Genetic Disorders and Biochemical Pathology Practice Questions

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: Examine the given pedigree chart. Which one of the following diseases is the most likely for this situation?

Beta-thalassemia. ***Beta-thalassemia*** - The pedigree shows an **autosomal recessive** inheritance pattern with **carrier parents** who are unaffected but have affected children of both sexes. - **Generation skipping** is typical, as both parents must be carriers for children to be affected, matching beta-thalassemia transmission. *Neurofibromatosis* - Follows an **autosomal dominant** pattern where affected individuals appear in every generation without skipping. - At least one parent would be affected if a child has the condition, which contradicts the pedigree pattern. *Colour blindness* - Shows **X-linked recessive** inheritance, primarily affecting **males** with minimal female involvement. - Affected males cannot pass the condition to their sons, only to carrier daughters, inconsistent with this pedigree. *Vitamin D resistant rickets* - Demonstrates **X-linked dominant** inheritance where affected fathers pass the condition to **all daughters** but no sons. - The pedigree pattern doesn't match this specific father-to-daughter transmission pattern.

Q: AST/ALT ratio > 2 is seen in deficiency of which enzyme?

Acid maltase. **Explanation:** The **AST/ALT ratio > 2** is a classic biochemical marker for **Pompe Disease (GSD Type II)**, caused by a deficiency of **Acid Maltase (α-1,4-glucosidase)**. **Why Acid Maltase is correct:** Unlike other Glycogen Storage Diseases (GSDs), Pompe disease is a lysosomal storage disorder. Acid maltase deficiency leads to glycogen accumulation in the lysosomes of **skeletal and cardiac muscles**. When these muscle cells are damaged, they release intracellular enzymes. While ALT is primarily liver-specific, **AST is found in high concentrations in both the liver and muscle**. In Pompe disease, the massive release of AST from damaged muscle tissue significantly outweighs the ALT levels, typically resulting in an AST/ALT ratio greater than 2. **Why other options are incorrect:** * **G-6-phosphatase (Von Gierke Disease):** Characterized by severe hypoglycemia, hyperuricemia, and lactic acidosis. While liver enzymes may be elevated, the ratio does not typically exceed 2 as the pathology is primarily hepatic. * **Branching enzyme (Andersen Disease):** Leads to the accumulation of abnormal glycogen (amylopectin-like). It presents with early liver cirrhosis, but the AST/ALT ratio is not a defining feature. * **Liver phosphorylase (Hers Disease):** A milder form of GSD affecting the liver; it does not cause the significant muscle breakdown required to skew the AST/ALT ratio. **High-Yield Clinical Pearls for NEET-PG:** * **Pompe Disease mnemonic:** "Pompe trashes the **Pump** (heart)." It is the only GSD that presents with **Hypertrophic Cardiomyopathy**. * **Biochemical marker:** Elevated **CPK (Creatine Phosphokinase)** and **LDH** are also seen due to muscle involvement. * **Diagnosis:** PAS-positive material in lysosomes; "lace-like" appearance of glycogen on biopsy. * **Note:** Outside of GSDs, an AST/ALT ratio > 2 is most commonly associated with **Alcoholic Liver Disease**.

Q: 'I' cells disease is due to a defect in which cellular organelle?

Golgi apparatus. **Explanation:** **I-cell disease (Inclusion Cell Disease)**, also known as Mucolipidosis II, is a rare lysosomal storage disorder. The primary defect lies in the **Golgi apparatus**, specifically involving the enzyme **UDP-N-acetylglucosamine-1-phosphotransferase**. 1. **Why Golgi apparatus is correct:** In a healthy cell, the Golgi apparatus tags acid hydrolases (lysosomal enzymes) with **Mannose-6-Phosphate (M6P)**. This tag acts as a "postal address," directing enzymes to the lysosomes. In I-cell disease, the deficiency of phosphotransferase means enzymes are not phosphorylated. Consequently, they are constitutively secreted into the extracellular space instead of being sent to lysosomes. This results in empty lysosomes and the accumulation of undigested substrates as "inclusion bodies" (I-cells) within the cytoplasm. 2. **Why other options are incorrect:** * **Peroxisome:** Defects here lead to disorders like Zellweger Syndrome or Adrenoleukodystrophy, involving long-chain fatty acid metabolism. * **Mitochondria:** Defects typically result in energy-failure syndromes (e.g., MELAS, MERFF) due to impaired oxidative phosphorylation. * **Lysosome:** While the *symptoms* manifest in the lysosome (due to lack of enzymes), the *primary defect* is the sorting machinery located in the Golgi apparatus. **High-Yield Clinical Pearls for NEET-PG:** * **Biochemical Hallmark:** High levels of lysosomal enzymes in the **plasma/serum** but absent within the cells. * **Clinical Presentation:** Coarse facial features, gingival hyperplasia, craniofacial abnormalities, joint contractures, and severe psychomotor retardation. * **Inheritance:** Autosomal Recessive. * **Key Enzyme:** Phosphotransferase (Golgi-resident).

