Genetic Disorders and Biochemical Pathology — MCQs

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

Question 181: In Baer's syndrome, what is observed?

A. Metabolic acidosis
B. Hypokalemia (Correct Answer)
C. Hyperkalemia
D. Decrease in urinary calcium

Explanation: **Explanation:** **Baer’s Syndrome** (also known as **Bartter-like syndrome**) refers to a group of rare autosomal recessive renal tubular disorders characterized by a defect in the thick ascending limb of the Loop of Henle. **Why Hypokalemia is correct:** The primary defect involves the **NKCC2 transporter**, the ROMK channel, or the CLC-Kb chloride channel. This leads to a failure of sodium, potassium, and chloride reabsorption. The resulting increased delivery of sodium to the distal tubule stimulates the renin-angiotensin-aldosterone system (RAAS). Elevated aldosterone promotes sodium reabsorption in exchange for potassium and hydrogen ions in the collecting duct, leading to significant **urinary potassium wasting** and subsequent **hypokalemia**. **Analysis of Incorrect Options:** * **Metabolic Acidosis:** Incorrect. Due to the excessive secretion of H+ ions (driven by aldosterone), patients actually develop **metabolic alkalosis**. * **Hyperkalemia:** Incorrect. As explained, the secondary hyperaldosteronism causes profound potassium depletion. * **Decrease in urinary calcium:** Incorrect. This is a characteristic of **Gitelman Syndrome**. In Bartter/Baer’s syndrome, there is typically **hypercalciuria** (increased urinary calcium) because the loss of the lumen-positive potential in the Loop of Henle inhibits paracellular calcium reabsorption. **High-Yield Clinical Pearls for NEET-PG:** * **Bartter vs. Gitelman:** Bartter syndrome presents early in life with polyuria and **hypercalciuria** (think "Loop diuretic-like effect"). Gitelman syndrome presents later with **hypocalciuria** and hypomagnesemia (think "Thiazide-like effect"). * **Key Triad:** Hypokalemia, Metabolic Alkalosis, and Normal to Low Blood Pressure. * **Differential:** Always rule out chronic vomiting or diuretic abuse, which can mimic these biochemical findings (Pseudo-Bartter’s).

Question 182: A 8-month-old infant is brought to the hospital presenting with loss of previously acquired motor skills. The infant also has hepatosplenomegaly. A liver biopsy reveals leukocytes with intracellular sphingomyelin accumulations. What is the possible diagnosis?

A. Gaucher disease
B. Tay-Sachs disease
C. Niemann-Pick disease (Correct Answer)
D. Pompe disease

Explanation: ### Explanation **Correct Answer: C. Niemann-Pick disease** **1. Why it is correct:** Niemann-Pick disease (specifically Types A and B) is caused by a deficiency of the enzyme **Acid Sphingomyelinase**. This leads to the accumulation of **sphingomyelin** within the lysosomes of macrophages (foam cells) in various tissues. The clinical presentation of an infant with neurodegeneration (loss of motor skills) and **hepatosplenomegaly** is classic for Type A. The biopsy finding of intracellular sphingomyelin accumulation is the definitive biochemical marker for this condition. **2. Why other options are incorrect:** * **Gaucher disease:** While it presents with hepatosplenomegaly and bone involvement, the accumulated substance is **glucocerebroside** (due to glucocerebrosidase deficiency), and biopsy would show "crinkled paper" Gaucher cells. * **Tay-Sachs disease:** This involves **GM2 ganglioside** accumulation. While it causes neurodegeneration and a cherry-red spot, it is distinguished by the **absence of hepatosplenomegaly**. * **Pompe disease:** This is a Glycogen Storage Disease (Type II) caused by acid maltase deficiency. It presents with severe **cardiomegaly** and muscle weakness, not sphingomyelin accumulation. **3. NEET-PG High-Yield Pearls:** * **Cherry-red spot:** Seen in both Niemann-Pick and Tay-Sachs. Use the presence of **hepatosplenomegaly** to differentiate (Present in Niemann-Pick; Absent in Tay-Sachs). * **Histology:** Look for **"Foam cells"** (lipid-laden macrophages) in Niemann-Pick. * **Inheritance:** Most sphingolipidoses are Autosomal Recessive (except Fabry disease, which is X-linked Recessive). * **Niemann-Pick Type C:** Caused by a defect in cholesterol transport (NPC1/NPC2 genes), not primarily sphingomyelinase.

