Genetic Disorders and Biochemical Pathology — MCQs

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

Question 441: Which of the following statements regarding mitochondrial genes is true?

A. Paternal transmission
B. Maternal transmission (Correct Answer)
C. Mendelian inheritance
D. Mitochondrial myopathy

Explanation: **Explanation:** **1. Why Maternal Transmission is Correct:** Mitochondrial DNA (mtDNA) is inherited exclusively through the **maternal line**. During fertilization, the sperm contributes its nuclear DNA to the zygote, but its mitochondria (located in the midpiece) are either excluded from the egg or targeted for degradation by the oocyte's ubiquitin-proteasome system. Consequently, all mitochondria in a developing embryo are derived from the mother's ovum. A mother affected by a mitochondrial mutation will pass it to **all** her children, but only her daughters can pass it to the next generation. **2. Why Other Options are Incorrect:** * **Paternal transmission:** As noted, paternal mitochondria do not contribute to the zygote's mitochondrial pool. * **Mendelian inheritance:** Mitochondrial inheritance is **Non-Mendelian** (cytoplasmic inheritance). Mendelian laws apply to nuclear DNA, where offspring receive 50% from each parent. * **Mitochondrial myopathy:** While this is a *type* of disease caused by mitochondrial mutations (e.g., MELAS, MERRF), it is a clinical diagnosis/manifestation, not a rule or characteristic of mitochondrial genes themselves. **3. High-Yield Clinical Pearls for NEET-PG:** * **Heteroplasmy:** The presence of a mixture of both mutant and wild-type mtDNA within a single cell. This explains the **variable expressivity** seen in mitochondrial diseases. * **Replicative Segregation:** During cell division, mitochondria replicate and sort randomly into daughter cells, leading to different proportions of mutant mtDNA in different tissues. * **Threshold Effect:** Clinical symptoms appear only when the proportion of mutant mtDNA exceeds a specific threshold in a tissue. * **Common Examples:** Leber’s Hereditary Optic Neuropathy (LHON), MERRF (Myoclonic Epilepsy with Ragged Red Fibers), and MELAS.

Question 442: What is the commonest enzyme deficiency?

A. Glucose-1-phosphatase
B. Glucose-6-phosphatase (Correct Answer)
C. Carbonic anhydrase
D. Cystathionine synthetase

Explanation: ### Explanation **Correct Option: B. Glucose-6-phosphatase** The question refers to the most common enzyme deficiency among the **Glycogen Storage Diseases (GSDs)**. Glucose-6-phosphatase is the enzyme deficient in **von Gierke disease (GSD Type I)**. It is the most frequent of all GSDs, accounting for approximately 25% of all cases. This enzyme is crucial for the final step of both gluconeogenesis and glycogenolysis, converting Glucose-6-phosphate into free glucose in the liver and kidneys. Its deficiency leads to severe fasting hypoglycemia, hepatomegaly (due to glycogen accumulation), and "doll-like" facies. **Analysis of Incorrect Options:** * **A. Glucose-1-phosphatase:** This is not a major clinical enzyme deficiency associated with a recognized metabolic syndrome in humans. * **C. Carbonic anhydrase:** While deficiencies exist (e.g., CA-II deficiency leading to osteopetrosis and renal tubular acidosis), they are extremely rare compared to GSD Type I. * **D. Cystathionine synthetase:** Deficiency of this enzyme causes **Homocystinuria**. While a high-yield topic for NEET-PG, its prevalence is significantly lower than that of von Gierke disease. **High-Yield Clinical Pearls for NEET-PG:** * **Von Gierke Disease (Type Ia):** Characterized by the "Biochemical Tetrad": **Hypoglycemia, Lactic acidosis, Hyperuricemia** (leading to gout), and **Hyperlipidemia**. * **Type Ib:** Deficiency of Glucose-6-phosphate **translocase**; presents similarly to Type Ia but with additional **neutropenia** and recurrent infections. * **Gold Standard Diagnosis:** DNA analysis (previously liver biopsy). * **Treatment:** Frequent cornstarch feeds to maintain glucose levels and prevent nocturnal hypoglycemia.

