Genetic Disorders and Biochemical Pathology — MCQs

Genetic Disorders and Biochemical Pathology Indian Medical PG Practice Questions and MCQs

Question 561: What is the mode of inheritance for Familial Hypercholesterolemia?

A. Autosomal dominant (Correct Answer)
B. Autosomal recessive
C. X-linked dominant
D. X-linked recessive

Explanation: **Explanation:** **Familial Hypercholesterolemia (FH)** is primarily caused by mutations in the **LDLR gene**, which encodes the Low-Density Lipoprotein (LDL) receptor. It follows an **Autosomal Dominant** inheritance pattern. In this condition, a single mutated allele (heterozygous state) is sufficient to reduce the number of functional LDL receptors by 50%, leading to significantly elevated plasma LDL levels and premature atherosclerosis. * **Why Autosomal Dominant is correct:** The disease manifests in both heterozygotes (1 in 250 people) and homozygotes (1 in 1 million). Because the "dosage" of the functional protein is critical for cholesterol clearance, the presence of one abnormal gene significantly alters the phenotype. * **Why others are incorrect:** * **Autosomal Recessive:** While a rare form (ARH) exists due to LDLRAP1 mutations, the classic FH (Type IIa Hyperlipoproteinemia) is classically dominant. * **X-linked:** The LDLR gene is located on **Chromosome 19**, an autosome; therefore, it does not show sex-linked inheritance patterns. **High-Yield Clinical Pearls for NEET-PG:** * **Molecular Defect:** Most commonly a mutation in the **LDL receptor**, but can also involve **ApoB-100** (ligand defect) or **PCSK9** (increased receptor degradation). * **Clinical Triad:** Extremely high LDL-C, **Tendon Xanthomas** (specifically the Achilles tendon), and **Arcus Senilis** (corneal arcus) at a young age. * **Homozygous FH:** Presents in childhood with LDL >600 mg/dL and myocardial infarction often before age 20. * **Treatment:** Statins are first-line; PCSK9 inhibitors (Evolocumab) are used for refractory cases.

Question 562: Excessive insulin levels are associated with which of the following conditions?

A. Diabetes mellitus
B. Pancreatic cancer (Correct Answer)
C. Zollinger-Ellison syndrome
D. Pheochromocytoma

Explanation: **Explanation:** The correct answer is **Pancreatic cancer**, specifically referring to **Insulinomas**, which are neuroendocrine tumors derived from pancreatic beta cells. These tumors autonomously secrete excessive amounts of insulin, leading to profound hypoglycemia. While not all pancreatic cancers cause hyperinsulinemia (adenocarcinomas typically do not), in the context of this MCQ, the insulinoma subtype is the classic association for excessive insulin levels. **Analysis of Options:** * **A. Diabetes mellitus:** Type 1 DM is characterized by an absolute insulin deficiency, while Type 2 DM involves insulin resistance. Although early Type 2 DM may show compensatory hyperinsulinemia, the hallmark of the disease progression is eventual beta-cell exhaustion and insulin deficiency. * **C. Zollinger-Ellison syndrome:** This condition is caused by a gastrin-secreting tumor (gastrinoma), usually in the pancreas or duodenum. It leads to excessive gastric acid production and peptic ulcers, not elevated insulin. * **D. Pheochromocytoma:** This is a catecholamine-secreting tumor of the adrenal medulla. Catecholamines (epinephrine/norepinephrine) actually **inhibit** insulin secretion via alpha-2 adrenergic receptors and promote glycogenolysis, leading to hyperglycemia. **High-Yield Clinical Pearls for NEET-PG:** * **Whipple’s Triad (for Insulinoma):** 1. Symptoms of hypoglycemia, 2. Low plasma glucose (<50 mg/dL), 3. Relief of symptoms after glucose administration. * **Diagnostic Marker:** In insulinoma, both **Insulin** and **C-peptide** levels are elevated (distinguishing it from exogenous insulin surreptitious injection, where C-peptide is low). * **Localization:** Most insulinomas are benign, solitary, and part of the **MEN1 syndrome** (3 Ps: Pituitary, Parathyroid, Pancreas).

Question 563: Hers disease is due to deficiency of which enzyme?

