Genetic Disorders and Biochemical Pathology Practice Questions

Q: In sickle cell anaemia, what is the underlying genetic defect?

A base substitution in DNA. Sickle cell anemia (SCA) is a classic example of a **missense mutation**, which is a type of **point mutation** involving a base substitution in the DNA sequence. ### Why Option C is Correct: The molecular basis of SCA involves a single base substitution in the **$\beta$-globin gene** located on chromosome 11. Specifically, the triplet codon **GAG** (which codes for Glutamic acid) is mutated to **GUG** (which codes for Valine) at the **6th position** of the $\beta$-chain. * **The Change:** Adenine (A) is replaced by Thymine (T) in the DNA template (transcribed as Uracil in mRNA). * **The Result:** Glutamic acid (a polar, hydrophilic amino acid) is replaced by Valine (a non-polar, hydrophobic amino acid). This creates a "sticky patch" on the hemoglobin molecule (HbS), leading to polymerization under deoxygenated conditions and the characteristic "sickling" of RBCs. ### Why Other Options are Incorrect: * **Options A & B (Insertion/Deletion):** These mutations typically cause a **frameshift**, altering the entire reading frame of the genetic code from the point of mutation. This usually results in a non-functional protein or a premature stop codon (nonsense mutation), which is seen in certain types of Thalassemia, but not in Sickle Cell Anemia. ### NEET-PG High-Yield Pearls: * **Inheritance:** Autosomal Recessive. * **Electrophoresis:** On alkaline electrophoresis, HbS moves **slower** than HbA toward the anode (due to the loss of negative charge from Glutamic acid). * **Protective Effect:** Heterozygotes (Sickle cell trait) show resistance to *Plasmodium falciparum* malaria. * **Diagnosis:** Solubility test (screening) and Hb Electrophoresis/HPLC (confirmatory).

Q: NARP syndrome is seen in which category of diseases?

Mitochondrial diseases. **Explanation:** **NARP syndrome** (Neurogenic muscle weakness, Ataxia, and Retinitis Pigmentosa) is a classic example of a **mitochondrial disease**. It is caused by a point mutation in the **MT-ATP6 gene** (specifically the T8993G or T8993C mutation) of the mitochondrial DNA (mtDNA). This gene encodes a subunit of ATP synthase (Complex V), the enzyme responsible for the final step of oxidative phosphorylation. A defect here leads to impaired ATP production, primarily affecting high-energy tissues like the brain, nerves, and retina. **Why other options are incorrect:** * **Glycogen storage diseases (GSDs):** These are caused by deficiencies in enzymes involved in glycogen synthesis or breakdown (e.g., Von Gierke, Pompe) [1]. They typically present with hepatomegaly, hypoglycemia, or primary myopathy rather than pigmentary retinopathy. * **Lysosomal storage diseases (LSDs):** These involve defects in lysosomal enzymes leading to the accumulation of macromolecules (e.g., Gaucher, Tay-Sachs) [1]. While they can have neurological features, the specific triad of NARP is absent. * **Lipid storage diseases:** These involve abnormal accumulation of lipids (e.g., Niemann-Pick) [1]. While some present with "cherry-red spots" in the macula, they do not involve the MT-ATP6 mutation characteristic of NARP. **High-Yield Clinical Pearls for NEET-PG:** * **Maternal Inheritance:** Like most mitochondrial diseases, NARP is inherited exclusively from the mother [2]. * **Heteroplasmy:** The severity of NARP depends on the ratio of mutant to normal mtDNA. * **Leigh Syndrome Connection:** If the mutation load of the T8993G mutation exceeds 90%, the phenotype shifts from NARP to the more severe **Maternally Inherited Leigh Syndrome (MILS)**, characterized by subacute necrotizing encephalomyelopathy [3]. * **Key Triad:** Remember NARP as **N**eurogenic weakness, **A**taxia, and **R**etinitis **P**igmentosa.

Q: Marfan syndrome, affecting the eyes, skeletal system, and cardiovascular system, is caused by a mutation in which gene?