Question 443: The genetic defect in Dubin-Johnson Syndrome is a mutation in which of the following?

A. Gene for multiple drug resistance protein 2 (MRP2) (Correct Answer)
B. UDP-glucuronosyltransferase gene
C. A mutation on chromosome 23
D. A gene associated with 'flash mutations'

Explanation: **Explanation:** **Dubin-Johnson Syndrome (DJS)** is an autosomal recessive disorder characterized by chronic, non-hemolytic **conjugated hyperbilirubinemia**. 1. **Why Option A is correct:** The fundamental defect in DJS is a mutation in the **ABCC2 gene**, which encodes the **Multidrug Resistance-associated Protein 2 (MRP2)**. MRP2 is an ATP-dependent transporter located on the canalicular membrane of hepatocytes. It is responsible for the efflux of conjugated bilirubin and other organic anions into the bile. A defect in this transporter leads to the accumulation of conjugated bilirubin within hepatocytes, which then leaks back into the blood. 2. **Why other options are incorrect:** * **Option B:** Mutations in the **UDP-glucuronosyltransferase (UGT1A1)** gene lead to unconjugated hyperbilirubinemia, seen in **Crigler-Najjar Syndrome** and **Gilbert Syndrome**. * **Option C:** DJS is an autosomal recessive condition linked to **Chromosome 10q24**, not chromosome 23 (Sex chromosomes). * **Option D:** 'Flash mutations' is not a standard genetic term associated with biliary transport disorders. **High-Yield Clinical Pearls for NEET-PG:** * **Black Liver:** A pathognomonic feature of DJS is a grossly **black/dark brown liver** due to the accumulation of epinephrine metabolites (melanin-like pigment) in lysosomes. * **Urinary Coproporphyrins:** Total urinary coproporphyrin levels are normal, but **Coproporphyrin I** constitutes >80% of the total (in normal individuals, Coproporphyrin III predominates). * **Rotor Syndrome vs. DJS:** Rotor syndrome is also a conjugated hyperbilirubinemia but lacks the liver pigmentation and has different urinary porphyrin patterns. * **Oral Cholecystography:** The gallbladder is typically **not visualized** in DJS.

Question 444: In Gaucher's disease, there is an accumulation of which substance inside the cells?

A. Galactosidases
B. Sphingomyelin
C. Glucosidases
D. Cerebrosides (Correct Answer)

Explanation: **Explanation:** **Gaucher’s disease** is the most common lysosomal storage disorder, inherited in an autosomal recessive pattern. It is caused by a deficiency of the enzyme **β-glucosidase** (also known as glucocerebrosidase). 1. **Why D is correct:** Under normal physiological conditions, glucocerebrosidase cleaves **glucocerebroside** (a type of cerebroside) into glucose and ceramide. When this enzyme is deficient, glucocerebrosides accumulate within the lysosomes of macrophages. These lipid-laden macrophages are known as **Gaucher cells**, which classically appear as having "crinkled paper" or "wrinkled tissue paper" cytoplasm. 2. **Why other options are incorrect:** * **A. Galactosidases:** Deficiency of β-galactosidase leads to Krabbe’s disease (accumulation of galactocerebroside) or GM1 gangliosidosis. * **B. Sphingomyelin:** Accumulation of sphingomyelin occurs in **Niemann-Pick disease** due to a deficiency of the enzyme sphingomyelinase. * **C. Glucosidases:** This refers to the enzyme itself, not the accumulated substance. While a deficiency of α-glucosidase causes Pompe disease, Gaucher is specifically a deficiency of β-glucosidase. **High-Yield Clinical Pearls for NEET-PG:** * **Clinical Triad:** Hepatosplenomegaly (most common finding), bone involvement (Erlenmeyer flask deformity of the femur, avascular necrosis), and pancytopenia. * **Biomarker:** Elevated levels of **serum acid phosphatase** and **chitotriosidase** are often seen. * **Treatment:** Enzyme Replacement Therapy (ERT) with recombinant glucocerebrosidase (Imiglucerase) is the gold standard. * **Note:** Unlike Niemann-Pick or Tay-Sachs, Gaucher disease (Type 1) typically does **not** present with a cherry-red spot on the macula.