A. Liver phosphorylase (Correct Answer)
B. Muscle phosphorylase
C. Branching enzyme
D. RBC phosphofructokinase

Explanation: **Explanation:** **Hers Disease (GSD Type VI)** is a glycogen storage disease caused by a deficiency of **Liver Phosphorylase**. This enzyme is responsible for the rate-limiting step of glycogenolysis in the liver, breaking down glycogen into glucose-1-phosphate. When deficient, glycogen accumulates in the liver, leading to hepatomegaly and mild fasting hypoglycemia (milder than Von Gierke’s because gluconeogenesis remains intact). **Analysis of Options:** * **Option A (Correct):** Liver phosphorylase deficiency leads to Hers disease. It presents with growth retardation and hepatomegaly in early childhood. * **Option B (Incorrect):** Deficiency of **Muscle Phosphorylase** causes **McArdle Disease (GSD Type V)**, characterized by exercise-induced muscle cramps and myoglobinuria. * **Option C (Incorrect):** Deficiency of the **Branching Enzyme** (α-1,4 → α-1,6 transglucosidase) causes **Andersen Disease (GSD Type IV)**, which typically leads to liver cirrhosis and early infantile death. * **Option D (Incorrect):** Deficiency of **Phosphofructokinase (PFK-1)** in muscles and RBCs causes **Tarui Disease (GSD Type VII)**, presenting similarly to McArdle disease but with associated hemolytic anemia. **High-Yield Clinical Pearls for NEET-PG:** * **Mnemonic:** Remember **"H"** for **H**ers and **H**epatic phosphorylase; **"M"** for **M**cArdle and **M**uscle phosphorylase. * Unlike Type I (Von Gierke), Hers disease typically has **normal** levels of lactate and uric acid. * Ketosis is a common finding in Hers disease during fasting. * **GSD Type VI and IX** (Phosphorylase kinase deficiency) are clinically similar and often grouped together as they both affect the activation of liver phosphorylase.

Question 564: What is the mode of inheritance for Becker muscular dystrophy?

A. X-linked recessive (Correct Answer)
B. X-linked dominant
C. Autosomal dominant
D. Autosomal recessive

Explanation: **Explanation:** **Becker Muscular Dystrophy (BMD)** is caused by mutations in the **DMD gene** located on the short arm of the **X chromosome (Xp21)**. This gene encodes for **dystrophin**, a vital protein that anchors the cytoskeleton of muscle fibers to the extracellular matrix. 1. **Why X-linked Recessive (XLR) is correct:** The DMD gene is located on the X chromosome. Because it is a recessive trait, the disease primarily affects males (who have only one X chromosome), while females are typically asymptomatic carriers. BMD is characterized by **"in-frame" mutations**, leading to the production of a truncated but partially functional dystrophin protein. This results in a milder clinical phenotype compared to Duchenne Muscular Dystrophy (DMD), which involves "out-of-frame" mutations and a total absence of dystrophin. 2. **Why other options are incorrect:** * **X-linked Dominant:** If this were the case, both males and females would be equally and severely affected in every generation, which does not match the clinical pedigree of BMD. * **Autosomal Dominant/Recessive:** These would imply the gene is located on non-sex chromosomes (1-22). While some Limb-Girdle Muscular Dystrophies (LGMD) follow these patterns, BMD is strictly linked to the X chromosome. **Clinical Pearls for NEET-PG:** * **Gowers' Sign:** Often positive, though onset is later (teens/early adulthood) than in Duchenne. * **Dystrophin Levels:** Reduced or qualitatively altered in BMD; absent in DMD. * **Cardiac Involvement:** Dilated cardiomyopathy is a common complication and can sometimes be the presenting feature. * **Lab Finding:** Significantly elevated **Creatine Kinase (CK)** levels. * **Inheritance Rule:** An affected father cannot pass the gene to his sons but will pass it to all his daughters (carriers).

Question 565: Fish odour syndrome can be prevented by the intake of which vitamin?

