Genetic Disorders and Biochemical Pathology — MCQs

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

Question 141: Prader Willi syndrome is an example of?

A. Digenic inheritance
B. Translocation
C. Genomic imprinting (Correct Answer)
D. Trisomy

Explanation: **Explanation:** **Prader-Willi Syndrome (PWS)** is a classic example of **Genomic Imprinting**, a phenomenon where the expression of a gene depends on whether it is inherited from the mother or the father. In PWS, there is a loss of function of specific genes on the **paternal chromosome 15 (15q11-q13)**. Under normal conditions, the maternal copy of these genes is silenced (imprinted) via methylation; therefore, if the paternal copy is deleted or inactive, the individual has no functional copies of these genes. **Analysis of Options:** * **Genomic Imprinting (Correct):** PWS occurs due to paternal deletion of 15q11-q13 (70%), Maternal Uniparental Disomy (25%), or imprinting center defects. Conversely, loss of the *maternal* copy of the same region leads to **Angelman Syndrome**. * **Digenic Inheritance:** Refers to diseases caused by the additive effect of mutations in two different genes (e.g., certain forms of Retinitis Pigmentosa). * **Translocation:** While a translocation can occasionally disrupt the PWS region, it is a structural mechanism, not the underlying genetic principle of the disease itself. * **Trisomy:** Refers to three copies of a chromosome (e.g., Trisomy 21 in Down Syndrome). PWS is typically associated with a microdeletion or disomy, not a trisomy. **High-Yield Clinical Pearls for NEET-PG:** * **Clinical Features:** Infantile hypotonia, hyperphagia leading to early-onset obesity, hypogonadism, small hands/feet, and mild intellectual disability. * **Diagnostic Gold Standard:** DNA Methylation analysis (detects abnormal imprinting). * **Mnemonic:** **P**rader-Willi = **P**aternal deletion; **A**ngelman = **M**aternal deletion (**A**bsent **M**other).

Question 142: Which transporter is defective in renal glucosuria?

A. GLUT 1
B. GLUT 2
C. SGLT 1
D. SGLT 2 (Correct Answer)

Explanation: **Explanation:** **Renal Glucosuria** is a benign condition characterized by the excretion of glucose in the urine despite having normal blood glucose levels. This occurs due to a defect in the reabsorption of glucose in the proximal convoluted tubule (PCT) of the kidney. **Why SGLT 2 is the correct answer:** Under normal physiological conditions, approximately 90% of filtered glucose is reabsorbed in the early part (S1 segment) of the PCT via **SGLT 2** (Sodium-Glucose Co-transporter 2). Mutations in the *SLC5A2* gene, which encodes SGLT 2, lead to Familial Renal Glucosuria. Because the transporter cannot effectively move glucose from the tubular lumen into the tubular cells, glucose remains in the filtrate and is excreted. **Analysis of Incorrect Options:** * **GLUT 1:** This is a basal glucose transporter found in RBCs, the blood-brain barrier, and the heart. It is not the primary transporter for bulk renal glucose reabsorption. * **GLUT 2:** This is a high-capacity, low-affinity transporter found in the liver, pancreas, and the basolateral membrane of the PCT. While it moves glucose out of the renal cell into the blood, defects in GLUT 2 cause **Fanconi-Bickel Syndrome**, which presents with hepatorenal glycogen accumulation, not isolated glucosuria. * **SGLT 1:** This transporter is primarily responsible for glucose and galactose absorption in the **small intestine**. In the kidney (S3 segment), it reabsorbs the remaining 10% of glucose. Defects in SGLT 1 cause Glucose-Galactose Malabsorption. **High-Yield Clinical Pearls for NEET-PG:** 1. **SGLT 2 Inhibitors (Gliflozins):** Drugs like Dapagliflozin and Canagliflozin target SGLT 2 to treat Type 2 Diabetes by inducing therapeutic glucosuria. 2. **SGLT vs. GLUT:** SGLTs use **secondary active transport** (sodium-dependent), whereas GLUTs use **facilitated diffusion**. 3. **Renal Threshold:** In healthy individuals, glucose appears in urine only when blood glucose exceeds **180 mg/dL**. In renal glucosuria, this threshold is significantly lowered.

Question 143: All of the following are true regarding G6PD deficiency except?

