythematosus (SLE):** Patients often produce **anti-Smith (anti-Sm) antibodies**, which are directed against snRNPs. This is a highly specific diagnostic marker for SLE. * **Spinal Muscular Atrophy (SMA):** This is another high-yield condition caused by defects in the **SMN1 gene**, which is essential for the assembly of snRNPs. * **Splice Site Rule:** Most introns begin with **GU** (5' donor site) and end with **AG** (3' acceptor site). Mutations here are classic causes of Thalassemia.

Question 614: Marfan syndrome, affecting the eyes, skeletal system, and cardiovascular system, is caused by a mutation in which gene?

A. Fibrillin 1 (Correct Answer)
B. Fibrillin 2
C. Fibulin
D. Elastin

Explanation: **Explanation:** **Marfan syndrome** is an autosomal dominant connective tissue disorder characterized by a mutation in the **FBN1 gene** located on chromosome **15q21**. This gene encodes **Fibrillin-1**, a large glycoprotein that serves as a major structural component of extracellular microfibrils. These microfibrils provide a scaffold for the deposition of elastin and are essential for maintaining the structural integrity of tissues like the aortic media, the suspensory ligaments of the lens (zonules), and the periosteum. **Why the other options are incorrect:** * **Fibrillin 2:** Mutations in the *FBN2* gene (chromosome 5) lead to **Congenital Contractural Arachnodactyly (Beals Syndrome)**. While it shares skeletal features with Marfan syndrome, it typically lacks the ocular and life-threatening cardiovascular complications. * **Fibulin:** Fibulins are glycoproteins associated with elastic fibers; however, mutations in *Fibulin-5* are associated with **Cutis Laxa**, not Marfan syndrome. * **Elastin:** While Marfan syndrome affects elastic tissues, the primary defect is in the fibrillin scaffold, not the elastin protein itself. Mutations in the elastin gene (*ELN*) are associated with **Williams syndrome** and isolated supravalvular aortic stenosis. **High-Yield Clinical Pearls for NEET-PG:** * **Cardiovascular:** The most common cause of death is **Aortic Dissection** or rupture, often preceded by cystic medial necrosis. * **Ocular:** Characterized by **Ectopia Lentis** (dislocation of the lens), typically **upward and outward** (superior-temporal). * **Pathophysiology:** Beyond structural defects, Fibrillin-1 deficiency leads to excessive signaling of **TGF-β** (Transforming Growth Factor-beta), which contributes to tissue overgrowth and weakening. * **Differential Diagnosis:** **Homocystinuria** mimics Marfanoid habitus but is distinguished by intellectual disability, thrombosis risk, and **downward** lens dislocation.

Question 615: Which type of ion channel is affected by mutations in the CFTR gene?

A. Calcium
B. Chloride (Correct Answer)
C. Potassium
D. Sodium

Explanation: ***Chloride***- The **CFTR** (Cystic Fibrosis Transmembrane Conductance Regulator) gene encodes an **ATP-gated chloride channel** that controls the movement of chloride ions across epithelial cell membranes.- Mutations in the CFTR gene cause defective chloride secretion and increased sodium and water reabsorption, leading to the dehydrated, thick mucus characteristic of **Cystic Fibrosis (CF)**.*Sodium*- While the lack of functional CFTR leads to excessive **sodium reabsorption** via the epithelial sodium channel (ENaC) in airways, CFTR itself is a chloride channel, not a sodium channel.- ENaC hyperactivity is a *secondary* effect resulting from the failure of CFTR to inhibit ENaC activity appropriately.*Potassium*- The primary role of the CFTR protein is not the regulation of potassium ions; potassium channels are distinct proteins involved in maintaining resting membrane potential and cell volume.- CFTR activity and the resultant disease phenotype are directly linked to chloride imbalance, not potassium transport defects.*Calcium*- CFTR does not function as a calcium channel; calcium channels are separate entities crucial for many cellular processes, including neurotransmitter release and muscle contraction.- Although intracellular calcium levels can sometimes modulate CFTR activity through signaling pathways, the channel protein itself transports chloride.

Question 616: A 6-month-old boy presents with recurrent bacterial and fungal infections, chronic diarrhea, and failure to thrive. He is diagnosed with severe combined immunodeficiency due to an autosomal recessive inheritance pattern. Which enzyme deficiency is responsible?

