Genetic Disorders and Biochemical Pathology Practice Questions

Q: Maternal disomy of chromosome 15 is seen in which of the following conditions?

Prader-Willi syndrome. **Explanation:** The correct answer is **Prader-Willi syndrome (PWS)**. This condition is a classic example of **genomic imprinting**, where the expression of a gene depends on whether it is inherited from the mother or the father. 1. **Why Prader-Willi Syndrome is correct:** PWS occurs due to the **loss of paternal expression** on chromosome **15q11-q13**. This can happen via three mechanisms: * **Paternal Deletion (70%):** Deletion of the active paternal alleles. * **Maternal Uniparental Disomy (UPD) (25-30%):** The child inherits two copies of chromosome 15 from the mother and **none from the father**. Since the maternal copies are normally "silenced" (imprinted), the child lacks the necessary active genes. * **Imprinting defects.** 2. **Why the other options are incorrect:** * **Angelman Syndrome:** This is the "mirror image" of PWS. It is caused by the **loss of maternal expression** (specifically the *UBE3A* gene) on chromosome 15. It most commonly occurs due to **maternal deletion** or **paternal uniparental disomy**. * **Klinefelter’s Syndrome (47, XXY):** A sex chromosome aneuploidy characterized by an extra X chromosome in males. It is not related to chromosome 15 or imprinting. * **Turner’s Syndrome (45, XO):** A sex chromosome monosomy in females. **High-Yield Clinical Pearls for NEET-PG:** * **Prader-Willi Presentation:** Neonatal hypotonia, hyperphagia (leading to early-onset obesity), intellectual disability, and hypogonadism. * **Angelman Presentation:** "Happy Puppet" syndrome—inappropriate laughter, seizures, ataxia, and severe intellectual disability. * **Mnemonic:** **P**ader-Willi = **P**aternal deletion / **M**aternal Disomy. **A**ngelman = **M**aternal deletion / **P**aternal Disomy.

Q: MELAS is an inherited condition which occurs due to deficiency of which mitochondrial respiratory chain complex?

Complex I. **Explanation:** **MELAS** (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes) is a multisystem mitochondrial disorder. The primary biochemical defect in MELAS is a deficiency in **Complex I (NADH: ubiquinone oxidoreductase)** of the mitochondrial respiratory chain. 1. **Why Complex I is correct:** Approximately 80% of MELAS cases are caused by a point mutation in the mitochondrial DNA (mtDNA) at position **A3243G**, which affects the **tRNA-Leu (UUR)** gene. This mutation impairs mitochondrial protein synthesis, specifically affecting the subunits of Complex I. This leads to a failure in the electron transport chain, decreased ATP production, and a shift toward anaerobic metabolism, resulting in the characteristic lactic acidosis. 2. **Why other options are incorrect:** * **Complex II:** Unlike other complexes, Complex II (Succinate dehydrogenase) is entirely encoded by **nuclear DNA**, not mtDNA. It is rarely the primary site of defect in classic MELAS. * **Complex III:** While some mitochondrial diseases involve Complex III, it is not the hallmark deficiency associated with the clinical presentation of MELAS. * **All of the above:** While severe mitochondrial dysfunction can eventually affect the entire chain, the specific diagnostic association for MELAS is Complex I. **High-Yield Clinical Pearls for NEET-PG:** * **Clinical Triad:** Stroke-like episodes (usually before age 40), Encephalopathy (seizures/dementia), and Lactic Acidosis. * **Genetics:** Shows **Maternal Inheritance** and **Heteroplasmy** (variable severity based on the ratio of mutant to normal mtDNA). * **Diagnosis:** Muscle biopsy shows **"Ragged Red Fibers"** (Gomori trichrome stain) due to compensatory subsarcolemmal mitochondrial proliferation. * **Biochemical Marker:** Elevated serum and CSF lactate levels.

