Genetic Disorders and Biochemical Pathology Practice Questions

Q: Prader Willi syndrome is an example of?

Genomic imprinting. **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).

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

Early onset Alzheimer's disease. **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).

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

Efflux of cysteine from the lysosome. ### 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.

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

Fragile X syndrome. **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:** 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.

Q: Which enzyme is deficient in Marfan's syndrome?

None of the above. **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**.

Q: Which gene mutation is associated with Hartnup disease?

SLC6A19. **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.

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

High fecal levels of tryptophan and indole derivatives. **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.

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

Tyrosine. **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).

Question 1

Prader Willi syndrome is an example of?

Accepted Answer

Genomic imprinting

Answer

Digenic inheritance

Answer

Translocation

Answer

Trisomy

Question 2

Which transporter is defective in renal glucosuria?

Accepted Answer

SGLT 2

Answer

GLUT 1

Answer

GLUT 2

Answer

SGLT 1

Question 3

All of the following are true regarding G6PD deficiency except?

Accepted Answer

Females are commonly affected

Answer

A recessive X-linked trait

Answer

Oxidative stress causes hemolysis

Answer

Protective against Plasmodium falciparum malaria

Question 4

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

Accepted Answer

Early onset Alzheimer's disease

Answer

Hirschsprung disease

Answer

Chronic myeloid leukemia (CML)

Answer

Late onset Alzheimer's disease

Question 5

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

Accepted Answer

Efflux of cysteine from the lysosome

Answer

Absorption of cysteine from the intestine

Answer

Absorption of cysteine from the renal tubules

Answer

Efflux of cysteine from the endoplasmic reticulum

Question 6

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

Accepted Answer

Fragile X syndrome

Answer

Down's syndrome

Answer

Trisomy 13

Answer

Turner's syndrome

Question 7

Which enzyme is deficient in Marfan's syndrome?

Accepted Answer

None of the above

Answer

Cystathionine beta-synthase

Answer

Lysyl oxidase

Answer

Collagenase

Question 8

Which gene mutation is associated with Hartnup disease?

Accepted Answer

SLC6A19

Answer

SLC5A18

Answer

SLC7A9

Answer

SLC3A1

Question 9

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

Accepted Answer

High fecal levels of tryptophan and indole derivatives

Answer

Burnt-sugar smell in urine

Answer

High plasma phenylalanine levels

Answer

Extremely high levels of citrulline in urine

Question 10

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

Accepted Answer

Tyrosine

Answer

Homogentisic acid

Answer

Phenyl acetate

Answer

Phenyl pyruvate

Genetic Disorders and Biochemical Pathology — MCQs

Genetic Disorders and Biochemical Pathology — MCQs

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