Q: The gene involved in Rett's syndrome is:

MeCP2. ### Explanation **Correct Answer: C. MeCP2** **Mechanism:** Rett syndrome is an X-linked dominant neurodevelopmental disorder caused by mutations in the **MECP2 gene** (Methyl-CpG-binding protein 2), located on the X chromosome (Xq28). The MeCP2 protein is a transcriptional repressor that binds to methylated CpG islands in DNA. It recruits histone deacetylases (HDACs) to condense chromatin, effectively "silencing" specific genes. In Rett syndrome, the absence of functional MeCP2 leads to the failure of gene silencing, causing inappropriate expression of genes during brain development, which results in neuronal dysfunction. **Analysis of Incorrect Options:** * **A. P53:** Known as the "Guardian of the Genome," this is a tumor suppressor gene. Mutations are associated with **Li-Fraumeni syndrome** and various cancers, not neurodevelopmental disorders. * **B. Rb:** The Retinoblastoma gene is a tumor suppressor that regulates the G1-S phase transition of the cell cycle. Mutations lead to **Retinoblastoma** and osteosarcoma. * **D. FGFR3:** Fibroblast Growth Factor Receptor 3 mutations lead to **Achondroplasia** (the most common form of dwarfism) due to constitutive activation that inhibits chondrocyte proliferation. **High-Yield Clinical Pearls for NEET-PG:** * **Demographics:** Almost exclusively affects **females**; it is usually lethal in hemizygous males in utero. * **Clinical Presentation:** Characterized by a period of normal development (6–18 months) followed by regression of language and motor skills. * **Pathognomonic Sign:** Repetitive, **stereotypical hand-wringing** or "hand-washing" movements. * **Other Features:** Microcephaly, seizures, ataxia, and sighing/hyperventilation.

Q: Which hormone levels are increased in Prader-Willi syndrome?

GHRH (Growth Hormone Releasing Hormone). **Explanation:** **Prader-Willi Syndrome (PWS)** is a complex genetic disorder caused by the loss of function of genes in the paternal copy of chromosome **15q11-q13**. The core pathophysiology involves **hypothalamic dysfunction**, which leads to multiple endocrine abnormalities. **Why GHRH is increased:** In PWS, there is a functional deficiency of **Growth Hormone (GH)**. This is not due to a primary pituitary defect, but rather a hypothalamic failure to appropriately stimulate the pituitary or a lack of feedback inhibition. Because GH and IGF-1 levels are chronically low, the hypothalamus attempts to compensate by increasing the secretion of **Growth Hormone Releasing Hormone (GHRH)**. Despite high GHRH, the GH pulse frequency and amplitude remain low, leading to short stature and increased fat mass. **Analysis of Incorrect Options:** * **TSH:** While hypothyroidism can occur in PWS due to hypothalamic-pituitary axis dysfunction, TSH levels are typically **low or inappropriately normal** (central hypothyroidism), not increased. * **Growth Hormone:** GH levels are characteristically **decreased** in PWS, which is why recombinant GH therapy is a standard treatment to improve height and body composition. * **Peptide YY:** This is an anorexigenic (appetite-suppressing) hormone. In PWS, Peptide YY levels are typically **decreased**, contributing to the hallmark hyperphagia and lack of satiety. **NEET-PG High-Yield Pearls:** * **Genetics:** Most common cause is **paternal deletion** (70%), followed by **maternal uniparental disomy** (25-30%). * **Ghrelin:** PWS is associated with significantly **elevated Ghrelin** levels (the "hunger hormone"), which drives the insatiable appetite. * **Clinical Triad:** Hypotonia (infancy), hyperphagia/obesity (childhood), and hypogonadism. * **Diagnostic Test:** DNA methylation analysis is the gold standard.

Q: What is the most common type of Class II mutation in cystic fibrosis?

