Genetic Disorders and Biochemical Pathology Practice Questions

Q: NARP syndrome is a part of which of the following group of disorders?

Mitochondrial diseases. **Explanation:** **NARP syndrome** (Neurogenic muscle weakness, Ataxia, and Retinitis Pigmentosa) is a classic example of a **Mitochondrial disease**. It is caused by a point mutation in the **MT-ATP6 gene**, which encodes a subunit of the mitochondrial ATP synthase (Complex V). This mutation impairs the oxidative phosphorylation pathway, leading to a deficit in cellular energy (ATP) production, which primarily affects high-energy-demand tissues like the brain and nerves. **Why other options are incorrect:** * **Glycogen storage diseases (GSDs):** These are caused by deficiencies in enzymes involved in glycogen synthesis or breakdown (e.g., Von Gierke, Pompe). They typically present with hypoglycemia, hepatomegaly, or exercise intolerance, rather than the neuro-ophthalmic triad of NARP. * **Lysosomal storage diseases (LSDs):** These result from defects in lysosomal acid hydrolases (e.g., Gaucher, Tay-Sachs), leading to the accumulation of undigested macromolecules. * **Lipid storage diseases:** These involve the abnormal accumulation of lipids (e.g., Niemann-Pick) due to enzymatic defects in lipid metabolism, distinct from mitochondrial DNA mutations. **High-Yield Clinical Pearls for NEET-PG:** * **Maternal Inheritance:** Like most mitochondrial disorders, NARP is inherited exclusively from the mother. * **Heteroplasmy:** The severity of NARP depends on the ratio of mutant to wild-type mitochondrial DNA. * **Leigh Syndrome Link:** If the mutation load in the MT-ATP6 gene exceeds 90%, the phenotype shifts from NARP to the more severe **Maternally Inherited Leigh Syndrome (MILS)**, characterized by subacute necrotizing encephalomyelopathy. * **Key Triad:** Always look for the combination of **Proximal Muscle Weakness + Sensory Ataxia + Salt-and-pepper Retinitis Pigmentosa**.

Q: A 54-year-old male with acute lymphocytic leukemia develops a blast crisis and is treated with intensive systemic chemotherapy. Following treatment, the patient will be at increased risk for the development of which of the following?

Uric acid kidney stones. **Explanation:** The correct answer is **D. Uric acid kidney stones.** This patient is experiencing **Tumor Lysis Syndrome (TLS)**, a high-yield oncological emergency in NEET-PG. When intensive chemotherapy is administered for high-grade malignancies like Acute Lymphocytic Leukemia (ALL) or Burkitt lymphoma, there is a massive, rapid breakdown of neoplastic cells. **Pathophysiology:** 1. **Nucleic Acid Breakdown:** As tumor cells lyse, their nuclei release large amounts of purines (adenine and guanine). 2. **Catabolism:** Purines are metabolized by **xanthine oxidase** into **uric acid**. 3. **Hyperuricemia:** The sudden surge in serum uric acid leads to its precipitation in the acidic environment of the renal collecting ducts. 4. **Urate Nephropathy:** This results in obstructive uropathy or the formation of radiolucent uric acid kidney stones. **Analysis of Incorrect Options:** * **A & B (Gallstones):** Bile pigment stones are associated with chronic hemolysis (e.g., Sickle Cell Anemia), while cholesterol stones are linked to obesity, female gender, and rapid weight loss. Chemotherapy-induced cell lysis specifically targets purine metabolism, not biliary components. * **C (Cystine stones):** These are caused by a congenital defect in the renal transport of COLA amino acids (Cystine, Ornithine, Lysine, Arginine), unrelated to malignancy or chemotherapy. **NEET-PG High-Yield Pearls:** * **Prevention of TLS:** Aggressive hydration and **Allopurinol** (xanthine oxidase inhibitor) or **Rasburicase** (recombinant urate oxidase that converts uric acid to soluble allantoin). * **Electrolyte Triad of TLS:** Hyperkalemia, Hyperphosphatemia, and **Hypocalcemia** (due to calcium-phosphate precipitation). * **Uric Acid Stones:** These are **radiolucent** on X-ray but visible on CT scans. They form best in **acidic urine**.