Question 183: Mutations in developmental transcription factors or their downstream target genes are rare causes of thyroid agenesis or dyshormonogenesis. All are examples of thyroid transcription factors, EXCEPT:

A. Thyroid transcription factor (TTF)-1
B. TTF-2
C. Paired homeobox-8 (PAX-8)
D. Sodium iodide symporter (Correct Answer)

Explanation: **Explanation:** The development and functional differentiation of the thyroid gland are regulated by a specific set of **Thyroid Transcription Factors (TTFs)**. Mutations in these factors lead to **Thyroid Dysgenesis** (agenesis, hypoplasia, or ectopy), which is the most common cause of congenital hypothyroidism. **Why the Correct Answer is Right:** * **Sodium Iodide Symporter (NIS):** This is a **transmembrane protein** (encoded by the *SLC5A5* gene) located on the basolateral membrane of thyroid follicular cells. It is a functional effector protein responsible for the active transport of iodine into the cell. While mutations in NIS cause **dyshormonogenesis** (specifically iodide transport defects), it is **not a transcription factor**; it is a transport protein. **Analysis of Incorrect Options:** * **TTF-1 (NKX2.1):** A homeodomain transcription factor expressed in the thyroid, lungs, and forebrain. Mutations lead to "Choreoathetosis-Hypothyroidism-Pulmonary Dysfunction Syndrome." * **TTF-2 (FOXE1):** A forkhead domain transcription factor. Mutations are associated with **Bamforth-Lazarus Syndrome** (thyroid agenesis, cleft palate, spiky hair, and choanal atresia). * **PAX-8:** A paired-box gene essential for the expression of thyroid-specific genes like Thyroglobulin (Tg) and Thyroid Peroxidase (TPO). Mutations typically result in thyroid hypoplasia or ectopy. **Clinical Pearls for NEET-PG:** * **Most common cause of Congenital Hypothyroidism:** Thyroid Dysgenesis (85%). * **Most common cause of Goitrous Congenital Hypothyroidism:** Mutation in the **TPO gene** (Dyshormonogenesis). * **Dual Oxidase 2 (DUOX2):** Required for $H_2O_2$ generation; mutations cause transient or permanent hypothyroidism. * **Pendred Syndrome:** Mutation in the *SLC26A4* (Pendrin) gene, characterized by sensorineural deafness and goiter.

Question 184: The process underlying differences in the expression of a gene, according to which parent has transmitted it, is called –

A. Anticipation
B. Mosaicism
C. Non-penetrance
D. Genomic imprinting (Correct Answer)

Explanation: **Explanation:** **1. Why Genomic Imprinting is Correct:** Genomic imprinting is an epigenetic process where certain genes are expressed in a **parent-of-origin-specific manner**. Although an individual inherits two copies of a gene (one from each parent), imprinting "silences" one copy through **DNA methylation** or histone modification. Therefore, the phenotype of the offspring depends entirely on which parent transmitted the active allele. **2. Analysis of Incorrect Options:** * **Anticipation (A):** Refers to the phenomenon where a genetic disorder (typically Trinucleotide Repeat Disorders like Huntington’s or Fragile X) becomes more severe or appears at an earlier age in successive generations. * **Mosaicism (B):** The presence of two or more populations of cells with different genotypes in one individual, arising from a post-zygotic mutation (e.g., Mosaic Turner Syndrome). * **Non-penetrance (C):** Occurs when an individual carries a dominant disease-causing mutation but does not manifest any clinical symptoms of the disease. **3. High-Yield Clinical Pearls for NEET-PG:** * **Classic Examples:** The best-known examples of imprinting involve **Chromosome 15q11-q13**: * **Prader-Willi Syndrome:** Deletion of the *paternal* allele (Maternal imprinting). Features: Obesity, hypotonia, and hypogonadism. * **Angelman Syndrome:** Deletion of the *maternal* allele (Paternal imprinting). Features: "Happy Puppet," seizures, and ataxia. * **Mechanism:** It occurs during **gametogenesis** (oogenesis or spermatogenesis) and is primarily mediated by **DNA Methyltransferase**. * **Uniparental Disomy (UPD):** If a child inherits both copies of a chromosome from one parent (and none from the other), it can result in imprinting disorders even without a deletion.

