Genetic Disorders and Biochemical Pathology — MCQs

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

Question 121: All of the following are autosomal dominant disorders except?

A. Tuberous sclerosis
B. Polyposis coli
C. Cystic fibrosis (Correct Answer)
D. Myotonic dystrophy

Explanation: **Explanation:** The correct answer is **Cystic fibrosis**, which is an **Autosomal Recessive (AR)** disorder. It is caused by a mutation in the *CFTR* gene on chromosome 7, leading to defective chloride transport and thick, viscid secretions in the lungs, pancreas, and reproductive tract. **Why the other options are incorrect:** * **Tuberous sclerosis:** An **Autosomal Dominant (AD)** neurocutaneous syndrome characterized by hamartomas in multiple organs (e.g., facial angiofibromas, cortical tubers, and renal angiomyolipomas). It involves mutations in *TSC1* (hamartin) or *TSC2* (tuberin) genes. * **Polyposis coli (Familial Adenomatous Polyposis):** An **AD** condition caused by mutations in the *APC* gene on chromosome 5q. It is characterized by the development of hundreds to thousands of adenomatous colonic polyps. * **Myotonic dystrophy:** An **AD** trinucleotide repeat disorder (CTG repeat in *DMPK* gene). It is the most common adult-onset muscular dystrophy, presenting with "anticipation" and inability to relax muscles after contraction. **High-Yield Clinical Pearls for NEET-PG:** * **Mnemonic for AD disorders:** "**V**ery **P**owerful **M**nemonic **H**elps **A**ll **D**octors" (**V**on Willebrand/Hippel-Lindau, **P**olyposis coli, **M**yotonic dystrophy/Marfan, **H**untington/Hereditary Spherocytosis, **A**chondroplasia, **D**ystrophies/Dystonia). * **Cystic Fibrosis Key Fact:** The most common mutation is **ΔF508**. It is the most common lethal genetic disease in Caucasians. * **General Rule:** Most structural protein defects are AD, while most enzyme deficiencies are AR (exceptions exist, like Acute Intermittent Porphyria which is AD).

Question 122: G-6-P deficiency occurs in which of the following diseases?

A. Forbes disease
B. Niemann Picks disease
C. Von-Gierke disease (Correct Answer)
D. Tay Sachs disease

Explanation: **Explanation:** The correct answer is **Von Gierke disease (GSD Type I)**. This condition is caused by a deficiency of the enzyme **Glucose-6-Phosphatase (G-6-Pase)**, which is responsible for the final step of both glycogenolysis and gluconeogenesis: converting Glucose-6-Phosphate into free glucose. In its absence, glucose cannot be released from the liver into the bloodstream, leading to severe **fasting hypoglycemia**. The accumulated Glucose-6-Phosphate is instead shunted into alternative pathways, resulting in the "biochemical signature" of the disease: **Hyperuricemia** (via the HMP shunt), **Lactic acidosis**, and **Hyperlipidemia**. **Analysis of Incorrect Options:** * **Forbes Disease (GSD Type III):** Caused by a deficiency of the **Debranching enzyme** (α-1,6-glucosidase). It presents similarly to Von Gierke but is generally milder and characterized by the accumulation of "limit dextrins." * **Niemann-Pick Disease:** A lysosomal storage disorder caused by a deficiency of **Sphingomyelinase**, leading to the accumulation of sphingomyelin. It is characterized by hepatosplenomegaly and "foam cells" on histology. * **Tay-Sachs Disease:** A lysosomal storage disorder caused by a deficiency of **Hexosaminidase A**, leading to the accumulation of GM2 gangliosides. It presents with neurodegeneration and a cherry-red spot on the macula, but no hepatomegaly. **High-Yield Clinical Pearls for NEET-PG:** * **Von Gierke Presentation:** Doll-like facies (fatty cheeks), massive hepatomegaly, and stunted growth. * **Treatment:** Frequent oral cornstarch (slow-release glucose) and avoidance of fructose/galactose. * **GSD Type Ib:** Includes the same biochemical features as Type Ia plus **neutropenia** and recurrent infections.

Question 123: A child presents with hepatomegaly and hypoglycemia. There is no improvement in blood sugar even after administration of epinephrine. What is the likely diagnosis?