A. B. Ornithine transcarbamylase
B. C. Hypoxanthine-guanine phosphoribosyltransferase
C. A. Phosphomannose isomerase
D. D. Adenosine deaminase (Correct Answer)

Explanation: ***Adenosine deaminase*** - The **autosomal recessive** form of **Severe Combined Immunodeficiency (SCID)** is most commonly caused by a deficiency in **Adenosine Deaminase (ADA)**, accounting for about 15% of all SCID cases. - ADA deficiency leads to the accumulation of toxic metabolites (*dATP*), which are highly toxic to rapidly dividing cells, especially **T and B lymphocytes**, resulting in profound lymphopenia and immunodeficiency. *Phosphomannose isomerase* - Deficiency in **Phosphomannose Isomerase (PMI)** causes Congenital Disorder of Glycosylation Type Ib (**CDG-Ib**), which presents with protein-losing enteropathy, hypoglycemia, and failure to thrive, but usually *not* recurrent bacterial and fungal infections severe enough to be classified as SCID. - CDG-Ib is a generalized metabolic disorder affecting **glycosylation**, primarily presenting with liver and gastrointestinal issues. *Ornithine transcarbamylase* - **Ornithine Transcarbamylase (OTC)** deficiency is the most common urea cycle disorder, typically presenting with acute **hyperammonemia** (lethargy, seizures, coma) after an initial period, especially following protein intake, not specifically severe SCID with recurrent infections. - OTC deficiency results in the impaired conversion of **carbamoyl phosphate** and **ornithine** to citrulline, leading to elevated ammonia levels. *Hypoxanthine-guanine phosphoribosyltransferase* - Deficiency in **Hypoxanthine-Guanine Phosphoribosyltransferase (HGPRT)** is responsible for **Lesch-Nyhan Syndrome**, an X-linked recessive disorder characterized by overproduction of **uric acid** (**hyperuricemia**), neurological dysfunction, and self-mutilation. - Although a purine metabolism disorder, it does not cause primary immunodeficiency like SCID; it mainly affects the **nervous system** and purine salvage pathway.

Question 617: A 2-month-old infant presents with poor feeding, vomiting, and lethargy. Laboratory studies show hyperammonemia and elevated levels of orotic acid in the urine. Which of the following is the most likely enzyme deficiency?

A. Orotidine 5′-phosphate decarboxylase deficiency
B. Carbamoyl phosphate synthetase I deficiency
C. Argininosuccinate lyase deficiency
D. Ornithine transcarbamylase (OTC) deficiency (Correct Answer)

Explanation: ***Ornithine transcarbamylase (OTC) deficiency*** - **Most common X-linked urea cycle disorder** presenting in infancy with hyperammonemia - **Classic triad:** Hyperammonemia + elevated urinary orotic acid + low blood urea nitrogen - **Biochemical mechanism:** OTC converts carbamoyl phosphate + ornithine → citrulline. When deficient, carbamoyl phosphate accumulates and spills into the pyrimidine synthesis pathway, producing excess orotic acid - Clinical features: poor feeding, vomiting, lethargy, seizures, developmental delay *Carbamoyl phosphate synthetase I (CPS I) deficiency* - Also causes hyperammonemia but **NO orotic aciduria** (defect occurs before OTC step) - Carbamoyl phosphate is not formed, so cannot enter pyrimidine pathway - Cannot be distinguished clinically from OTC deficiency without measuring orotic acid *Argininosuccinate lyase deficiency* - Causes hyperammonemia with elevated **argininosuccinate** in blood/urine - Does not cause orotic aciduria (defect is downstream of OTC) - May present with trichorrhexis nodosa (brittle hair) *Orotidine 5′-phosphate decarboxylase deficiency* - Causes hereditary **orotic aciduria** but **NO hyperammonemia** (not a urea cycle disorder) - Defect in de novo pyrimidine synthesis pathway - Presents with megaloblastic anemia, growth retardation, responds to uridine supplementation

Question 618: A breastfed infant presents with lethargy, hepatomegaly, and cataracts. Which of the following enzyme deficiencies is most likely responsible for this presentation?

