Genetic Disorders and Biochemical Pathology — MCQs

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

Question 31: A child presents with pellagra-like symptoms, aminoaciduria, and a family history of one affected sibling and three unaffected siblings, while the parents are normal. What is the diagnosis?

A. Phenylketonuria
B. Alkaptonuria
C. Maple syrup urine disease
D. Hartnup disease (Correct Answer)

Explanation: ### Explanation **Correct Option: D. Hartnup disease** **Underlying Concept:** Hartnup disease is an **autosomal recessive** disorder caused by a mutation in the **SLC6A19 gene**, which encodes a sodium-dependent neutral amino acid transporter in the proximal renal tubules and the small intestine. This leads to the malabsorption and excessive urinary loss of neutral amino acids, most notably **Tryptophan**. Tryptophan is a precursor for **Niacin (Vitamin B3)** synthesis. A deficiency in Tryptophan results in secondary Niacin deficiency, manifesting as **Pellagra-like symptoms** (the 3 Ds: Dermatitis, Diarrhea, and Dementia). The family history described (normal parents, affected siblings) is classic for an autosomal recessive inheritance pattern. **Why other options are incorrect:** * **A. Phenylketonuria (PKU):** Caused by a deficiency of Phenylalanine Hydroxylase. It presents with intellectual disability, "mousy" body odor, and hypopigmentation, not pellagra-like rashes. * **B. Alkaptonuria:** A deficiency of Homogentisate Oxidase. It is characterized by urine that turns black upon standing, ochronosis (bluish-black pigmentation of connective tissue), and arthritis. * **C. Maple Syrup Urine Disease (MSUD):** Caused by a deficiency in the Branched-Chain Alpha-Keto Acid Dehydrogenase complex. It presents in neonates with poor feeding, seizures, and a characteristic "maple syrup" odor in the urine. **NEET-PG High-Yield Pearls:** * **Clinical Triad of Hartnup:** Photosensitive skin rash (Pellagra-like), cerebellar ataxia, and neutral aminoaciduria. * **Diagnosis:** Confirmed by detecting neutral amino acids (Alanine, Valine, Threonine, Isoleucine, Leucine, Phenylalanine, Tryptophan, Tyrosine, Histidine) in the urine via chromatography. * **Treatment:** High-protein diet and **Nicotinamide (Niacin)** supplementation. * **Key differentiator:** Unlike dietary Pellagra, Hartnup disease shows significant **aminoaciduria**.

Question 32: Alpha-1-antitrypsin deficiency is associated with a gene located on which chromosome?

A. Chromosome 10
B. Chromosome 14 (Correct Answer)
C. Chromosome 17
D. Chromosome 11

Explanation: **Explanation:** **Alpha-1-Antitrypsin (AAT) Deficiency** is an autosomal codominant disorder caused by mutations in the **SERPINA1 gene**. This gene is located on the **long arm of Chromosome 14 (14q32.1)**. AAT is a serine protease inhibitor (serpin) synthesized primarily in the liver; its main function is to inhibit neutrophil elastase in the lungs, thereby preventing alveolar destruction. * **Why Chromosome 14 is correct:** The SERPINA1 gene locus is part of a cluster of serpin genes located on 14q. Mutations here (most commonly the **PiZ variant**) lead to protein misfolding, causing liver cirrhosis (due to accumulation of polymers in hepatocytes) and panacinar emphysema (due to unchecked elastase activity). **Analysis of Incorrect Options:** * **Chromosome 10:** Associated with conditions like PTEN hamartoma tumor syndrome and RET proto-oncogene mutations (MEN 2). * **Chromosome 11:** Home to the Beta-globin gene cluster (Sickle cell anemia, Beta-thalassemia) and the WT1 gene (Wilms tumor). * **Chromosome 17:** Associated with NF1 (Neurofibromatosis type 1), TP53 (Li-Fraumeni syndrome), and BRCA1. **High-Yield Clinical Pearls for NEET-PG:** * **Histology:** Liver biopsy shows **PAS-positive, diastase-resistant globules** in periportal hepatocytes. * **Genetics:** The normal allele is **M**, and the most severe deficiency allele is **Z** (PiZZ phenotype). * **Clinical Presentation:** Suspect AAT deficiency in a young, non-smoker presenting with **panacinar emphysema** (classically involving lower lobes) and unexplained liver disease. * **Electrophoresis:** On serum protein electrophoresis, there is a characteristic **absence of the Alpha-1 globulin peak**.