Q: What is the biochemical defect in Zellweger syndrome?

Peroxisomal biogenesis disorder. **Biochemical Explanation:** Zellweger syndrome (Cerebro-hepato-renal syndrome) is the most severe form of the **Peroxisomal Biogenesis Disorders (PBD)**. It is caused by mutations in the **PEX genes**, which encode proteins called **peroxins**. These proteins are essential for the assembly of peroxisomes and the import of enzymes into the peroxisomal matrix. Without functional peroxisomes, the cell cannot perform critical metabolic processes, most notably the **beta-oxidation of Very Long Chain Fatty Acids (VLCFA)** and the synthesis of plasmalogens (essential for myelin). This leads to the accumulation of VLCFAs in the blood and tissues, causing severe neurological and multi-organ dysfunction. **Analysis of Incorrect Options:** * **Option B (Lysosomal targeting disorder):** This refers to **I-cell disease**, where a defect in N-acetylglucosaminyl-1-phosphotransferase prevents the addition of the Mannose-6-Phosphate tag, causing enzymes to be secreted extracellularly rather than sent to lysosomes. * **Option C (Defect in glycosylation):** This describes **Congenital Disorders of Glycosylation (CDG)**, which typically involve defects in the synthesis of N-linked oligosaccharide chains. * **Option D (Trisomy 21):** This is **Down Syndrome**, a chromosomal numerical abnormality, not a primary metabolic or organelle biogenesis defect. **High-Yield Clinical Pearls for NEET-PG:** * **Clinical Triad:** Hypotonia (floppy baby), seizures, and distinctive facial features (high forehead, widened fontanelles). * **Diagnostic Marker:** Elevated levels of **VLCFA** (e.g., C26:0 and C26:1) in the plasma. * **Organ Involvement:** Hepatomegaly, jaundice, and renal cysts are common. * **Prognosis:** Usually fatal within the first year of life.

Q: All of the following statements about the inheritance of Myotonic Dystrophy are true, except?

Type 2 gene is located on Chromosome 19.. Explanation: Myotonic Dystrophy (DM) is the most common adult-onset muscular dystrophy, characterized by autosomal dominant inheritance and multisystem involvement. 1. Why Option C is the correct answer (The False Statement): The gene for Myotonic Dystrophy Type 2 (DM2), known as the CNBP (formerly ZNF9) gene, is located on Chromosome 3q21. In contrast, the gene for Myotonic Dystrophy Type 1 (DM1), the DMPK gene, is located on Chromosome 19q13.3. Therefore, stating that the Type 2 gene is on Chromosome 19 is factually incorrect. 2. Analysis of other options: * Option A & D: DM1 is caused by an unstable expansion of a CTG trinucleotide repeat in the 3' untranslated region of the DMPK (Dystrophia Myotonica Protein Kinase) gene. This is the most common form. * Option B: DM2 (Proximal Myotonic Myopathy or PROMM) is caused by a CCTG tetranucleotide repeat expansion in the CNBP (CCHC-type zinc finger nucleic acid binding protein) gene. Clinical Pearls for NEET-PG: * Anticipation: This phenomenon (increasing severity/earlier onset in successive generations) is prominent in DM1 but generally absent in DM2. * Clinical Features: Look for "Hatchet facies," frontal balding, cataracts, cardiac conduction defects, and "grip myotonia" (difficulty releasing a handshake). * DM1 vs. DM2: DM1 affects distal muscles first (ptisosis, distal limb weakness), while DM2 primarily affects proximal muscles (hip and shoulder girdles). * Diagnosis: Gold standard is Genetic Testing (PCR/Southern Blot) to identify repeat expansions.