A. Choline (Correct Answer)
B. Niacin
C. Pantothenic acid
D. Riboflavin

Explanation: **Explanation:** **Fish Odor Syndrome (Trimethylaminuria)** is a metabolic disorder characterized by the body's inability to convert **trimethylamine (TMA)**—a compound with a pungent, fishy smell—into the odorless **trimethylamine N-oxide (TMAO)**. This conversion is normally catalyzed by the enzyme **Flavin-containing monooxygenase 3 (FMO3)**. **Why Choline is the Correct Answer:** While the question asks which vitamin intake can "prevent" or manage the condition, it refers to the dietary modification of precursors. Trimethylamine is produced by intestinal bacteria from dietary precursors, primarily **Choline**, betaine, and lecithin. Therefore, **restricting the intake of Choline** (found in eggs, liver, and legumes) is the primary dietary intervention to prevent the accumulation of TMA and the resulting malodor. *Note: In some clinical contexts, Riboflavin (Vitamin B2) is supplemented to enhance residual FMO3 enzyme activity, but Choline restriction remains the definitive dietary "prevention" strategy for symptom management.* **Analysis of Incorrect Options:** * **Niacin (B3):** Involved in redox reactions (NAD/NADP) but has no direct role in the FMO3 pathway or TMA metabolism. * **Pantothenic acid (B5):** A precursor to Coenzyme A; it is essential for fatty acid metabolism but unrelated to fish odor syndrome. * **Riboflavin (B2):** While Riboflavin is a cofactor for FMO3 and is often used as a *treatment* to boost enzyme function, the fundamental dietary prevention strategy focuses on limiting the substrate, Choline. **High-Yield Clinical Pearls for NEET-PG:** * **Enzyme Deficiency:** FMO3 (located on chromosome 1q23). * **Clinical Presentation:** Offensive "rotting fish" body odor in sweat, urine, and breath; often exacerbated during puberty or menstruation. * **Diagnosis:** Measurement of TMA to TMAO ratio in urine. * **Management:** Low-choline diet, short courses of antibiotics (neomycin/metronidazole) to reduce gut flora, and acidic soaps (pH 5.5–6.5) to retain TMA in a less volatile salt form.

Question 566: All are important pathological features noted in ATP7B gene mutation, EXCEPT?

A. Low serum ceruloplasmin
B. Low serum free copper (Correct Answer)
C. Low serum copper
D. Positive copper balance

Explanation: **Explanation:** The question describes **Wilson’s Disease (Hepatolenticular Degeneration)**, an autosomal recessive disorder caused by a mutation in the **ATP7B gene** on chromosome 13. This gene encodes a P-type ATPase responsible for transporting copper into the Golgi apparatus for incorporation into apoceruloplasmin and for excreting excess copper into bile. **Why "Low serum free copper" is the correct answer (The Exception):** In Wilson’s disease, copper cannot be excreted into bile or bound to ceruloplasmin. Consequently, copper leaks out of hepatocytes into the blood in its **unbound (free) form**. Therefore, **serum free copper is actually elevated** (>25 µg/dL), leading to its deposition in tissues like the liver, brain (basal ganglia), and cornea (Kayser-Fleischer rings). **Analysis of Incorrect Options:** * **A. Low serum ceruloplasmin:** This is a hallmark of the disease. Failure to incorporate copper into apoceruloplasmin leads to the release of an unstable molecule that is rapidly degraded in the circulation. * **C. Low serum copper:** Since ~90% of total serum copper is normally bound to ceruloplasmin, a significant drop in ceruloplasmin levels leads to a decrease in **total** serum copper, even though the "free" fraction is high. * **D. Positive copper balance:** Due to the defect in biliary excretion, copper progressively accumulates in the body, creating a state of positive copper balance. **High-Yield Clinical Pearls for NEET-PG:** * **Gold Standard Diagnosis:** Liver biopsy showing increased copper content (>250 µg/g dry weight). * **Screening Test:** Serum ceruloplasmin (usually <20 mg/dL). * **Most Sensitive/Initial Test:** 24-hour urinary copper excretion (>100 µg/day). * **Treatment:** Chelators like **D-Penicillamine** (first-line) or Trientine; Zinc (inhibits intestinal absorption). * **Neurological Sign:** "Giant Panda" sign on MRI midbrain.

Question 567: Which X-linked recessive disorder is characterized by mental retardation and self-mutilation?