Question 33: Down syndrome is characterized by which chromosomal abnormality?

A. Trisomy of chromosome 21 (Correct Answer)
B. Trisomy of chromosome 18
C. Monosomy of chromosome 18
D. Monosomy of chromosome 21

Explanation: **Explanation:** **Down Syndrome (Trisomy 21)** is the most common chromosomal disorder and the leading genetic cause of intellectual disability. It occurs due to the presence of an extra copy of chromosome 21, resulting in a total of 47 chromosomes. The underlying mechanism is usually **meiotic non-disjunction** (95% of cases), most commonly occurring during maternal meiosis I. Other causes include Robertsonian translocation (4%) and mosaicism (1%). **Analysis of Options:** * **Option A (Correct):** Trisomy 21 is the definitive chromosomal hallmark of Down Syndrome. * **Option B:** Trisomy 18 characterizes **Edwards Syndrome**, which presents with "rocker-bottom" feet, micrognathia, and clenched fists with overlapping fingers. * **Option C:** Monosomy 18 is rare and typically incompatible with life or results in severe developmental defects (e.g., De Grouchy syndrome); it is not associated with Down Syndrome. * **Option D:** Monosomy 21 is an extremely rare condition that is generally lethal in utero; autosomal monosomies are typically not viable. **NEET-PG High-Yield Pearls:** * **Risk Factor:** Advanced maternal age (>35 years) is the most significant risk factor for non-disjunction. * **Biochemical Screening (Quadruple Test):** Characterized by **decreased** AFP and uE3, and **increased** hCG and Inhibin-A (Mnemonic: **HI**gh = **H**CG and **I**nhibin). * **Clinical Features:** Simian crease, Brushfield spots (iris), epicanthal folds, and increased nuchal translucency on ultrasound. * **Associated Pathologies:** Early-onset Alzheimer’s (due to APP gene on Chr 21), Endocardial cushion defects (ASD/VSD), and increased risk of ALL/AML (M7).

Question 34: What is true about Crigler-Najjar syndrome type II?

A. Diglucuronide deficiency
B. Autosomal recessive inheritance (Correct Answer)
C. Kernicterus is a common feature
D. Phenobarbital is not useful for treatment

Explanation: **Explanation:** Crigler-Najjar Syndrome (CNS) is a rare genetic disorder characterized by non-hemolytic unconjugated hyperbilirubinemia due to a deficiency of the enzyme **UDP-glucuronosyltransferase (UGT1A1)**. **1. Why the correct answer is right:** * **Autosomal Recessive Inheritance:** Both Type I and Type II Crigler-Najjar syndromes are inherited in an autosomal recessive pattern. While Type II was historically thought to be autosomal dominant with variable penetrance, modern molecular genetics has confirmed its **autosomal recessive** nature. **2. Why the incorrect options are wrong:** * **Option A:** In CNS Type II (Arias Syndrome), there is a partial deficiency of UGT1A1 (enzyme activity is <10%). Consequently, **monoglucuronides** are formed, but there is a relative deficiency in the conversion to **diglucuronides**. However, the primary pathology is the enzyme deficiency itself, not just the end-product ratio. * **Option C:** Kernicterus (bilirubin encephalopathy) is a hallmark of **Type I**, where bilirubin levels often exceed 20–50 mg/dL. In **Type II**, bilirubin levels are lower (usually 6–20 mg/dL), and kernicterus is **rare**, typically occurring only during periods of severe illness or fasting. * **Option D:** Phenobarbital is a potent inducer of the UGT1A1 enzyme. It is highly **effective** in Type II, reducing serum bilirubin by more than 25%. It is notably **ineffective in Type I** because there is a total absence of the enzyme to induce. **High-Yield Clinical Pearls for NEET-PG:** * **Type I vs. Type II:** The "Phenobarbital Test" is the classic differentiator. If bilirubin drops, it is Type II (Arias Syndrome). * **Enzyme Activity:** Type I = 0% activity; Type II = <10% activity. * **Treatment:** Type I requires lifelong phototherapy and eventually a liver transplant; Type II is managed with Phenobarbital. * **Gilbert Syndrome:** The mildest form of UGT1A1 deficiency (~30% activity), also inherited autosomal recessively.