Fibrillin 1. **Explanation:** **Marfan syndrome** is an autosomal dominant connective tissue disorder characterized by a mutation in the **FBN1 gene** located on chromosome **15q21**. This gene encodes **Fibrillin-1**, a large glycoprotein that serves as a major structural component of extracellular microfibrils. These microfibrils provide a scaffold for the deposition of elastin and are essential for maintaining the structural integrity of tissues like the aortic media, the suspensory ligaments of the lens (zonules), and the periosteum. **Why the other options are incorrect:** * **Fibrillin 2:** Mutations in the *FBN2* gene (chromosome 5) lead to **Congenital Contractural Arachnodactyly (Beals Syndrome)**. While it shares skeletal features with Marfan syndrome, it typically lacks the ocular and life-threatening cardiovascular complications. * **Fibulin:** Fibulins are glycoproteins associated with elastic fibers; however, mutations in *Fibulin-5* are associated with **Cutis Laxa**, not Marfan syndrome. * **Elastin:** While Marfan syndrome affects elastic tissues, the primary defect is in the fibrillin scaffold, not the elastin protein itself. Mutations in the elastin gene (*ELN*) are associated with **Williams syndrome** and isolated supravalvular aortic stenosis. **High-Yield Clinical Pearls for NEET-PG:** * **Cardiovascular:** The most common cause of death is **Aortic Dissection** or rupture, often preceded by cystic medial necrosis. * **Ocular:** Characterized by **Ectopia Lentis** (dislocation of the lens), typically **upward and outward** (superior-temporal). * **Pathophysiology:** Beyond structural defects, Fibrillin-1 deficiency leads to excessive signaling of **TGF-β** (Transforming Growth Factor-beta), which contributes to tissue overgrowth and weakening. * **Differential Diagnosis:** **Homocystinuria** mimics Marfanoid habitus but is distinguished by intellectual disability, thrombosis risk, and **downward** lens dislocation.

Q: A 6-month-old boy presents with recurrent bacterial and fungal infections, chronic diarrhea, and failure to thrive. He is diagnosed with severe combined immunodeficiency due to an autosomal recessive inheritance pattern. Which enzyme deficiency is responsible?

D. Adenosine deaminase. ***Adenosine deaminase*** - The **autosomal recessive** form of **Severe Combined Immunodeficiency (SCID)** is most commonly caused by a deficiency in **Adenosine Deaminase (ADA)**, accounting for about 15% of all SCID cases. - ADA deficiency leads to the accumulation of toxic metabolites (*dATP*), which are highly toxic to rapidly dividing cells, especially **T and B lymphocytes**, resulting in profound lymphopenia and immunodeficiency. *Phosphomannose isomerase* - Deficiency in **Phosphomannose Isomerase (PMI)** causes Congenital Disorder of Glycosylation Type Ib (**CDG-Ib**), which presents with protein-losing enteropathy, hypoglycemia, and failure to thrive, but usually *not* recurrent bacterial and fungal infections severe enough to be classified as SCID. - CDG-Ib is a generalized metabolic disorder affecting **glycosylation**, primarily presenting with liver and gastrointestinal issues. *Ornithine transcarbamylase* - **Ornithine Transcarbamylase (OTC)** deficiency is the most common urea cycle disorder, typically presenting with acute **hyperammonemia** (lethargy, seizures, coma) after an initial period, especially following protein intake, not specifically severe SCID with recurrent infections. - OTC deficiency results in the impaired conversion of **carbamoyl phosphate** and **ornithine** to citrulline, leading to elevated ammonia levels. *Hypoxanthine-guanine phosphoribosyltransferase* - Deficiency in **Hypoxanthine-Guanine Phosphoribosyltransferase (HGPRT)** is responsible for **Lesch-Nyhan Syndrome**, an X-linked recessive disorder characterized by overproduction of **uric acid** (**hyperuricemia**), neurological dysfunction, and self-mutilation. - Although a purine metabolism disorder, it does not cause primary immunodeficiency like SCID; it mainly affects the **nervous system** and purine salvage pathway.

Q: A disease with mitochondrial inheritance is inherited from which family member?

Mother. ***Mother*** - Mitochondrial inheritance is characterized by **maternal transmission** because almost all mitochondria in the zygote are derived from the **oocyte** (mother's egg cell). - Therefore, an affected mother will pass the disease to all of her children (sons and daughters), irrespective of sex. *Grandmother (paternal)* - The paternal grandmother passes her mitochondria to the **father**, but the father cannot transmit them to his offspring. - Inheritance is strictly maternal, meaning the genetic input from the paternal line (including the paternal grandmother) is **irrelevant** for mitochondrial DNA. *Father* - The **sperm contributes negligible mitochondrial DNA** to the fertilized egg; hence, fathers cannot pass on mitochondrial diseases to their children. - Paternal mitochondria are typically **ubiquitinated and degraded** following fertilization. *Both mother and father* - Inheritance from both parents is characteristic of **nuclear DNA** (Mendelian) disorders, such as autosomal dominant or recessive patterns. - Mitochondrial inheritance is distinctively **uniparental** and does not involve DNA contribution from both parents.