A. Von Gierke's disease (Correct Answer)
B. Anderson's disease
C. Pompe's disease
D. McArdle's disease

Explanation: ### Explanation **1. Why Von Gierke’s Disease (Type I GSD) is the Correct Answer:** The clinical triad of **hepatomegaly**, **fasting hypoglycemia**, and **failure to respond to epinephrine** is classic for Von Gierke’s disease. This condition is caused by a deficiency of **Glucose-6-Phosphatase**, the final enzyme required for both glycogenolysis and gluconeogenesis. * **Mechanism:** Epinephrine normally stimulates glycogen breakdown into Glucose-1-Phosphate, which is then converted to Glucose-6-Phosphate (G6P). However, because the G6Pase enzyme is missing, G6P cannot be converted into free glucose to enter the bloodstream. Consequently, blood sugar levels remain low despite hormonal stimulation. **2. Why the Other Options are Incorrect:** * **Anderson’s Disease (Type IV):** Caused by a branching enzyme deficiency. It presents with cirrhosis and "limit dextrin" accumulation, but hypoglycemia is not the primary presenting feature. * **Pompe’s Disease (Type II):** Caused by lysosomal acid maltase deficiency. It primarily affects the heart (massive cardiomegaly) and muscles. Blood sugar levels are typically **normal** because cytoplasmic glycogenolysis is intact. * **McArdle’s Disease (Type V):** Caused by muscle phosphorylase deficiency. It presents with muscle cramps and myoglobinuria after exercise. It does **not** cause hypoglycemia or hepatomegaly as the liver enzyme is unaffected. **3. NEET-PG High-Yield Pearls:** * **Biochemical Hallmarks:** Look for "Hyper-LACH": **H**yperuricemia (Gout), **L**actic **A**cidosis, **C**holesterolemia (Hyperlipidemia), and **H**ypoglycemia. * **Diagnostic Clue:** If the question mentions "doll-like facies" or "protuberant abdomen," think Von Gierke’s. * **Glucagon Test:** Similar to epinephrine, administration of glucagon will fail to raise blood glucose in these patients but will significantly increase lactate levels.

Question 124: In Von Gierke's disease, the levels of ketone bodies are increased due to all EXCEPT:

A. The patients have hypoglycemia
B. The patients have low blood glucose
C. More mobilization of fats
D. Oxaloacetate is required for gluconeogenesis (Correct Answer)

Explanation: **Explanation:** **Von Gierke’s Disease (GSD Type I)** is caused by a deficiency of **Glucose-6-Phosphatase**. This enzyme is the final common step for both glycogenolysis and gluconeogenesis. Its absence leads to severe fasting hypoglycemia. **Why Option D is the Correct Answer (The "Except"):** In Von Gierke’s disease, **gluconeogenesis is blocked** at the final step (conversion of G6P to Glucose). Because the pathway is "stalled" at the end, the body does not continue to consume oxaloacetate (OAA) for gluconeogenesis as effectively as it would in a normal fasting state. In fact, the metabolic block leads to an accumulation of glycolytic intermediates. Therefore, the statement that OAA is being depleted specifically for gluconeogenesis is incorrect in the context of this disease's pathology; rather, the ketosis is driven by the massive shift toward fatty acid oxidation due to the hormonal response to hypoglycemia. **Analysis of Incorrect Options:** * **Options A & B:** These are synonymous. The lack of G6Pase means the liver cannot release glucose into the blood, leading to profound **hypoglycemia**. * **Option C:** Low blood glucose triggers a high **Glucagon:Insulin ratio**. This stimulates hormone-sensitive lipase, leading to increased **lipolysis** and mobilization of free fatty acids (FFAs). These FFAs undergo β-oxidation in the liver, producing excess Acetyl-CoA, which is diverted into **ketogenesis**. **NEET-PG High-Yield Pearls:** * **Clinical Tetrad:** Hypoglycemia, Lactic Acidosis (due to blocked gluconeogenesis), Hyperuricemia (G6P shunted to Pentose Phosphate Pathway), and Hyperlipidemia. * **Physical Exam:** "Doll-like" facies and massive hepatomegaly (due to glycogen and lipid storage). * **Diagnostic Key:** Administration of glucagon or epinephrine **fails** to raise blood glucose but increases lactate levels.

Question 125: A 10-year-old child presents with recurrent skin lesions on the face and upper extremities that rapidly progress to cancer. Xeroderma pigmentosa is considered a possible differential. Which of the following enzymes is defective in this condition?

