Genetic Disorders and Biochemical Pathology Practice Questions

Q: A 15-year-old female patient presents with pain in the calf muscles on exercise. Routine investigation reveals burgundy-colored urine after exercise. Histopathology of muscle shows deposits of glycogen in excess. What is the diagnosis?

McArdle's disease. ### Explanation **Correct Option: C. McArdle’s Disease (GSD Type V)** The clinical presentation of **exercise-induced muscle pain** (cramps) and **burgundy-colored urine** (myoglobinuria) is classic for McArdle’s disease. * **Mechanism:** It is caused by a deficiency of **muscle phosphorylase** (myophosphorylase). This enzyme is essential for breaking down muscle glycogen into glucose-1-phosphate. * **Pathology:** Since glycogen cannot be degraded during exercise, it accumulates in the muscle (subsarcolemmal deposits). The lack of ATP leads to muscle cell damage (rhabdomyolysis), releasing myoglobin into the urine, causing the characteristic burgundy color. **Incorrect Options:** * **A. Von Gierke’s Disease (GSD Type I):** Caused by Glucose-6-Phosphatase deficiency. It primarily affects the **liver**, presenting with severe fasting hypoglycemia, hepatomegaly, and hyperuricemia, but no muscle symptoms. * **B. Pompe’s Disease (GSD Type II):** Caused by Lysosomal acid alpha-glucosidase deficiency. It affects the **heart** and muscles globally. It typically presents in infancy with cardiomegaly and hypotonia ("floppy baby"), not exercise-induced cramps in teenagers. * **D. Cori’s Disease (GSD Type III):** Caused by Debranching enzyme deficiency. It presents similarly to Von Gierke’s but is milder and involves both liver and muscle; however, it does not typically cause myoglobinuria. **High-Yield Clinical Pearls for NEET-PG:** * **"Second Wind" Phenomenon:** Patients with McArdle’s often feel better after a few minutes of exercise as the body switches to using free fatty acids and blood glucose. * **Ischemic Forearm Exercise Test:** Shows a **failure of blood lactate to rise** (hallmark diagnostic feature), as glycogen cannot be converted to lactate. * **Biochemical marker:** Elevated serum Creatine Kinase (CK) levels.

Q: Fabry’s disease is caused due to deficiency of which enzyme?

Alpha Galactosidase. **Explanation:** **Fabry’s disease** is a lysosomal storage disorder (Sphingolipidosis) characterized by the deficiency of the enzyme **Alpha-galactosidase A**. This deficiency leads to the systemic accumulation of **Globotriaosylceramide (Gb3)**, also known as ceramide trihexoside, within the lysosomes of vascular endothelial cells and other tissues. * **Why Option A is correct:** Alpha-galactosidase A is responsible for cleaving the terminal galactose from globotriaosylceramide. Its absence causes progressive cellular damage, primarily affecting the kidneys, heart, and nervous system. * **Why Option B is incorrect:** Deficiency of **Ceramidase** leads to **Farber disease**, characterized by painful joint swelling, hoarseness (laryngeal involvement), and subcutaneous nodules. * **Why Option C is incorrect:** Deficiency of the **Debranching enzyme** (Amylo-1,6-glucosidase) causes **Cori’s disease (GSD Type III)**, a glycogen storage disorder presenting with hepatomegaly and hypoglycemia. **High-Yield Clinical Pearls for NEET-PG:** 1. **Inheritance:** Fabry’s is unique among sphingolipidoses as it is **X-linked Recessive** (most others are Autosomal Recessive). 2. **Early Signs:** Characterized by **Angiokeratomas** (dark red skin spots), **Hypohidrosis** (decreased sweating), and **Acroparesthesia** (burning pain in extremities). 3. **Late Complications:** Progressive **Renal failure** (most common cause of death), hypertrophic cardiomyopathy, and early-onset stroke. 4. **Ocular Finding:** **Cornea verticillata** (whorl-like corneal opacities) is a classic diagnostic sign. 5. **Treatment:** Enzyme Replacement Therapy (ERT) with Agalsidase beta.