Question 185: Leiden mutation is classified as which type of mutation?

A. Non-sense mutation
B. Mis-sense mutation (Correct Answer)
C. Frame shift mutation
D. Trinucleotide repeat mutation

Explanation: **Factor V Leiden** is the most common inherited cause of hypercoagulability (thrombophilia). It is caused by a specific point mutation in the *F5* gene. ### 1. Why Mis-sense Mutation is Correct A **mis-sense mutation** occurs when a single nucleotide change results in a codon that codes for a different amino acid. In Factor V Leiden, a single base substitution occurs at position 1691 (**G → A**), which leads to the replacement of the amino acid **Arginine with Glutamine** at position 506 (**Arg506Gln**). * **Biochemical Pathology:** This mutation occurs at the specific cleavage site where **Activated Protein C (APC)** normally inactivates Factor Va. The structural change renders Factor Va resistant to cleavage (APC resistance), leading to a prothrombotic state and increased risk of Venous Thromboembolism (VTE). ### 2. Why Other Options are Incorrect * **Non-sense mutation:** This involves a point mutation that creates a premature stop codon (UAG, UAA, UGA), resulting in a truncated, usually non-functional protein. * **Frame shift mutation:** This occurs due to the insertion or deletion of nucleotides (not in multiples of three), which shifts the reading frame and alters all subsequent amino acids. * **Trinucleotide repeat mutation:** This involves the expansion of specific three-base sequences (e.g., CAG in Huntington’s disease or CGG in Fragile X syndrome). ### 3. Clinical Pearls for NEET-PG * **Inheritance:** Autosomal Dominant. * **Key Finding:** Activated Protein C (APC) resistance. * **Clinical Presentation:** Recurrent Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE). * **Diagnosis:** Screening is done via the APC resistance test (clotting assay); confirmation is via PCR for the G1691A mutation. * **High-Yield Fact:** Heterozygotes have a 5-10 fold increased risk of thrombosis, while homozygotes have an 80-fold increased risk.

Question 186: Hypoglycemia is more severe in type 1 Glycogen storage disease as compared to type 6 Glycogen storage disease because:

A. No gluconeogenesis in type 1 disease (Correct Answer)
B. No gluconeogenesis in type 6 disease
C. Both
D. Type 1 disease affects muscles and liver both

Explanation: **Explanation:** The severity of hypoglycemia in Glycogen Storage Diseases (GSD) depends on whether the body can utilize alternative pathways to maintain blood glucose levels during fasting. **1. Why Option A is correct:** * **Type 1 GSD (von Gierke Disease)** is caused by a deficiency of **Glucose-6-Phosphatase**. This enzyme is the "final common gateway" for both **Glycogenolysis** (breakdown of glycogen) and **Gluconeogenesis** (synthesis of glucose from non-carbohydrate sources like lactate and amino acids). * Because this enzyme is missing, the liver cannot release free glucose into the blood from *either* pathway. This leads to profound, life-threatening fasting hypoglycemia. **2. Why other options are incorrect:** * **Option B:** **Type 6 GSD (Hers Disease)** is a deficiency of **Liver Glycogen Phosphorylase**. This enzyme is only involved in glycogenolysis. In Type 6, the gluconeogenesis pathway remains **intact** because Glucose-6-Phosphatase is functional. The liver can still produce glucose from lactate and alanine, making the hypoglycemia much milder. * **Option D:** Type 1a affects the liver, kidney, and intestinal mucosa. It does **not** affect muscles because muscles lack Glucose-6-Phosphatase even in healthy individuals (muscles do not contribute to blood glucose). **High-Yield Clinical Pearls for NEET-PG:** * **Biochemical Hallmarks of Type 1:** Hyperuricemia (Gout), Hyperlactatemia, Hyperlipidemia (doll-like facies), and Hepatomegaly. * **Lactate Paradox:** In Type 1, administration of glucagon increases lactate but not glucose. In Type 6, lactate levels remain relatively normal because gluconeogenesis consumes it. * **Type 1b:** Includes the same features as 1a plus **neutropenia** and recurrent infections due to a glucose-6-phosphate translocase deficiency.

Question 187: A breast-fed infant presented with frequent vomiting and weight loss. Several days later, the infant developed jaundice, hepatomegaly, and bilateral cataracts. What is the most likely cause for these symptoms?