Q: Congenital adrenal hyperplasia due to 11 beta hydroxylase deficiency presents with all the following except?

Metabolic acidosis. In **11β-hydroxylase deficiency**, the final step of cortisol synthesis is blocked. This leads to an accumulation of precursor steroids, specifically **11-deoxycorticosterone (DOC)** and **11-deoxycortisol**. [1] **1. Why Metabolic Acidosis is the Correct Answer:** 11-deoxycorticosterone (DOC) is a potent **mineralocorticoid**. Excess DOC acts on the renal collecting ducts similarly to aldosterone, causing sodium retention and the excretion of potassium and hydrogen ions ($H^+$). The loss of $H^+$ ions leads to **Metabolic Alkalosis**, not acidosis. Therefore, metabolic acidosis is the "except" in this clinical presentation. **2. Why the other options are incorrect:** * **Hypertension (D) and Hypernatremia (C):** The mineralocorticoid effect of excess DOC causes significant water and sodium retention, leading to volume expansion and hypertension. This distinguishes 11β-hydroxylase deficiency from 21-hydroxylase deficiency (where salt-wasting and hypotension occur). [1] * **Hypokalemia (B):** Increased mineralocorticoid activity promotes potassium secretion into the urine, resulting in low serum potassium levels. **Clinical Pearls for NEET-PG:** * **The "Rule of 1s":** If the enzyme deficiency starts with **1** (11β-hydroxylase or 17α-hydroxylase), it causes **Hypertension** (due to mineralocorticoid excess). * **Virilization:** Since the block is below the androgen pathway, excess substrate is shunted toward androgens. This causes **ambiguous genitalia** in females and **precocious puberty** in males. [1] * **Differential:** 11β-hydroxylase deficiency presents with hypertension + virilization, whereas 17α-hydroxylase deficiency presents with hypertension + sexual infantilism (no androgens).

Q: What is the gene affected in Gilbert's syndrome?

UGT1A1. **Explanation:** **Gilbert’s Syndrome** is a common, benign autosomal recessive condition characterized by mild, unconjugated hyperbilirubinemia. 1. **Why UGT1A1 is Correct:** The condition is caused by a mutation in the **UGT1A1 gene** (specifically a TA repeat expansion in the promoter region). This gene encodes the enzyme **Uridine diphosphate-glucuronosyltransferase**, which is responsible for conjugating bilirubin with glucuronic acid in the liver. In Gilbert’s syndrome, enzyme activity is reduced to approximately 30% of normal, leading to impaired conjugation and a rise in indirect (unconjugated) bilirubin. 2. **Why the Other Options are Incorrect:** * **MRP2 (Multidrug Resistance-associated Protein 2):** Mutations in this gene lead to **Dubin-Johnson Syndrome**. MRP2 is a canalicular multispecific organic anion transporter; its deficiency prevents the excretion of *conjugated* bilirubin into the bile. * **MRP3:** This transporter is involved in the basolateral transport of bile acids and organic anions back into the blood; it is not the primary defect in common hereditary hyperbilirubinemias. * **Unknown:** The genetic basis of Gilbert's syndrome is well-established as the UGT1A1 mutation. **High-Yield Clinical Pearls for NEET-PG:** * **Triggers:** Jaundice typically appears during periods of **stress, fasting, infection, or strenuous exercise**. * **Lab Findings:** Isolated elevation of unconjugated bilirubin with normal ALT, AST, and Alkaline Phosphatase. No hemolysis (normal Hgb/Reticulocyte count). * **Crigler-Najjar Syndrome:** Also involves the UGT1A1 gene but represents a more severe deficiency (Type I: 0% activity; Type II/Arias Syndrome: <10% activity). * **Diagnosis:** Often a diagnosis of exclusion; the "Fasting Test" (bilirubin increases upon calorie restriction) was historically used.

Q: Which of the following inborn errors of metabolism is associated with mental retardation?