Question 35: Renal osteodystrophy is due to:

A. Increased synthesis of calcitriol in the kidney
B. No synthesis of calcitriol in the kidney
C. Decreased synthesis of calcitriol in the kidney (Correct Answer)
D. Fluctuating production of calcitriol in the kidney

Explanation: **Explanation:** Renal osteodystrophy is a complex bone pathology occurring in Chronic Kidney Disease (CKD). The primary biochemical driver is the **decreased synthesis of calcitriol (1,25-dihydroxycholecalciferol)**. **Why Option C is Correct:** In healthy kidneys, the enzyme **1-alpha-hydroxylase** converts 25-hydroxyvitamin D into its active form, calcitriol. In CKD, the loss of functional renal parenchyma leads to a deficiency of this enzyme. Decreased calcitriol results in: 1. **Reduced intestinal calcium absorption**, leading to hypocalcemia. 2. **Secondary Hyperparathyroidism:** Low calcium and high phosphate levels trigger the Parathyroid Glands to secrete excess PTH, which causes bone resorption to maintain serum calcium, leading to osteitis fibrosa cystica. **Why Other Options are Incorrect:** * **Option A:** Increased synthesis would lead to hypercalcemia and suppressed PTH, the opposite of renal osteodystrophy. * **Option B:** While synthesis is severely impaired, it is rarely "zero" until end-stage; "decreased synthesis" more accurately describes the progressive pathophysiology. * **Option C:** Calcitriol levels do not fluctuate; they show a steady, progressive decline as the Glomerular Filtration Rate (GFR) drops. **High-Yield Clinical Pearls for NEET-PG:** * **Hyperphosphatemia:** Failing kidneys cannot excrete phosphate. High phosphate directly suppresses 1-alpha-hydroxylase and complexes with calcium, further worsening hypocalcemia. * **FGF-23:** This hormone rises early in CKD to lower phosphate but also inhibits 1-alpha-hydroxylase, contributing to early calcitriol deficiency. * **Management:** Treatment involves phosphate binders (e.g., Sevelamer) and administration of active Vitamin D (Calcitriol) rather than inactive Ergocalciferol.

Question 36: Which is the limiting amino acid in the Maple Syrup Urine Disease?

A. Tyrosine
B. Tryptophan (Correct Answer)
C. Phenylalanine
D. None of the above

Explanation: ### Explanation **Correct Answer: B. Tryptophan** **Underlying Medical Concept:** Maple Syrup Urine Disease (MSUD) is caused by a deficiency in the **Branched-Chain Alpha-Keto Acid Dehydrogenase (BCKAD)** complex. This leads to the accumulation of Branched-Chain Amino Acids (BCAAs)—**Leucine, Isoleucine, and Valine**—and their corresponding alpha-keto acids in the blood and brain. The high concentration of Leucine outcompetes other Large Neutral Amino Acids (LNAAs) for transport across the blood-brain barrier via the **LAT1 transporter**. Since **Tryptophan** shares this same transporter, its entry into the brain is significantly inhibited. Consequently, Tryptophan becomes the **limiting amino acid** for protein synthesis and neurotransmitter production (like Serotonin) within the central nervous system, contributing to the neurotoxicity seen in MSUD. **Analysis of Incorrect Options:** * **A & C (Tyrosine and Phenylalanine):** While these are also Large Neutral Amino Acids that compete with Leucine for brain entry, Tryptophan is typically the least abundant and most severely restricted in the brain's amino acid pool during MSUD crises. * **D (None of the above):** Incorrect, as the competitive inhibition of amino acid transport is a well-documented biochemical feature of the disease. **High-Yield Clinical Pearls for NEET-PG:** * **Enzyme Deficient:** BCKAD (requires Thiamine/B1, Lipoate, CoA, FAD, NAD). * **Diagnostic Marker:** Presence of **Alloisoleucine** in plasma (pathognomonic). * **Clinical Sign:** "Maple syrup" or "burnt sugar" odor in urine due to **alpha-keto-isovalerate**. * **Management:** Dietary restriction of BCAAs; some patients respond to high-dose **Thiamine (Vitamin B1)** supplementation.

