Genetic Disorders and Biochemical Pathology Practice Questions

Q: What is true about Gilbert syndrome?

Phenobarbitone improves the condition. **Explanation:** **Gilbert Syndrome** is a common, benign autosomal recessive condition characterized by reduced activity of the enzyme **UDP-glucuronosyltransferase (UGT1A1)**, typically to about 30% of normal levels. 1. **Why Option C is Correct:** **Phenobarbitone** is a potent inducer of microsomal enzymes, including UGT1A1. By inducing the expression of the remaining functional enzyme, it enhances the conjugation of bilirubin, thereby lowering serum bilirubin levels and improving the clinical jaundice. 2. **Why Other Options are Incorrect:** * **Option A:** It is characterized by **Unconjugated hyperbilirubinemia**. Since the defect lies in the conjugation process in the liver, unconjugated bilirubin accumulates. * **Option B:** **Starvation (fasting)**, dehydration, stress, and illness actually **exacerbate** the condition. Fasting reduces the availability of UDP-glucuronic acid and decreases hepatic uptake, leading to a transient rise in bilirubin. * **Option D:** It is a **benign, asymptomatic** condition. It does not lead to liver damage or kernicterus and has a normal life expectancy. **High-Yield Clinical Pearls for NEET-PG:** * **Genetic Defect:** Most commonly due to a TATAA box mutation in the *UGT1A1* gene. * **Trigger Factors:** Jaundice typically appears during periods of stress, fasting, or strenuous exercise. * **Diagnosis:** Suspected when there is isolated unconjugated hyperbilirubinemia (<3 mg/dL) with normal liver enzymes (ALT/AST) and no evidence of hemolysis. * **Comparison:** Unlike **Crigler-Najjar Syndrome Type I** (zero enzyme activity) and **Type II** (Arias Syndrome, <10% activity), Gilbert syndrome is the mildest form of hereditary glucuronidation defects.

Q: Bilirubin UDP glucuronyl transferase activity is absent in which of the following conditions?

Crigler-Najjar syndrome type I. **Explanation:** The enzyme **UDP-glucuronosyltransferase (UGT1A1)** is responsible for the conjugation of bilirubin in the liver, converting insoluble unconjugated bilirubin into water-soluble conjugated bilirubin. **1. Why Option A is Correct:** **Crigler-Najjar Syndrome Type I (CN-I)** is characterized by a **complete absence** (0% activity) of the UGT1A1 enzyme. This leads to severe, life-threatening unconjugated hyperbilirubinemia shortly after birth. Because bilirubin cannot be conjugated, it crosses the blood-brain barrier, posing a high risk of **kernicterus**. It does not respond to phenobarbital. **2. Why Other Options are Incorrect:** * **Crigler-Najjar Syndrome Type II (Arias Syndrome):** There is a **severe deficiency** rather than a total absence. Enzyme activity is typically **<10%** of normal. It is less severe than Type I and usually responds to phenobarbital (which induces enzyme production). * **Gilbert Syndrome:** There is a **mild reduction** in enzyme activity (approximately **30%** of normal) due to a promoter mutation. It results in mild, fluctuating jaundice often triggered by stress or fasting. * **Rotor Syndrome:** This is a defect in **hepatic storage/uptake** of bilirubin, not conjugation. It presents with conjugated hyperbilirubinemia. **High-Yield Clinical Pearls for NEET-PG:** * **Inheritance:** CN-I is Autosomal Recessive; Gilbert is usually Autosomal Recessive (TATAA box mutation). * **Phenobarbital Test:** Used to differentiate CN-I (no response) from CN-II (bilirubin levels decrease). * **Treatment for CN-I:** Phototherapy is the immediate management, but **Liver Transplantation** is the only definitive cure. * **Dubin-Johnson vs. Rotor:** Both cause conjugated hyperbilirubinemia, but Dubin-Johnson features a **black liver** due to melanin-like pigment, whereas Rotor does not.

Q: Very low activity of adenosine deaminase in red blood cells and high levels of dATP is consistent with which diagnosis?