Homocystinuria. **Explanation:** **Homocystinuria (Correct Answer):** Homocystinuria is an autosomal recessive disorder, most commonly caused by a deficiency of the enzyme **Cystathionine β-synthase (CBS)**. This leads to the accumulation of homocysteine and methionine. Elevated levels of homocysteine are neurotoxic and interfere with the cross-linking of collagen and elastin. Clinical manifestations include **mental retardation**, ectopia lentis (downward dislocation), marfanoid habitus, and a high risk of thromboembolism. Mental retardation is a hallmark feature that distinguishes it from similar-looking conditions like Marfan syndrome. **Incorrect Options:** * **Alkaptonuria:** Caused by a deficiency of **Homogentisate oxidase**. It is characterized by the triad of dark urine (on standing), ochronosis (pigmentation of connective tissue), and arthritis in later life. It is generally **not** associated with intellectual disability. * **Pentosuria:** A benign condition caused by a deficiency of **L-xylulose reductase**, leading to the excretion of L-xylulose in the urine. It is asymptomatic and does not affect mental development. **NEET-PG High-Yield Pearls:** * **Diagnostic Test:** Cyanide-nitroprusside test (positive in Homocystinuria). * **Treatment:** High doses of **Vitamin B6 (Pyridoxine)** are effective in about 50% of cases (B6-responsive). * **Differential Diagnosis:** Unlike Marfan syndrome (Upward lens dislocation, normal IQ), Homocystinuria presents with **Downward lens dislocation** and **Mental retardation**. * **Mnemonic for Homocystinuria:** **HOMOCY** (Homocysteine ↑, Osteoporosis, Mental retardation, Ocular changes, Cardiovascular/Cerebrovascular stroke, Kyphosis).

Q: What is the most common cause of congenital adrenal hyperplasia?

21-Hydroxylase deficiency. **Explanation:** Congenital Adrenal Hyperplasia (CAH) is a group of autosomal recessive disorders caused by a deficiency of enzymes required for cortisol synthesis. **Why 21-Hydroxylase deficiency is correct:** Deficiency of **21-Hydroxylase** is the most common cause, accounting for **>90-95% of all CAH cases**. This enzyme is responsible for converting progesterone to 11-deoxycorticosterone and 17-hydroxyprogesterone to 11-deoxycortisol. Its absence leads to decreased cortisol and aldosterone, with a compensatory increase in ACTH. This "shunts" precursors toward the androgen pathway, leading to virilization. **Why the other options are incorrect:** * **11-beta-Hydroxylase deficiency:** The second most common cause (~5-8%). It presents with virilization but is uniquely characterized by **hypertension** due to the accumulation of 11-deoxycorticosterone (a mineralocorticoid). * **17-alpha-Hydroxylase deficiency:** Rare. It leads to a decrease in both cortisol and sex hormones, resulting in **delayed puberty/sexual infantilism** and hypertension (due to excess mineralocorticoids). * **3-beta-Hydroxysteroid dehydrogenase deficiency:** Very rare. It affects all three pathways (mineralocorticoids, glucocorticoids, and sex steroids), often leading to ambiguous genitalia in both males and females. **High-Yield Clinical Pearls for NEET-PG:** * **Classic Presentation:** Salt-wasting (hypotension, hyponatremia, hyperkalemia) and ambiguous genitalia in females. * **Diagnostic Marker:** Elevated **17-hydroxyprogesterone (17-OHP)** levels. * **Treatment:** Glucocorticoid (Hydrocortisone) and Mineralocorticoid (Fludrocortisone) replacement. * **Rule of Thumb:** If the enzyme starts with **'1'** (11, 17), it causes **Hypertension**. If it ends with **'1'** (21, 11), it causes **Virilization**.

Q: The following pedigree is associated with which of the following conditions?