Question 445: Mousy odour of urine is characteristic of which of the following conditions?

A. Phenylketonuria (Correct Answer)
B. Maple syrup urine disease
C. Tyrosinemia
D. Homocystinuria

Explanation: **Explanation:** **Phenylketonuria (PKU)** is the correct answer. It is an autosomal recessive disorder caused by a deficiency of the enzyme **phenylalanine hydroxylase (PAH)** or its cofactor, tetrahydrobiopterin (BH4). This deficiency leads to the accumulation of phenylalanine, which is alternatively metabolized into phenylketones such as **phenylacetate**. The excretion of phenylacetate in the urine is responsible for the characteristic **"mousy" or "musty" odor**. Clinical features include intellectual disability, seizures, and hypopigmentation (due to decreased melanin synthesis). **Analysis of Incorrect Options:** * **Maple Syrup Urine Disease (MSUD):** Caused by a deficiency in the branched-chain alpha-keto acid dehydrogenase complex. It results in urine that smells like **maple syrup or burnt sugar** due to the accumulation of isoleucine. * **Tyrosinemia (Type I):** Caused by a deficiency of fumarylacetoacetate hydrolase. It is characterized by a **"cabbage-like" or "boiled egg"** odor of the urine. * **Homocystinuria:** Caused by a deficiency of cystathionine beta-synthase. While it presents with marfanoid habitus and ectopia lentis, it does not typically present with a distinct diagnostic urine odor. **High-Yield Clinical Pearls for NEET-PG:** * **Isovaleric Acidemia:** Sweaty feet odor. * **Trimethylaminuria:** Fishy odor. * **Hypermethioninemia:** Rancid butter or boiled cabbage odor. * **Guthrie Test:** A bacterial inhibition assay used for neonatal screening of PKU. * **Dietary Management:** PKU requires a diet low in phenylalanine and supplementation with **Tyrosine**, which becomes an essential amino acid in these patients.

Question 446: All of the following are true about Lesch-Nyhan syndrome except:

A. Hyperuricemia
B. Mental retardation
C. Stone production
D. Occurs equally in both sexes (Correct Answer)

Explanation: **Explanation:** Lesch-Nyhan Syndrome (LNS) is an inborn error of purine metabolism caused by a complete deficiency of the enzyme **Hypoxanthine-Guanine Phosphoribosyltransferase (HGPRT)**. **Why Option D is the Correct Answer (The Exception):** Lesch-Nyhan syndrome is an **X-linked recessive disorder**. This means the gene mutation is located on the X chromosome. Consequently, it affects **males almost exclusively**, while females are typically asymptomatic carriers. It does not occur equally in both sexes. **Analysis of Incorrect Options (True Statements about LNS):** * **A. Hyperuricemia:** HGPRT is essential for the purine salvage pathway. Its deficiency leads to the accumulation of PRPP (Phosphoribosyl pyrophosphate), which stimulates *de novo* purine synthesis. This results in excessive production and breakdown of purines into **Uric Acid**, causing severe hyperuricemia. * **B. Mental Retardation:** LNS is characterized by severe neurological dysfunction, including intellectual disability (mental retardation), spasticity, choreoathetosis, and a hallmark behavioral symptom: **self-mutilation** (biting of lips and fingers). * **C. Stone Production:** Due to the massive overproduction of uric acid, patients develop **Urate urolithiasis** (kidney stones) and "orange sand" crystals (sodium urate) in the diapers of affected infants. **NEET-PG High-Yield Pearls:** * **Enzyme Deficiency:** HGPRT (converts Hypoxanthine to IMP and Guanine to GMP). * **Mnemonic (HGPRT):** **H**yperuricemia, **G**out, **P**issed off (self-mutilation), **R**etardation, **T**one (dystonia). * **Diagnosis:** Hyperuricemia + Hyperuricosuria + Low HGPRT activity in fibroblasts/erythrocytes. * **Treatment:** Allopurinol or Febuxostat (manages uric acid but does not reverse neurological symptoms).