Severe combined immunodeficiency disease. **Explanation:** **1. Why the Correct Answer is Right:** Adenosine Deaminase (ADA) is a critical enzyme in the **purine salvage pathway**. It converts adenosine to inosine and deoxyadenosine to deoxyinosine. A deficiency in ADA leads to the toxic accumulation of **deoxyadenosine**, which is subsequently phosphorylated into **dATP (deoxyadenosine triphosphate)**. High levels of dATP act as a potent allosteric inhibitor of **Ribonucleotide Reductase**, the enzyme responsible for synthesizing all four deoxyribonucleotides (dNTPs) required for DNA synthesis. Without dNTPs, lymphocytes (T-cells and B-cells) cannot proliferate, leading to **Severe Combined Immunodeficiency Disease (SCID)**. ADA deficiency accounts for approximately 15% of all SCID cases and is inherited in an autosomal recessive pattern. **2. Why the Other Options are Incorrect:** * **Organophosphorus poisoning:** This involves the inhibition of **Acetylcholinesterase**, leading to a cholinergic crisis (SLUDGE symptoms). It has no relation to purine metabolism or dATP levels. * **Cyanide poisoning:** Cyanide inhibits **Cytochrome c oxidase (Complex IV)** in the electron transport chain, halting aerobic respiration. It does not affect ADA activity. * **Acquired Immunodeficiency Disease (AIDS):** While AIDS also involves immune failure, it is caused by the **HIV virus** infecting CD4+ T-cells. It is an acquired condition, not a primary genetic enzyme deficiency. **3. Clinical Pearls for NEET-PG:** * **First Gene Therapy:** ADA deficiency was the first disease treated with human gene therapy (1990). * **Inheritance:** ADA-SCID is **Autosomal Recessive**, whereas the most common form of SCID is X-linked (IL-2 receptor mutation). * **Diagnosis:** Look for "absent thymic shadow" on X-ray and lymphopenia in a neonate with recurrent infections. * **Treatment:** Enzyme replacement therapy (PEG-ADA), Bone Marrow Transplant, or Gene Therapy.

Q: Congenital adrenal hyperplasia is most likely a result of which of the following?

Defects in adrenal steroidogenic enzymes. **Explanation:** **Congenital Adrenal Hyperplasia (CAH)** is a group of autosomal recessive disorders characterized by a deficiency in one of the enzymes required for the synthesis of cortisol from cholesterol in the adrenal cortex. **1. Why Option A is Correct:** The primary pathology in CAH is a **defect in adrenal steroidogenic enzymes**. The most common deficiency (95% of cases) is **21-hydroxylase**. When cortisol synthesis is impaired, the lack of negative feedback leads to an overproduction of **Adrenocorticotropic Hormone (ACTH)** by the pituitary. Chronic ACTH stimulation causes **hyperplasia** of the adrenal cortex and shunts precursor steroids into the androgen pathway, leading to virilization. **2. Why Other Options are Incorrect:** * **Option B (Addison’s Disease):** This is primary adrenal insufficiency, usually due to autoimmune destruction or infection (TB). While it involves low cortisol, it is an acquired destruction of the gland, not a congenital enzymatic defect. * **Option C (Defects in ACTH secretion):** CAH actually features *increased* ACTH secretion. A defect/deficiency in ACTH would lead to secondary adrenal insufficiency and adrenal *atrophy*, not hyperplasia. * **Option D (Defects in CBG):** Corticosteroid-binding globulin (Transcortin) carries cortisol in the blood. Defects here affect total cortisol levels but do not cause the enzymatic block or androgen excess seen in CAH. **High-Yield Clinical Pearls for NEET-PG:** * **Most common enzyme deficiency:** 21-hydroxylase (leads to high 17-OH Progesterone). * **Classic Presentation:** Ambiguous genitalia in females, salt-wasting crisis (hyponatremia, hyperkalemia, hypotension) in males. * **11β-hydroxylase deficiency:** Differentiated by the presence of **hypertension** (due to 11-deoxycorticosterone buildup). * **Treatment:** Glucocorticoid replacement (to suppress ACTH) and mineralocorticoids if salt-wasting.