A. A recessive X-linked trait
B. Females are commonly affected (Correct Answer)
C. Oxidative stress causes hemolysis
D. Protective against Plasmodium falciparum malaria

Explanation: ### Explanation **Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency** is the most common enzyme deficiency worldwide, characterized by the inability of red blood cells (RBCs) to maintain adequate levels of reduced glutathione. **Why Option B is the Correct Answer (The False Statement):** G6PD deficiency follows an **X-linked recessive** inheritance pattern. This means the gene is located on the X chromosome. Males (XY) are hemizygous and therefore **commonly affected**. Females (XX) are typically asymptomatic carriers because the normal X chromosome compensates for the defective one. Females are only affected if they are homozygous (rare) or due to skewed **Lyonization** (inactivation of the healthy X chromosome). **Analysis of Other Options:** * **Option A (X-linked recessive):** This is the correct inheritance pattern. It primarily affects males, while females act as carriers. * **Option C (Oxidative stress causes hemolysis):** G6PD is the rate-limiting enzyme in the HMP shunt, producing **NADPH**. NADPH is essential to keep glutathione in its reduced state, which neutralizes reactive oxygen species (ROS). Without G6PD, oxidative stress (from fava beans, infections, or drugs like Primaquine) leads to hemoglobin denaturation and hemolysis. * **Option D (Protective against Malaria):** G6PD deficiency provides a selective survival advantage against *Plasmodium falciparum* malaria. The parasite cannot thrive in G6PD-deficient cells due to high oxidative stress and premature clearance of infected RBCs by the spleen. **High-Yield Clinical Pearls for NEET-PG:** * **Bite Cells & Degmacytes:** Formed when splenic macrophages pluck out Heinz bodies. * **Heinz Bodies:** Denatured hemoglobin precipitates (visible with Supravital stains like Crystal Violet). * **Triggers:** "SAD" mnemonic – **S**ulfa drugs/Septra, **A**ntimalarials (Primaquine), **D**apsone, and Fava beans. * **Diagnosis:** During an acute hemolytic episode, G6PD levels may appear **falsely normal** because young reticulocytes have higher enzyme levels; testing should be repeated after 6–8 weeks.

Question 144: Which of the following disorders is most commonly associated with Down's syndrome?

A. Hirschsprung disease
B. Chronic myeloid leukemia (CML)
C. Late onset Alzheimer's disease
D. Early onset Alzheimer's disease (Correct Answer)

Explanation: **Explanation:** **Correct Option: D. Early onset Alzheimer's disease** The association between Down’s syndrome (Trisomy 21) and early-onset Alzheimer’s disease is rooted in genetics. The gene encoding the **Amyloid Precursor Protein (APP)** is located on **chromosome 21**. Individuals with Down’s syndrome have three copies of this gene, leading to an overproduction of APP and subsequent accumulation of **amyloid-beta plaques** in the brain. By age 40, nearly all patients with Down’s syndrome exhibit neuropathological changes characteristic of Alzheimer’s, often manifesting clinically in their 40s or 50s. **Analysis of Incorrect Options:** * **A. Hirschsprung disease:** While there is an increased risk of Hirschsprung disease in Down’s syndrome (approximately 2–3% of cases), it is less universally associated than the neuropathological changes of Alzheimer’s. * **B. Chronic myeloid leukemia (CML):** Down’s syndrome is strongly associated with **Acute Leukemia**, specifically **AML (M7 subtype/Megakaryoblastic)** in children under 3 and **ALL** in children over 3. It is not typically associated with CML. * **C. Late onset Alzheimer's disease:** Late-onset (sporadic) Alzheimer’s usually occurs after age 65 and is associated with the **APOE-ε4 allele**, whereas the Down’s association is specifically "early-onset" due to the gene dosage effect of APP. **High-Yield Clinical Pearls for NEET-PG:** * **Most common cardiac defect:** Atrioventricular Septal Defect (Endocardial cushion defect). * **Gastrointestinal:** Duodenal atresia ("Double bubble" sign). * **Hematology:** Transient Myeloproliferative Disorder (TMD) is unique to neonates with Down's. * **Biochemical Screening (Quadruple Test):** Low AFP, Low Unconjugated Estriol (uE3), **High hCG, and High Inhibin-A** (Mnemonic: **HI**gh = **H**CG & **I**nhibin).