Q: Which of the following statements is FALSE regarding G6PD deficiency?

It is an autosomal recessive condition.. **Explanation:** **1. Why Option A is False (The Correct Answer):** Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency is not autosomal recessive; it is an **X-linked recessive** disorder. This means it primarily affects males, while females are typically asymptomatic carriers (unless affected by skewed lyonization). This is a high-yield distinction in medical genetics. **2. Analysis of Other Options:** * **Option B:** G6PD is the rate-limiting enzyme in the Pentose Phosphate Pathway (PPP), responsible for producing **NADPH**. NADPH is essential for maintaining a pool of reduced glutathione, which neutralizes reactive oxygen species. Without it, exposure to oxidant stress (e.g., Fava beans, infections, or drugs like Primaquine and Sulfa drugs) leads to uncontrolled oxidative damage and **hemolysis**. * **Option C:** Oxidative stress causes hemoglobin to denature and precipitate into insoluble inclusions called **Heinz bodies**. When splenic macrophages attempt to remove these inclusions, they leave behind "Bite cells" (degmacytes). * **Option D:** In the most common variants (like G6PD A-), the enzyme has a shortened half-life. Since RBCs cannot synthesize new proteins, **older RBCs** have the lowest enzyme activity and are the first to undergo hemolysis during an oxidative challenge. **Clinical Pearls for NEET-PG:** * **Inheritance:** X-linked Recessive (like Hemophilia and DMD). * **Morphology:** Heinz bodies (Crystal violet stain) and Bite cells. * **Protective Effect:** G6PD deficiency provides a survival advantage against *Plasmodium falciparum* malaria. * **Diagnosis:** Enzyme assays should not be performed during an acute hemolytic episode, as the older cells (with low enzyme levels) have already lysed, potentially leading to a false-normal result.

Q: A male infant's parents report that male children over three generations in the mother's family have been affected by a progressive disorder involving multiple organ systems. These children had coarse facial features, corneal clouding, joint stiffness, hepatosplenomegaly, and mental retardation, and many died in childhood. At autopsy, some of the children had subendothelial coronary arterial deposits that caused myocardial infarction. Laboratory testing of the infant shows increased urinary excretion of mucopolysaccharides. Bone marrow biopsy reveals that the accumulated mucopolysaccharides are found in macrophages ('balloon cells' filled with minute vacuoles). Which of the following enzyme deficiencies is most likely to be seen in this infant?

a-l-Iduronidase. ### Explanation The clinical presentation describes a classic case of **Hurler Syndrome (Mucopolysaccharidosis Type IH)**. **1. Why the Correct Answer is Right:** The patient exhibits the hallmark "gargoyle" features: coarse facial features, corneal clouding, hepatosplenomegaly, and skeletal deformities (dysostosis multiplex). The accumulation of **dermatan sulfate** and **heparan sulfate** due to a deficiency of **$\alpha$-L-iduronidase** leads to multi-organ dysfunction. The "balloon cells" in the bone marrow are macrophages engorged with undegraded glycosaminoglycans (GAGs). A critical high-yield point is the **coronary artery involvement**; GAG deposition in the coronary subendothelium leads to narrowing and early myocardial infarction, a common cause of death in these patients. **2. Why the Incorrect Options are Wrong:** * **Adenosine deaminase:** Deficiency causes Severe Combined Immunodeficiency (SCID), presenting with recurrent infections and lymphopenia, not GAG accumulation or coarse features. * **Glucocerebrosidase:** Deficiency causes **Gaucher Disease**. While it features hepatosplenomegaly and "wrinkled tissue paper" macrophages, it lacks corneal clouding and urinary mucopolysaccharides. * **Glucose-6-phosphatase:** Deficiency causes **Von Gierke Disease** (GSD Type I), presenting with hypoglycemia, lactic acidosis, and "doll-like" facies, but not skeletal stiffness or corneal clouding. **3. Clinical Pearls for NEET-PG:** * **Hurler vs. Hunter:** Both have similar features, but **Hunter Syndrome (MPS II)** is X-linked recessive, lacks corneal clouding, and is caused by **Iduronate-2-sulfatase** deficiency ("The Hunter needs clear eyes to see the X"). * **Inheritance:** Hurler syndrome is Autosomal Recessive. * **Diagnosis:** Initial screening via urinary GAGs; confirmed by enzyme assay or genetic testing.