Q: Leigh disease is due to the accumulation of which substance?

None of the above. **Explanation:** **Leigh Disease (Subacute Necrotizing Encephalomyelopathy)** is a progressive neurodegenerative disorder primarily caused by defects in mitochondrial energy metabolism. The correct answer is **None of the above** because Leigh disease is characterized by a failure of oxidative phosphorylation, leading to the accumulation of **Lactic Acid** and **Pyruvate** in the blood and cerebrospinal fluid (CSF), rather than the substances listed in the options. **Why the other options are incorrect:** * **Glycogen:** Accumulation of glycogen is seen in Glycogen Storage Diseases (e.g., Von Gierke or Pompe disease), not Leigh disease. * **Pyridoxine (Vitamin B6):** This is a cofactor, not a metabolic byproduct that accumulates. Pyridoxine deficiency or dependency can cause seizures, but it is unrelated to the pathology of Leigh disease. * **Sphingomyelin:** Accumulation of sphingomyelin is the hallmark of Niemann-Pick Disease (Type A and B), a lysosomal storage disorder. **Clinical Pearls for NEET-PG:** 1. **Biochemical Defect:** The most common cause is a deficiency in the **Pyruvate Dehydrogenase (PDH) complex** or defects in the **Respiratory Chain Complexes** (Complex I, II, IV, or V). 2. **Genetics:** It can be inherited via mitochondrial DNA (maternally) or nuclear DNA (autosomal recessive). 3. **Imaging:** A high-yield finding on MRI is bilateral, symmetrical necrotic lesions in the **basal ganglia**, thalamus, and brainstem. 4. **Clinical Presentation:** Typically presents in infancy with psychomotor regression, hypotonia, and seizures.

Q: A child presents with anemia, kinky hair, intellectual disability, and seizures. Which of the following is the most likely diagnosis?

Menkes disease. **Explanation:** The correct answer is **Menkes disease**. This is an X-linked recessive disorder caused by a mutation in the **ATP7A gene**, which encodes a copper-transporting ATPase. This defect leads to impaired intestinal absorption of copper and its subsequent deficiency in the body. **Why Menkes Disease is Correct:** Copper is a vital cofactor for several enzymes. The clinical features observed in this child are directly linked to these enzymatic failures: * **Kinky Hair (Pili torti):** Due to failure of **Lysyl oxidase**, which requires copper to cross-link keratin and collagen. * **Intellectual Disability & Seizures:** Due to deficiency of **Cytochrome c oxidase** (energy production) and **Dopamine β-hydroxylase** (catecholamine synthesis). * **Anemia:** Copper is essential for **Hephaestin and Ceruloplasmin**, which are required for iron metabolism. **Why Other Options are Incorrect:** * **Down Syndrome:** Presents with characteristic facies (upslanting palpebral fissures, epicanthic folds), hypotonia, and cardiac defects, but not kinky hair. * **Iron Deficiency Anemia:** While it causes anemia and pica, it does not present with the neurological deterioration or the pathognomonic hair changes seen here. * **Lesch-Nyhan Syndrome:** An X-linked disorder of purine metabolism (HGPRT deficiency) characterized by self-mutilation and hyperuricemia, not kinky hair. **High-Yield Clinical Pearls for NEET-PG:** * **ATP7A vs. ATP7B:** Remember **A**TP7**A** is for **A**bsorption (Menkes - Deficiency), while **A**TP7**B** is for **B**iliary excretion (Wilson - Toxicity). * **Diagnosis:** Low serum copper, low serum ceruloplasmin, and "steely" or "kinky" hair under light microscopy. * **Treatment:** Early administration of copper histidine (parenteral) may improve outcomes, though the prognosis remains poor.

Q: Fanconi-Bickel syndrome is due to a mutation in the gene encoding which of the following transporters?