A. Topoisomerase
B. 3' → 5' Exonuclease
C. Endonuclease (Correct Answer)
D. Helicase

Explanation: **Explanation:** **Xeroderma Pigmentosum (XP)** is an autosomal recessive genetic disorder characterized by extreme sensitivity to ultraviolet (UV) radiation. The core defect lies in the **Nucleotide Excision Repair (NER)** pathway, which is responsible for repairing DNA damage caused by UV light, specifically **Pyrimidine dimers** (Thymine dimers). 1. **Why Endonuclease is Correct:** In a healthy individual, the NER pathway utilizes a specific **UV-specific Endonuclease** (also known as *uvrABC exinuclease*) to recognize the bulky DNA lesion and make incisions on both sides of the damaged strand. In XP patients, this enzyme is deficient or defective. Consequently, DNA damage accumulates, leading to mutations in proto-oncogenes and tumor suppressor genes, resulting in early-onset skin cancers (Basal Cell Carcinoma, Squamous Cell Carcinoma, and Melanoma). 2. **Why Other Options are Incorrect:** * **Topoisomerase:** These enzymes relieve torsional strain (supercoiling) during DNA replication and transcription. They are not involved in the NER pathway. * **3' → 5' Exonuclease:** This represents the **proofreading activity** of DNA Polymerase. Deficiencies here lead to increased mutation rates during replication but are not the cause of XP. * **Helicase:** While specific helicases (like XPB and XPD) are subunits of the TFIIH complex involved in NER, the classic biochemical defect traditionally tested in XP is the initial "nicking" step performed by the **Endonuclease**. (Note: Bloom Syndrome and Werner Syndrome involve DNA helicase defects). **High-Yield Clinical Pearls for NEET-PG:** * **Clinical Presentation:** Severe sunburn after minimal sun exposure, "parchment-like" skin, freckle-like pigmentations, and a 1000-fold increased risk of skin cancer. * **Inheritance:** Autosomal Recessive. * **Associated Condition:** Cockayne Syndrome also involves NER defects but presents with "Mickey Mouse" facies and dwarfism without a significant increase in skin cancer. * **Diagnostic Test:** Chromosomal breakage studies or measuring unscheduled DNA synthesis in cultured fibroblasts.

Question 126: NARP syndrome is a type of:

A. Mitochondrial function disorder (Correct Answer)
B. Glycogen storage disorder
C. Lysosomal storage disorder
D. Lipid storage disorder

Explanation: **Explanation:** **NARP syndrome** (Neurogenic muscle weakness, Ataxia, and Retinitis Pigmentosa) is a classic example of a **Mitochondrial function disorder**. 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 ATP production that primarily affects tissues with high energy demands, such as the nervous system and retina. **Why the other options are incorrect:** * **Glycogen storage disorders (GSDs):** These are caused by deficiencies in enzymes involved in glycogen synthesis or breakdown (e.g., Von Gierke or Pompe disease), primarily affecting the liver and skeletal muscles. * **Lysosomal storage disorders (LSDs):** These result from defects in lysosomal enzymes leading to the accumulation of undigested macromolecules (e.g., Gaucher or Tay-Sachs disease). * **Lipid storage disorders:** These involve the abnormal accumulation of lipids due to enzymatic defects in lipid metabolism (e.g., Niemann-Pick disease). **High-Yield Clinical Pearls for NEET-PG:** * **Maternal Inheritance:** Like most mitochondrial DNA (mtDNA) disorders, NARP is inherited exclusively from the mother. * **Heteroplasmy:** The severity of NARP depends on the ratio of mutant to wild-type mtDNA within cells. * **Leigh Syndrome Link:** If the mutation load of the MT-ATP6 gene exceeds 90%, the phenotype shifts from NARP to the more severe **Maternally Inherited Leigh Syndrome (MILS)**, characterized by infantile-onset necrotizing encephalopathy. * **Key Triad:** Always look for the combination of **Proximal neurogenic weakness, Ataxia, and Vision loss (Retinitis Pigmentosa)** in clinical vignettes.

Question 127: All of the following are true about Galactosemia EXCEPT?

A. Galactose 1 phosphate and galactitol have toxic effects on various organs
B. Patients are symptomatic immediately after birth (Correct Answer)
C. Jaundice and liver dysfunction commonly seen
D. E.coli sepsis is an important cause of mortality

Explanation: **Explanation:** **Why Option B is the Correct Answer (The "EXCEPT"):** Classic Galactosemia (deficiency of **Galactose-1-phosphate uridyltransferase/GALT**) does not present *immediately* at birth because the fetus is protected by maternal metabolism in utero. Symptoms only manifest **after the initiation of milk feeding** (breast milk or cow’s milk formula), which contains lactose. Lactose is broken down into glucose and galactose; once galactose enters the system and cannot be metabolized, toxic metabolites begin to accumulate. Symptoms typically appear within the first few days to a week of life. **Analysis of Other Options:** * **Option A:** True. The deficiency leads to the accumulation of **Galactose-1-phosphate** (toxic to liver, kidneys, and brain) and **Galactitol** (produced via aldose reductase). Galactitol is osmotically active and is the primary cause of **cataracts**. * **Option C:** True. Accumulation of metabolites in the liver leads to hepatomegaly, jaundice (conjugated or unconjugated), and eventually cirrhosis if untreated. * **Option D:** True. There is a well-documented, high-yield association between Galactosemia and **Neonatal E. coli sepsis**. It is believed that inhibited leucocyte bactericidal activity or increased galactose levels enhance bacterial virulence. **High-Yield Clinical Pearls for NEET-PG:** * **Enzyme Deficiency:** Most common is GALT (Classic Galactosemia). * **Screening:** Reducing substances in urine (Benedict's test positive) but a negative glucose oxidase test (Dipstick). * **Clinical Triad:** Oil-drop cataracts, Liver failure, and Intellectual disability. * **Management:** Immediate withdrawal of milk; switch to **Soy-based formula** or lactose-free formula. * **Note:** Even with treatment, many patients develop long-term complications like ovarian failure and speech deficits.