A. Lesch-Nyhan syndrome (Correct Answer)
B. Fragile X syndrome
C. Down syndrome
D. All of the above

Explanation: **Explanation:** **Lesch-Nyhan Syndrome (LNS)** is the correct answer because it is a classic X-linked recessive disorder caused by a complete deficiency of the enzyme **Hypoxanthine-Guanine Phosphoribosyltransferase (HGPRT)**. This enzyme is crucial for the purine salvage pathway. Its absence leads to the overproduction of uric acid and an accumulation of PRPP (Phosphoribosyl pyrophosphate). Clinically, it is uniquely characterized by the triad of **hyperuricemia** (gout, renal stones), **neurological impairment** (intellectual disability, spasticity), and hallmark **self-mutilating behavior** (compulsive biting of lips and fingers). **Why other options are incorrect:** * **Fragile X Syndrome:** While it is an X-linked cause of mental retardation and may involve some behavioral issues (like hand-flapping), it is not typically associated with the severe, compulsive self-mutilation seen in LNS. It is caused by a CGG trinucleotide repeat expansion in the *FMR1* gene. * **Down Syndrome:** This is a chromosomal disorder (Trisomy 21), not X-linked recessive. While it causes intellectual disability, it does not present with self-mutilation or hyperuricemia. **High-Yield Clinical Pearls for NEET-PG:** * **Mnemonic for HGPRT deficiency:** **H**yperuricemia, **G**out, **P**issed off (aggression/self-mutilation), **R**etardation, **T**one (dystonia). * **Biochemical marker:** Increased levels of **De novo purine synthesis** to compensate for the failed salvage pathway. * **Treatment:** Allopurinol or Febuxostat (to manage uric acid), but these do not improve neurological symptoms. * **Inheritance:** Exclusively affects males; females are typically asymptomatic carriers.

Question 568: Which of the following is NOT an enzyme deficiency responsible for gout?

A. PRPP synthase
B. Enzyme responsible for pseudogout (Correct Answer)
C. 5-phosphoribosyl pyrophosphate amidotransferase
D. Glucose-6-phosphatase

Explanation: **Explanation** Gout is a disorder of purine metabolism characterized by hyperuricemia and the deposition of monosodium urate crystals in joints. The correct answer is **B (Enzyme responsible for pseudogout)** because pseudogout is caused by the deposition of **calcium pyrophosphate dihydrate (CPPD)** crystals, not uric acid. It is typically associated with abnormalities in pyrophosphate metabolism (e.g., mutations in the ANKH gene) or hyperparathyroidism, rather than the purine pathway. **Analysis of Incorrect Options:** * **PRPP Synthase (Option A):** Overactivity (gain-of-function mutation) of this enzyme leads to increased production of PRPP, which accelerates de novo purine synthesis, resulting in hyperuricemia and gout. * **5-phosphoribosyl pyrophosphate amidotransferase (Option C):** This is the rate-limiting enzyme of purine synthesis. Loss of feedback inhibition or overactivity leads to excessive purine production and subsequent gout. * **Glucose-6-phosphatase (Option D):** Deficiency causes **Von Gierke Disease (GSD Type I)**. This leads to gout via two mechanisms: (1) Shunting of G6P into the Pentose Phosphate Pathway, increasing PRPP levels, and (2) Lactic acidosis, which competes with uric acid for excretion in the kidneys. **High-Yield Clinical Pearls for NEET-PG:** * **Lesch-Nyhan Syndrome:** Deficiency of HGPRT (salvage pathway) leads to severe gout, self-mutilation, and intellectual disability. * **Crystal Morphology:** Gout shows **needle-shaped**, negatively birefringent crystals (yellow when parallel). Pseudogout shows **rhomboid-shaped**, positively birefringent crystals (blue when parallel). * **Drug of Choice:** NSAIDs for acute gout; Allopurinol (Xanthine Oxidase inhibitor) for chronic management.

Question 569: Which of the following is TRUE about Turner's syndrome?

