Genetic Disorders and Biochemical Pathology — MCQs

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

Question 171: Sickle cell anemia is due to which type of mutation?

A. Frame-shift mutation
B. Base substitution mutation (Correct Answer)
C. Trinucleotide repeat
D. Splice site mutation

Explanation: **Explanation:** **Sickle Cell Anemia (SCA)** is a classic example of a **Point Mutation**, specifically a **Base Substitution**. 1. **Why Option B is Correct:** In SCA, there is a single base substitution in the **6th codon** of the **$\beta$-globin gene** on chromosome 11. The DNA sequence changes from **GAG to GTG**. This results in the replacement of **Glutamic acid** (a polar, hydrophilic amino acid) with **Valine** (a non-polar, hydrophobic amino acid) at the 6th position of the $\beta$-polypeptide chain. This single change causes the hemoglobin (HbS) to polymerize under deoxygenated conditions, leading to the characteristic "sickling" of RBCs. 2. **Why Other Options are Incorrect:** * **A. Frame-shift mutation:** This involves the insertion or deletion of nucleotides (not in multiples of three), altering the entire reading frame. Examples include certain types of **$\beta$-Thalassemia** and Duchenne Muscular Dystrophy. * **C. Trinucleotide repeat:** This involves the expansion of specific three-base sequences. Examples include **Huntington’s disease** (CAG) and **Fragile X syndrome** (CGG). * **D. Splice site mutation:** This occurs at the intron-exon junctions, leading to improper mRNA processing. This is a common cause of **$\beta$-Thalassemia**. **High-Yield Clinical Pearls for NEET-PG:** * **Inheritance:** Autosomal Recessive. * **Electrophoresis:** HbS moves **slowest** toward the anode compared to HbA and HbF (due to loss of negative charge from Glutamic acid). * **Protective Effect:** Heterozygotes (Sickle cell trait) are protected against *Plasmodium falciparum* malaria. * **Diagnosis:** Solubility test (screening) and Hb Electrophoresis (confirmatory).

Question 172: Which of the following statements regarding Ataxia Telangiectasia is TRUE?

A. It is an autosomal dominant disorder.
B. It is associated with an increased risk of developing squamous cell carcinoma of the skin.
C. It involves a defect in gene repair mechanisms. (Correct Answer)
D. It is most commonly observed in adults.

Explanation: **Explanation:** **Ataxia Telangiectasia (AT)** is a multisystem disorder caused by a mutation in the **ATM (Ataxia-Telangiectasia Mutated) gene** located on chromosome 11q22-23. The ATM protein is a serine-threonine kinase that plays a critical role in detecting **double-stranded DNA breaks**. When DNA damage occurs (e.g., from ionizing radiation), ATM activates cell cycle checkpoints (like p53) to stop the cell cycle for repair or trigger apoptosis. A defect in this gene leads to genomic instability, explaining why **Option C** is correct. **Analysis of Incorrect Options:** * **Option A:** AT is an **autosomal recessive** disorder, not dominant. Consanguinity is often a risk factor. * **Option B:** While AT patients have a high risk of malignancies, they are specifically predisposed to **lymphomas and leukemias** (due to defective V(D)J recombination) rather than squamous cell carcinoma. Skin cancers are more characteristic of Xeroderma Pigmentosum (defect in nucleotide excision repair). * **Option D:** AT is a **pediatric-onset** disease. Symptoms like progressive cerebellar ataxia usually manifest when the child begins to walk, and telangiectasias appear later (ages 3–6). **High-Yield Clinical Pearls for NEET-PG:** 1. **Clinical Triad:** Cerebellar ataxia, Oculocutaneous telangiectasia, and Recurrent sinopulmonary infections (due to IgA deficiency). 2. **Diagnostic Marker:** Elevated **Alpha-Fetoprotein (AFP)** levels after age 2 is a highly characteristic laboratory finding. 3. **Radiosensitivity:** Patients are hypersensitive to **ionizing radiation** (X-rays/CT scans); diagnostic imaging should be used sparingly. 4. **Other DNA Repair Defects:** Contrast with *Xeroderma Pigmentosum* (UV/Pyrimidine dimers) and *Lynch Syndrome* (Mismatch repair).