Q: For the development of sickle cell disease, the codon for the amino acid glutamate is replaced with the codon for which amino acid at the 6th position of the beta-globin gene?

Valine. ### Explanation **Correct Option: A (Valine)** Sickle Cell Anemia is a classic example of a **point mutation (missense mutation)**. In the $\beta$-globin chain of hemoglobin, the amino acid **Glutamate** (which is polar and negatively charged) is replaced by **Valine** (which is non-polar and hydrophobic) at the **6th position**. * **Molecular Level:** The DNA codon **GAG** (coding for Glutamate) changes to **GTG** (coding for Valine). * **Pathophysiology:** This substitution creates a "sticky patch" on the surface of the hemoglobin molecule. Under deoxygenated conditions, these hydrophobic patches interact, leading to the polymerization of HbS into long fibers, which distorts the RBC into a sickle shape. **Incorrect Options:** * **B (Phenylalanine):** While hydrophobic, it is not involved in the standard sickle cell mutation. * **C (Asparagine):** This is a polar amino acid; its substitution does not cause the polymerization characteristic of HbS. * **D (Serine):** Serine is a polar amino acid and is not the substituent in sickle cell disease. **High-Yield NEET-PG Pearls:** 1. **HbC Disease:** Glutamate is replaced by **Lysine** at the same 6th position of the $\beta$-chain. (Mnemonic: **S**ickle = **V**aline; **C** = Ly**s**ine). 2. **Electrophoresis:** On alkaline electrophoresis, HbA moves fastest toward the anode, followed by HbF, HbS, and HbC (Mnemonic: **A** Fat **S**anta **C**laus). 3. **Protective Effect:** Heterozygotes (Sickle cell trait) show resistance to *Plasmodium falciparum* malaria. 4. **Diagnosis:** The definitive test is **Hemoglobin Electrophoresis** or HPLC; the screening test is the **Sickling test** (using Sodium metabisulfite).

Q: Enzyme replacement therapy is not available for which of the following diseases?

Hunter disease. **Explanation:** The correct answer is **Hunter disease (Mucopolysaccharidosis II)**. While Enzyme Replacement Therapy (ERT) exists for many lysosomal storage disorders, its effectiveness is severely limited in diseases with significant **Central Nervous System (CNS) involvement**. The blood-brain barrier (BBB) prevents intravenously administered enzymes from reaching the brain. Hunter disease (caused by a deficiency of **Iduronate-2-sulfatase**) often presents with severe neurodegeneration. While ERT (Idursulfase) is FDA-approved for the *systemic* manifestations of Hunter syndrome, it does not cross the BBB and therefore cannot treat the cognitive decline. In the context of NEET-PG questions, Hunter disease is often highlighted as the condition where ERT fails to address the primary neurological pathology compared to others. **Analysis of Incorrect Options:** * **Gaucher Disease (Type 1):** The gold standard for ERT. **Imiglucerase** (recombinant glucocerebrosidase) effectively treats hepatosplenomegaly and hematological issues. * **Hurler Disease (MPS I):** Treated with **Laronidase**. While it has CNS involvement, the standard of care often involves Hematopoietic Stem Cell Transplant (HSCT) to address neurological issues, but ERT is widely available for systemic management. * **Pompe Disease:** Treated with **Alglucosidase alfa**. It is a glycogen storage disease (Type II) where ERT effectively targets cardiac and skeletal muscle. **High-Yield Clinical Pearls for NEET-PG:** * **Hunter vs. Hurler:** Hunter syndrome is **X-linked Recessive** and lacks corneal clouding ("The Hunter needs clear vision to see the X"). * **Gaucher Disease:** Most common lysosomal storage disorder; look for "Crinkled paper" appearance of macrophages. * **Fabry Disease:** Another X-linked disorder where ERT (Agalsidase beta) is used.