Q: Find the type of inheritance?

Mitochondrial. ***Mitochondrial*** - **Maternal inheritance** pattern where all offspring of an affected mother are affected, as mitochondria are inherited exclusively from the mother. - Shows **no paternal transmission** and affects both sexes equally without skipping generations through the maternal line. *Autosomal dominant* - Requires only **one copy** of the mutated gene to express the trait, with affected individuals in every generation. - Shows **vertical transmission** with approximately **50% risk** to each offspring, regardless of sex. *X-linked dominant* - Affects **more females than males** and shows transmission from affected fathers to **all daughters** but no sons. - Affected males cannot pass the trait to their sons, and affected females have a **50% risk** to each child. *Autosomal recessive* - Requires **two copies** of the mutated gene to express the trait, often showing **horizontal transmission** within generations. - Typically shows **consanguinity** in family history and affects both sexes equally with **25% risk** to siblings.

Q: Which of the following is FALSE regarding hereditary fructose intolerance?

Hyperglycemia.. **Explanation:** Hereditary Fructose Intolerance (HFI) is an autosomal recessive disorder caused by a deficiency of **Aldolase B** (Fructose 1-phosphate aldolase). **Why Option C is the correct (False) statement:** HFI is characterized by **severe hypoglycemia**, not hyperglycemia. The deficiency leads to the intracellular accumulation of **Fructose 1-phosphate (F1P)**. This "trapping" of inorganic phosphate depletes the cellular ATP and Pi pools. Low Pi levels inhibit **Glycogen Phosphorylase**, preventing glycogenolysis, while the lack of ATP and high F1P levels inhibit **Gluconeogenesis**. The inability to perform these two processes results in profound postprandial hypoglycemia following fructose ingestion. **Analysis of other options:** * **Option A:** Correct. Aldolase B is the specific enzyme deficient in HFI. * **Option B:** Correct. Without Aldolase B, Fructose 1-phosphate cannot be cleaved into DHAP and Glyceraldehyde, leading to its accumulation in hepatocytes, enterocytes, and proximal tubule cells. * **Option D:** Correct. Aldolase B is primarily expressed in the **liver, kidney, and small intestine**. Consequently, HFI manifests with hepatic failure (jaundice, cirrhosis) and renal tubular dysfunction (Fanconi-like syndrome). **NEET-PG High-Yield Pearls:** * **Clinical Presentation:** Symptoms appear when an infant is weaned from breast milk and introduced to fruits/sucrose (fructose + glucose). * **Key Finding:** Reducing sugars in urine (Clinitest positive) but negative glucose oxidase test (Dipstick). * **Management:** Strict removal of fructose, sucrose, and sorbitol from the diet. * **Contrast:** Essential Fructosuria (Fructokinase deficiency) is a benign, asymptomatic condition.

Q: Cirrhosis can be seen in all of the following metabolic diseases EXCEPT?