Question 173: The phenomenon where subsequent generations are at risk of earlier and more severe disease is known as:

A. Anticipation (Correct Answer)
B. Pleiotropy
C. Imprinting
D. Mosaicism

Explanation: **Explanation:** **Correct Answer: A. Anticipation** Anticipation is a genetic phenomenon where a disease manifests at an **earlier age of onset** and with **increased severity** in successive generations. This is most commonly associated with **Trinucleotide Repeat Expansion** disorders. As the gene is passed from parent to offspring, the number of repeats often increases (expands) during gametogenesis; a higher number of repeats typically correlates with more severe symptoms and earlier presentation. Classic examples include **Huntington’s disease** (CAG repeats), **Fragile X syndrome** (CGG repeats), and **Myotonic Dystrophy** (CTG repeats). **Incorrect Options:** * **B. Pleiotropy:** Refers to a single gene mutation affecting multiple, seemingly unrelated phenotypic traits or organ systems (e.g., Marfan syndrome affecting the heart, eyes, and skeleton). * **C. Imprinting:** An epigenetic process where the expression of a gene depends on whether it was inherited from the mother or the father (e.g., Prader-Willi and Angelman syndromes). * **D. Mosaicism:** The presence of two or more populations of cells with different genotypes in one individual, derived from a single zygote (e.g., Turner syndrome 45,X/46,XX). **High-Yield Clinical Pearls for NEET-PG:** * **Huntington’s Disease:** Shows paternal transmission bias for anticipation (repeats expand more during spermatogenesis). * **Fragile X Syndrome:** Shows maternal transmission bias for expansion. * **Friedreich’s Ataxia:** An exception; it is an autosomal recessive trinucleotide repeat disorder (GAA) but does not typically show classic anticipation. * **Diagnosis:** Gold standard for detecting repeat expansions is **PCR** or **Southern Blot**.

Question 174: In Familial hypercholesterolemia, which of the following is primarily affected?

A. LDL receptor (Correct Answer)
B. Apo protein A
C. Apo protein C
D. Lipoprotein lipase

Explanation: **Explanation:** **Familial Hypercholesterolemia (FH)** is an autosomal dominant disorder characterized by significantly elevated plasma levels of Low-Density Lipoprotein (LDL) cholesterol. **1. Why Option A is Correct:** The primary defect in FH is a mutation in the **LDL receptor (LDLR) gene**. Under normal conditions, the LDL receptor on the liver surface binds to Apo B-100 on LDL particles to facilitate their endocytosis. A deficiency or dysfunction of these receptors leads to decreased clearance of LDL from the blood, resulting in severe hypercholesterolemia and premature atherosclerosis. (Note: Mutations in *Apo B-100* or *PCSK9* can also cause FH, but LDLR mutation is the most common cause). **2. Why Incorrect Options are Wrong:** * **Apo protein A:** This is the primary protein component of **HDL** (the "good" cholesterol). Deficiencies are associated with Tangier disease, not FH. * **Apo protein C:** Apo C-II is a cofactor for Lipoprotein Lipase (LPL). Deficiency leads to **Type I Hyperlipoproteinemia** (Familial Chylomicronemia Syndrome), characterized by high triglycerides, not isolated high LDL. * **Lipoprotein lipase (LPL):** LPL deficiency also leads to **Type I Hyperlipoproteinemia**, resulting in massive elevation of chylomicrons and triglycerides. **3. High-Yield Clinical Pearls for NEET-PG:** * **Classification:** FH is classified as **Fredrickson Type IIa Hyperlipoproteinemia**. * **Clinical Features:** Look for **Tendon Xanthomas** (especially the Achilles tendon) and **Xanthelasmas** (eyelids). * **Genetics:** Homozygous individuals present in childhood with myocardial infarction; Heterozygous individuals typically present in their 30s-40s. * **Treatment:** Statins are the first-line treatment (they upregulate the expression of remaining functional LDL receptors).

Question 175: What is the chromosomal complement in individuals with Klinefelter's syndrome?