Question 1

NARP syndrome is a part of which of the following group of disorders?

Accepted Answer

Mitochondrial diseases

Answer

Glycogen storage diseases

Answer

Lysosomal storage diseases

Answer

Lipid storage diseases

Question 2

A 54-year-old male with acute lymphocytic leukemia develops a blast crisis and is treated with intensive systemic chemotherapy. Following treatment, the patient will be at increased risk for the development of which of the following?

Accepted Answer

Uric acid kidney stones

Answer

Bile pigment gallstones

Answer

Cholesterol gallstones

Answer

Cystine kidney stones

Question 3

Which of the following is NOT a mitochondrial disorder?

Accepted Answer

Fragile X Syndrome

Answer

Pearson Syndrome

Answer

MERRF (Myoclonic Epilepsy Ragged Red Fibre)

Answer

MELAS (Mitochondrial Encephalopathy Lactic Acidosis and Stroke-like episode)

Question 4

What is the biochemical defect in Zellweger syndrome?

Accepted Answer

Peroxisomal biogenesis disorder

Answer

Lysosomal targeting disorder

Answer

Defect in glycosylation of proteins

Answer

Trisomy 21

Question 5

All of the following statements about the inheritance of Myotonic Dystrophy are true, except?

Accepted Answer

Type 2 gene is located on Chromosome 19.

Answer

Type 1 is caused by mutation in the DMPK gene.

Answer

Type 2 is caused by mutation in the CNBP gene.

Answer

Type 1 is caused by a CTG trinucleotide repeat expansion.

Question 6

A young adult presents with progressive intellectual deterioration, weakness, ataxia, and seizures. Laboratory tests demonstrate an abnormality of an important mitochondrial enzyme. Which of the following conditions is this person most likely suffering from?

Accepted Answer

Leigh's disease

Answer

Adrenoleukodystrophy

Answer

Central pontine myelinolysis

Answer

Krabbe's disease

Question 7

Which of the following statements is FALSE regarding G6PD deficiency?

Accepted Answer

It is an autosomal recessive condition.

Answer

It commonly manifests as hemolysis upon exposure to oxidant stress.

Answer

Heinz bodies are typically observed.

Answer

Older red blood cells are more susceptible to hemolysis.

Question 8

A male infant's parents report that male children over three generations in the mother's family have been affected by a progressive disorder involving multiple organ systems. These children had coarse facial features, corneal clouding, joint stiffness, hepatosplenomegaly, and mental retardation, and many died in childhood. At autopsy, some of the children had subendothelial coronary arterial deposits that caused myocardial infarction. Laboratory testing of the infant shows increased urinary excretion of mucopolysaccharides. Bone marrow biopsy reveals that the accumulated mucopolysaccharides are found in macrophages ('balloon cells' filled with minute vacuoles). Which of the following enzyme deficiencies is most likely to be seen in this infant?

Accepted Answer

a-l-Iduronidase

Answer

Adenosine deaminase

Answer

Glucocerebrosidase

Answer

Glucose-6-phosphatase

Question 9

For the development of sickle cell disease, the codon for the amino acid glutamate is replaced with the codon for which amino acid at the 6th position of the beta-globin gene?

Accepted Answer

Valine

Answer

Phenylalanine

Answer

Aspargine

Answer

Serine

Question 10

Enzyme replacement therapy is not available for which of the following diseases?

Accepted Answer

Hunter disease

Answer

Gaucher disease

Answer

Hurler disease

Answer

Pompe disease

Genetic Disorders and Biochemical Pathology — MCQs

Genetic Disorders and Biochemical Pathology — MCQs

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