A. Galactosemia (Correct Answer)
B. Juvenile Diabetes Mellitus
C. Hereditary Fructose Intolerance
D. Gaucher Disease

Explanation: **Explanation:** The clinical presentation of **Galactosemia** (specifically Classic Galactosemia due to **GALT deficiency**) typically manifests shortly after the introduction of milk (breast milk or formula), which contains lactose. Lactose is broken down into glucose and galactose. In GALT deficiency, the accumulation of **Galactose-1-phosphate** causes hepatotoxicity (jaundice, hepatomegaly) and renal damage. The formation of **galactitol** via aldose reductase in the lens leads to osmotic swelling and the development of **bilateral oil-drop cataracts**. **Why other options are incorrect:** * **Juvenile Diabetes Mellitus:** Presents with polyuria, polydipsia, and weight loss, but not with neonatal jaundice, hepatomegaly, or cataracts in the first few days of life. * **Hereditary Fructose Intolerance (HFI):** Symptoms (vomiting, hypoglycemia) only appear after the introduction of **fructose or sucrose** (e.g., fruit juices or honey). Since the infant is exclusively breast-fed, HFI is ruled out as breast milk contains lactose, not fructose. * **Gaucher Disease:** A lysosomal storage disorder presenting with hepatosplenomegaly and bone pain, but it does not typically cause acute neonatal jaundice or cataracts. **High-Yield Clinical Pearls for NEET-PG:** * **Enzyme Deficit:** Most common is Galactose-1-phosphate uridyltransferase (**GALT**). * **Cataract Mechanism:** Accumulation of **Galactitol** in the lens. * **Diagnostic Clue:** Presence of **reducing sugars in urine** (Clinitest positive) but a **negative glucose oxidase test** (Dipstick). * **Risk:** Infants with Galactosemia are at a significantly increased risk of **E. coli sepsis**. * **Treatment:** Immediate withdrawal of milk; switch to soy-based or lactose-free formula.

Question 188: Glucose-6-phosphatase deficiency is seen in which of the following conditions?

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

Explanation: **Explanation:** **Von Gierke’s Disease (Type I Glycogen Storage Disease)** is the correct answer. It is caused by a deficiency of the enzyme **Glucose-6-phosphatase**, which is responsible for the final step of both glycogenolysis and gluconeogenesis (converting Glucose-6-phosphate to free glucose). Because the liver cannot release glucose into the bloodstream, patients present with severe fasting hypoglycemia, hepatomegaly (due to glycogen accumulation), and metabolic derangements like lactic acidosis, hyperuricemia, and hyperlipidemia. **Analysis of Incorrect Options:** * **Tay-Sachs Disease:** A lysosomal storage disorder (Sphingolipidosis) caused by a deficiency of **Hexosaminidase A**, leading to the accumulation of GM2 ganglioside. It presents with neurodegeneration and a cherry-red spot on the macula. * **Pompe’s Disease (Type II GSD):** Caused by a deficiency of **Lysosomal α-1,4-glucosidase** (Acid Maltase). It is unique because it is both a GSD and a lysosomal storage disease, primarily affecting the heart (massive cardiomegaly) and muscles. * **Anderson’s Disease (Type IV GSD):** Caused by a deficiency of the **Branching enzyme**. This leads to the accumulation of abnormal glycogen with long outer chains (amylopectin-like), resulting in infantile liver cirrhosis and failure. **High-Yield Clinical Pearls for NEET-PG:** * **Type Ia:** Deficiency of Glucose-6-phosphatase enzyme. * **Type Ib:** Deficiency of Glucose-6-phosphate **translocase** (presents with additional findings of neutropenia and recurrent infections). * **Key Biochemical Marker:** Hyperlactatemia is a hallmark of Von Gierke’s, distinguishing it from Cori’s disease (Type III), where lactate levels are typically normal. * **Management:** Frequent oral glucose/cornstarch and avoidance of fructose/galactose.

Question 189: The gene responsible for Ataxia Telangiectasia is located on which chromosome?