Question 145: The protein defective in cystinosis is responsible for which of the following functions?

A. Absorption of cysteine from the intestine
B. Absorption of cysteine from the renal tubules
C. Efflux of cysteine from the endoplasmic reticulum
D. Efflux of cysteine from the lysosome (Correct Answer)

Explanation: ### Explanation **Correct Answer: D. Efflux of cysteine from the lysosome** **Mechanism:** Cystinosis is an autosomal recessive lysosomal storage disorder caused by a mutation in the **CTNS gene**, which encodes the protein **cystinosin**. Cystinosin is an integral membrane protein that functions as a specialized transporter responsible for the **efflux of cystine** (the disulfide dimer of cysteine) out of the lysosome into the cytosol. When this protein is defective, cystine accumulates and forms crystals within the lysosomes of various tissues, leading to cellular damage and organ dysfunction. **Analysis of Incorrect Options:** * **Options A & B:** These refer to **Cystinuria**, not cystinosis. Cystinuria is caused by a defect in the **COAL transporter** (Cysteine, Ornithine, Arginine, Lysine) in the proximal renal tubules and small intestine. It leads to kidney stones, not systemic lysosomal storage. * **Option C:** The defect in cystinosis is specifically localized to the **lysosomal membrane**, not the endoplasmic reticulum. **High-Yield Clinical Pearls for NEET-PG:** * **Infantile Nephropathic Cystinosis:** The most common and severe form. * **Renal Manifestation:** It is a classic cause of **Fanconi Syndrome** (proximal tubular acidosis, glycosuria, phosphaturia, and aminoaciduria) in children. * **Ocular Finding:** Photophobia due to **corneal cystine crystals** (visible on slit-lamp exam). * **Diagnosis:** Measurement of **intracellular cystine levels in polymorphonuclear leukocytes**. * **Treatment:** **Cysteamine**, which converts cystine into cysteine and cysteine-cysteamine mixed disulfides that can exit the lysosome via alternative transporters.

Question 146: Which of the following conditions is characterized by a trinucleotide repeat expansion?

A. Fragile X syndrome (Correct Answer)
B. Down's syndrome
C. Trisomy 13
D. Turner's syndrome

Explanation: **Explanation:** **1. Why Fragile X Syndrome is Correct:** Fragile X syndrome is the most common inherited cause of intellectual disability and is a classic example of a **trinucleotide repeat expansion** disorder. It involves an abnormal expansion of the **CGG repeat** in the 5' untranslated region of the **FMR1 gene** on the X chromosome. * **Normal:** < 55 repeats. * **Premutation:** 55–200 repeats (associated with ataxia and ovarian failure). * **Full Mutation:** > 200 repeats, leading to hypermethylation of the promoter, gene silencing, and loss of the FMRP protein. **2. Why the Other Options are Incorrect:** * **Down’s Syndrome (Trisomy 21):** Caused by a numerical chromosomal aberration (aneuploidy), usually due to meiotic non-disjunction, not a DNA sequence expansion. * **Trisomy 13 (Patau Syndrome):** Another numerical chromosomal disorder characterized by an extra copy of chromosome 13. * **Turner’s Syndrome (45, XO):** A chromosomal deletion disorder (monosomy X) resulting from the complete or partial absence of one X chromosome. **3. NEET-PG High-Yield Clinical Pearls:** * **Clinical Features:** Large ears, long face, macroorchidism (post-pubertal), and mitral valve prolapse. * **Anticipation:** This phenomenon occurs where the disease severity increases or age of onset decreases in successive generations due to further expansion of the repeats. * **Other Repeat Disorders:** * **CAG:** Huntington’s Disease (Autosomal Dominant). * **GAA:** Friedreich’s Ataxia (Autosomal Recessive). * **CTG:** Myotonic Dystrophy. * **Diagnosis:** PCR is used for small expansions; **Southern Blot** is the gold standard for full mutations.

Question 147: Which enzyme is deficient in Marfan's syndrome?