GLUT2. **Explanation:** **Fanconi-Bickel Syndrome (FBS)** is a rare autosomal recessive disorder of carbohydrate metabolism caused by a mutation in the **SLC2A2 gene**, which encodes the **GLUT2** transporter. **1. Why GLUT2 is correct:** GLUT2 is a high-capacity, low-affinity bidirectional transporter found in the liver, pancreas (beta cells), small intestine, and proximal renal tubules. In FBS, the deficiency of GLUT2 leads to: * **Liver:** Impaired export of glucose, leading to glycogen accumulation (Glycogen Storage Disease Type XI) and hepatomegaly. * **Kidney:** Failure to reabsorb glucose, galactose, and other solutes in the proximal tubule, resulting in **Proximal Renal Tubular Acidosis (Fanconi Syndrome)** characterized by glucosuria, phosphaturia, and aminoaciduria. **2. Why the other options are incorrect:** * **GLUT1:** Primarily found in RBCs and the Blood-Brain Barrier. Deficiency leads to seizures and developmental delay (De Vivo disease). * **GLUT4:** The insulin-responsive transporter found in skeletal muscle and adipose tissue. It is not involved in FBS. * **Na+/Iodine Symporter (NIS):** Responsible for iodine uptake in the thyroid gland; mutations lead to congenital hypothyroidism, not carbohydrate metabolism disorders. **Clinical Pearls for NEET-PG:** * **Classic Triad:** Hepatomegaly (due to glycogen accumulation), rickets (due to hypophosphatemia), and growth retardation. * **Laboratory Hallmark:** Post-prandial hyperglycemia and fasting hypoglycemia (due to inability to mobilize liver glucose). * **Key Distinction:** Unlike other GSDs, FBS involves both glucose and galactose intolerance.

Q: Which genetic disorder is caused by a microdeletion on chromosome 15?

Prader-Willi syndrome. ### Explanation **Correct Answer: C. Prader-Willi Syndrome** **Prader-Willi Syndrome (PWS)** is caused by the loss of expression of a cluster of genes on the **paternal chromosome 15 (q11-q13)**. This occurs most commonly via a **microdeletion** (70% of cases) or maternal uniparental disomy (25%). Because these genes are normally silenced on the maternal chromosome due to **genomic imprinting**, the loss of the paternal contribution results in the disease. * **Clinical Features:** Neonatal hypotonia, hyperphagia leading to early-onset obesity, hypogonadism, and intellectual disability. --- ### Analysis of Incorrect Options: * **A. WAGR Syndrome:** Caused by a microdeletion on **chromosome 11 (11p13)** involving the *WT1* and *PAX6* genes. It is characterized by Wilms tumor, Aniridia, Genitourinary anomalies, and Range of developmental delays. * **B. DiGeorge Syndrome:** Caused by a microdeletion on **chromosome 22 (22q11.2)**. It results from the failure of the 3rd and 4th pharyngeal pouches to develop, leading to CATCH-22 features (Cardiac defects, Abnormal facies, Thymic aplasia, Cleft palate, Hypocalcemia). * **D. Charcot-Marie-Tooth Syndrome (CMT):** Most commonly (CMT1A) caused by a **duplication** (not deletion) of the *PMP22* gene on **chromosome 17**. It is a hereditary motor and sensory neuropathy. --- ### NEET-PG High-Yield Pearls: * **Angelman Syndrome ("Happy Puppet"):** The "sister" disorder to PWS, caused by a microdeletion of the same region (15q11-q13) but on the **maternal** chromosome (loss of *UBE3A* gene). * **Genomic Imprinting:** Remember that PWS/Angelman are classic examples of imprinting, where the phenotype depends on the **parent of origin**. * **Diagnosis:** The gold standard for detecting these microdeletions is **FISH** (Fluorescence In Situ Hybridization) or chromosomal microarray.

Q: Complete deficiency of UDP glucuronyl transferase (UGT) is seen in which of the following conditions?