Q: Which of the following accumulates in the mucopolysaccharidosis associated with Natowicz disease?

Hyaluronic acid. ***Hyaluronic acid***- Natowicz disease is synonymous with **Mucopolysaccharidosis type IX (MPS IX)**, a highly rare lysosomal storage disorder.- This condition is caused by a deficiency in the enzyme **hyaluronidase (HYAL1)**, which results in the failure to degrade **hyaluronic acid**, leading to its massive accumulation.*Dermatan sulfate*- Accumulation of **dermatan sulfate** is the defining characteristic of MPS I (Hurler, Scheie), MPS II (Hunter), and MPS VI (Maroteaux-Lamy).- These disorders generally involve widespread visceral, skeletal, and neurological pathology, unlike the localized features of MPS IX.*Heparan sulfate*- **Heparan sulfate** accumulates primarily in the various subtypes of **Sanfilippo syndrome (MPS III)**, as well as MPS I and II.- MPS III is predominantly characterized by progressive **neurocognitive decline** with relatively mild somatic features compared to other MPS types.*Keratan sulfate*- Accumulation of **keratan sulfate** is the metabolic hallmark of **Morquio syndrome (MPS IV)**, a disorder primarily presenting with severe skeletal dysplasia.- MPS IV involves deficiencies in either *N*-acetylgalactosamine-6-sulfatase or $\beta$-galactosidase, not hyaluronidase.

Q: Zellweger syndrome is associated with which cellular organelle?

A. Peroxisomes. ***A. Peroxisomes*** - Zellweger syndrome is a severe disorder belonging to the group of **peroxisomal biogenesis disorders (PBDs)**, resulting from a failure to form functional peroxisomes due to mutations in *PEX* genes. - Functional peroxisomes are essential for the metabolism of substances like **very long-chain fatty acids (VLCFAs)** and plasmalogens; their absence leads to the accumulation of these toxic molecules. *B. Mitochondria* - **Mitochondria** are the powerhouse organelles responsible for cellular energy production via oxidative phosphorylation. - Mitochondrial disorders present with distinct features like lactic acidosis, myopathy, and neurodegeneration, which differ from the characteristic peroxisomal dysfunction seen in Zellweger syndrome. *C. Lysosomes* - **Lysosomes** are crucial for degrading cellular waste products and macromolecules; defects in these organelles cause **lysosomal storage diseases** (e.g., mucopolysaccharidoses). - Although some symptoms overlap, Zellweger syndrome is specifically defined by **peroxisomal dysfunction**, not primary lysosomal enzyme deficiency. *D. Ribosomes* - **Ribosomes** are responsible for synthesizing proteins via translation of mRNA. - Defects in ribosomes typically impair **global protein synthesis** or specific tissue development (ribosomopathies), which is distinct from the primary metabolic defects seen in Zellweger syndrome.

Q: A patient presented to the OPD with liver damage. The picture depicts the patient having their eyes examined. Which of the following substances is responsible for this condition?

Copper. ***Copper*** - The image displays a **Kayser-Fleischer ring**, a greenish-gold ring at the corneal limbus, which is a hallmark sign of **Wilson's disease**. This condition, combined with liver damage, points to an issue with copper metabolism. - Wilson's disease is an autosomal recessive disorder caused by a mutation in the **ATP7B gene**, leading to impaired biliary excretion and subsequent toxic accumulation of **copper** in the liver, brain, and cornea. *Glucose* - Elevated **glucose** levels, as seen in diabetes mellitus, can cause ocular complications such as **diabetic retinopathy** and **cataracts**, but not Kayser-Fleischer rings. - While diabetes can be associated with liver disease (e.g., **NAFLD**), the combination of this specific eye finding and liver damage is not characteristic of glucose-related pathology. *Galactose* - Excess **galactose** is characteristic of **galactosemia**, an inherited metabolic disorder that can cause liver failure and cirrhosis, similar to Wilson's disease. - However, the classic ocular finding in galactosemia is the formation of **"oil-droplet" cataracts**, not the Kayser-Fleischer rings shown in the image. *Mannose* - Disorders of **mannose** metabolism are typically classified as **congenital disorders of glycosylation (CDGs)**. - These rare genetic disorders present with a wide spectrum of multi-systemic symptoms, including neurological and developmental issues, but are not associated with the development of Kayser-Fleischer rings.