A. 45, XO
B. 47, XXX
C. 46, XY
D. 47, XXY (Correct Answer)

Explanation: **Explanation:** **1. Why Option D is Correct:** Klinefelter’s syndrome is the most common sex chromosome disorder affecting males, occurring in approximately 1 in 600 live births. It is characterized by the presence of an **extra X chromosome** in a phenotypic male, resulting in the **47, XXY** karyotype. This occurs primarily due to **meiotic non-disjunction** of the sex chromosomes during gametogenesis (more commonly maternal in origin). The presence of the Y chromosome ensures male differentiation, but the extra X chromosome leads to testicular dysgenesis and subsequent androgen deficiency. **2. Analysis of Incorrect Options:** * **Option A (45, XO):** This represents **Turner Syndrome**, characterized by a phenotypic female with short stature and streak ovaries. * **Option B (47, XXX):** This is **Triple X Syndrome** (Superfemale), which typically presents in females who may be asymptomatic or have mild learning disabilities. * **Option C (46, XY):** This is the normal male chromosomal complement. **3. NEET-PG High-Yield Clinical Pearls:** * **Clinical Features:** Tall stature, eunuchoid body proportions (increased arm span), gynecomastia, small firm testes, and infertility (azoospermia). * **Biochemical Profile:** Due to testicular atrophy (specifically Leydig cell dysfunction and seminiferous tubule hyalinization), there is **decreased Testosterone**, **increased LH**, and **increased FSH** (Hypergonadotropic Hypogonadism). * **Cytogenetics:** A **Barr body** (inactivated X chromosome) is visible on a buccal smear, which is normally absent in males. * **Associated Risks:** Increased risk of breast cancer, extragonadal germ cell tumors, and autoimmune diseases (like SLE).

Question 176: All of the following are lysosomal storage disorders, except?

A. Gaucher's disease
B. Tay-Sachs disease
C. Niemann-Pick disease
D. Von Gierke's disease (Correct Answer)

Explanation: **Explanation:** The correct answer is **Von Gierke’s disease** because it is a **Glycogen Storage Disease (GSD Type I)**, not a Lysosomal Storage Disorder (LSD). It is caused by a deficiency of the enzyme **Glucose-6-Phosphatase** in the liver and kidneys. Unlike LSDs, where undigested substrates accumulate within lysosomes, Von Gierke’s involves the accumulation of glycogen in the **cytosol** and endoplasmic reticulum, leading to severe fasting hypoglycemia, hepatomegaly, and hyperuricemia. **Analysis of Incorrect Options:** * **Gaucher’s Disease:** The most common LSD. It is caused by a deficiency of **$\beta$-Glucocerebrosidase**, leading to the accumulation of glucocerebroside in macrophages (Gaucher cells). * **Tay-Sachs Disease:** An LSD caused by a deficiency of **Hexosaminidase A**, resulting in the accumulation of GM2 gangliosides. It is characterized by a cherry-red spot on the macula and neurodegeneration. * **Niemann-Pick Disease:** An LSD caused by a deficiency of **Sphingomyelinase**, leading to sphingomyelin accumulation. It presents with hepatosplenomegaly and a cherry-red spot. **NEET-PG High-Yield Pearls:** 1. **Pompe’s Disease (GSD Type II)** is the only Glycogen Storage Disease that is *also* classified as a Lysosomal Storage Disorder (deficiency of lysosomal $\alpha$-1,4-glucosidase). 2. **Enzyme Replacement Therapy (ERT)** is available for Gaucher’s but not for Von Gierke’s (managed by frequent cornstarch feeds). 3. **I-Cell Disease** is a unique LSD where multiple lysosomal enzymes are missing due to a failure in Golgi trafficking (Mannose-6-Phosphate tagging).

Question 177: What is the chance of a child having cystic fibrosis if one parent is a carrier and the other is unaffected and not a carrier?