A. Cystathionine beta-synthase
B. Lysyl oxidase
C. Collagenase
D. None of the above (Correct Answer)

Explanation: **Explanation:** **1. Why "None of the above" is correct:** Marfan’s syndrome is **not an enzymopathy**; it is a structural protein defect. It is an autosomal dominant disorder caused by a mutation in the **FBN1 gene** located on chromosome 15. This gene encodes **Fibrillin-1**, a large glycoprotein that serves as a scaffold for elastin. Defective fibrillin leads to mechanical weakness in connective tissues and excessive activation of TGF-β signaling, resulting in the characteristic skeletal, ocular, and cardiovascular manifestations. **2. Analysis of Incorrect Options:** * **A. Cystathionine beta-synthase:** Deficiency of this enzyme causes **Homocystinuria**. This is a crucial differential diagnosis for Marfan’s because both present with a "marfanoid habitus." However, Homocystinuria is autosomal recessive, involves intellectual disability, and features downward lens dislocation (ectopia lentis), whereas Marfan’s features upward dislocation. * **B. Lysyl oxidase:** This copper-dependent enzyme is responsible for cross-linking collagen and elastin. Its activity is impaired in **Menkes disease** (due to copper transport failure) and some forms of Ehlers-Danlos syndrome, but not in Marfan’s. * **C. Collagenase:** These are enzymes that break down native collagen. While matrix metalloproteinases (MMPs) play a role in tissue remodeling, their deficiency is not the primary cause of Marfan’s syndrome. **3. High-Yield Clinical Pearls for NEET-PG:** * **Chromosome:** 15 (Mnemonic: **15** letters in "Marfan Syndrome"). * **Cardiovascular:** Mitral Valve Prolapse (MVP) and **Aortic Root Dilation/Dissection** (most common cause of death). * **Ocular:** **Ectopia lentis** (typically **upward** and outward/Superotemporal). * **Skeletal:** Arachnodactyly, Pectus excavatum, and increased arm span to height ratio. * **Diagnosis:** Based on the **Ghent criteria**.

Question 148: Which gene mutation is associated with Hartnup disease?

A. SLC5A18
B. SLC6A19 (Correct Answer)
C. SLC7A9
D. SLC3A1

Explanation: **Explanation:** **Hartnup disease** is an autosomal recessive metabolic disorder caused by a mutation in the **SLC6A19 gene**. This gene encodes a sodium-dependent neutral amino acid transporter (B0AT1) primarily expressed in the proximal renal tubules and the intestinal mucosa. The defect leads to the malabsorption of neutral amino acids, most significantly **Tryptophan**. Since Tryptophan is a precursor for Niacin (Vitamin B3), its deficiency results in pellagra-like symptoms. **Analysis of Options:** * **SLC6A19 (Correct):** Responsible for transporting neutral amino acids (e.g., Tryptophan, Alanine, Phenylalanine). Mutation leads to neutral aminoaciduria. * **SLC3A1 & SLC7A9 (Incorrect):** These genes encode the subunits of the transporter for dibasic amino acids (Cystine, Ornithine, Arginine, Lysine - "COAL"). Mutations here cause **Cystinuria**, characterized by hexagonal cystine stones. * **SLC5A18 (Incorrect):** This gene is associated with the transport of different substrates (like choline) and is not involved in the pathogenesis of Hartnup disease. **NEET-PG High-Yield Pearls:** * **Clinical Triad:** The "3 Ds" of Pellagra (Dermatitis, Diarrhea, Dementia) + **Cerebellar Ataxia**. * **Biochemical Hallmark:** Neutral aminoaciduria (detected via chromatography) but **normal** levels of proline and hydroxyproline (distinguishes it from Fanconi syndrome). * **Diagnosis:** Increased urinary excretion of Indican (due to bacterial degradation of unabsorbed tryptophan in the gut). * **Treatment:** High-protein diet and **Nicotinamide** supplementation.

Question 149: Which of the following clinical laboratory observations is suggestive of Hartnup disease?