Question 37: Gene mutations in Cystic fibrosis occur at which location?

A. Short arm of chromosome 7
B. Long arm of chromosome 5
C. Long arm of chromosome 7 (Correct Answer)
D. Short arm of chromosome 3

Explanation: **Explanation:** **Cystic Fibrosis (CF)** is an autosomal recessive multisystem disorder caused by mutations in the **CFTR (Cystic Fibrosis Transmembrane Conductance Regulator)** gene. 1. **Why Option C is Correct:** The CFTR gene is located on the **long arm (q arm)** of **chromosome 7**, specifically at position **7q31.2**. This gene encodes a chloride channel protein found in the apical membrane of epithelial cells. The most common mutation is the **ΔF508** (deletion of phenylalanine at position 508), which leads to protein misfolding and degradation in the endoplasmic reticulum. 2. **Why Other Options are Incorrect:** * **Option A:** While chromosome 7 is correct, the mutation is on the long arm (q), not the short arm (p). * **Option B (Chromosome 5):** The long arm of chromosome 5 is associated with conditions like **Familial Adenomatous Polyposis (FAP)** (APC gene at 5q21) and Cri-du-chat syndrome (deletion of 5p). * **Option D (Chromosome 3):** Mutations on chromosome 3 are associated with **Von Hippel-Lindau (VHL) disease** (3p25) and Alkaptonuria (3q21). **High-Yield Clinical Pearls for NEET-PG:** * **Diagnosis:** The gold standard is the **Sweat Chloride Test** (Pilocarpine iontophoresis); levels **>60 mEq/L** are diagnostic. * **Pathophysiology:** Defective chloride transport leads to thick, viscid secretions. In the lungs, this causes bronchiectasis and recurrent infections (notably *Pseudomonas*); in the pancreas, it causes insufficiency and malabsorption. * **Infertility:** 95% of males are infertile due to **Congenital Bilateral Absence of Vas Deferens (CBAVD)**. * **Newborn Screening:** Elevated **Immunoreactive Trypsinogen (IRT)** is the initial screening marker.

Question 38: Anticipation is seen in which of the following?

A. Translocation
B. Chromosome breaking
C. Trinucleotide-repeat expansion (Correct Answer)
D. Mitochondrial mutation

Explanation: **Explanation:** **1. Why Trinucleotide-repeat expansion is correct:** **Anticipation** is a genetic phenomenon where a disease manifests at an earlier age and with increased severity in successive generations. This is the hallmark of **Trinucleotide-repeat expansion** disorders. During gametogenesis, these unstable repeats (e.g., CAG, CGG, GAA) tend to expand in number. A higher number of repeats correlates with earlier onset and more severe symptoms. Classic examples include **Huntington’s disease** (paternal transmission) and **Fragile X syndrome** (maternal transmission). **2. Why the other options are incorrect:** * **A. Translocation:** This involves the rearrangement of parts between non-homologous chromosomes (e.g., t(9;22) in CML). While it causes genetic disease, it does not typically show progressive worsening across generations. * **B. Chromosome breaking:** This refers to structural instability (seen in conditions like Fanconi anemia or Ataxia-telangiectasia). It leads to increased cancer risk and DNA repair defects but not anticipation. * **C. Mitochondrial mutation:** These exhibit **maternal inheritance** and **heteroplasmy** (variable expression due to the ratio of mutant to normal mtDNA). While severity varies, it does not follow the specific pattern of repeat expansion seen in anticipation. **3. High-Yield Clinical Pearls for NEET-PG:** * **Huntington’s Disease:** CAG repeat (C-A-G: **C**audate **A**trophy, **G**ABA decrease). * **Fragile X Syndrome:** CGG repeat (**C**hin/prognathism, **G**iant **G**onads/macroorchidism). * **Friedreich Ataxia:** GAA repeat (**G**ait **A**taxia). * **Myotonic Dystrophy:** CTG repeat (**C**ataracts, **T**oupee/balding, **G**onadal atrophy). * **Sherman Paradox:** Another term for anticipation specifically described in Fragile X syndrome.

Question 39: A 10-month-old male child presents with vomiting upon ingesting fruits, despite maintaining normal weight. He was exclusively breastfed until this point. The physician suspects fructose intolerance. Which enzyme would be deficient in this child?