Crigler-Najjar Type I. **Explanation:** The core concept here is the conjugation of bilirubin in the liver by the enzyme **UDP-glucuronosyltransferase (UGT1A1)**. Deficiencies in this enzyme lead to unconjugated hyperbilirubinemia. **1. Why Crigler-Najjar Type I is correct:** In **Crigler-Najjar Type I**, there is a **complete (total) absence** of UGT1A1 activity. This results in severe unconjugated hyperbilirubinemia (often >20 mg/dL) shortly after birth. Because there is no conjugation, bile is colorless, and patients are at high risk for **kernicterus** (brain damage due to bilirubin deposition). It does not respond to phenobarbital. **2. Why the other options are incorrect:** * **Crigler-Najjar Type II (Arias Syndrome):** There is a **partial deficiency** (usually <10% of normal activity). It is less severe than Type I, and jaundice can be managed with **phenobarbital**, which induces the remaining enzyme activity. * **Gilbert’s Syndrome:** This is a **mild reduction** in UGT1A1 activity (about 30% of normal). It is often asymptomatic and presents as mild, fluctuating jaundice triggered by stress, fasting, or illness. * **Dubin-Johnson Syndrome:** This is a defect in **canalicular transport (MRP2 protein)**, not UGT. It causes **conjugated** hyperbilirubinemia and is characterized by a "black liver" due to pigment deposition. **Clinical Pearls for NEET-PG:** * **Inheritance:** Crigler-Najjar Type I is Autosomal Recessive. * **Treatment:** Phototherapy is the immediate treatment for CN-I, but **Liver Transplantation** is the only definitive cure. * **Phenobarbital Test:** Used to differentiate CN-I (no response) from CN-II (bilirubin levels drop). * **Gold Standard Diagnosis:** Genetic testing or liver biopsy (showing absence of UGT activity).

Q: Sapropterin is used in the treatment of which of the following conditions?

Phenylketonuria. **Explanation:** **Sapropterin** is a synthetic form of **Tetrahydrobiopterin (BH4)**, which acts as a vital cofactor for the enzyme **Phenylalanine Hydroxylase (PAH)**. 1. **Why Phenylketonuria (PKU) is correct:** Classic PKU is caused by a deficiency in PAH, which converts Phenylalanine to Tyrosine. However, some patients have "BH4-responsive PKU." In these cases, the PAH enzyme has a reduced affinity for its cofactor. Administering Sapropterin (synthetic BH4) can stabilize the mutant PAH enzyme and increase its activity, effectively lowering blood phenylalanine levels. It is also used in cases where PKU is caused by a primary deficiency in BH4 synthesis or regeneration. 2. **Why other options are incorrect:** * **Hereditary Fructose Intolerance:** Caused by a deficiency of **Aldolase B**. Treatment involves strict dietary restriction of fructose and sucrose. * **Galactosemia:** Most commonly caused by **GALT** (Galactose-1-phosphate uridyltransferase) deficiency. Treatment requires a lactose-free (galactose-free) diet. * **Gaucher’s Disease:** A lysosomal storage disorder caused by **Glucocerebrosidase** deficiency. Treatment involves Enzyme Replacement Therapy (ERT) with Alglucerase or Imiglucerase. **High-Yield Clinical Pearls for NEET-PG:** * **Mousy/Musty Odor:** A classic clinical sign of PKU due to phenylacetic acid in sweat and urine. * **Maternal PKU:** If a mother with PKU does not control phenylalanine levels during pregnancy, the fetus may suffer from microcephaly, mental retardation, and congenital heart defects. * **Guthrie Test:** A bacterial inhibition assay used for neonatal screening of PKU. * **BH4 Deficiency:** Also affects the synthesis of neurotransmitters like Dopamine and Serotonin (as BH4 is a cofactor for Tyrosine and Tryptophan hydroxylases).