McArdle disease. **Explanation:** The correct answer is **McArdle disease (Option C)**. This is because McArdle disease (Glycogen Storage Disease Type V) is a **purely muscular disorder**. It is caused by a deficiency of **muscle glycogen phosphorylase (myophosphorylase)**. Since the enzyme defect is localized strictly to skeletal muscle, the liver is unaffected, and there is no risk of cirrhosis or hepatic dysfunction. Clinical features are limited to exercise intolerance, muscle cramps, and myoglobinuria. **Why the other options are incorrect:** * **Tyrosinemia (Type I):** Caused by a deficiency of fumarylacetoacetate hydrolase. The accumulation of toxic metabolites (like succinylacetone) leads to severe progressive liver damage, early-onset cirrhosis, and a high risk of hepatocellular carcinoma. * **Galactosemia:** Deficiency of Galactose-1-phosphate uridyltransferase (GALT) leads to the accumulation of Galactose-1-phosphate in the liver. This is hepatotoxic and results in neonatal jaundice, hepatomegaly, and eventually cirrhosis if lactose is not removed from the diet. * **Hereditary Fructose Intolerance (HFI):** Deficiency of Aldolase B leads to the trapping of Fructose-1-phosphate in hepatocytes. This depletes intracellular ATP and inorganic phosphate, causing hepatic dysfunction, jaundice, and cirrhosis upon ingestion of fructose or sucrose. **NEET-PG High-Yield Pearls:** * **GSDs with Liver Involvement:** Type I (von Gierke), Type III (Cori), and Type IV (Andersen) involve the liver. **Type IV** is particularly known for causing early, progressive cirrhosis. * **GSDs with Muscle Involvement:** Type V (McArdle) and Type VII (Tarui). * **Key Diagnostic:** In McArdle disease, the **Ischemic Forearm Exercise Test** shows a failure of blood lactate to rise, which is a classic exam favorite.

Question 1

What is true about Gilbert syndrome?

Accepted Answer

Phenobarbitone improves the condition

Answer

Conjugated hyperbilirubinemia

Answer

Starvation improves the condition

Answer

Life-threatening

Question 2

Bilirubin UDP glucuronyl transferase activity is absent in which of the following conditions?

Accepted Answer

Crigler-Najjar syndrome type I

Answer

Crigler-Najjar syndrome type II

Answer

Rotor syndrome

Answer

Gilbert syndrome

Question 3

Very low activity of adenosine deaminase in red blood cells and high levels of dATP is consistent with which diagnosis?

Accepted Answer

Severe combined immunodeficiency disease

Answer

Organophosphorus poisoning

Answer

Cyanide poisoning

Answer

Acquired immunodeficiency disease

Question 4

A screening test for phenylketonuria (PKU) is performed on umbilical cord blood from a fair-skinned blond, blue-eyed infant born to dark-complexioned parents. The test is reported as negative, and no dietary restrictions are imposed. At 1 year of age, the child is seen again, this time with obvious signs of severe mental retardation, and a diagnosis of PKU is made. The diagnosis was missed at birth because:

Accepted Answer

the test was performed too early, before the enzyme deficiency manifested significantly.

Answer

cord blood is not a good source of fetal blood.

Answer

the screening (Guthrie) test has low sensitivity.

Answer

the test should have been performed on maternal blood.

Question 5

Congenital adrenal hyperplasia is most likely a result of which of the following?

Accepted Answer

Defects in adrenal steroidogenic enzymes

Answer

Addison's disease

Answer

Defects in ACTH secretion

Answer

Defects in corticosteroid-binding globulin

Question 6

A single gene defect causing multiple unrelated problems is termed as the following?

Accepted Answer

Pleiotropism

Answer

Pseudodominance

Answer

Penetrance

Answer

Anticipation

Question 7

Find the type of inheritance?

Accepted Answer

Mitochondrial

Answer

Autosomal dominant

Answer

X-linked dominant

Answer

Autosomal recessive

Question 8

Which of the following is FALSE regarding hereditary fructose intolerance?

Accepted Answer

Hyperglycemia.

Answer

Deficiency of fructose 1-phosphate aldolase.

Answer

Accumulation of fructose 1-phosphate in tissues.

Answer

Liver and kidneys are involved.

Question 9

Cirrhosis can be seen in all of the following metabolic diseases EXCEPT?

Accepted Answer

McArdle disease

Answer

Tyrosinemia

Answer

Galactosemia

Answer

Hereditary fructose intolerance

Question 10

Which of the following statements about mitochondrial disorders is FALSE?

Accepted Answer

Elevated free-floating blood lactate does not support the diagnosis

Answer

May present at any age and by mode of inheritance

Answer

Include Pearson's syndrome

Answer

Features may include retinitis pigmentosa

Genetic Disorders and Biochemical Pathology — MCQs

Genetic Disorders and Biochemical Pathology — MCQs

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