Question 128: Pellagra-like clinical syndrome is found in which of the following conditions?

A. Homocystinuria
B. Histidinuria
C. Cystinosis
D. Hartnup disease (Correct Answer)

Explanation: **Explanation:** **Hartnup disease** is the correct answer because it is an autosomal recessive disorder characterized by a defect in the **SLC6A19 transporter**. This protein is responsible for the absorption of neutral amino acids (especially **Tryptophan**) in the small intestine and their reabsorption in the renal proximal tubules. Tryptophan is a vital precursor for the endogenous synthesis of **Niacin (Vitamin B3)**; approximately 60 mg of Tryptophan yields 1 mg of Niacin. In Hartnup disease, the profound deficiency of Tryptophan leads to secondary Niacin deficiency, resulting in the classic **Pellagra-like triad** of Dermatitis (photosensitive rash), Diarrhea, and Dementia (ataxia/psychosis). **Analysis of Incorrect Options:** * **Homocystinuria:** Caused by a deficiency of Cystathionine $\beta$-synthase. It presents with ectopia lentis, intellectual disability, and thromboembolism, but not pellagra-like symptoms. * **Histidinuria:** A benign condition involving elevated histidine in urine; it does not interfere with the Niacin pathway. * **Cystinosis:** A lysosomal storage disorder characterized by the accumulation of cystine crystals in organs (kidneys, eyes). It leads to Fanconi syndrome but not Niacin deficiency. **High-Yield Clinical Pearls for NEET-PG:** * **Diagnosis:** Confirmed by detecting **neutral aminoaciduria** (using paper chromatography) while excluding basic amino acids. * **Management:** High-protein diet and **Nicotinamide** supplementation. * **Differential for Pellagra:** Nutritional B3 deficiency, Carcinoid syndrome (Tryptophan diverted to Serotonin), and Isoniazid therapy (depletes B6, a cofactor for Niacin synthesis).

Question 129: In sickle cell trait, how many bands are typically found in hemoglobin electrophoresis?

A. 2 (Correct Answer)
B. 1
C. 4
D. 5

Explanation: **Explanation:** In **Sickle Cell Trait (HbAS)**, the individual is a heterozygote, meaning they possess one normal adult hemoglobin gene ($\beta^A$) and one mutated sickle gene ($\beta^S$). Consequently, their red blood cells contain two distinct types of hemoglobin: **HbA** ($\alpha_2\beta^A_2$) and **HbS** ($\alpha_2\beta^S_2$). On alkaline hemoglobin electrophoresis (pH 8.6), these two variants migrate at different speeds due to their net charge, resulting in **two distinct bands**. * **Why Option A is correct:** HbS results from a point mutation where glutamic acid (negative charge) is replaced by valine (neutral) at the 6th position of the beta-globin chain. This loss of negative charge makes HbS move slower toward the anode than HbA, creating two separate bands. Typically, HbA > HbS (approx. 60:40 ratio). * **Why Option B is incorrect:** A single band is seen in normal individuals (HbAA) or those with homozygous sickle cell disease (HbSS), where only one major type of hemoglobin is present. * **Why Options C & D are incorrect:** Four or five bands are not characteristic of simple sickle cell trait. Multiple bands might be seen in complex compound heterozygous states (e.g., HbSC disease with fetal hemoglobin) or when using specialized techniques like Isoelectric Focusing, but not in standard screening for sickle trait. **High-Yield Clinical Pearls for NEET-PG:** * **Electrophoresis Speed:** Remember the mnemonic **"A Fat Santa Claus"** for migration speed toward the Anode (Fastest to Slowest): **HbA > HbF > HbS > HbC**. * **Sickle Cell Trait:** These individuals are usually asymptomatic and provide a protective advantage against *Plasmodium falciparum* malaria. * **Diagnosis:** While electrophoresis shows two bands, the **Sickling Test** (using sodium metabisulfite) and **Solubility Test** will also be positive.

Question 130: Which of the following statements is FALSE regarding G6PD deficiency?

A. It is an autosomal recessive condition. (Correct Answer)
B. It commonly manifests as hemolysis upon exposure to oxidant stress.
C. Heinz bodies are typically observed.
D. Older red blood cells are more susceptible to hemolysis.

Explanation: **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.

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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