Q: ABO blood group inheritance is an example of:

Codominance. **Explanation:** The ABO blood group system is a classic example of **Multiple Allelism** and **Codominance**. It is governed by the *I* gene, which has three alleles: $I^A$, $I^B$, and $i$. 1. **Why Codominance is Correct:** Codominance occurs when two different alleles at a locus are both fully expressed in the phenotype of a heterozygote. In individuals with the **AB blood group**, both the $I^A$ and $I^B$ alleles are dominant over $i$ but are codominant with each other. Consequently, both A and B antigens are expressed simultaneously on the red blood cell surface. 2. **Why other options are incorrect:** * **Mitochondrial inheritance:** This follows a maternal pattern (all children of an affected mother are affected). ABO genes are nuclear, located on **Chromosome 9**. * **Allelic exclusion:** This is a process where only one allele of a gene is expressed while the other is silenced (e.g., B-lymphocytes expressing only one type of light chain). In ABO, both alleles are expressed. * **Sex-linked inheritance:** These traits are carried on X or Y chromosomes (e.g., Hemophilia). ABO is an **autosomal** trait. **High-Yield Clinical Pearls for NEET-PG:** * **Bombay Phenotype:** A rare condition where the individual lacks the **H-substance** (precursor). They phenotypically test as 'O' group but can only receive blood from another Bombay phenotype donor. * **Universal Donor/Recipient:** O negative is the universal donor (no antigens); AB positive is the universal recipient (no antibodies). * **Gene Location:** The ABO gene is located on the long arm of **Chromosome 9 (9q34.2)**. * **Biochemical Nature:** A and B antigens are sugar moieties added to the H-substance by specific glycosyltransferases.

Question 1

A 15-year-old female patient presents with pain in the calf muscles on exercise. Routine investigation reveals burgundy-colored urine after exercise. Histopathology of muscle shows deposits of glycogen in excess. What is the diagnosis?

Accepted Answer

McArdle's disease

Answer

Von Gierke's disease

Answer

Pompe's disease

Answer

Cori's disease

Question 2

Fabry’s disease is caused due to deficiency of which enzyme?

Accepted Answer

Alpha Galactosidase

Answer

Ceramidase

Answer

Debranching enzyme

Answer

None of the above

Question 3

Which of the following statements regarding sickle cell disease is FALSE?

Accepted Answer

A sticky patch is generated as a result of the replacement of a polar residue with a nonpolar residue.

Answer

A single nucleotide change results in the substitution of glutamic acid with valine.

Answer

Hemoglobin S (HbS) confers resistance against malaria.

Answer

The binding of deoxygenated hemoglobin A (HbA) terminates fiber polymerization.

Question 4

Leigh disease is due to the accumulation of which substance?

Accepted Answer

None of the above

Answer

Glycogen

Answer

Pyridoxine

Answer

Sphingomyelin

Question 5

A child presents with anemia, kinky hair, intellectual disability, and seizures. Which of the following is the most likely diagnosis?

Accepted Answer

Menkes disease

Answer

Down syndrome

Answer

Iron deficiency anemia

Answer

Lesch Nyhan syndrome

Question 6

Fanconi-Bickel syndrome is due to a mutation in the gene encoding which of the following transporters?

Accepted Answer

GLUT2

Answer

GLUT1

Answer

GLUT4

Answer

Na+/iodine channels

Question 7

Which genetic disorder is caused by a microdeletion on chromosome 15?

Accepted Answer

Prader-Willi syndrome

Answer

WAGR syndrome

Answer

DiGeorge syndrome

Answer

Charcot-Marie-Tooth syndrome

Question 8

Complete deficiency of UDP glucuronyl transferase (UGT) is seen in which of the following conditions?

Accepted Answer

Crigler-Najjar Type I

Answer

Crigler-Najjar Type II

Answer

Gilbert's syndrome

Answer

Dubin-Johnson syndrome

Question 9

Sapropterin is used in the treatment of which of the following conditions?

Accepted Answer

Phenylketonuria

Answer

Hereditary Fructose Intolerance

Answer

Galactosemia

Answer

Gaucher's disease

Question 10

ABO blood group inheritance is an example of:

Accepted Answer

Codominance

Answer

Mitochondrial inheritance

Answer

Allelic exclusion

Answer

Sex-linked inheritance

Genetic Disorders and Biochemical Pathology — MCQs

Genetic Disorders and Biochemical Pathology — MCQs

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