A. Burnt-sugar smell in urine
B. High plasma phenylalanine levels
C. Extremely high levels of citrulline in urine
D. High fecal levels of tryptophan and indole derivatives (Correct Answer)

Explanation: **Explanation:** **Hartnup disease** is an autosomal recessive disorder caused by a mutation in the **SLC6A19 gene**, which encodes a sodium-dependent neutral amino acid transporter. This defect occurs in both the **proximal renal tubules** and the **intestinal mucosa**. 1. **Why Option D is correct:** Because the intestinal transport of neutral amino acids (especially **Tryptophan**) is defective, these amino acids remain in the gut. Colonic bacteria act upon the unabsorbed tryptophan, converting it into **indole derivatives**. Consequently, patients exhibit high fecal levels of tryptophan and indoles. These indoles are absorbed into the portal circulation and excreted in the urine (e.g., indican), sometimes leading to the "Blue Diaper Syndrome." 2. **Why other options are incorrect:** * **Option A:** A "burnt-sugar" or maple syrup smell in urine is characteristic of **Maple Syrup Urine Disease (MSUD)**, caused by a deficiency in the branched-chain alpha-keto acid dehydrogenase complex. * **Option B:** High plasma phenylalanine levels are the hallmark of **Phenylketonuria (PKU)**, typically due to a deficiency of phenylalanine hydroxylase. * **Option C:** Extremely high levels of citrulline (Citrullinemia) indicate a defect in the urea cycle, specifically the enzyme **argininosuccinate synthetase**. **Clinical Pearls for NEET-PG:** * **The 3 D’s:** Hartnup disease presents with Pellagra-like symptoms: **Dermatitis** (photosensitive rash), **Diarrhea**, and **Dementia** (ataxia/neuropsychiatric symptoms). * **Biochemical Basis:** The symptoms arise because Tryptophan is a precursor for **Niacin (Vitamin B3)** synthesis. * **Diagnosis:** Characterized by **neutral aminoaciduria** (alanine, serine, threonine, valine, leucine, isoleucine, phenylalanine, tyrosine, and tryptophan). * **Treatment:** High-protein diet and **Nicotinamide** supplementation.

Question 150: Mousy urine odor in a child is due to a defect in the conversion of phenylalanine to which of the following substances?

A. Tyrosine (Correct Answer)
B. Homogentisic acid
C. Phenyl acetate
D. Phenyl pyruvate

Explanation: **Explanation:** The clinical presentation of **mousy urine odor** in a child is a hallmark sign of **Phenylketonuria (PKU)**. This autosomal recessive disorder is primarily caused by a deficiency of the enzyme **Phenylphenylalanine hydroxylase (PAH)**. **1. Why Tyrosine is Correct:** Under normal physiological conditions, Phenylalanine hydroxylase converts the essential amino acid **Phenylalanine into Tyrosine**. When this enzyme is defective, phenylalanine cannot be converted to tyrosine, leading to its accumulation in the blood and tissues. Tyrosine becomes a "conditionally essential" amino acid in these patients. **2. Why Incorrect Options are Wrong:** * **Homogentisic acid:** This is an intermediate in the tyrosine degradation pathway. A defect in its breakdown (due to homogentisate oxidase deficiency) leads to **Alkaptonuria**, characterized by urine that turns black upon standing, not a mousy odor. * **Phenyl acetate & Phenyl pyruvate:** These are **alternative metabolites** (phenylketones) produced when phenylalanine levels are high. While these substances are actually responsible for the mousy odor, the question asks which substance phenylalanine *fails* to be converted into due to the primary defect. **3. NEET-PG High-Yield Pearls:** * **Enzyme Defect:** Most commonly Phenylalanine hydroxylase; rarely due to deficiency of **Dihydrobiopterin reductase (BH4)**. * **Clinical Features:** Intellectual disability, "mousy" or "musty" body odor, fair skin/blue eyes (due to decreased melanin synthesis from tyrosine), and seizures. * **Diagnosis:** Guthrie Test (bacterial inhibition assay) or Tandem Mass Spectrometry. * **Management:** Dietary restriction of phenylalanine and supplementation of tyrosine. Avoid **Aspartame** (contains phenylalanine).

Practice by Chapter

Single Gene Disorders

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Biochemical Diagnosis of Genetic Disorders

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Inborn Errors of Metabolism

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Lysosomal Storage Diseases

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Glycogen Storage Diseases

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Disorders of Lipoprotein Metabolism

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Disorders of Purine and Pyrimidine Metabolism

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Hemoglobinopathies

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Porphyrias

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Biochemical Markers for Disease Diagnosis

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Newborn Screening for Genetic Disorders

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Enzyme Replacement Therapy

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