Q: A child has elevated liver enzyme levels. A ring-like structure is noted on ocular examination. Which of the following is the cause for this?

Copper. ***Copper***- The combination of elevated **liver enzymes** (hepatitis/cirrhosis) and the characteristic **Kayser-Fleischer (KF) rings** visible on ocular examination is pathognomonic for **Wilson's disease**.- **Wilson's disease** is an inherited disorder involving defective biliary excretion of **copper**, causing its toxic accumulation in tissues, notably the liver, brain, and cornea.*Zinc*- Zinc is an essential trace element, but its deficiency presents primarily with **acrodermatitis enteropathica**, not hepatic failure and KF rings.- Zinc supplementation is sometimes used as a treatment for Wilson's disease because it inhibits the absorption of **copper** in the gut.*Selenium*- Deficiency of **Selenium** is associated with **Keshan disease** (cardiomyopathy) and impaired antioxidant protection, rather than liver disease with corneal rings.- High levels of selenium, though rare, can lead to hair loss and nail changes (**selenosis**).*Iron*- Excessive accumulation of **Iron** causes **hemochromatosis**, which leads to hepatomegaly, cirrhosis, and **bronze diabetes**.- Iron overload does not result in the formation of **Kayser-Fleischer rings**; these rings are exclusively caused by **copper** deposition in the Descemet membrane.

Question 1

In sickle cell anaemia, what is the underlying genetic defect?

Accepted Answer

A base substitution in DNA

Answer

A base insertion in DNA

Answer

A base deletion in DNA

Answer

None of the above

Question 2

NARP syndrome is seen in which category of diseases?

Accepted Answer

Mitochondrial diseases

Answer

Glycogen storage diseases

Answer

Lysosomal storage diseases

Answer

Lipid storage diseases

Question 3

Marfan syndrome, affecting the eyes, skeletal system, and cardiovascular system, is caused by a mutation in which gene?

Accepted Answer

Fibrillin 1

Answer

Fibrillin 2

Answer

Fibulin

Answer

Elastin

Question 4

A female child presents with virilization and hypertension with low plasma renin. What is the most likely diagnosis?

Accepted Answer

11 β hydroxylase deficiency

Answer

21α hydroxylase deficiency

Answer

3β hydroxylase deficiency

Answer

Conn’s syndrome

Question 5

A 6-month-old boy presents with recurrent bacterial and fungal infections, chronic diarrhea, and failure to thrive. He is diagnosed with severe combined immunodeficiency due to an autosomal recessive inheritance pattern. Which enzyme deficiency is responsible?

Accepted Answer

D. Adenosine deaminase

Answer

B. Ornithine transcarbamylase

Answer

C. Hypoxanthine-guanine phosphoribosyltransferase

Answer

A. Phosphomannose isomerase

Question 6

A disease with mitochondrial inheritance is inherited from which family member?

Accepted Answer

Mother

Answer

Father

Answer

Both mother and father

Answer

Grandmother (paternal)

Question 7

Which of the following accumulates in the mucopolysaccharidosis associated with Natowicz disease?

Accepted Answer

Hyaluronic acid

Answer

Dermatan sulfate

Answer

Heparan sulfate

Answer

Keratan sulfate

Question 8

Zellweger syndrome is associated with which cellular organelle?

Accepted Answer

A. Peroxisomes

Answer

C. Lysosomes

Answer

D. Ribosomes

Answer

B. Mitochondria

Question 9

A patient presented to the OPD with liver damage. The picture depicts the patient having their eyes examined. Which of the following substances is responsible for this condition?

Accepted Answer

Copper

Answer

Glucose

Answer

Galactose

Answer

Mannose

Question 10

A child has elevated liver enzyme levels. A ring-like structure is noted on ocular examination. Which of the following is the cause for this?

Accepted Answer

Copper

Answer

Zinc

Answer

Selenium

Answer

Iron

Genetic Disorders and Biochemical Pathology — MCQs

Genetic Disorders and Biochemical Pathology — MCQs

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