A. Galactose-1-phosphate uridyltransferase (GALPUT) (Correct Answer)
B. Galactokinase
C. Aldolase B
D. Fructokinase

Explanation: ***Correct: Galactose-1-phosphate uridyltransferase (GALPUT)*** - This deficiency causes **Classic Galactosemia**, the most severe form of galactosemia - Leads to accumulation of toxic metabolites: **galactose-1-phosphate** (causes systemic toxicity) and **galactitol** (causes cataracts) - **Clinical presentation** matches perfectly: breastfed infant (lactose from breast milk is broken down to galactose), lethargy, hepatomegaly, and cataracts - The systemic buildup of **galactose-1-phosphate** causes severe hepatotoxicity, jaundice, and CNS effects (lethargy) - **Galactitol** accumulation in the lens causes osmotic damage leading to cataracts - Treatment requires **complete galactose/lactose elimination** from diet *Incorrect: Galactokinase* - Deficiency causes a **milder form of galactosemia** (Type II) - Presents almost exclusively with **cataracts only** due to galactitol accumulation - Does **NOT** cause accumulation of the highly toxic galactose-1-phosphate - Therefore does **NOT** cause hepatomegaly, liver dysfunction, or systemic symptoms like lethargy - If this were the diagnosis, the infant would only have cataracts without hepatomegaly *Incorrect: Aldolase B* - Deficiency causes **Hereditary Fructose Intolerance (HFI)** - Symptoms occur with **fructose or sucrose** ingestion (typically after weaning when fruits/formula introduced) - Clinical features: vomiting, hypoglycemia, hepatomegaly, and jaundice with fructose exposure - Does **NOT** cause cataracts - Since this is a **breastfed infant** (lactose/galactose, not fructose), and cataracts are present, HFI is ruled out *Incorrect: Fructokinase* - Deficiency causes **Essential Fructosuria**, a completely **benign condition** - Clinically **asymptomatic** - considered a benign inborn error of metabolism - Results in fructose accumulation and urinary excretion without any systemic effects - Does **NOT** cause hepatomegaly, cataracts, lethargy, or any clinical symptoms - Often discovered incidentally on routine urinalysis

Question 619: A patient presents with multiple colonic polyps and has been diagnosed with colorectal carcinoma. There is a strong family history of Hereditary Non-Polyposis Colorectal Cancer (HNPCC). Which DNA repair mechanism is most likely defective in this condition?

A. Double-strand break repair
B. Nucleotide excision repair
C. Base excision repair
D. Mismatch repair (Correct Answer)

Explanation: ***Mismatch repair***- **HNPCC (Lynch syndrome)** is caused by inherited germline mutations in genes (e.g., *MLH1*, *MSH2*) that are responsible for the **mismatch repair (MMR)** pathway. - The failure of MMR leads to the accumulation of errors, specifically in repetitive DNA sequences, resulting in **microsatellite instability** which drives carcinogenesis.*Nucleotide excision repair*- This mechanism repairs bulky helix-distorting lesions in DNA, most commonly **pyrimidine dimers** caused by UV radiation. - A classic disease associated with defective **NER** is **Xeroderma Pigmentosum**, which presents with extreme sun sensitivity and a high risk of skin cancers.*Base excision repair*- This pathway primarily corrects small, non-helix distorting damage, such as oxidized or alkylated bases, utilizing enzymes like **DNA glycosylases**.- While fundamental for DNA maintenance, primary defects in BER are not the underlying cause of pathogenesis in **Lynch syndrome**.*Double-strand break repair*- This mechanism repairs severe damage where the entire DNA helix is broken, typically via **Homologous Recombination (HR)** or **Non-Homologous End Joining (NHEJ)**. - Defects in HR are often linked to hereditary breast and ovarian cancers (e.g., *BRCA1*/ *BRCA2* mutations) and are distinct from the pathogenesis of **HNPCC**.

Question 620: A disease with mitochondrial inheritance is inherited from which family member?

A. Father
B. Mother (Correct Answer)
C. Both mother and father
D. Grandmother (paternal)

Explanation: ***Mother*** - Mitochondrial inheritance is characterized by **maternal transmission** because almost all mitochondria in the zygote are derived from the **oocyte** (mother's egg cell). - Therefore, an affected mother will pass the disease to all of her children (sons and daughters), irrespective of sex. *Grandmother (paternal)* - The paternal grandmother passes her mitochondria to the **father**, but the father cannot transmit them to his offspring. - Inheritance is strictly maternal, meaning the genetic input from the paternal line (including the paternal grandmother) is **irrelevant** for mitochondrial DNA. *Father* - The **sperm contributes negligible mitochondrial DNA** to the fertilized egg; hence, fathers cannot pass on mitochondrial diseases to their children. - Paternal mitochondria are typically **ubiquitinated and degraded** following fertilization. *Both mother and father* - Inheritance from both parents is characteristic of **nuclear DNA** (Mendelian) disorders, such as autosomal dominant or recessive patterns. - Mitochondrial inheritance is distinctively **uniparental** and does not involve DNA contribution from both parents.

Practice by Chapter

Single Gene Disorders

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Biochemical Diagnosis of Genetic Disorders

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Inborn Errors of Metabolism

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Lysosomal Storage Diseases

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Glycogen Storage Diseases

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Disorders of Lipoprotein Metabolism

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Disorders of Purine and Pyrimidine Metabolism

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Hemoglobinopathies

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Porphyrias

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Biochemical Markers for Disease Diagnosis

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Newborn Screening for Genetic Disorders

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Enzyme Replacement Therapy

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