A. Short stature
B. Streak gonads
C. Normal intelligence (Correct Answer)
D. Normal breast development

Explanation: **Explanation:** Turner’s syndrome (45,X) is the most common sex chromosome abnormality in females. The correct answer is **Normal intelligence**, as most individuals with Turner’s syndrome have a normal IQ, although they may occasionally face specific neurocognitive challenges, such as difficulties with visuospatial processing or non-verbal memory. **Analysis of Options:** * **A & B (Short stature and Streak gonads):** These are the **most consistent clinical features** of Turner’s syndrome. Short stature is caused by the haploinsufficiency of the *SHOX* gene. Streak gonads (gonadal dysgenesis) occur because oocytes undergo accelerated atresia, leading to primary amenorrhea and infertility. Since these are classic pathological findings, they are "true" features, but in the context of multiple-choice questions, "Normal intelligence" is often highlighted to differentiate it from autosomal trisomies (like Down syndrome) where intellectual disability is the rule. * **D (Normal breast development):** This is **incorrect**. Due to streak gonads, there is a deficiency of estrogen. This leads to a failure of secondary sexual characteristics, resulting in poor breast development (Tanner Stage I/II) and a "shield chest" with widely spaced nipples. **High-Yield Clinical Pearls for NEET-PG:** * **Karyotype:** 45,XO is most common (50%), but mosaicism (45,X/46,XX) and structural abnormalities (isochromosome Xq) also occur. * **Cardiovascular:** Bicuspid aortic valve (most common) and Coarctation of the aorta. * **Renal:** Horseshoe kidney. * **Physical Signs:** Webbed neck (cystic hygroma remnant), lymphedema of hands/feet at birth, and cubitus valgus. * **Hormonal Profile:** Hypergonadotropic hypogonadism (High FSH/LH, Low Estrogen).

Question 570: Enzyme replacement therapy is available for the treatment of which of the following disorders?

A. Gaucher's disease (Correct Answer)
B. Niemann-Pick disease
C. Hunter syndrome
D. Phenylketonuria

Explanation: **Explanation:** **Enzyme Replacement Therapy (ERT)** involves the intravenous administration of a functional recombinant enzyme to compensate for a deficiency in patients with lysosomal storage disorders (LSDs). **Why Gaucher’s Disease is Correct:** Gaucher’s disease, the most common lysosomal storage disorder, is caused by a deficiency of **Glucocerebrosidase (β-glucosidase)**. It was the first LSD for which ERT was developed. **Imiglucerase** (recombinant glucocerebrosidase) is the gold standard treatment, effectively reducing hepatosplenomegaly and improving hematological parameters (anemia and thrombocytopenia). **Analysis of Incorrect Options:** * **Niemann-Pick Disease:** While ERT (Olipudase alfa) has recently been approved for Type B (Non-neuronopathic), it is not yet considered the conventional "textbook" answer for ERT in many competitive exams compared to Gaucher’s. Type A and C (neurological forms) do not respond to ERT as the enzyme cannot cross the blood-brain barrier. * **Hunter Syndrome (MPS II):** Although ERT (Idursulfase) exists for Hunter syndrome, Gaucher’s remains the classic example of successful ERT implementation in biochemistry curricula. (Note: In some clinical contexts, both A and C could be correct, but Gaucher is the primary prototype). * **Phenylketonuria (PKU):** This is a metabolic disorder of amino acids, not a lysosomal storage disease. It is primarily managed via **dietary restriction of phenylalanine** and supplementation of tyrosine. **High-Yield Clinical Pearls for NEET-PG:** * **Gaucher Cells:** Characterized by a "wrinkled paper" or "crumpled silk" appearance of the cytoplasm (lipid-laden macrophages). * **First ERT:** Ceredase (alglucerase) derived from human placenta was the first, now replaced by recombinant Imiglucerase. * **Other ERT Examples:** Fabry disease (Agalsidase beta), Pompe disease (Alglucosidase alfa), and Hurler syndrome (Laronidase). * **Limitation:** ERT is generally ineffective for the **neuropathic** symptoms of these diseases (e.g., Gaucher Type 2/3) because the enzymes are large proteins that cannot cross the **blood-brain barrier**.

Practice by Chapter

Single Gene Disorders

Practice Questions

Biochemical Diagnosis of Genetic Disorders

Practice Questions

Inborn Errors of Metabolism

Practice Questions

Lysosomal Storage Diseases

Practice Questions

Glycogen Storage Diseases

Practice Questions

Disorders of Lipoprotein Metabolism

Practice Questions

Disorders of Purine and Pyrimidine Metabolism

Practice Questions

Hemoglobinopathies

Practice Questions

Porphyrias

Practice Questions

Biochemical Markers for Disease Diagnosis

Practice Questions

Newborn Screening for Genetic Disorders

Practice Questions

Enzyme Replacement Therapy

Practice Questions

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