Genetic Disorders and Biochemical Pathology Practice Questions

Q: 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?

Hartnup disease. ### 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**.

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

Chromosome 14. **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**.

Q: Down syndrome is characterized by which chromosomal abnormality?

Trisomy of chromosome 21. **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).

Q: Renal osteodystrophy is due to:

Decreased synthesis of calcitriol in the kidney. **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.

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

Tryptophan. ### 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.

Q: Gene mutations in Cystic fibrosis occur at which location?

Long arm of chromosome 7. **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.

Q: Anticipation is seen in which of the following?

Trinucleotide-repeat expansion. **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.

Q: 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?

Aldolase B. ### 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 1

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?

Accepted Answer

Hartnup disease

Answer

Phenylketonuria

Answer

Alkaptonuria

Answer

Maple syrup urine disease

Question 2

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

Accepted Answer

Chromosome 14

Answer

Chromosome 10

Answer

Chromosome 17

Answer

Chromosome 11

Question 3

Down syndrome is characterized by which chromosomal abnormality?

Accepted Answer

Trisomy of chromosome 21

Answer

Trisomy of chromosome 18

Answer

Monosomy of chromosome 18

Answer

Monosomy of chromosome 21

Question 4

What is true about Crigler-Najjar syndrome type II?

Accepted Answer

Autosomal recessive inheritance

Answer

Diglucuronide deficiency

Answer

Kernicterus is a common feature

Answer

Phenobarbital is not useful for treatment

Question 5

Renal osteodystrophy is due to:

Accepted Answer

Decreased synthesis of calcitriol in the kidney

Answer

Increased synthesis of calcitriol in the kidney

Answer

No synthesis of calcitriol in the kidney

Answer

Fluctuating production of calcitriol in the kidney

Question 6

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

Accepted Answer

Tryptophan

Answer

Tyrosine

Answer

Phenylalanine

Answer

None of the above

Question 7

Gene mutations in Cystic fibrosis occur at which location?

Accepted Answer

Long arm of chromosome 7

Answer

Short arm of chromosome 7

Answer

Long arm of chromosome 5

Answer

Short arm of chromosome 3

Question 8

Anticipation is seen in which of the following?

Accepted Answer

Trinucleotide-repeat expansion

Answer

Translocation

Answer

Chromosome breaking

Answer

Mitochondrial mutation

Question 9

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?

Accepted Answer

Aldolase B

Answer

Hexokinase

Answer

Fructokinase

Answer

Glucose-6-phosphatase

Question 10

What is the most common enzyme deficiency in humans?

Accepted Answer

Glucose-6-phosphate dehydrogenase

Answer

Glucose-6-phosphatase

Answer

Hexokinase

Answer

Glucose-1,6-diphosphatase

Genetic Disorders and Biochemical Pathology — MCQs

Genetic Disorders and Biochemical Pathology — MCQs

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