A. Chromosome 1
B. Chromosome 5
C. Chromosome 11 (Correct Answer)
D. Chromosome 12

Explanation: **Explanation:** **Ataxia Telangiectasia (AT)** is an autosomal recessive multisystem disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, and immunodeficiency. **1. Why Chromosome 11 is Correct:** The gene responsible for this condition is the **ATM (Ataxia-Telangiectasia Mutated) gene**, which is located on the long arm of **Chromosome 11 (11q22.3)**. The ATM gene encodes a PI3K-related serine/threonine protein kinase that plays a critical role in the **DNA damage response**. It specifically detects double-strand breaks (DSBs) and activates cell cycle checkpoints (via p53) to allow for repair or apoptosis. Failure of this mechanism leads to genomic instability. **2. Analysis of Incorrect Options:** * **Chromosome 1:** Associated with conditions like Gaucher disease (GBA gene) and Factor V Leiden. * **Chromosome 5:** Associated with Spinal Muscular Atrophy (SMN1 gene) and Familial Adenomatous Polyposis (APC gene). * **Chromosome 12:** Associated with Phenylketonuria (PAH gene) and Vitamin D-dependent rickets Type 1A. **3. High-Yield Clinical Pearls for NEET-PG:** * **Triad:** Cerebellar ataxia (early childhood), Telangiectasias (conjunctiva/skin), and IgA deficiency (recurrent sinopulmonary infections). * **Biochemical Marker:** Characteristically elevated **Alpha-Fetoprotein (AFP)** levels in children >2 years. * **Radiosensitivity:** Patients are hypersensitive to ionizing radiation (X-rays/CT scans) because they cannot repair double-strand DNA breaks. * **Malignancy Risk:** High risk of developing lymphomas and leukemias due to chromosomal instability.

Question 190: A 40-year-old woman presents with progressive palmoplantar pigmentation. X-ray of the spine shows calcification of intervertebral discs. On adding Benedict's reagent to her urine, a greenish-brown precipitate forms, and the supernatant fluid appears blue-black. What is the diagnosis?

A. Phenylketonuria
B. Alkaptonuria (Correct Answer)
C. Tyrosinemia type-2
D. Argininosuccinic aciduria

Explanation: ### Explanation The clinical presentation is a classic description of **Alkaptonuria**, an autosomal recessive disorder caused by a deficiency of the enzyme **Homogentisate Oxidase**. This enzyme is part of the phenylalanine and tyrosine catabolic pathway. **Why Alkaptonuria is the Correct Answer:** 1. **Biochemical Basis:** The enzyme deficiency leads to the accumulation of **Homogentisic Acid (HGA)**. When urine is exposed to air or an oxidizing/alkaline agent (like Benedict’s reagent), HGA is oxidized to benzoquinone acetate, which polymerizes into a black pigment (alkapton). 2. **Benedict’s Test:** HGA is a strong reducing agent. It reduces the copper in Benedict’s reagent (forming the greenish-brown precipitate) while simultaneously oxidizing into a dark pigment, turning the supernatant **blue-black**. 3. **Clinical Features:** Excess HGA binds to connective tissue (collagen), a process called **Ochronosis**. This results in: * **Ochronotic Arthritis:** Specifically affecting large joints and the spine (calcification of intervertebral discs). * **Pigmentation:** Darkening of the sclera and ear cartilage, and palmoplantar pigmentation. **Why Other Options are Incorrect:** * **Phenylketonuria (PKU):** Caused by Phenylalanine Hydroxylase deficiency. Presents with intellectual disability, "mousy" odor, and hypopigmentation, not dark urine or ochronosis. * **Tyrosinemia Type-2 (Richner-Hanhart Syndrome):** Caused by Tyrosine Aminotransferase deficiency. Presents with painful palmoplantar hyperkeratosis and dendritic corneal ulcers, but lacks the dark urine/disc calcification. * **Argininosuccinic Aciduria:** A urea cycle disorder presenting with hyperammonemia and "trichorrhexis nodosa" (brittle hair). It does not involve pigmentary changes or HGA. **High-Yield NEET-PG Pearls:** * **Triad of Alkaptonuria:** Homogentisic aciduria (dark urine), Ochronosis (pigmentation), and Arthritis. * **Diagnostic Test:** Ferric chloride test (turns urine transiently deep blue). * **Management:** Low protein diet (restriction of Phenylalanine and Tyrosine) and **Nitisinone**, which inhibits 4-hydroxyphenylpyruvate dioxygenase to prevent HGA formation.

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

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