Question 447: Primaquine may cause hemolysis in patients with which of the following conditions?

A. Glucose-6-phosphate dehydrogenase (G6PD) deficiency (Correct Answer)
B. NADP deficiency
C. Methemoglobin reductase deficiency
D. Crabbe disease

Explanation: **Explanation:** **1. Why G6PD Deficiency is Correct:** Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme of the **Hexose Monophosphate (HMP) Shunt**. Its primary role in RBCs is to reduce NADP+ to **NADPH**. NADPH is essential for maintaining a pool of **reduced glutathione**, which acts as an antioxidant to neutralize reactive oxygen species (ROS) like hydrogen peroxide. Drugs like **Primaquine** (an antimalarial) induce oxidative stress. In G6PD-deficient individuals, the inability to generate sufficient NADPH leads to the oxidation of hemoglobin. This results in the formation of **Heinz bodies** (denatured hemoglobin precipitates), which damage the RBC membrane, leading to acute hemolysis. **2. Analysis of Incorrect Options:** * **NADP deficiency:** While NADPH is central to the process, clinical pathology is defined by the enzyme deficiency (G6PD) rather than a primary dietary or genetic lack of the NADP+ cofactor itself. * **Methemoglobin reductase deficiency:** This leads to **Congenital Methemoglobinemia** (Type I or II). While it affects the oxidation state of iron (Fe3+ instead of Fe2+), it does not typically cause acute hemolysis triggered by Primaquine. * **Krabbe disease:** This is a **lysosomal storage disorder** caused by a deficiency of galactocerebrosidase, leading to the accumulation of galactosylsphingosine. It affects the myelin sheath in the nervous system, not RBC redox metabolism. **3. High-Yield Clinical Pearls for NEET-PG:** * **Inheritance:** G6PD deficiency is an **X-linked recessive** disorder. * **Morphology:** Look for **Heinz bodies** (supravital stain) and **Bite cells** (formed by splenic macrophages removing Heinz bodies). * **Triggers:** Infections (most common), Fava beans (Favism), and drugs (Primaquine, Sulphonamides, Nitrofurantoin, Dapsone). * **Protective Effect:** G6PD deficiency provides a survival advantage against *Plasmodium falciparum* malaria.

Question 448: The ferric chloride (FeCl3) test for phenylketonuria in urine typically results in which color?

A. Green (Correct Answer)
B. Blue
C. Red
D. Purple

Explanation: ### Explanation **Correct Answer: A. Green** **Medical Concept:** Phenylketonuria (PKU) is an autosomal recessive disorder caused by a deficiency of the enzyme **phenylalanine hydroxylase**. This leads to the accumulation of phenylalanine, which is alternatively metabolized into **phenylpyruvate** (a phenylketone). In the Ferric Chloride (FeCl₃) test, the ferric ions react with the enol group of phenylpyruvate in the urine to produce a characteristic **transient blue-green or olive-green color**. **Analysis of Incorrect Options:** * **B. Blue:** While some metabolites can produce a bluish tint, the classic diagnostic color for PKU is green. A deep blue color is more characteristic of Alkaptonuria (though it typically turns black upon standing). * **C. Red:** A red or reddish-brown color in a FeCl₃ test is indicative of **salicylates** (aspirin) or **ketone bodies** (acetoacetate) in the urine. * **D. Purple:** A purple color is typically seen in the presence of salicylates or phenol derivatives. **High-Yield Clinical Pearls for NEET-PG:** * **The "Mousy" Odor:** Phenylacetic acid in the sweat and urine of PKU patients gives off a characteristic "mousy" or "musty" odor. * **Screening vs. Diagnosis:** The FeCl₃ test is a non-specific screening tool and is no longer the gold standard. Modern screening uses **Guthrie’s bacterial inhibition assay** or Tandem Mass Spectrometry. * **Associated Findings:** Patients often present with intellectual disability, seizures, and **hypopigmentation** (fair skin/blue eyes) because phenylalanine is a competitive inhibitor of tyrosinase, impairing melanin synthesis. * **Other FeCl₃ Results:** * Alkaptonuria (Homogentisic acid) → Transient Blue/Green. * Maple Syrup Urine Disease (Ketoacids) → Navy Blue. * Tyrosinemia → Pale Green.