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

Explanation: ### Explanation **Correct Option: A. Aldolase B** The clinical presentation describes **Hereditary Fructose Intolerance (HFI)**. This autosomal recessive disorder is caused by a deficiency of **Aldolase B**, an enzyme primarily found in the liver, kidney, and small intestine. * **Pathophysiology:** Aldolase B cleaves Fructose-1-Phosphate (F1P) into DHAP and Glyceraldehyde. In its absence, **F1P accumulates** intracellularly, sequestering inorganic phosphate ($P_i$). This depletion of $P_i$ inhibits glycogenolysis and gluconeogenesis, leading to severe postprandial hypoglycemia and vomiting. * **Clinical Correlation:** Symptoms typically appear when the infant is weaned from breast milk (which contains lactose) and introduced to fruits, juices, or honey (which contain **fructose** and **sucrose**). **Analysis of Incorrect Options:** * **B. Hexokinase:** This enzyme has a low affinity for fructose and is not the primary pathway for fructose metabolism in the liver. * **C. Fructokinase:** Deficiency causes **Essential Fructosuria**. This is a benign, asymptomatic condition where fructose is excreted in the urine (reducing sugar positive) because F1P does not accumulate to trap phosphate. * **D. Glucose-6-phosphatase:** Deficiency leads to **Von Gierke Disease (GSD Type I)**. While it causes hypoglycemia and hepatomegaly, it is not specifically triggered by fruit ingestion and presents with lactic acidosis and hyperuricemia. **High-Yield NEET-PG Pearls:** * **The "Trap":** Fructokinase deficiency is *asymptomatic*; Aldolase B deficiency is *symptomatic*. * **Reducing Sugars:** In HFI, urine dipstick for glucose is negative, but the **Clinitest (Benedict’s test)** is positive for reducing sugars. * **Management:** Strict avoidance of fructose, sucrose (fructose + glucose), and sorbitol.

Question 40: What is the most common enzyme deficiency in humans?

A. Glucose-6-phosphate dehydrogenase (Correct Answer)
B. Glucose-6-phosphatase
C. Hexokinase
D. Glucose-1,6-diphosphatase

Explanation: ### Explanation **Correct Answer: A. Glucose-6-phosphate dehydrogenase (G6PD)** **Why it is correct:** G6PD deficiency is the most common clinically significant enzyme deficiency worldwide, affecting over 400 million people. It is an **X-linked recessive** disorder. The G6PD enzyme is the rate-limiting step in the **Pentose Phosphate Pathway (HMP Shunt)**, responsible for producing **NADPH**. In RBCs, NADPH is crucial for maintaining a pool of reduced glutathione, which neutralizes reactive oxygen species (ROS). Without G6PD, oxidative stress (from infections, fava beans, or drugs like Primaquine) leads to hemoglobin denaturation, forming **Heinz bodies** and resulting in episodic hemolytic anemia. **Why the other options are incorrect:** * **B. Glucose-6-phosphatase:** Deficiency of this enzyme causes **von Gierke disease (GSD Type I)**. While it is the most common Glycogen Storage Disease, its overall prevalence in the general population is much lower than G6PD deficiency. * **C. Hexokinase:** This is the first enzyme of glycolysis. A total deficiency would be incompatible with life; partial deficiencies are extremely rare causes of non-spherocytic hemolytic anemia. * **D. Glucose-1,6-diphosphatase:** This is a rare metabolic intermediate regulator; its deficiency is not a recognized common clinical entity in standard medical curricula. **High-Yield Clinical Pearls for NEET-PG:** * **Inheritance:** X-linked Recessive (mostly affects males). * **Peripheral Smear:** Look for **Heinz bodies** (supravital stain) and **Bite cells** (degluticytes) formed by splenic macrophages. * **Protective Effect:** G6PD deficiency provides a selective advantage against *Plasmodium falciparum* malaria. * **Triggers to Remember:** Fava beans, Sulfa drugs, Primaquine, Nitrofurantoin, and Infections. * **Diagnosis:** Fluorescent spot test or quantitative spectrophotometry (Note: Do not test during an acute hemolytic episode as young reticulocytes have normal enzyme levels, leading to a false negative).

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

Want unlimited practice?

Get full access to all questions, explanations, and performance tracking.

Start For Free