Deletion. **Explanation:** Cystic Fibrosis (CF) is caused by mutations in the **CFTR gene** (Chromosome 7). These mutations are categorized into six classes based on the functional defect of the protein. **Why Deletion is Correct:** The most common mutation worldwide (found in ~70% of cases) is the **ΔF508 mutation**. This is a **three-nucleotide deletion** resulting in the loss of the amino acid phenylalanine at position 508. This specific mutation falls under **Class II**, where the protein is synthesized but fails to fold correctly. Consequently, it is retained in the endoplasmic reticulum and degraded by the proteasome, never reaching the cell membrane. **Analysis of Incorrect Options:** * **Missense Mutation:** While missense mutations occur in CF (e.g., G551D), they typically belong to **Class III** (defective gating/regulation), where the protein reaches the membrane but does not open properly. * **Frameshift & Nonsense Mutations:** These generally belong to **Class I** (defective synthesis). They result in premature stop codons, leading to a complete lack of CFTR protein production. **High-Yield Clinical Pearls for NEET-PG:** * **Inheritance:** Autosomal Recessive. * **Diagnosis:** Sweat Chloride Test (>60 mEq/L) is the gold standard. * **Organ Involvement:** Recurrent *Pseudomonas* infections, pancreatic insufficiency (steatorrhea), and bilateral absence of vas deferens (infertility). * **Newer Drugs:** **Lumacaftor** acts as a "chaperone" specifically for Class II (ΔF508) mutations to help the protein reach the surface.

Q: Cleidocranial dysplasia is due to a defect in which gene?

RUNX2. **Explanation:** **Cleidocranial Dysplasia (CCD)** is an autosomal dominant skeletal disorder characterized by the triad of delayed closure of cranial sutures (fontanelles), absent or hypoplastic clavicles, and multiple supernumerary teeth. 1. **Why RUNX2 is correct:** The condition is caused by a mutation in the **RUNX2 gene** (located on chromosome 6p21). RUNX2 (Runt-related transcription factor 2) is a master transcription factor essential for **osteoblast differentiation** and chondrocyte maturation. Without functional RUNX2, the precursor mesenchymal cells cannot differentiate into osteoblasts, leading to defective intramembranous and endochondral ossification. 2. **Why the other options are incorrect:** * **RANKL (Option A):** This ligand is involved in osteoclast activation. Mutations or imbalances in the RANK/RANKL pathway are associated with Osteopetrosis or Paget’s disease, not CCD. * **HOXD13 (Option C):** Mutations in this homeobox gene lead to **Synpolydactyly** (fusion and extra digits). It governs limb pattern formation rather than generalized bone ossification. * **COL2A1 (Option D):** This gene encodes Type II collagen. Mutations result in **Type II Collagenopathies**, such as Stickler syndrome and Achondrogenesis Type II, characterized by joint problems and vitreoretinal degeneration. **High-Yield Clinical Pearls for NEET-PG:** * **Dental Findings:** CCD is a classic cause of **delayed eruption of permanent teeth** and the presence of multiple **supernumerary teeth**. * **Physical Sign:** Patients can often "bring their shoulders together" in the midline due to the absence of clavicles. * **Stature:** Patients typically have short stature and a "brachycephalic" (wide) skull.

Question 1

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 2

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 3

Examine the given pedigree chart. Which one of the following diseases is the most likely for this situation?

Accepted Answer

Beta-thalassemia

Answer

Neurofibromatosis

Answer

Colour blindness

Answer

Vitamin D resistant rickets

Question 4

AST/ALT ratio > 2 is seen in deficiency of which enzyme?

Accepted Answer

Acid maltase

Answer

G-6-phosphatase

Answer

Branching enzyme

Answer

Liver phosphorylase

Question 5

'I' cells disease is due to a defect in which cellular organelle?

Accepted Answer

Golgi apparatus

Answer

Peroxisome

Answer

Mitochondria

Answer

Lysosome

Question 6

The gene involved in Rett's syndrome is:

Accepted Answer

MeCP2

Answer

P53

Answer

Rb

Answer

FGFR3

Question 7

Which of the following genetic factors does NOT increase susceptibility and modify the severity of pancreatic injury in acute pancreatitis?

Accepted Answer

ATP7a gene mutation

Answer

Cationic trypsinogen mutations

Answer

Pancreatic secretory trypsin inhibitor

Answer

CFTR

Question 8

Which hormone levels are increased in Prader-Willi syndrome?

Accepted Answer

GHRH (Growth Hormone Releasing Hormone)

Answer

TSH

Answer

Growth hormone

Answer

Peptide YY

Question 9

What is the most common type of Class II mutation in cystic fibrosis?

Accepted Answer

Deletion

Answer

Missense mutation

Answer

Frameshift

Answer

Nonsense

Question 10

Cleidocranial dysplasia is due to a defect in which gene?

Accepted Answer

RUNX2

Answer

RANKL

Answer

HOXD13

Answer

COL2A1

Genetic Disorders and Biochemical Pathology — MCQs

Genetic Disorders and Biochemical Pathology — MCQs

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