Question 449: Megaloblastic anemia resistant to treatment is seen with which of the following conditions?

A. Anticonvulsant therapy
B. Hepatic cirrhosis
C. Orotic aciduria (Correct Answer)
D. All of the above

Explanation: **Explanation:** **Orotic Aciduria** is the correct answer because it causes a unique form of megaloblastic anemia that is **refractory (resistant)** to treatment with Vitamin B12 and Folic acid. 1. **Mechanism (Why C is correct):** Hereditary Orotic Aciduria (Type I) is caused by a deficiency of the bifunctional enzyme **UMP Synthase** (Orotate phosphoribosyltransferase and OMP decarboxylase). This block prevents the conversion of orotic acid to UMP, leading to a **pyrimidine deficiency**. Since pyrimidines are essential for DNA synthesis, their absence results in megaloblastic changes in the bone marrow. Because the defect is downstream of the folate/B12 pathways, supplementing these vitamins does not bypass the block. Treatment requires **Uridine supplementation**, which provides a source of pyrimidines via the salvage pathway. 2. **Why A and B are incorrect:** * **Anticonvulsant therapy:** Drugs like Phenytoin interfere with folate absorption or metabolism. This anemia **responds** to folic acid supplementation. * **Hepatic cirrhosis:** Megaloblastic changes here are usually due to poor dietary intake of folate, increased requirements, or direct ethanol toxicity. These typically **respond** to nutritional correction. **High-Yield Clinical Pearls for NEET-PG:** * **Differentiating Feature:** Unlike Ornithine Transcarbamylase (OTC) deficiency (where orotic acid is also high), Hereditary Orotic Aciduria presents with **normal ammonia levels** and **megaloblastic anemia**. * **Clinical Presentation:** Look for a child with failure to thrive, developmental delay, and orotic acid crystals in the urine ("needle-shaped" crystals). * **Treatment of Choice:** Oral **Uridine triacetate** (bypasses the metabolic block).

Question 450: Which blood group has the NAG transferase antigen present but lacks the galactosyl transferase?

A. Group A (Correct Answer)
B. Group B
C. Group AB
D. Group O

Explanation: **Explanation:** The ABO blood group system is determined by the presence of specific terminal sugars on the H-substance (a precursor carbohydrate chain). These sugars are added by specific glycosyltransferase enzymes encoded by the ABO gene. * **Group A (Correct):** Individuals with blood group A possess the **A-gene**, which codes for the enzyme **N-acetylgalactosaminyltransferase (NAG transferase)**. This enzyme attaches **N-acetylgalactosamine (NAG)** to the H-substance. They lack the galactosyltransferase enzyme, which is specific to Group B. * **Group B:** These individuals possess the **B-gene**, which codes for **galactosyltransferase**. This enzyme attaches **D-galactose** to the H-substance. They lack NAG transferase. * **Group AB:** These individuals have both genes and therefore possess **both** NAG transferase and galactosyltransferase, resulting in both A and B antigens on the red cell surface. * **Group O:** This is a "null" phenotype. The O-gene is non-functional and does not produce a functional transferase. Consequently, the H-substance remains unmodified (only H-antigen is present). **High-Yield NEET-PG Pearls:** 1. **Immunodominant Sugars:** Group A = N-acetylgalactosamine; Group B = D-galactose; Group O = L-fucose (terminal sugar of H-substance). 2. **Bombay Phenotype:** Lacks the *H-gene* (cannot even make H-substance); types as Group O but has potent anti-H antibodies. 3. **Secretors:** The presence of A, B, or H antigens in body fluids (saliva, semen) is determined by the **FUT2 (Se) gene**.

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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