All of the above. ***All of the above*** - The pedigree demonstrates **autosomal recessive inheritance** pattern, characterized by affected individuals having unaffected parents and horizontal transmission within generations. - All three conditions (**thalassemia**, **cystic fibrosis**, and **homocystinuria**) follow **autosomal recessive inheritance**, making this the correct comprehensive answer. *Thalassemia* - This is indeed an **autosomal recessive** hemoglobinopathy affecting **beta-globin chain synthesis**, consistent with the pedigree pattern. - However, this option is incomplete as it doesn't account for the other conditions that also match the inheritance pattern shown. *Cystic fibrosis* - This **autosomal recessive** disorder affects the **CFTR gene** causing defective chloride transport, matching the pedigree pattern. - Like thalassemia, this is a correct individual answer but incomplete since other conditions also fit the inheritance pattern. *Homocystinuria* - This **autosomal recessive** metabolic disorder involves deficiency of **cystathionine beta-synthase** enzyme in methionine metabolism. - While correctly matching the inheritance pattern, this option alone doesn't encompass all possible conditions represented by the pedigree.

Question 1

Maternal disomy of chromosome 15 is seen in which of the following conditions?

Accepted Answer

Prader-Willi syndrome

Answer

Klinefelter's syndrome

Answer

Angelman syndrome

Answer

Turner's syndrome

Question 2

MELAS is an inherited condition which occurs due to deficiency of which mitochondrial respiratory chain complex?

Accepted Answer

Complex I

Answer

Complex II

Answer

Complex III

Answer

All the above

Question 3

Congenital adrenal hyperplasia due to 11 beta hydroxylase deficiency presents with all the following except?

Accepted Answer

Metabolic acidosis

Answer

Hypokalemia

Answer

Hypernatremia

Answer

Hypertension

Question 4

In a study of inheritance of the cystic fibrosis gene (CFTR), genetic mutations in carriers and affected individuals were documented. Based on these findings, investigators determined that there is no simple screening test to detect all carriers of CFTR gene mutations. Which of the following is most likely to be the greatest limitation to the development of a screening test for CFTR mutations?

Accepted Answer

The frequency of mutations among ethnic groups limits sensitivity.

Answer

Both copies of the gene must be abnormal for detection.

Answer

Fluorescence in situ hybridization is labor-intensive and expensive.

Answer

Less than 1 in 10,000 individuals is a heterozygote.

Question 5

Which of the following is NOT a cause of Type 2 renal tubular acidosis?

Accepted Answer

Essential fructosuria

Answer

Cystinosis

Answer

Lowe syndrome

Answer

Galactosemia

Question 6

What is the gene affected in Gilbert's syndrome?

Accepted Answer

UGT1A1

Answer

MRP2

Answer

Unknown

Answer

MRP 3

Question 7

A young male presented with an X-linked recessive disorder characterized by hyperuricemia and mild mental retardation. What is the underlying biochemical defect?

Accepted Answer

Hypoxanthine-guanine phosphoribosyltransferase deficiency

Answer

Deficiency in branched-chain amino acid metabolites

Answer

Defective homogentisate oxidase enzyme

Answer

Phenylalanine hydroxylase deficiency

Question 8

Which of the following inborn errors of metabolism is associated with mental retardation?

Accepted Answer

Homocystinuria

Answer

Alkaptonuria

Answer

Pentosuria

Answer

All of the above

Question 9

What is the most common cause of congenital adrenal hyperplasia?

Accepted Answer

21-Hydroxylase deficiency

Answer

11-Hydroxylase deficiency

Answer

17-a-Hydroxylase deficiency

Answer

3-beta-Hydroxysteroid dehydrogenase deficiency

Question 10

The following pedigree is associated with which of the following conditions?

Accepted Answer

All of the above

Answer

Thalassemia

Answer

Cystic fibrosis

Answer

Homocystinuria

Genetic Disorders and Biochemical Pathology — MCQs

Genetic Disorders and Biochemical Pathology — MCQs

On this page

Practice by Chapter

Want unlimited practice?