A. 0%
B. 25% (Correct Answer)
C. 50%
D. 100%

Explanation: ### Explanation **1. Understanding the Correct Answer (B):** Cystic Fibrosis (CF) is an **Autosomal Recessive (AR)** disorder caused by mutations in the *CFTR* gene on chromosome 7. For a child to manifest the disease, they must inherit two defective alleles (homozygous recessive). In this scenario: * **Parent 1 (Carrier):** Genotype **Aa** (one normal allele, one mutant allele). * **Parent 2 (Unaffected/Non-carrier):** Genotype **AA** (two normal alleles). Using a Punnett Square (Aa x AA), the possible offspring genotypes are: * 50% **AA** (Unaffected, non-carrier) * 50% **Aa** (Unaffected carrier) * **0% aa** (Affected with Cystic Fibrosis) **Wait!** There is a discrepancy in the provided key. Mathematically, the chance of having the disease (aa) is **0%**. However, in medical entrance exams, if "25%" is marked as correct, it typically refers to the standard AR inheritance pattern where *both* parents are carriers (Aa x Aa). If the question strictly defines one parent as a non-carrier (AA), the biological risk is 0%. **2. Analysis of Incorrect Options:** * **Option A (0%):** This is the genetically accurate answer for the specific scenario described (Aa x AA). * **Option B (25%):** This is the risk when **both** parents are carriers (Aa x Aa). This is the most "high-yield" number for AR disorders in exams. * **Option C (50%):** This is the risk if one parent is affected (aa) and the other is a carrier (Aa)—a scenario known as "Pseudodominance." * **Option D (100%):** This only occurs if both parents are affected (aa x aa). **3. NEET-PG Clinical Pearls:** * **Most common mutation:** ΔF508 (deletion of phenylalanine at position 508), leading to protein misfolding in the ER. * **Diagnosis:** Sweat Chloride Test (>60 mEq/L) is the gold standard. * **Key Association:** Congenital Bilateral Absence of Vas Deferens (CBAVD) leading to male infertility. * **Screening:** Immunoreactive Trypsinogen (IRT) in newborns.

Question 178: A child presents with microcephaly, blue eyes, fair skin, and mental retardation. The ferric chloride test is positive. What is the likely diagnosis?

A. Phenylketonuria (Correct Answer)
B. Homocystinuria
C. Tyrosinosis
D. Alkaptonuria

Explanation: ### Explanation **Correct Option: A. Phenylketonuria (PKU)** The clinical presentation of microcephaly, intellectual disability (mental retardation), and hypopigmentation (blue eyes, fair skin) is classic for **Phenylketonuria**. * **Pathophysiology:** PKU is most commonly caused by a deficiency of the enzyme **Phenylalanine Hydroxylase (PAH)**, leading to the accumulation of Phenylalanine. * **Biochemical Basis of Symptoms:** The lack of Tyrosine (a precursor to melanin) results in fair skin and blue eyes. The accumulation of Phenylalanine and its metabolites (phenylpyruvate, phenyllactate) is neurotoxic, causing microcephaly and mental retardation. * **Diagnostic Test:** The **Ferric Chloride test** detects Phenylpyruvic acid in the urine, yielding a characteristic **blue-green** color. **Why Incorrect Options are Wrong:** * **B. Homocystinuria:** Characterized by ectopia lentis (downward dislocation), marfanoid habitus, and thromboembolic episodes. The cyanide-nitroprusside test is used for screening, not ferric chloride. * **C. Tyrosinosis (Tyrosinemia Type I):** Presents with liver failure, renal tubular dysfunction (Fanconi syndrome), and a "cabbage-like" odor. * **D. Alkaptonuria:** Caused by Homogentisate oxidase deficiency. It presents with ochronosis (darkening of tissues) and arthritis. While the ferric chloride test can be positive (transient deep blue), it lacks the triad of hypopigmentation and mental retardation. **High-Yield Clinical Pearls for NEET-PG:** * **Mousy/Musty Odor:** A hallmark sign of PKU due to phenylacetic acid in sweat and urine. * **Guthrie Test:** A bacterial inhibition assay used for neonatal screening of PKU. * **Management:** Dietary restriction of Phenylalanine and supplementation of Tyrosine (which becomes an essential amino acid in these patients). * **Maternal PKU:** If a mother with PKU does not maintain a strict diet during pregnancy, the fetus may suffer from microcephaly and congenital heart defects, even if the fetus is heterozygous.

Question 179: A 7-year-old boy presents with compulsive self-mutilation and intellectual disability. He requires physical restraints due to his behavior. Laboratory investigations reveal an elevated serum uric acid level. What is the enzyme deficiency associated with this disorder?

A. PRPP Synthetase
B. Xanthine oxidase
C. Hypoxanthine Guanine Phosphoribosyl transferase (Correct Answer)
D. Glucose 6 Phosphatase

Explanation: ### Explanation The clinical presentation of **compulsive self-mutilation** (biting of lips and fingers), **intellectual disability**, and **hyperuricemia** in a young boy is pathognomonic for **Lesch-Nyhan Syndrome**. **1. Why the Correct Answer is Right:** Lesch-Nyhan Syndrome is an X-linked recessive disorder caused by a complete deficiency of **Hypoxanthine-Guanine Phosphoribosyltransferase (HGPRT)**. This enzyme is crucial for the **Purine Salvage Pathway**, where it converts hypoxanthine to IMP and guanine to GMP. * **Biochemical Mechanism:** When HGPRT is deficient, these bases cannot be salvaged and are instead degraded into **uric acid**. Furthermore, the lack of salvage leads to an accumulation of **PRPP** (Phosphoribosyl pyrophosphate), which over-activates *de novo* purine synthesis, further exacerbating uric acid production. **2. Why Incorrect Options are Wrong:** * **PRPP Synthetase:** Overactivity (not deficiency) of this enzyme leads to increased purine production and gout, but it does not typically present with the specific neurobehavioral feature of self-mutilation. * **Xanthine Oxidase:** Deficiency of this enzyme leads to **Hereditary Xanthinuria**, characterized by *low* serum uric acid levels and xanthine stones. * **Glucose-6-Phosphatase:** Deficiency causes **Von Gierke Disease (GSD Type I)**. While it causes hyperuricemia (due to diverted G6P entering the HMP shunt and increasing PRPP), the primary features are hepatomegaly, hypoglycemia, and lactic acidosis, not self-mutilation. **3. NEET-PG High-Yield Pearls:** * **Mnemonic for HGPRT:** **H**yperuricemia, **G**out, **P**issed off (aggression/self-mutilation), **R**etardation (intellectual disability), **T**one (dystonia). * **Inheritance:** X-linked recessive (affects males). * **Treatment:** Allopurinol or Febuxostat (manages uric acid but does not fix neurological symptoms). * **Diagnostic finding:** "Orange sand" crystals in the diaper (sodium urate crystals).

Question 180: Deficiency of the enzyme hexosaminidase A subunit causes which of the following diseases?

A. Tay-Sachs disease (Correct Answer)
B. Hurler's syndrome
C. Fabry disease
D. Pompe disease

Explanation: ### Explanation **1. Correct Option: A. Tay-Sachs Disease** Tay-Sachs disease is an autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme **Hexosaminidase A**. This enzyme is responsible for the degradation of **GM2 gangliosides**. Its deficiency leads to the accumulation of these lipids in the lysosomes of neurons, resulting in progressive neurodegeneration. A classic clinical hallmark is the **"Cherry-red spot"** on the macula. **2. Analysis of Incorrect Options:** * **B. Hurler’s Syndrome:** This is a Mucopolysaccharidosis (MPS I) caused by a deficiency of **$\alpha$-L-iduronidase**. It leads to the accumulation of heparan sulfate and dermatan sulfate, characterized by gargoylism, corneal clouding, and hepatosplenomegaly. * **C. Fabry Disease:** This is an X-linked recessive disorder caused by a deficiency of **$\alpha$-galactosidase A**. It results in the accumulation of ceramide trihexoside. Clinical features include angiokeratomas, peripheral neuropathy, and renal failure. * **D. Pompe Disease:** This is a Glycogen Storage Disease (Type II) caused by a deficiency of **Lysosomal $\alpha$-1,4-glucosidase** (Acid Maltase). It leads to glycogen accumulation in the heart and muscles, causing hypertrophic cardiomyopathy. **3. High-Yield Clinical Pearls for NEET-PG:** * **Tay-Sachs vs. Niemann-Pick:** Both present with a cherry-red spot, but Tay-Sachs has **no hepatosplenomegaly**, whereas Niemann-Pick (Sphingomyelinase deficiency) does. * **Histology:** Look for **"Onion-skin"** lysosomes (whorled membranes) in Tay-Sachs. * **Genetics:** Common in the Ashkenazi Jewish population. * **Mnemonic:** Tay-Sa**X** lacks He**X**osaminidase A.

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

Want unlimited practice?

Get full access to all questions, explanations, and performance tracking.

Start For Free